Progress in Neurobiology 98 (2012) 99–143

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Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

The neurobiology of depression in later-life: Clinical, neuropsychological,

neuroimaging and pathophysiological features
Sharon L. Naismith *, Louisa M. Norrie, Loren Mowszowski, Ian B. Hickie
Ageing Brain Centre, Clinical Research Unit, Brain & Mind Research Institute, University of Sydney, Sydney, NSW, Australia

A R T I C L E I N F O A B S T R A C T

Article history: As the population ages, the economic and societal impacts of neurodegenerative and neuropsychiatric
Received 19 December 2011 disorders are expected to rise sharply. Like dementia, late-life depressive disorders are common and are
Received in revised form 3 May 2012 linked to increased disability, high healthcare utilisation, cognitive decline and premature mortality.
Accepted 9 May 2012
Considerable heterogeneity in the clinical presentation of major depression across the life cycle may
Available online 17 May 2012
reflect unique pathophysiological pathways to illness; differentiating those with earlier onset who have
grown older (early-onset depression), from those with illness onset after the age of 50 or 60 years (late-
Keywords:
onset depression). The last two decades have witnessed significant advances in our understanding of the
Depression
neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical
Late-life depression
Late-onset functioning are implicated. New biomedical models extend well beyond perturbations of traditional
Cognitive monoamine systems to include altered neurotrophins, endocrinologic and immunologic system
Neuroimaging dysfunction, inflammatory processes and gene expression alterations. This more recent research has
Genetic highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute
to the various phenotypic presentations. This review highlights the major features of late-life depression,
with specific reference to its associated aetiological, clinical, cognitive, neuroimaging, neuropathological,
inflammatory and genetic correlates. Data examining the efficacy of pharmacological, non-
pharmacological and novel treatments for depression are discussed. Ultimately, future research must
aim to evaluate whether basic biomedical knowledge can be successfully translated into enhanced
health outcomes via the implementation of early intervention paradigms.
ß 2012 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

2. Neural circuitry relevant to depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
3. Phenotypic features of late-life depression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
3.1. ‘Vascular’ depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.2. Risk factors for ‘vascular’ and late-onset depression. . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.3. Depression as a cardiovascular risk factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
3.4. Depression and illness burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4. Neuropsychological features of late-life depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
4.1. Predictors of cognitive decline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
4.2. The relationship between late-life depression, mild cognitive impairment and dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Abbreviations: 5HTTLPR, serotonin transporter gene; 5-HT, serotonin; ACC, anterior cingulate cortex; AD, Alzheimer’s disease; BDNF, brain-derived neurotrophic factor;
BOLD, blood oxygen level dependent; Cho, choline; CM, cerebral metabolism; CNS, central nervous system; Cr, creatine; CVD, cardiovascular disease; DLPFC, dorsolateral
prefrontal cortex; DTI, diffusion tensor imaging; ECT, electroconvulsive therapy; EoD, early-onset depression; FA, fractional anisotropy; FDG, fluorodeoxyglucose; fMRI,
functional magnetic resonance imaging; HDL, high density lipoprotein; HMPAO, hexamethyl-propylene amine oxime; HPA, hypothalamic pituitary axis; LLD, late-life
depression; LoD, late-onset depression; MCI, mild cognitive impairment; MD, major depression; MEG, magnetoencephalography; mI, myoinositol; MRI, magnetic resonance
imaging; MRS, magnetic resonance spectroscopy; MTHFR, methylenetetrahydrofolate reductase; MTR, magnetization transfer ratio; NAA, N-acetyl aspartate; OFC,
orbitofrontal cortex; PET, positron emission tomography; PFC, prefrontal cortex; PiB, Pittsburgh B; rCBF, regional cerebral blood flow; RCT, randomised controlled trial; SPECT,
single photon emission computed tomography; SSRI, selective serotonin reuptake inhibitor; VRFs, vascular risk factors; WMLs, white matter lesions.
* Corresponding author at: Clinical Research Unit, Brain & Mind Research Institute, 94 Mallett Street, Camperdown NSW, Australia. Tel.: +61 2 9351 0781;
fax: +61 2 9351 0855.
E-mail address: sharon.naismith@sydney.edu.au (S.L. Naismith).

0301-0082/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.pneurobio.2012.05.009
100 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143

5. Structural neuroimaging studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

5.1. Volumetric findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.1.1. Whole brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.1.2. Frontal lobe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
5.1.3. Limbic regions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.1.4. The striatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.1.5. Significance of volumetric changes in LLD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.2. White matter changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.2.1. Macrostructural findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
5.2.2. Microstructural findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6. Macromolecular findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6.1. Magnetization transfer ratio. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
6.2. Magnetic resonance spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
7. Functional neuroimaging studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
7.1. Positron emission tomography (PET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
7.1.1. Associations with clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
7.1.2. Medication and treatment effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
7.1.3. Summary of PET studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
7.2. Single photon emission computed tomography (SPECT). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
7.2.1. Associations with clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
7.2.2. Medication effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
7.2.3. Relationship to cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
7.2.4. Summary of SPECT studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
7.3. Functional magnetic resonance imaging (fMRI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
7.3.1. Behavioural and cognitive paradigms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
7.3.2. Summary of fMRI studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7.4. Resting state fMRI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8. Neuropathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
9. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
9.1. Brain-derived neurotrophic factor gene (BDNF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
9.2. Serotonin transporter gene (5HTTLPR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
9.3. Apolipoprotein E gene (Apoe) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
9.4. Genes implicated in systemic vascular risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
10. The role of inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
11. Prognosis in late-life depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
12. Treatment approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
12.1. Pharmacological treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
12.2. Non-pharmacological treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
13. A focus on prevention for late-life depression? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
14. Summary and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

1. Introduction ideation), appetite disturbance or weight change, loss of libido,

sexual dysfunction, non-localized pain, low energy, altered sleep–
As the population ages, the economic and societal impacts of wake cycle and daytime fatigue. Indeed, disturbances of sleep
neurodegenerative and other neuropsychiatric disorders are appear to be linked directly to cognitive impairment (Cho et al.,
expected to rise sharply (Access Economics, 2009; Bloom et al., 2008; Dew et al., 1997; Naismith et al., 2009b, 2011b). Hence, new
2011; Smith, 2011). While dementia is emphasized, late-onset treatments recognise the significance of incorporating sleep and
depressive disorders are also common and disabling (Hickie and circadian realignment into disease management (Hickie and
Scott, 1998; Naismith et al., 2007). Hence, these conditions are now Rogers, 2011).
the focus of considerable public health and clinical attention There is considerable heterogeneity in the clinical presentation
(Hickie et al., 2006; Highet et al., 2002; Kessler et al., 2010; of MD across the life cycle (Hickie et al., 2009). Younger patients
Naismith et al., 2009b; Ustun et al., 2004). The prevalence of may have clinical profiles characterized by high trait anxiety and
clinically significant depressive syndromes in those people over 60 quite variable patterns of circadian, sleep, energy and appetite
years of age (i.e. ‘late-life depression’ or LLD) ranges from 9% to 18% disturbance (Hansell et al., 2011). Those in mid-life present the
and incidence rates of 19.3 per 1000 person years have been more stereotypic picture of anhedonia in combination with sleep
reported (Beekman et al., 1995; Luijendijk et al., 2008; Mulsant and disturbance, weight loss and cognitive and motor impairments
Ganguli, 1999). LLD has been linked to increased rates of suicide (American Psychiatric Association, 1994). In later-life, clinical
and premature mortality (Gareri et al., 2002) and more frequent phenotypes are again more variable (Blazer, 2003). This may well
use of health care with significantly higher health care costs reflect different neuropathological pathways to illness – largely
(Katon, 2003). differentiating those with earlier onset who have grown older from
The core symptoms of major depression (MD) are persistently those who are experiencing clinical depression for the first time.
depressed mood or anhedonia (i.e. loss of pleasure in normal daily Certainly, modelling of genetic and environmental risk factors over
activities). Typically patients also report cognitive impairment the life course suggest distinctly differing pathways in early, mid
(slowed reaction time, poor concentration and memory), dysfunc- and later-life (Gillespie et al., 2004). It would appear that the
tional thoughts (e.g. inappropriate guilt, worthlessness, suicidal relevance of genetic risk to vascular risk factors particularly
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
increases with age (especially after age 50 years), while those
associated with earlier onset forms of depression decline as people
grow older (particularly after age 20 years (Kendler et al., 2009,
2008)).
Consequently, treatment responsiveness and longitudinal
course also vary considerably (Hybels et al., 2009). Additional
clinical concepts such as ‘‘depression without sadness’’ (Blazer,
2003) and a depletion syndrome characterized by withdrawal,
apathy and lack of vigour (Adams, 2001) have also been described.
Most importantly, for those with the more severe forms of LLD
(particularly those of late-onset), neuropsychological deficits
including executive dysfunction and observable psychomotor
change are prominent (Hickie et al., 2007a; Naismith et al.,
2003). The risk of progression to permanent cognitive impairment
in this type of depression has also been emphasized (Alexopoulos,
2005; Baldwin et al., 2006; Kohler et al., 2010a). Minor depression
(depressed mood accompanied by one to three additional
symptoms), has been found to be more prevalent in older adults
than full threshold MD. However, these ‘sub-threshold’ disorders
are associated with impairments similar to that of MD, including
decreased levels of physical function, poorer self-rated health and
increased days lost due to disability (Beekman et al., 1995).
While a wide range of pharmacological and psychological
treatments for MD are moderately effective, as many as 50% of
patients across all age groups will not achieve remission with their
first treatment (Roose and Schatzberg, 2005). Ultimately, 20–30%
will not achieve full recovery despite access to multiple interven-
tions (Whyte et al., 2004). Even with optimal treatment, only 34%
of the total disease burden of MD (measured as ‘years lived with
disability’) can be averted (Andrews et al., 2004). Those persons
who achieve full recovery remain at high risk for further episodes
(Maj et al., 1992). Recovery may well be slower in older patients
with conventional treatments (Wilhelm et al., 1994). Hence,
ongoing disability in this group and reliance on other formal and
informal caring networks is high (Alexopoulos et al., 2002a;
Beekman et al., 1997; Steffens et al., 1999a). Recurrence rates in
community dwelling elders are more than three times as high as
incidence rates (Luijendijk et al., 2008).
Although much remains to be discovered about the pathophys-
iology of both early and later-onset clinical depression, the last two
decades have seen significant advances. Neurobiological theories
have been greatly informed by detailed genetic, neuroimaging,
neuropsychology, pathology and interventional studies. These
indicate that structural and functional abnormalities within key
fronto-subcortical neural networks underpin many of the clinical
phenomena (Mayberg, 1997, 2007). Concurrently, advances in
molecular, cellular and systems neuroscience have enriched more
advanced biomedical models. New models extend well beyond
perturbations of traditional monoamine systems to include altered
neurotrophins, endocrinologic and immunologic system dysfunc-
tion, inflammatory processes and gene expression alterations
(Belmaker and Agam, 2008; Drevets et al., 2008a; Hickie et al.,
2001a, 1999, 2007b; Insel, 2009a; Krishnan and Nestler, 2010;
Mayberg, 2003).
Genomic variations and early brain development are now
viewed as fundamental factors that ultimately bias individual
brain circuitry towards illness resilience or vulnerability (Insel,
2009a). The influence of these intrinsic factors is then shaped by
ongoing environmental exposures. These extend well beyond the
initial intra-uterine and early childhood period. Specifically, it has
become increasingly clear that major deviations in brain develop-
ment continue to occur throughout the adolescent and early adult
years (Giedd et al., 1999) in association with the onset of major
psychiatric disorders. Hence, the concept of ‘pre-emptive’ psychi-
atry has evolved to link evidence of the developmental basis of the
major mental disorders with clinical studies focusing on the
101
potential benefits of prevention and early intervention across the
life cycle (Insel, 2009b). Clinical staging models for psychotic and
severe mood disorders (Hickie et al., in press; McGorry et al., 2006)
have highlighted the need to recognise early clinical phenotypes,
and related biomedical markers, so that treatments can be
provided before progression of illness and disability become
well-established. While these models have not yet been fully
elaborated for the more common forms of depression, available
data support the notion that cognitive change and disability
emerge early in the illness course (Hamilton et al., 2011; Hermens
et al., 2011).
A major advance in detailing the various pathophysiologies that
underpin the clinical phenotype of MD has been to focus on
differential pathways to illness. Age of onset has emerged as the
most robust correlate of these putative trajectories. A key
differentiation is between those disorders that have their onset
early in life (early-onset depression, EoD, typically with first
symptoms emerging in the adolescent and early adult periods)
compared with those that emerge for the first time after the age of
50 or 60 years (late-onset depression, LoD) (Hickie et al., 2009;
Insel, 2009b; Krishnan and Nestler, 2010). Despite extensive data
demonstrating that in LLD there are many modifiable risk factors
for illness onset, ‘pre-emptive’ or ‘early intervention’ approaches
have not yet been operationalised or extensively evaluated.
Compared with EoD, the neurobiological models of LoD intrinsi-
cally place less emphasis on the developmental determinants of
amygdala circuitry, and other frontotemporal changes. Instead
they highlight the critical nature of intercurrent medical and other
vascular risk factors that result in structural disruptions of key
fronto-subcortical circuits. Further, these more specific models for
LoD are not only relevant to onset but have major ramifications for
determining response to treatment, development of new inter-
ventions and longitudinal course. Importantly, the persistence or
progression of these illness pathways put patients at high risk for
chronic disability and possible development of dementia (Schweit-
zer et al., 2002; Sheline et al., 2010).
This review highlights the major features of LLD (including
LoD), with specific reference to its associated aetiological, clinical,
cognitive, neuroimaging, neuropathological, inflammatory and
genetic correlates. Data examining the efficacy of various
pharmacological, non-pharmacological and novel treatments for
depression will then be discussed with a view to highlighting the
future directions for both research and clinical practice. Depression
in dementia will not be examined.
2. Neural circuitry relevant to depression
The fronto-subcortical model of MD requires the consideration
and integration of the functional neuroanatomical circuits that
were eloquently described by Alexander in 1986 (Alexander et al.,
1986). While the motor circuit is perhaps the best understood of
the networks, the other loops appear to be organised in parallel and
are termed the oculomotor, dorsolateral prefrontal, lateral
orbitofrontal and anterior cingulate loops (Alexander et al.,
1986; Cummings, 1993; Saint-Cyr, 2003), each of which are
convergent upon different frontal regions. Behavioural markers of
each circuit can be reproduced by lesions at various points along
the path, from the cerebral cortex, white matter, or subcortical
nuclei. The circuits are also discrete (i.e. non-overlapping) and
spatially constrained. They are widely separated at the level of the
cortex. However, at subcortical levels, the circuits are closer in
proximity. Thus, subcortical lesions can impair multiple circuits
simultaneously, producing a varied array of symptoms (Royall
et al., 2002). Due to the dense interconnections between the
circuits, disruption at any level of the fronto-subcortical circuit
could result in dysfunction in other areas (Soares and Mann, 1997).
102 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
Thus, in concert with the presence of genetic or other predisposing
factors, such disruption could indirectly or directly contribute to a
constellation of depressive, cognitive or movement phenotypes
(Drevets, 1998; Hickie et al., 1997a; Soares and Mann, 1997).
Of the five circuits described, at least three are likely to be
relevant to depression (e.g. see Drevets, 1998, 2000 for reviews)
namely those that incorporate the orbitofrontal cortex (OFC),
dorsolateral prefrontal cortex (DLPFC) and anterior cingulate (ACC)
regions. The OFC is a component of the paralimbic cortical circuit
that is involved in several higher-order association functions
including the integration of emotion, behaviour and various
sensory processes. In addition to thalamic connections, the OFC has
reciprocal connections with the amygdala, the temporal neocortex
and the insula, and has dense connections with the ventromedial
caudate nucleus. The DLPFC is connected to the ACC, amygdala and
dorsolateral caudate nucleus. The ACC circuit receives input from
the hippocampus, amygdala and paralimbic cortex and projects to
the ventral striatum and nucleus accumbens (Byrum et al., 1999;
Cummings, 1993; Royall et al., 2002). More recently the ACC has
been identified as of critical importance in the pathophysiology of
depression via its two major subdivisions: the dorsal ACC, which
contributes to a ‘dorsal’ network including the hippocampus and
DLPFC, and the perigenual ACC, which projects to the amygdala,
hypothalamus and OFC amongst others, comprising the ‘ventral’
network (Phillips et al., 2003). The dorsal ‘cognitive/executive’
network is postulated to be important for executive functions, and
plays a key role in the cognitive regulation of emotional responses
whereas the ventral or ‘affective/emotional’ network appears to be
involved in assessing the salience of emotional input as well as the
generation and regulation of emotional response (Phillips et al.,
2003). The fundamental role played by limbic structures is
illustrated in their dense interconnections within these key neural
circuits, as well as the associations between specific regions and
clinical features of mood disorder. In particular, the amygdala,
extensively connected to the hippocampus, striatum and the
orbital and medial prefrontal cortices, is of primary importance in
assessing the emotional significance of sensory input, and
modulating monoamine and steroid secretion in response to
aversive or novel stimuli (Drevets et al., 2008b). Furthermore the
hippocampus, lying at the junction of the dorsal and perigenual
ACC as well as the neuroendocrine regulatory networks (specifi-
cally the hypothalamic pituitary axis), is a vulnerable region, and
extensive evidence points to its key role in mood disorders,
including the memory deficits commonly observed in LLD (Hickie
et al., 2005b; Steffens, 2008; Steffens et al., 2011).
Recent data suggests that improvements in cognitive function
are associated with discrete functional networks that are separate
from those associated with improvements in mood (Diaconescu
et al., 2010). However, further research is required in order to
elucidate whether abnormalities within specific or multiple loops
are associated with different phenotypes of depressive disorder,
including those with clear genetic vulnerabilities to early-onset or
late-onset forms. While some data support the notion that certain
neurobiological changes (e.g. frontal and limbic) relate to the
duration of illness and lack of access to appropriate treatments
(Drevets et al., 2008a), there has been a paucity of studies
commencing prior to illness onset to fully elucidate the contribu-
tion of neurodevelopmental versus illness-specific processes.
In addition to the prefrontal and limbic circuitry, there is
considerable data supporting the involvement of the basal ganglia
and specifically, the striatum, in the pathophysiology of MD. The
striatum is comprised of both input and output nuclei, and cortical
input to the striatum has a regional pattern. Whereas the putamen
is primarily innervated by the sensorimotor cortex, the caudate
nucleus receives preferential input from the frontal, temporal,
parietal and cingulate cortex. Additionally, ventral parts of the
caudate and putamen receive input from the limbic and paralimbic
cortex, hippocampus and amygdala. Early studies noted that there
was a higher incidence of depressive disorders in patients with
lesions or strokes in the basal ganglia or its surrounding regions
(Cummings, 1985; Goodwin, 1997). Similarly, diseases primarily
affecting the basal ganglia are often accompanied by depressive
symptoms. For example, MD is the most common psychiatric
disturbance of Parkinson’s disease, is often a prodromal feature
and is evident in 17–25% of patients (see review by Slaughter et al.,
2001). Although the basal ganglia have traditionally been
considered to be primarily involved in motor functioning,
increasing recognition is being given to their role in the integration
of emotional, cognitive and motor behaviour (Balleine and
O’Doherty, 2010). Specifically, animal studies have highlighted
the critical role of the dorsomedial and dorsolateral striatum in
goal-directed action and habit learning respectively (see review by
Balleine and O’Doherty, 2010). While some human studies have
certainly confirmed the regional specificity of the basal ganglia
(e.g. anterior caudate) in some components of cognition (O’Doh-
erty et al., 2004), this field is in its infancy and no known studies
have explored these potential relationships in depressive dis-
orders. Ultimately, demarcation of specific regions of the basal
ganglia that are anatomically and functionally discrete may
provide greater insights into their role in cognitive and/or mood
disturbance.
Comprehensive neurobiological theories of MD need to
encompass not only neural circuitry but also the various
neurotransmitter systems. Regardless of their origin, aspects of
fronto-subcortical circuitry funnel information from widespread
cortical areas and utilise a vast array of neurotransmitters. In this
regard, there has been considerable preoccupation with the
monoamine hypothesis of depression and accordingly much
experimental, neuroimaging and treatment-based research has
been focused on serotonergic, noradrenergic and/or dopaminergic
neurotransmission (Hickie et al., 2009).
Much of our knowledge regarding serotonin (5-HT) functioning
arose from the implementation of techniques such as post-mortem
studies and neuroendocrine response to serotonergic challenge.
Such studies revealed deficits in 5-HT1A (frontal regions and
temporal pole) and in 5-HT2 binding (frontal, temporal and parietal
regions) (Bowen et al., 1989). However, as noted by Meltzer et al.
(1998) in their review of serotonin in LLD, there are many
inconsistencies in the post-mortem studies, possibly due to
confounds such as use of antidepressant therapies, differences
in post-mortem delay, tissue preparation, selection of markers for
specific receptor subtypes, participant selection bias and the
various mechanisms of action of prior antidepressant therapy (i.e.
agonists versus antagonists). Other studies utilising cerebrospinal
fluid (e.g. Jones et al., 1990) have, however, confirmed that
serotonin is implicated in MD, though there has been a lack of
correlation with clinical symptoms. More recently, serotonin
pharmacologic challenge studies (using serotonin releasing agent
fenfluramine) (e.g. Lerer et al., 1996) have confirmed blunted
prolactin response in MD that may also differ according to age,
suggesting an increased vulnerability to MD in older people.
More recently, the interactions of the various neurotransmitter
systems have received increased attention. For instance, via five
different postsynaptic receptors, dopamine has both inhibitory and
excitatory effects on fronto-subcortical functioning. Dopaminergic
connections between the substantia nigra and limbic system play a
role in the integration of emotional input and motor activity,
cognition and motivation. Both cholinergic and serotonergic
systems are involved in the modulation of these dopaminergic
pathways. Additionally, glutamatergic corticostriatal and thala-
mocortical projections, via interactions with both cholinergic and
dopaminergic systems, contribute to a negative feedback loop,
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
which serves to limit cortical overstimulation (see review by Tekin
and Cummings, 2002). The neurotransmitter systems are begin-
ning to be incorporated into theories of neuroplasticity. For
instance serotonin is important in the regulation of N-methyl-D-
aspartate receptor activity, which in turn modulates synaptic
plasticity (Bennett, 2010). Furthermore, functional imaging in LLD
patients treated with the selective serotonin reuptake inhibitor
(SSRI) citalopram implicates an interaction between subcortical
dopamine and serotonin systems with cortical glutamatergic
function (Diaconescu et al., 2010).
The relevance of considering the interactions of various
neuropharmacological systems in MD is underscored by the
increasing availability of dual acting antidepressant agents that
target multiple systems. For example, the availability of selective
noradrenergic and serotonergic agents has allowed for more
personalised approaches to treatment, while more recently, there
has been increasing emphasis on considering the specific
phenotypic features of the depressive disorder (Hickie et al.,
2009; Hickie and Rogers, 2011). This is especially relevant in LLD,
where each patient presents with a unique constellation of
depressive, cognitive and somatic symptoms, often complicated
by concomitant medical morbidity (Hickie et al., 2009). For
example, those with predominant underlying cerebrovascular
Table 1
Clinical, aetiological, and prognostic features of early-onset and late-onset depression.
Early-onset depression
Description  Development of depressive and/or anxiety
symptoms early in life, typically before age
25
 Profile generally indicative of frontotemporal
and amygdala change
Clinical features  Anxiety features
 Prominent heritability
 Development of awareness to social cues
Relationship to  Depression is a risk factor for cardiovascular
cardiovascular disease and adverse outcomes including
disease stroke and myocardial infarction
Genetic  Gene susceptibility most operative early in
vulnerabilities development, with vulnerability emerging in
childhood and adolescence
Prognosis  Possibly longer time to remission after
treatment with antidepressants
Treatment  Possible preferential response to
serotonergic agents
 High-rate of non-response to initial
antidepressant
 May require lithium augmentation
 Non-pharmacological therapy (e.g. cognitive
behavioural therapy) useful in targeting
anxiety or dysfunctional thoughts
Note: Late-life depression includes those with early-onset depression, with recurrent episodes throughout life, as well as those in whom depression has arisen for the first
time after the age 50 or 60. For the latter group, cerebrovascular disease or early neurodegenerative changes may also contribute to the phenotypic profile.
103
disease (see Section 3.1) have a poorer response to antidepressants,
particularly SSRIs. In these sufferers with likely frontostriatal
impairments, dopamine-acting agents or psychotropics with
catecholaminergic activity may assist recovery (Andreescu and
Reynolds, 2011).
3. Phenotypic features of late-life depression
Although there are certainly commonalities in depressive
features throughout the age spectrum, LLD may have distinct
medical, clinical, cognitive, neuroimaging, neuropathological,
inflammatory and genetic features when contrasted with depres-
sion in younger people (Alexopoulos, 2005; Brodaty et al., 2001;
Herrmann et al., 2007; Hickie and Scott, 1998; Hickie et al., 2009;
Thomas et al., 2009). Upon considering the clinical phenotype of
LLD, it is important to note that multiple underlying pathophy-
siologies may be operative (see Table 1) including the long-term
illness-specific effects of EoD, the underlying brain changes that
might give rise to LoD (see Fig. 1a), and the potential role of
underlying prodromal neurodegenerative disease. While the age
used to define EoD versus LoD tends to vary across studies, age 50,
60 and 65 are commonly used. Regardless of the cut-off employed,
the concept of LoD has been a catalyst for a plethora of research
Late-onset depression
‘Vascular’ depression Neurodegenerative
 Development of depression after age 50 or 60  May include more pronounced hippocampal
years and temporal lobe change, particularly with
 Profile indicative of fronto-subcortical underlying Alzheimer’s pathology
dysfunction
 Psychomotor change  May additionally include emerging changes
 Executive dysfunction in memory consolidation and language
 Apathy
 Treatment resistance
 Absence of family history
 Increased rates of:  Cerebrovascular disease may play a role in
* Cerebrovascular disease risk for depression, cognitive decline and
* Hypertension more rapid progression of Alzheimer’s
* Diabetes pathology
* Heart disease
* Hypercholesterolaemia
* White matter lesions on neuroimaging
 Genetic susceptibility relates to systemic  For those whose depression occurs in the
vascular risk, associated with context of incipient underlying
methylenetetrahydrofolate and serotonin neurodegenerative change, genetic
transporter genes associations between BDNF and/or ApoE and
volumetric reductions in key brain regions
may be important
 Poorer treatment outcomes
 Associated with increased mortality and progression to dementia
 Presence of white matter lesions and cognitive impairment, particularly executive functioning
may predict poor prognosis
 Management and reduction of vascular risk  Consider role of acetylcholinesterase
 Possible preferential response to therapies inhibitors
increasing dopamine and/or noradrenaline  Non-pharmacological therapies (e.g.
 Consider antidepressant augmentation with cognitive training, problem solving therapy)
Ca channel blockers may be useful when cognitive dysfunction is
 Additional clinical features such as present
melancholia and psychosis may require
consideration of tricyclics, lithium,
antipsychotics and electroconvulsive
therapy
 Non-pharmacological therapies (e.g.
cognitive training, problem solving therapy)
may be useful when cognitive dysfunction is
present
104 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143

Fig. 1. (a) Clinical and cognitive correlates of neurobiological changes documented in late-life depression. (b) Neuroimaging and neuropathological changes documented in
late-life depression. Abbreviations: BDNF, brain-derived neurotrophic factor; 5HTTLPR, serotonin transporter; apoE, apolipoprotein E; 5-HT, serotonin; BOLD, blood oxygen
dependent level; cho, choline; Cr, creatine; GFAP, glial fibrillary acidic protein; DTI, diffusion tensor imaging; fMRI, functional magnetic resonance imaging; mI, myoinositol;
MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; MTI, magnetization transfer imaging; NAA, N-acetyl aspartate; PET, positron emission
tomography; rCBF, regional cerebral blood flow; SPECT, single photon emission tomography; WMLs, white matter lesions. *Includes studies reporting non-specific prefrontal/
frontal changes.
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
that has sought to identify the pathophysiological mechanisms
underlying those forms of depression emerging in later-life. In
addition to identifying unique clinical features such as absence of a
family history of affective disorder, less personality dysfunction
and more psychomotor change (Brodaty et al., 1997; Hickie et al.,
1995), this research has identified the preponderance of white
matter lesions (WMLs), seen as ‘hyperintense’ on T2-weighted
images. Such lesions have been linked to LLD generally, and more
specifically to those with LoD (e.g. Alexopoulos et al., 1997; Hickie
et al., 1995; Krishnan et al., 1997; O’Brien et al., 1996) (see
structural neuroimaging Section 5.1). Although in this review we
have primarily focused on early versus late-onset of disease, it is
nonetheless important to recognise the limitations of this
categorical approach to disease conceptualisation. In particular,
one must consider the selection factors that may be operative
when comparing the two phenotypes. That is, those with severe
illnesses may have had high mortality, and premature death due to
several factors such as increased medical comorbidity, substance
misuse, vascular disease, and suicide (Bunker et al., 2003; Shah
et al., 2011). Of those who survive, many of these factors, as well
other detrimental effects may have been operative to impact on
brain functioning (e.g. neuroendocrine, inflammatory and immu-
nological changes, medication effects). Additionally, in the clinical
context, it can be extremely difficult to ascertain retrospectively
the timing of depression onset, and commonly, depression in early
life may have escaped formal medical recognition or treatment, an
effect which may be less pronounced in future cohorts with greater
public health recognition, reduced stigmatisation of depression
and increased rates of treatment for depression (Hickie, 2004;
Hickie et al., 2005c, 2009; Highet et al., 2006). Despite these
limitations, however, the differentiation of LLD phenotypes has
proved immensely useful, in terms of delineating the pathophysi-
ology and neurobiological profile of LLD. Techniques aimed at
investigating features linked with hypothesized pathophysiology,
that do not rely on broad age cut-offs, may now be more useful in
clarifying depression phenotypes and the various pathways to
illness onset and longitudinal decline (Box 1).
3.1. ‘Vascular’ depression
While the precise aetiology of WMLs is unclear, it is likely that
they predominantly reflect underlying cerebrovascular disease
including small vessel ischaemic change (Greenstein et al., 2010;
Thomas et al., 2002). The strong link between WMLs, vascular risk
factors (VRFs) and depression, led to the ‘vascular’ depression
hypothesis (Alexopoulos et al., 1997; Hickie et al., 1995; Krishnan
et al., 1992; Steffens and Krishnan, 1998). Approaches to
characterizing ‘vascular’ depression have on the one hand
emphasized the importance of neuroimaging changes, ‘‘MRI-
defined vascular depression’’ (Krishnan et al., 2004), and on the
Box 1. Clinical characteristics of late-life depression.
 Depression in adults over age 60
 Fronto-subcortical circuitry abnormalities
 May be classified into early-onset or late-onset, but often this
is difficult to establish conclusively
 Late-onset phenotype may relate to underlying cerebrovas-
cular disease, evidenced by greater vascular risk factors or
white matter lesions on neuroimaging
 Late-onset phenotype may have more pronounced cognitive
impairment and greater progression to dementia syn-
dromes
 Late-onset phenotype may have greater treatment resis-
tance
105
other, the role of neuropsychologically determined cognitive
impairments, such as encompassed in the ‘‘depression-dysexecu-
tive syndrome’’ (Alexopoulos et al., 2002c). In addition to having
later ages of onset, those with ‘vascular’ depression also tend to be
older, have treatment resistance, psychomotor change, less family
history of affective disorder, cognitive impairment (particularly
executive dysfunction) and greater progression to dementia
(Hickie and Scott, 1998; Sheline et al., 2010; Steffens and Krishnan,
1998). There is now strong, though not unanimous (Almeida,
2008), support for the concept of ‘vascular’ depression. With the
ongoing sophistication of neuroimaging techniques, this area
continues to be the subject of empirical research. In particular, it
now aims to better characterize the pathophysiological mecha-
nisms and disruptions to neural circuitry predisposing to or
perpetuating depressive syndromes. Currently, it appears as
though some degree of lesion burden is required in order to
significantly contribute to depressive syndromes, although this is
certainly not absolute and further research will be needed to
identify whether the strategic location of lesions or the overall
burden of lesions is pertinent (Sheline et al., 2008; Tupler et al.,
2002). Certainly the literature regarding risk of post-stroke
depression based on stroke location is inconsistent (Bhogal
et al., 2004). The observation that many older people may have
cerebrovascular disease and yet do not develop depressive
syndromes also raises the question regarding possible neurobio-
logical and/or individually specific (e.g. personality) protective
factors. Additionally, there is some suggestion that VRFs do not
account totally for WML severity, thus suggesting that other non-
vascular factors may contribute to lesion burden (Teper and
O’Brien, 2008). Nonetheless, it is widely accepted that regardless of
their aetiology, WMLs confer vulnerability to mood disorders by
disrupting key fronto-subcortical circuitry (see Fig. 1b). In addition
to WMLs, a pre-existing vulnerability to depression may be
necessary as well as environmental stressors.
3.2. Risk factors for ‘vascular’ and late-onset depression
Regarding individual VRFs for ‘vascular’ depression and LoD,
this literature is extensive and has been the subject of many review
papers (e.g. Alexopoulos, 2003; Camus et al., 2004; Thomas et al.,
2004). In brief, risk factors are those generally considered to be
risks for cardiovascular disease (CVD) including hypertension,
diabetes, hypercholesterolaemia, heart disease, obesity and
smoking. Data supporting the link between depression and CVD
stems from both clinical as well as community and epidemiological
studies and further suggests that this relationship is bidirectional.
Hypertension may be particularly relevant to the aetiology of LLD
due to the chronic effects of this condition on the small vessels of the
brain. However, there are some mixed findings in this area. For
instance, a large population-based study (part of the Cardiovascular
Health study, n = 3660) showed that higher CES-D scores (Centre for
Epidemiological Studies Depression Scale) were significantly
associated with the presence of hypertension (Steffens et al.,
1999a). By contrast, some cross-sectional or short-term prospective
studies have not supported this relationship (Kim et al., 2006; Mast
et al., 2008; Stewart et al., 2001). It is worth noting that hypertension
is a less stable construct than some other VRFs and this may explain
some of the variability in findings. For instance, blood pressure
varies in response to physiological and psychological determinants,
and its treatment may also modify depression risk. Additionally, the
relationship between hypertension, WMLs and depression may be
confounded by the presence or absence of pre-existing treatment for
hypertension. Importantly, data suggests that the cerebral damage
induced by VRFs is likely to be irreversible if management is
commenced too late, thus potentially confounding many cross-
sectional studies (see Naismith et al., 2009a for a review). In this
106 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
regard prospective longitudinal studies have been informative and
have generally supported the association between the accumulation
of VRFs and depression in older adults (e.g. Hickie et al., 2003; Lyness
et al., 2000; Mast et al., 2008).
A marker of CVD that has been less well studied is carotid
intima-media thickness, which has been found to correlate well
with atherosclerosis (Bots et al., 1997). Studies in middle-aged and
older adults have shown that common carotid intima-media
thickness is higher in those with LoD depression and is related to
WMLs (Chen et al., 2006), but not to depression severity (Smith
et al., 2009c). Whilst carotid intima-media thickness provides
some indication of underlying macrovascular disease, measures of
retinal vasculature (arteriolar and venular diameters) provide a
marker for cerebral microvascular disease (Ikram et al., 2006).
Larger retinal venular diameters have also been associated with
markers of atherosclerosis including raised levels of total
cholesterol and lowered high density lipoprotein (HDL) cholester-
ol, smoking as well as inflammatory markers such as C-Reactive
Protein (CRP) (Ikram et al., 2004). Moreover, larger retinal venular
diameters have been associated with marked progression of WMLs
over a 2-year follow-up period, as evidenced by the Rotterdam
Study of Aging (7046 adults aged >55 years without dementia)
(Ikram et al., 2006). Interestingly this association remained after
adjustment for VRFs. The relationship between venular diameter
and WML progression was most attenuated when CRP levels were
taken into account. The authors thus suggested that this may
indicate a role for inflammation in the pathogenesis of cerebral
small vessel disease (Ikram et al., 2006). However further analysis
of this cohort has not demonstrated any relationship between
retinal markers of cerebral microvascular disease and incident LLD
(Ikram et al., 2010), results which confirm the findings of two
similarly negative cross-sectional studies (Nguyen et al., 2008; Sun
et al., 2007).
Finally, although not strictly a VRF, stroke is associated with an
increased risk for depression (see review by Robinson and Spalleta,
2010), although the data on the role of lesion location and risk for
depression is inconsistent (Bhogal et al., 2004). In some studies, up
to 40% of patients will develop depression in the acute post-stroke
period (from a few weeks to 6 months) (see review by Robinson
and Spalleta, 2010). Stroke lesions are associated with depletion of
monoamines, as well as increased production of pro-inflammatory
cytokines and cortisol (for review, see Spalletta et al., 2006). Much
recent work has been directed at the prevention of post-stroke
depression with antidepressants, based on the rationale that by
modifying the biological factors such as reduced neurogenesis and
monoamine alterations, depression risk will be reduced (see
review by Ramasubbu, 2011). Results have been inconsistent, with
one meta-analysis supporting the role of antidepressants (Chen
et al., 2007), and one showing no benefit (Hackett et al., 2008).
3.3. Depression as a cardiovascular risk factor
Of critical significance, an emerging body of literature suggests
that the relationship between depression and CVD is bidirectional
(Schrader et al., 2005; Thomas et al., 2004). Depression has been
shown to have a relatively strong association with the develop-
ment of CVD as indexed by fatal coronary heart disease or
myocardial infarction. This finding has been demonstrated by a
number of longitudinal studies published over the last 40 years
and is particularly apparent in men (Nicholson et al., 2006).
Reviews have further indicated that the risk is not confined merely
to major depressive disorder but exists across the range of
depressive symptom severity. This has been suggested to reflect
either common aetiological factors including genetic risk or
differential stress responsivity in the hypothalamic pituitary axis
(HPA) amongst those with CVD and depression (McCaffery et al.,
2006) as well as elevated platelet reactivity, or increased immune
system reactions. Depression is also a risk factor for poor outcome
of established CVD (Lichtman et al., 2008), which may in part be
due to the above or behavioural risk confounders such as smoking,
lack of exercise or poor adherence. Fewer studies exist that have
investigated prospectively the relationship between depression
and individual VRFs. Depression has, however, been found to be a
risk factor for diabetes (Knol et al., 2006), though the converse is
not always evident (Kim et al., 2006).
While the underlying mechanisms for the bidirectional
relationship between CVD and LLD remain unclear, the link is
certainly plausible when one considers that they share environ-
mental risk factors. Interestingly, however, the relationship
between the two remains strong even when such confounding
factors are strictly controlled (Rugulies, 2002). It is likely that
shared genetic factors may be important, and in this regard, the
methylenetetrahydrofolate reductase (MTHFR) gene (see relation-
ship with genetics in Section 9) has received considerable
attention. This gene is involved in homocysteine metabolism;
raised levels are considered to be a VRF and contribute to CVD
(Clarke et al., 1991). Homocysteine is derived from the demethyl-
ation of the amino acid methionine. It is metabolized via
remethylation using B12 and folic acid as co-factors, and cleared
via transulfuration to cysteine and glutathione, a process requiring
B6 and B12 (Folstein et al., 2007). A number of studies have
variously supported the link between homocysteine and LLD
generally (Almeida et al., 2008; Bjelland et al., 2003), LoD
specifically (Chen et al., 2005) and some have shown a link
between the MTHFR gene mutation and LoD (Hickie et al., 2001a).
The mechanism for this association may lie in cerebral microvas-
culature changes, via oxidative stress-related endothelial dysfunc-
tion (i.e. the impairment of the vascular endothelium’s ability to
control vasomotor tone) (Welch and Loscalzo, 1998), or via direct
neurotoxic effects, related to DNA strand breakage or apoptosis
(Santos et al., 2009). A recent study found that in older
hypertensives, plasma homocysteine levels were associated with
increased rates of progressive WMLs and hippocampal atrophy
(Firbank et al., 2010). However, data from small clinical studies of
patients with LoD has shown that the association between total
plasma homocysteine levels and depression is apparent even after
controlling for WMLs, thus suggesting that the relationship
between homocysteine and depression is not simply underpinned
by WML (potentially vascular) pathology (Chen et al., 2005).
Finally, endothelial dysfunction, involved in the development of
atherosclerosis and thrombosis (Davignon and Ganz, 2004;
Rubanyi, 1993), may contribute to the link between vascular
disease and depression. In support of this notion, measures of
endothelial dysfunction have indeed been associated with
depression (Rajagopalan et al., 2001). These have also been linked
with raised cortisol (Ghiadoni et al., 2000) as well as pro-
inflammatory cytokines thus suggesting that homocysteine
metabolism, endothelial dysfunction and the inflammatory system
may have interdependent roles in the pathogenesis of LLD (Santos
et al., 2009). It is likely that other factors are also important (as
reviewed by Musselman et al., 1998; Teper and O’Brien, 2008). For
instance, both platelet activation (Bruce and Musselman, 2005)
and autonomic dysfunction manifested in heart rate variability
(Carney et al., 2005) have been associated with depression.
3.4. Depression and illness burden
Although there are bidirectional relationships between depres-
sion and vascular disease, LLD is also clearly associated with other
medical conditions as well as illness burden in late life. For
instance, depression is associated with increased risk of low bone
mineral density (a risk factor for osteoporosis) (Wu et al., 2009),
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
and metabolic syndrome and insulin resistance (Laudisio et al.,
2009). Moreover disorders common in elderly populations may be
frequently comorbid with depression. For instance, chronic
obstructive pulmonary disease (Chen et al., 2007), chronic renal
disease (Hedayati et al., 2012), stroke (Ramasubbu, 2011),
Parkinson’s disease (Naismith and Lewis, 2011), hip fracture
(Kamholz and Unutzer, 2007) and obstructive sleep apnoea (Harris
et al., 2009) all have high rates of depression. As the number of
comorbid conditions increases, so does the risk for depression
(Luber et al., 2001). Depression is frequently associated with poor
clinical outcomes, substantial functional impairment and reduced
quality of life across a range of common comorbid conditions
(Hedayati et al., 2012; Lenze et al., 2004; Naismith et al., 2010a;
Robinson and Spalleta, 2010). In addition, depression is associated
with increased mortality rates (Penninx et al., 1999); for example,
depression has a negative impact on the mortality associated with
stroke (Ramasubbu and Patten, 2003), and it increases the risk for
all causes of cardiovascular mortality when comorbid with
diabetes (Pan et al., 2011).
The relationship between depression and co-occurring medical
illness is likely to be complex and reciprocal. As for the relationship
between LLD and vascular disease, not only are the direct biological
effects associated with comorbidity likely to increase the risk of
depression, but LLD itself is associated with a surfeit of destructive
mediators, such as altered glucose tolerance, HPA dysfunction and
a pro-inflammatory milieu (Wolkowitz et al., 2011) as discussed
above. In addition, behavioural, social and cognitive components
may lead to poor adherence with treatment plans, reduced social
contact or maladaptive behaviours, thereby increasing the risk for
physical disorder and illness.
4. Neuropsychological features of late-life depression
Neuropsychological (cognitive) deficits in older people with
depression have been well described and predominantly include
impairments in processing speed, executive functions (i.e. ‘frontal’
or higher-order functions) as well as in aspects of learning and
memory (Herrmann et al., 2007; Kohler et al., 2010a; Naismith
et al., 2006; Sheline et al., 2006) (see Fig. 1a). Indeed, in 18–57% of
older patients, these deficits may be of sufficient severity to
warrant a diagnosis of dementia (Alexopoulos et al., 1993). While it
was previously thought that such deficits would abate with
adequate treatment, this notion is no longer widely accepted.
Instead, it appears that at least some degree of cognitive
dysfunction may persist with symptom resolution (Devanand
et al., 2003).
While not easily detected on gross bedside examinations,
evidence indicates that deficits may be more pronounced in those
with later ages of depression onset (Naismith et al., 2003). Greater
deficits on tests of executive functioning and memory (Kohler
et al., 2010a; Naismith et al., 2003; Rapp et al., 2005; Salloway
et al., 1996) have been reported in association with increasing ages
of onset or in those specifically with LoD (compared to EoD).
However, some cross-sectional data has shown that the effect of
age of onset on cognition is not significant once age and vascular
burden are considered (Lesser et al., 1996; Sheline et al., 2006). In
those with LoD, symptom severity may also be an important
determinant of the extent of cognitive change (Elderkin-Thompson
et al., 2003).
Executive dysfunction in LLD and more particularly LoD is
common and includes deficits in planning, organization, sequenc-
ing, response inhibition, problem solving and set-shifting (Herr-
mann et al., 2007; Naismith et al., 2003; Pisljar et al., 2008;
Salloway et al., 1996). Of concern, the presence of executive deficits
is associated with poor clinical outcomes and prognosis. For
instance, executive dysfunction appears to be related to symptom
107
persistence, recurrence, and poor treatment responsiveness
(Baldwin et al., 2004; Sneed et al., 2007). A recent large-scale
randomised controlled trial found that executive dysfunction, as
well as deficits in processing speed and memory predicted
treatment remission following a 12-week trial of sertraline
(Sheline et al., 2010). Executive dysfunction in LLD is therefore
particularly problematic from a prognostic and clinical perspec-
tive. Indeed, the term ‘depression-executive dysfunction syn-
drome’ has been proposed to describe this sub-group with
prominent executive and psychomotor change, apathy, dispropor-
tionate disability and less guilt and insight (Alexopoulos et al.,
2002c). In addition to clinical features, executive deficits are
associated with poor psychosocial functioning and difficulties in
instrumental activities of daily living (Kiosses et al., 2000, 2001;
Lockwood et al., 2000; Mackin and Arean, 2009). Recent data also
shows that financial capacity in LLD is largely predicted by
executive deficits, rather than by depression severity (Mackin and
Arean, 2009).
Although no known studies have concurrently linked executive
dysfunction and structural brain changes with treatment resis-
tance in MD, there is evidence that prefrontal cortex reductions
may mediate the response to antidepressants, thus adding support
to the notion that executive deficits are likely to reflect more
permanent disruption of frontal circuitry (Gunning et al., 2009). It
is also likely that executive deficits in LLD are reflective of the
deleterious effects of cerebrovascular disease on critical fronto-
subcortical pathways. Several studies have demonstrated signifi-
cant associations between WMLs and performance on measures of
executive functioning such as cognitive flexibility and phonemic
fluency (Breteler et al., 1994), working memory, inhibition and task
switching (Kennedy and Raz, 2009). In LLD specifically, Kohler et al.
(2010b) have reported a significant negative association between
increased ratings of WMLs in the deep white matter and
periventricular regions and scores on memory and executive
functioning measures over an 18-month period, in 35 older adults
with LLD compared to healthy controls. These authors concluded
that cerebrovascular disease contributes significantly to the
persistence of such cognitive impairments in LLD. Additionally,
other studies have provided more indirect evidence to support the
relationship between cerebrovascular disease and executive
functions. For example, Baldwin et al. (2004) reported significantly
impaired executive functioning and a higher WML burden in
antidepressant non-responders relative to control and responder
groups; however the association between these two outcomes was
not reported. Additionally, Salloway et al. (1996) reported a
significant correlation between subcortical hyperintensity burden
and general cognitive impairment, using a cognitive index score
which comprised the summed standardised scores for all cognitive
tests administered, including measures of executive functioning.
Deficits in the domains of processing speed are also prominent
in LLD. Some research has even suggested that such decrements
may underpin impairments in other domains of functioning
(Sheline et al., 2006), although this may not extend to measures of
episodic memory (Delaloye et al., 2008). Slowed psychomotor
speed is a key feature of ‘vascular’ depression, and a recent meta-
analysis suggested that psychomotor speed may be impaired to the
same degree as executive function in those with LoD (Herrmann
et al., 2007). In addition to executive and memory deficits, slowed
processing speed may also be associated with poor treatment
response (Hickie et al., 1995; Sheline et al., 2010; Simpson et al.,
1997; Story et al., 2008), thus suggesting the utility of considering
cognitive function when determining treatment responsiveness.
Changes in processing speed in older patients with depression has
been linked to underlying neurobiological changes including
smaller caudate nucleus volumes (Naismith et al., 2002), and
reduced regional cerebral blood flow in the striatum (Hickie et al.,
108 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
1999, 2007a). Some studies have also examined the role of genetic
risk factors and in this regard there is some data linking the MTHFR
gene mutation (a CVD risk factor) to slow processing speed (Hickie
et al., 2001a; Naismith et al., 2003), though there is also some
contradictory evidence in this field (Hong et al., 2009).
Memory deficits as measured by neuropsychological testing
may not be as severe as deficits within the domains of processing
speed and executive functioning, but nonetheless do relate to the
patient’s overall complaints of cognitive dysfunction. They are also
predictive of functional disability (Naismith et al., 2007). In
general, the literature pertaining to memory deficits in LLD is more
heterogeneous. In some reports, memory decline is certainly
associated with later ages of depression onset (Kohler et al.,
2010a). However, this relationship has not been reported in other
clinical (e.g. (Naismith et al., 2003; Rapp et al., 2005), or meta-
analytic (Herrmann et al., 2007) studies. The lack of clarity
regarding the nature and extent of memory change in LLD may be
due to a number of factors. Firstly, there are likely diverse
aetiologies underpinning memory difficulties including the effects
of cerebrovascular disease, early neurodegenerative changes and
the chronic effects of depressive illness on the hippocampus (see
Table 1). The mechanism by which depression itself may cause
memory decline remains to be determined but there is evidence
suggesting that the down-regulation of the HPA axis may be
relevant, as well as the associated neurotoxic effects of gluco-
corticoids, and reduced expression of brain-derived neurotrophic
factor (BDNF) (Duman et al., 2006). There is emerging evidence
linking poorer memory performance and hippocampal functioning
in depression (Hickie et al., 2005b). Poorer memory functioning in
LLD certainly appears to be associated with reduced hippocampal
volume. Reduced hippocampal volume was also associated with
persistence of memory problems at 6-month follow-up intervals
(O’Brien et al., 2004). Indeed, over 2-year follow-up intervals,
hippocampal volume reduction is more prominent in older people
with depressive disorders compared to controls, and is predictive
of cognitive decline on the MMSE, a measure of gross cognitive
functioning (Steffens et al., 2011).
When evaluating memory functioning in LLD, it is important to
consider which aspects of memory processing are impaired. That
is, insights regarding underlying pathophysiological changes can
be gleaned by determining whether difficulties are apparent in
memory ‘encoding’, ‘storage’ or ‘retrieval’. Commonly, learning
problems are merely referred to as ‘memory’ problems, wherein
they may actually reflect ‘encoding’ problems. The differentiation
of these various aspects of memory is relevant since they likely
reflect dysfunction within distinct neurobiological circuitry, with
the former reflecting dysfunction within prefrontal or frontotem-
poral circuits and the latter being reflective of mesial temporal lobe
dysfunction including hippocampal compromise (Shallice et al.,
1994; Tulving and Markowitsch, 1997). In addition to aetiological
and definitional constraints, there are likely other factors mediat-
ing memory performance in LLD. For instance, recent data suggests
that sleep–wake disturbance may be relevant to both encoding and
memory storage deficits in older people with depression, even
after controlling for depressive symptom severity (Naismith et al.,
2009b, 2011b). Additionally, some data suggest that inpatients
tend to demonstrate greater memory decrements relative to
outpatients (Basso and Bornstein, 1999), and that concomitant
anxiety may play a key role in memory encoding (Kizilbash et al.,
2002). With regard to pharmacological treatment, there is
evidence to suggest that both single-acting and dual-acting
antidepressants may have beneficial effects on memory function
in LLD. A small study investigating the effects of sertraline therapy
found improvements in both short- and long-term storage
(Doraiswamy et al., 2003), however the lack of a control group
in this study means that practice effects cannot be discounted.
Box 2. Neuropsychological features of late-life depression.
 Fronto-subcortical profile
 Executive functions, processing speed, learning and memo-
ry may be affected
 Deficits may persist despite symptom resolution
 Deficits may reflect underlying cerebrovascular disease,
deleterious illness-specific effects and/or early neurodegen-
erative changes
 Late-onset phenotype may have more pronounced cognitive
impairment and greater progression to dementia syn-
dromes
Furthermore, a more recent study found that duloxetine was
associated with significant improvements in verbal learning and
memory compared to placebo in older depressed adults, although
it is not clear whether this effect is separate from the effects on
mood, particularly as the duloxetine group had higher depression
scores at baseline (Raskin et al., 2007). Interestingly, some data
shows that even prior to commencing treatment, serum antic-
holinergicity plays a role in memory decrements in LLD (Nebes
et al., 1997). Thus, it may be worth considering the potential
impact of anticholinergic medications on cognition, an effect that
may be more pronounced with the tricyclic antidepressants.
While data suggests that the effects of electroconvulsive
therapy (ECT) on episodic memory resolve over time, there is,
however, adequate data supporting the notion that retrograde
amnesia may be persistent following ECT. In this regard, future
studies exploring the role of alternative anaesthetics (e.g.
ketamine) are required (for review, see Gregory-Roberts et al.,
2010). Of critical significance, memory impairments may be a
prognostic indicator and are associated with treatment respon-
siveness (Culang et al., 2009; Sheline et al., 2010; Story et al., 2008)
and disability (Naismith et al., 2007). Efforts directed at early
detection and treatment of memory deficits are warranted, and
preliminary data suggests that cognitive training strategies may
prove useful (Naismith et al., 2011a, 2009c) (Box 2).
4.1. Predictors of cognitive decline
As noted above, cognitive deficits in LLD and particularly LoD
often persist despite antidepressant treatment (Devanand et al.,
2003; Nebes et al., 2003) or adequate symptom resolution
(Dahabra et al., 1998; Portella et al., 2003; Trichard et al., 1995).
Although processing speed and executive function deficits are
likely to be specifically implicated in the overall profile (Murphy
and Alexopoulos, 2004; Nebes et al., 2003), there is some
suggestion that selective improvement in executive function
relative to memory may occur (Butters et al., 2000). This failure
to normalise cognitive performance with treatment is certainly
conceivable if the underlying cause of the cognitive deficits is due
to structural damage in white matter tracts, which is unlikely to be
reversible.
While a dearth of studies exist in this area, clinical predictors of
longitudinal decline in LoD include increasing severity of depres-
sion at baseline, inflammatory markers such as higher erythrocyte
sedimentation, and VRFs such as lowered HDL cholesterol and
increased body mass index (Baldwin et al., 2006). Over a 4-year
period, one study showed that later age of depression onset was
associated with memory and executive decline (Kohler et al.,
2010a), although not all studies suggest that age of onset alone is
useful (Brodaty et al., 2001; Dahabra et al., 1998; Krishnan et al.,
1995). In a study examining the role of anxiety over a 4-year
period, comorbid Generalised Anxiety Disorder or Panic Disorder
was associated with specific decline in memory performance in
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
those with LLD. Although participants in this study were not
stratified by age at onset of depression, the impact of age at onset of
anxiety on cognitive functioning in LLD was investigated and an
association between later age at onset of anxiety and worse
cognitive function in LLD was found (DeLuca et al., 2005). Other
clinical predictors include apathy, which appears to be a good
indicator of dementia risk (Bartolini et al., 2005). Neurobiological
correlates may be particularly relevant and one study showed that
smaller left hippocampal volumes were related to incident
dementia over a follow-up period of up to five years (Steffens
et al., 2002b). As expected, WML burden is another predictor of
conversion to dementia (Potter and Steffens, 2007), and suggests
the need to target possible underlying CVD early (Naismith et al.,
2009a). In terms of cognitive predictors, some longitudinal studies
have shown that baseline memory impairment is relevant
(Baldwin et al., 2006; Kohler et al., 2010a). This observation is
supported by recent studies demonstrating that decreases in
hippocampal volume over a 2-year period are predictive of general
cognitive decline (Steffens et al., 2011). Additionally, according to a
recent five year follow-up study of depressed older adults, both
memory deficits and executive dysfunction best predict conver-
sion to dementia (Potter et al., 2012).
Personality factors that may increase the risk for dementia have
not been well evaluated. Interesting links between personality
traits, such as neuroticism and reduced openness, and cognitive
decline have been suggested (Kuzma et al., 2011). Such factors may
be associated with dysregulation of cortisol (Tyrka et al., 2006),
that in turn, has been implicated in dementia.
4.2. The relationship between late-life depression, mild cognitive
impairment and dementia
Up to 60% of patients with LLD meet criteria for mild cognitive
impairment (MCI) (Adler et al., 2004; Lee et al., 2007), a syndrome
that is considered to be a prodromal or ‘at risk’ state for dementia.
Indeed, depression itself has been recognised internationally to be
a prodromal feature for cognitive decline (Steffens et al., 2007)
with more severe symptoms representing a greater risk for MCI
(Lee et al., 2007); moreover epidemiological studies have
supported the ‘prodromal’ nature of depression, demonstrating
an association between dementia and depressive episodes
occurring for the first time in close proximity to dementia onset
(Berger et al., 1999; Chen et al., 1999; Rasmuson et al., 2001). In
those with MCI, rates of depression vary, with recent reviews
suggesting a median depression prevalence of 44.3% in hospital-
based studies and 15.7% in population-based studies (see Panza
et al., 2010 for a review).
Studies have shown that the combination of depression and
MCI is associated with a two-fold risk of developing Alzheimer’s
disease (AD) with an earlier age of onset (Modrego and Ferrandez,
2004). Other studies suggest that those with LLD tend to
predominantly progress to vascular forms of dementia (Baldwin
et al., 2006; Hickie et al., 1997b). Two recent large community-
based studies have demonstrated that increasing levels of
depressive symptoms are associated with increasing risk of
dementia (Saczynski et al., 2010) and that recurrent depression
is particularly pernicious (Dotson et al., 2010). Even in those
patients who may initially demonstrate improvement in mood and
cognitive symptoms, follow-up data over mean intervals of eight
years has shown that while patients may initially demonstrate a
recurrence of depressive episodes, cognitive impairment is
increasingly apparent and eventually, around 79% of patients will
present with a dementia syndrome (Kral and Emery, 1989).
Further, it has been estimated that geriatric depression with
‘reversible dementia’ has a yearly rate of ‘irreversible dementia’
two-and-a-half to six times higher than that of the general geriatric
109
population and therefore constitutes a significant risk factor
(Alexopoulos and Chester, 1992). The risk to dementia conversion
may be particularly high when depression is accompanied by
cognitive impairment and progressive WMLs (Potter and Steffens,
2007). This data collectively suggests that LLD with cognitive
impairment may represent an early manifestation or prodromal
feature of cognitive decline and/or dementia (see Panza et al.,
2010).
Data from a number of community studies suggests that
depression itself presents an independent risk factor for cognitive
decline (Jorm et al., 1991; Ownby et al., 2006). Indeed, recent
longitudinal data, as well as a meta-analysis, demonstrated a
population attributable risk fraction of depression for dementia of
around 10%; with estimates that a reduction of 10% in depression
prevalence could lead to 326 000 less cases of dementia worldwide
(Barnes and Yaffe, 2011). Such data highlights the importance of
eliminating the impact of depression when considering dementia
reduction strategies (Ritchie et al., 2010). Identification of
therapeutic targets for improving cognitive functioning in this
‘at risk’ group is clearly warranted for both symptomatic
improvement, as well as for potential disease modification
(Naismith et al., 2009a).
In terms of mechanisms, it is not yet clear how depression
contributes to dementia, and this may be partly due to the
heterogeneity in longitudinal illness trajectories (i.e. vascular, AD,
Lewy body dementia). The notion of a shared aetiological
foundation between LLD and AD has received some attention,
and various studies have investigated the role of amyloid and tau
protein deposition in LLD, and progression to dementia. For
instance, a small post-mortem study found a predominance of AD
pathology in individuals with LoD and varying levels of cognitive
impairment (Sweet et al., 2004). More recent work utilising
position emission tomography (PET) has further highlighted the
potential role of amyloid/tau deposition in the interface between
depression and dementia. Utilising different imaging techniques
(see Section 7.1), Butters et al. (2008) found that half a group of
individuals with treated LLD had evidence of cerebral amyloid
deposition in a cortical pattern characteristic of early AD, and
Kumar et al. (2011) found that protein (amyloid and tau) binding
was significantly higher in individuals with LLD (who did not meet
criteria for MCI) than in controls, although in a pattern that differed
from that typically observed in patients with AD. Amyloid and tau
are of primary importance for neuronal injury and death in AD;
animal studies have demonstrated increased amyloid deposition
after administration of glucocorticoids (at levels usually associated
with stress response), thus suggesting a possible mechanism for
the relationship between LLD and dementia (see review by Caraci
et al., 2010). It is, however, worth noting that AD pathology is not
the only pathophysiological mechanism by which cognitive
decline may ensue. For instance, as noted above, the longitudinal
link to vascular forms of dementia has been documented (Baldwin
et al., 2006; Hickie et al., 1997b) and, in turn, cerebrovascular
disease has been established as a risk factor for AD. Conversely, a
recent community study investigating the association between
LLD and neuropathological changes found that depression is
associated with subcortical and hippocampal neuronal loss but not
with cerebrovascular or Alzheimer’s pathology (Tsopelas et al.,
2011). A novel finding of this study was that depression was
associated with Lewy bodies in the substantia nigra and locus
ceruleus. Therefore, in some patients, synucleinopathy may even
contribute to cognitive decline. Overall, the lack of clear
neuropathological substrates in LLD again highlights the hetero-
geneity of the disease, and the potential for LLD to progress to a
multitude of illness trajectories. In this regard, it is also possible
that ongoing immunological and inflammatory changes contribute
to cognitive decline as well as disease-specific mechanisms
110 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
relating to glucocorticoids and neurotrophins (see Table 1). For
instance, there is evidence to suggest that reduction of BDNF is
implicated in the pathophysiology of MD (Duman et al., 2006;
Nestler et al., 2002) and these reductions appear to relate to
depressive symptom severity. BDNF is a neurotrophin that
promotes neuronal differentiation, growth and survival. It plays
a role in use-dependent plasticity mechanisms such as long-term
potentiation and is critical in cognitive processes such as learning,
memory and executive functions (Duman et al., 2006). Recent
work suggests that particular genetic polymorphisms of BDNF are
associated with larger hippocampal volumes in depressed elderly
compared with non-depressed controls who have the same
genotype, and may have a neuroprotective role (Kanellopoulos
et al., 2011). Thus, there appears to be a complex interplay between
BDNF, depression, hippocampal functioning and cognition. An
enriched understanding of how these contributing aetiological
factors relate to symptoms and brain changes will ultimately help
to develop treatments targeted at neuroprotection and reduction
of cognitive decline.
In considering the link between depression and dementia, it is
also important to recognise that while LLD may be a prodromal or
concomitant feature of many neurodegenerative diseases includ-
ing AD, Parkinson’s disease and vascular dementia, the longitudi-
nal trajectory of those presenting with depressive symptoms in
later-life is not yet well delineated, particularly in non-clinical
samples. Indeed, recent large studies of community dwelling older
adults without dementia at baseline have found that, although
depression at baseline is associated with an increased risk for
dementia over extended follow-up periods, many of those who
were depressed did not go on to suffer dementia. In the
Framingham Heart Study (Saczynski et al., 2010) depressed
participants had a 50% increased risk for dementia compared to
non-depressed participants but this represented only 21.6% of the
depressed group; in other words 79.4% of depressed elders did not
develop dementia. Similarly, the Maastricht Aging Study found
that out of 180 depressed (defined as falling within the upper
quartile on the revised 90-item Symptom Checklist) participants in
the cohort of 771 non-demented community dwelling elders, only
14 (8%) developed dementia over a 9-year period (Kohler et al.,
2009). Whilst this represented an increased risk for dementia
compared to non-depressed participants, it also highlights that the
development of dementia in the context of LLD is by no means
automatic. Therefore, primary and secondary strategies aimed at
identifying ‘at risk’ individuals and targeting modifiable risk
factors should be implemented early in this group (Naismith et al.,
2009a).
5. Structural neuroimaging studies
Major advances in the neurobiology of depression were made in
the 1990s with the advent and accessibility of magnetic resonance
imaging (MRI). A large body of structural neuroimaging research
has ensued and initially included quantitative measurement of key
structures including volumetric analysis of prefrontal, striatal and
limbic regions (see reviews by Soares and Mann, 1997; Steffens
and Krishnan, 1998), though notably such methods do not inform
us as to the aetiology or nature of the volume loss (e.g. glial,
neuronal, other). Concurrently, the greater resolution of white
matter offered by MRI, as opposed to computed tomography, led to
a preponderance of qualitative studies examining the location and
severity of WMLs. More recently, further sophistication of
neuroimaging acquisition and analysis techniques has enabled
the more detailed examination of white matter tracts using
diffusion tensor imaging. The specific structural neuroimaging
findings in LLD have been reviewed by a number of groups
(Herrmann et al., 2008; Schweitzer et al., 2001; Vaishnavi and
Taylor, 2006) and will be outlined here with specific reference to
age of onset, fronto-subcortical circuitry and clinical correlates (see
Fig. 1a and b).
5.1. Volumetric findings
5.1.1. Whole brain
Although in mid-life samples an association between smaller
whole brain volumes and depression has been demonstrated
(Hickie et al., 2005b; Naismith et al., 2002), MRI studies of whole
brain volumes in LLD have generally not demonstrated significant
differences between depressed elders and healthy controls
(Andreescu et al., 2008; Ballmaier et al., 2004b; Krishnan et al.,
1993; Kumar et al., 1998). Of those that have examined LoD
specifically, Pantel et al. (1997) found that this sub-group had
significantly smaller whole brain volumes compared to healthy
controls. However, more recent studies have failed to confirm this
finding (Ballmaier et al., 2004a). Differences in ventricular size
between individuals with LLD and controls have been more
consistently found (Alexopoulos et al., 1992; Shima et al., 1984),
and larger ventricular sizes appear to correlate with the age of
depression onset. Despite the apparent lack of alterations in whole
brain volumes, there is a wealth of data relating to specific regional
volumetric differences associated with LLD. Sophisticated imaging
techniques, including three-dimensional anatomical surface
modelling techniques, have demonstrated more clearly some of
these changes, as well as their relationship with age of depression
onset.
5.1.2. Frontal lobe
Numerous studies have demonstrated decreases in frontal lobe
volume in those with LLD (Kumar et al., 2000a, 1998; Lavretsky
et al., 2005). This has been shown specifically in LoD (Almeida et al.,
2003), which has also been associated with attenuation of the
‘normal’ frontal volumetric asymmetry (Kumar et al., 2000b).
However, there are some conflicting results, with Kumar et al.
(1999) failing to find any linear relationship between age of
depression onset and total or focal brain volumes. Frontal lobe
changes in this group may also be mediated by gender. Lavretsky
et al. (2004) reported that in depressed elders, males have smaller
frontal lobe volumes compared with females. Taki et al. (2005) also
found gender differences, with depressed males showing signifi-
cant decreases in the medial frontal lobe, as well as in the right
precentral gyrus compared with male controls. These results were
not present in females.
A number of studies (Ballmaier et al., 2004c; Dotson et al., 2009;
Lai et al., 2000; Lavretsky et al., 2007) have specifically examined
subregions of the prefrontal cortex (PFC) in LLD. In accordance with
the neural circuitry implicated in depressive disorders, reductions
in the OFC, ACC and gyrus rectus have been demonstrated in
depressed elders compared with controls (Ballmaier et al., 2004c;
Elderkin-Thompson et al., 2009; Lavretsky et al., 2007; Lee et al.,
2003). While not all studies suggest that the LoD phenotype is
associated with specific PFC subregion volumetric reductions
(Ballmaier et al., 2004a), some have shown that grey matter
reductions in frontal superior, orbital, middle and medial superior
regions correlate with later age of depression onset (Andreescu
et al., 2008). Notably, even sub-threshold depressive symptoms
appear to relate to volumetric reductions. For instance, depressive
symptoms have been found to be associated with reductions in the
cingulate gyrus and OFC, although age also played a role in
mediating this relationship (Dotson et al., 2009).
5.1.2.1. Associations with clinical and cognitive features. There is
some data to support a link between PFC volume reductions and
clinical symptoms, cognition and functional capacity; although a
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
clear regionally specific relationship has not yet emerged. For
instance, volumetric reductions of the left frontotemporal region
have been correlated with psychotic symptoms as well as cognitive
impairments in the domains of psychomotor speed and executive
function in those patients with LoD (Simpson et al., 1999). By
contrast, apathy in LLD has been associated with ACC volume
reductions (Lavretsky et al., 2007). Volumetric reductions in the
medial orbitofrontal gyri were correlated with functional disability
in LLD (Taylor et al., 2003b). Another study showed that smaller
OFC, gyrus rectus and ACC volumes were related to poorer
executive function (Elderkin-Thompson et al., 2009) in healthy
elderly, a relationship that was attenuated in depressed elders.
This may indicate that depressed elders are less likely to benefit
from larger volumes of these key regions in comparison to control
subjects. Thus, rather than focussing on volumetric change, it may
be necessary to consider other underlying pathophysiological
contributors to function (Elderkin-Thompson et al., 2009).
5.1.2.2. Medication effects. There is some suggestion that antide-
pressant medication may mediate frontal volumetric changes.
Specifically, antidepressant exposure may protect against frontal
grey matter loss in LLD. For instance, Lavretsky et al. (2005) found
that depressed elders had smaller total and grey matter volumes of
the OFC but that those with prior antidepressant exposure had
larger total OFC volume compared to the drug naı̈ve group.
Additionally, consistent with data linking executive dysfunction
with prognosis (e.g. Sheline et al., 2010), volumetric changes in the
PFC may be associated with treatment responsiveness. For
instance, reductions in dorsal and rostral ACC volumes have been
associated with failure of LLD to respond to escitalopram
treatment (Gunning et al., 2009). A number of possibilities may
account for these findings: smaller regional PFC volumes may
predispose to failure to respond to antidepressant therapy.
Alternatively neurotrophic effects of antidepressant medication
may lead to the increases seen in grey matter volume. Further-
more, since a negative association between OFC volume and
subcortical grey matter lesion severity (basal ganglia) has been
demonstrated in LLD (Lee et al., 2003), cerebrovascular disease
may play a key role in mediating volumetric changes.
5.1.3. Limbic regions
The limbic system comprises a set of brain structures that
collectively play a role in emotion, behaviour, memory and
olfaction and which is linked to other key neurohormonal systems
including the circadian system (see review by Gerstner and Yin,
2010). Of these structures, the hippocampus has been most
extensively investigated in MD as well as LLD more specifically.
While the amygdala clearly plays a vital role in the EoD phenotype,
and particularly in the modulation of anxiety, fear and social
behaviours, it has been less well studied in LLD.
5.1.3.1. The hippocampus. The hippocampus is integrally involved
in mood regulation due to its connections to key frontal and
subcortical regions including the amygdala, hypothalamus, basal
ganglia and PFC. There is evidence to suggest that it plays a direct
role in the serotonergic HPA functioning (see review by MacQueen
and Frodl, 2011). It is an especially plastic and vulnerable region,
sensitive to the effects of hypoxia, cerebral insult and excess
glucocorticoids, as well as excitatory neurotransmitters, due to the
large numbers of receptors (McEwen and Olie, 2005). The
hippocampus has been the subject of renewed interest in
neuropsychiatry and regenerative neuroscience in recent years,
since animal studies have now suggested that this primitive
structure is capable of neurogenesis. This research is of particular
interest in LLD as a wealth of both animal and human studies have
concurrently demonstrated that antidepressant medications
111
promote neurotrophins such as BDNF, which in turn, may promote
hippocampal neurogenesis, or at least provide some neuroprotec-
tion from the deleterious effects of glucocorticoids (Chen et al.,
2001; Malberg et al., 2000; Perera et al., 2007; Wang et al., 2008a).
While there are some negative studies, human studies in
younger patients with depression as well as LLD largely support
the notion that depression is associated with hippocampal volume
reduction. For instance, Sheline et al. (1996) found that duration of
depression predicts hippocampal volume loss in women. Consis-
tent with this finding, studies in adults have found that although
hippocampal dysfunction (as measured by memory performance)
is present in both those with first episode depression as well as
those with multiple previous episodes of depression, hippocampal
volume reductions appear to be apparent only in those with past
depressive episodes (MacQueen et al., 2003). Furthermore, in older
adults, bilateral hippocampal-entorhinal volume reductions have
been found to be associated with greater years of cumulative
depressive illness (Bell-McGinty et al., 2002) and smaller
hippocampal volumes appear to be linked with treatment
responsiveness (Hsieh et al., 2002) as well as gross cognitive
decline over two year follow-up periods (Steffens et al., 2009).
Interestingly the relationship between hippocampal volumes and
depression may preferentially relate to the duration of untreated
illness, as no known relationship has been demonstrated between
hippocampal volume loss and duration of depression whilst on
antidepressant therapy, nor with duration of exposure to
antidepressant therapy (Sheline et al., 2003).
In particular, when examining LLD, it is important to consider
the contributing effects of early neurodegenerative disease, as well
as vascular disease when interpreting hippocampal change. In this
regard, studies have found volumetric reductions in both LoD and
EoD (Hickie et al., 2005b; Lloyd et al., 2004; Steffens et al., 2000).
Some of these have also linked smaller hippocampal size in LoD
with poorer memory performance (Hickie et al., 2005b) or smaller
left hippocampal volume and later development of dementia in
depressed non-demented elders (Steffens et al., 2002b), as well as
early-onset subtypes (Bell-McGinty et al., 2002; Sheline et al.,
1999). Furthermore, a recent large cohort study demonstrated that
whilst having ever been depressed was associated with smaller
hippocampal volumes, those with EoD had smaller hippocampal
volumes compared with controls whilst those with LoD had
smaller entorhinal cortex volumes (Gerritsen et al., 2011). Again,
this data suggests that volumetric changes in LLD can reflect
multiple pathophysiological processes. In this regard, there are a
range of immunological, inflammatory, vascular and neurodegen-
erative factors of potential relevance.
With respect to the ‘neurotoxic’ effects of depressive illness, a
failure of the termination of glucocorticoid secretion at the end of a
stressor may be related to degeneration in key brain regions that
regulate the HPA axis, including the hippocampus; this degenera-
tion in turn may relate to cumulative exposure to glucocorticoids
throughout the lifespan thus setting up a feed-forward cascade
(Sapolsky et al., 1986). As recently reviewed by MacQueen and
Frodl (2011), in animal models, stress is associated with a decrease
in the size, length and number of hippocampal dendrites, and
disrupts hippocampal neurogenesis, though one must be cautious
in extrapolation of these findings to humans since species-
dependent effects have also been observed. As neurogenesis
appears to be integral to neuroplasticity, altered neurogenesis may
be critically involved in reduced antidepressant responsiveness
and may directly impact on pathogenesis such that vulnerability to
depression is enhanced and perpetuated. Further support for the
role of stress on hippocampal integrity also stems from data linking
stress with poor memory, as well as the observation that extended
or high dose treatment with glucocorticoids has a negative impact
on hippocampus-dependent memory consolidation (for review see
112 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
MacQueen and Frodl, 2011; Sapolsky et al., 2000). Studies
involving human subjects have demonstrated altered glucocorti-
coid regulation in patients with both depression (Keller et al.,
2006) and dementia (Rasmuson et al., 2001), however evidence for
cortisol as a mediating mechanism between depression and
hippocampal atrophy is inconsistent. One longitudinal study
examining the relationship between hippocampal volume, cogni-
tive impairment and hypercortisolaemia, found no association
between hippocampal volume reduction in depressed elders and
increased cortisol levels (O’Brien et al., 2004). This finding was
replicated in a recent study that found that differences in
hippocampal and entorhinal cortex volumes in EoD and LoD were
not explained by HPA axis activity (Gerritsen et al., 2011). Possibly
these results may relate to measurement factors, in that cortisol
levels were measured from salivary samples over a three day
period, and thus may not accurately reflect total exposure to
glucocorticoids over a lifetime. Also, other potentially relevant
steroids such as dehydroepiandrosterone (Magri et al., 2006) were
not measured. However these findings suggest that there may be
other deleterious processes at work. The link between stress and
glutamatergic excess must be considered, particularly given the
well-established role of this excitatory neurotransmitter in
learning and memory formation (Pittenger and Duman, 2008).
In addition, inflammatory changes associated with depression (see
Section 10) as well as disturbances in neurotrophic factors such as
BDNF (see Section 9.1) are likely to be important. den Heijer et al.
(2011) found no evidence that smaller hippocampal volumes
preceded the development of LLD but that depression may lead to a
faster rate of hippocampal volume decline. The apolipoprotein
epsilon 4 allele may also be a relevant contributor to the increased
likelihood of dementia in older people with depressive symptoms
(Kim et al., 2002), though further prospective studies are required
to support this association. Overall, this data suggests that
hippocampal change in LLD likely has multiple pathophysiological
underpinnings, some of which may directly relate to the duration
of treated or untreated depressive illness, and some of which likely
reflect age-related or neurodegenerative brain changes (see Table
1).
5.1.3.2. Hippocampal morphology. More recent work utilising
computational image analysis methods have evaluated hippocam-
pal shape differences. Shape and volumetric differences in the left
hippocampus were found in a group of non-remitted depressed
elders when compared with healthy controls and remitted
depressed elders (Zhao et al., 2008). These changes roughly
corresponded with regions CA1 and CA2. The remitted group and
controls had no such changes. Consistent with these findings,
Ballmaier et al. (2008) demonstrated significant regional surface
contractions bilaterally in the hippocampal head, corresponding to
the CA1 and CA2 subfields and subiculum in LLD compared with
controls. Moreover significant reductions in the left hippocampus,
concentrated in the anterior subiculum and lateral posterior CA1
subfield, were found in older people with LoD compared with EoD.
In the LoD group, memory performance was significantly related to
hippocampal deficit patterns. These differential hippocampal
deficit patterns in LoD and their relationship with memory
performance are interesting in the light of similar patterns of
CA1 and subiculum involvement found in patients with MCI that
later developed Alzheimer’s disease (Apostolova et al., 2006; Wang
et al., 2003), and add weight to the hypothesis that LoD is part of a
neurodegenerative process. On the other hand, the CA1 and CA2
subregions have been suggested to be particularly vulnerable to
ischaemic damage (see review by Nikonenko et al., 2009), and thus,
such changes may reflect the ischaemic small vessel disease that is
seen commonly in LoD. Furthermore since the anterior hippocam-
pus has rich connections with the PFC, subregions of which have
also been found to be smaller in LoD (Ballmaier et al., 2004c),
disruption of the efferent and afferent connections between the
hippocampus and the thalamus, basal ganglia and PFC by
ischaemic disease could contribute to depression vulnerability.
5.1.3.3. Relationship with clinical and cognitive features. As noted
above, reductions in the hippocampus in MD have been directly
associated with memory performance (Hickie et al., 2005b), a
finding which is not surprising given the well-documented role of
this structure in memory functioning (Squire, 1992). Hippocampal
volumetric reductions have also been associated with failure to
respond to antidepressant treatment (Hsieh et al., 2002), and there
is a suggestion that the hippocampus may modulate antidepres-
sant effects (Mongeau et al., 1997). The findings of Zhao et al.
(2008) may be seen in this light. An alternative explanation may be
that antidepressants exert neurotrophic effects on the hippocam-
pus, accounting for the lack of shape or volume differences in
remitted depressed elders compared to controls. Further research
in this area is warranted given that amelioration of hippocampal
change may ultimately reduce cognitive decline associated with
depression, which in turn would have major impacts on disability,
daily functioning, quality of life, and may possibly even slow rates
of progression to dementia (Naismith et al., 2009a).
5.1.3.4. The amygdala. Studies investigating amygdala structure
in younger samples have yielded variable findings, with both
reductions (Caetano et al., 2004; Sheline et al., 1998; von Gunten
et al., 2000) and increases (Frodl et al., 2003; Lange and Irle, 2004)
in volumes of this structure evident. This variation may be related
to the effects of antidepressant medication. Indeed, this notion is
supported by a recent meta-analysis of 13 studies that demon-
strated that the proportion of medicated depressed participants in
a study determined the difference in amygdala volume between
depressed and non-depressed subjects, and found that unmedi-
cated depression is associated with decreased amygdala volumes
(Hamilton et al., 2008). There has been a paucity of research
specifically examining amygdala volumes in older depressed
samples. This relative negligence is surprising given the critical
role of this structure for emotion regulation, particularly
processing emotional, fear-related and social information. Addi-
tionally the amygdala is important in the modulation of
monoamine and corticosteroid release in response to aversive
or novel stimuli (Savitz and Drevets, 2009). Of those that have
examined this structure in older samples, some evidence for a
reduction in volume is emerging. For example, an investigation of
patterns of brain atrophy in 14 patients with LoD, showed reduced
volumes of the right amygdala in comparison with control
participants (Egger et al., 2008). Hickie et al. (2007b) also noted
smaller amygdala volumes in 45 older patients with moderate to
severe depression in comparison to controls. A further study of
morphology has demonstrated significant shape variation in the
left and right amygdalae in depressed elders, most prominently in
the anterior portion, a region typically associated with the
basolateral nuclei (Tamburo et al., 2009). These core nuclei are
highly connected to the hippocampus and prefrontal cortex, are
densely populated with glucocorticoid receptors (Johnson et al.,
2005), and have been shown to be glutamatergic. Previously,
Sheline et al. (1998) reported that MD in an adult cohort was
associated with volumetric decrease in the basolateral nuclei.
Thus, it has been postulated that stress induced glucocorticoid
toxicity may play a selective role in amygdala dysfunction in LLD
(Hamilton et al., 2008). The neuropathological finding of reduced
numbers of oligodendrocytes, which play a role in extracellular
glutamate homeostasis (Damelio et al., 1990), in the amygdala of
depressed individuals (Hamidi et al., 2004) provides some support
for this hypothesis. Such reductions may lead to toxic levels of
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
extracellular glutamate, thus contributing to neural degeneration.
Interestingly, animal studies have demonstrated that inducing
electroconvulsive seizures leads to the generation of oligoden-
drocytes in the rat amygdala (Wennstrom et al., 2004). Taken
together with the findings that medicated depression is associat-
ed with increased amygdala volumes (Hamilton et al., 2008), this
data provides some suggestion that the amygdala is capable of
neuroplasticity.
5.1.4. The striatum
Some researchers have shown reductions in the size of the
striatum in LLD (for reviews see Lorenzetti et al., 2009; Steffens and
Krishnan, 1998). Significant bilateral volume reductions of the
caudate have been demonstrated in elderly depressed subjects;
these reductions are generally localized to the head of the caudate
nucleus, particularly on the left (Butters et al., 2009; Figiel et al.,
1991a; Krishnan and Figiel, 1989; Krishnan et al., 1992; Mendez
et al., 1989; Starkstein et al., 1987). Moreover, a negative
correlation between age and caudate nucleus volumes in
depressed adults (Krishnan et al., 1992), as well as age at onset
of depression and caudate volumes (Greenwald et al., 1997) has
been demonstrated.
It has been hypothesised that the functional significance of the
relationship between caudate volume reductions and depression is
related to degeneration in the dopaminergic connections between
the caudate and cortical and limbic areas important for mood
regulation (Krishnan et al., 1992). Interestingly, increasing volume
of anterior WMLs have been found to be associated with smaller
total and right caudate volume in depressed elders (Hannestad
et al., 2006), suggesting that vascular disease may play a role in
caudate atrophy via disruption of frontostriatal connections. No
known studies to-date have examined specific subregions of the
caudate nucleus. This may prove to be more pertinent to the
refinement of comprehensive pathophysiological models of LLD
given the differential roles of specific subregions of the caudate
nucleus in aspects of cognitive, emotional and behavioural
functioning (Balleine and O’Doherty, 2010). In particular, the
ventral striatum may play a role in the motivational control of
action, whilst the dorsal striatum may play a role in the control of
decision-making mediated by reward. Thus, it appears that the
striatum plays a larger role in executive functions than previously
acknowledged (Balleine and O’Doherty, 2010). One recent study
used three-dimensional surface mapping techniques in a group of
patients with LLD and control subjects and demonstrated that
volumetric reductions were most pronounced in anterior regions,
which in turn were associated with more severe depressive
symptoms, but not with age of onset or years of cumulative illness
(Butters et al., 2009). Further studies using such sophisticated
imaging analysis techniques are now required in order to
determine the relevance of topographically and functionally
distinct regions of the caudate nucleus.
5.1.4.1. Relationship with clinical and cognitive features. There
appears to be a paucity of research in this area. This may partly
reflect the few studies that have been conducted, publication bias
or may even include lack of reference to specific subregions of the
caudate nucleus. As noted above, caudate nucleus volumes have
been correlated with depression severity (Butters et al., 2009) in
some older depressed samples and others have demonstrated links
with psychomotor speed (Naismith et al., 2002); a key determinant
of treatment response (Hickie et al., 1996; Story et al., 2008).
5.1.5. Significance of volumetric changes in LLD
Further studies are required in order to determine what
volumetric reductions actually reflect. For instance, they may
simply represent changes in neuropil, alterations in glial cell
113
density or synaptic density. Neuropathological studies have
demonstrated declines in the density and the size of neurons in
the PFC as well as reductions in glial cell density in limbic regions
(see Section 7). Cerebrovascular disease, as exemplified by WMLs
(see Section 5.2) in fronto-subcortical regions, is likely to disrupt
regional blood flow and metabolism as well as disturb local
synaptic transmission. Thus, via disruption to their connections,
WMLs may be implicated in the atrophy of cortical and subcortical
regions. Finally early cerebral development may be altered via
genetic polymorphisms, leading to volumetric reductions in key
brain regions which then place an individual at risk of depression
and cognitive syndromes emerging later in life in the context of
ongoing medical and psychosocial risk factors (see Section 8).
Further studies regarding gene expression are now required in
order to determine the mechanisms by which relevant vulnerabil-
ity genes are expressed.
5.2. White matter changes
5.2.1. Macrostructural findings
Research in ageing samples indicates that white matter
volume generally declines with age (Gunning-Dixon et al.,
2009), and it appears that the frontal and temporal regions are
most vulnerable. As aforementioned, WMLs are areas of hyper-
intensity appearing on T2-weighted and fluid attenuation
inversion recovery (FLAIR) MRI images; they may occur in both
the deep white and subcortical grey matter as well as in
periventricular regions. They are typically classified by pattern
(e.g. punctate or confluent) and region (periventricular, deep
white matter, subcortical grey regions) and can be rated visually
using standardised rating scales (Fazekas et al., 1987; Scheltens
et al., 1993; Wahlund et al., 2001). More recent research has
utilised volumetric measurement as opposed to visual rating
scales as it is able to provide more information on WML location
and size (Anbeek et al., 2004), and there is evidence to suggest that
visual rating scales are less sensitive in differentiating clinical
groups (van Straaten et al., 2006). Histopathological examination
reveals a significant proportion of WMLs represent areas of
infarction, axonal loss, gliosis and/or ischaemic demyelination,
and an increased proportion of WMLs in the frontal lobes appear
ischaemic in depressed compared to control subjects (Thomas
et al., 2002). They are strongly associated with age and VRFs
(Awad et al., 1986; Liao et al., 1997; Longstreth et al., 2001). The
presence of perivascular spaces indicative of microangiopathy are
also common in LLD and recent studies using pressure myography
have shown abnormalities of subcutaneous small artery structure
and function, even when compared to controls with similar
cardiovascular profiles (Greenstein et al., 2010). In clinical
practice, however, it is important to consider that specific
neuroradiological investigation must purposively examine for
other underlying causes of WMLs, including those reflecting
infectious or inflammatory conditions or demyelination.
As previously outlined (Section 3), LLD is characterized by more
frequent and intense WMLs in comparison to control subjects, a
finding that is even more prominent in those with later ages of
depression onset (Coffey et al., 1993; de Groot et al., 2000; Figiel
et al., 1991b; Herrmann et al., 2008; Hickie et al., 1995; Krishnan
and McDonald, 1995; Kumar et al., 2000a; Steffens et al., 2002a,
1999b; Tupler et al., 2002). In the 1990s, several seminal studies
were published in this area, which collectively highlighted the link
between WMLs, VRFs and age at onset of depression (Alexopoulos
et al., 1997; Hickie et al., 1995, 1997b; Krishnan et al., 1997). As
outlined above, there has since been a wealth of data that has
explored the association between WMLs and both LLD and LoD;
these studies have been reviewed elsewhere (e.g. Herrmann et al.,
2008).
114 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
One outstanding issue with regard to the role of WMLs in the
aetiology of LLD pertains to the importance of lesion location as
opposed to lesion volume. Early reports using visual rating scales
linked increasing severity of WMLs with new onset depression
(Lesser et al., 1991; Nebes et al., 2002). More recent research
utilising semi-automated volumetric measurement has found
greater WML volumes in LLD compared with healthy controls
(Taylor et al., 2005a). Interestingly in a study evaluating the
internal validity of ‘vascular’ depression as a unique diagnostic
subtype, latent class analysis of two independent clinical samples
found that only deep white matter lesion burden (as compared to
executive dysfunction, late-onset of depression and subcortical
grey matter hyperintensities) was necessary to determine
membership to the ‘vascular’ depression group (Sneed et al.,
2008). These studies therefore suggest that lesion volume is a key
determinant of symptom onset.
On the other hand, there is also data to support the critical role
of lesion location. For instance, frontal lesions (Firbank et al., 2004;
Sheline et al., 2008; Taylor et al., 2003a), and more specifically
lesions in the medial OFC (MacFall et al., 2001), are associated with
LLD depression. In a sample of 22 patients with LoD and controls,
Dalby et al. (2010) reported that while no significant differences
were found between groups with regard to the number and
volume of WMLs, patients displayed a significantly higher lesion
density in the right superior frontal gyrus (the boundary zone of
white matter underlying the medial PFC, ACC and the OFC), and in
the white matter area between the left precentral and post-central
gyrus (an area approximating Brodmanns area 6, comprising the
premotor cortex and supplementary area). It is interesting to note
from this study, however, that five patients demonstrated no
evidence of WMLs, reaffirming that these features are not a
necessary condition for all patients who develop depression for the
first time in later-life. Sheline et al. (2008) also found that the
strategic location of WMLs, but not whole brain volumes played a
significant role in LLD and distinguished patients with LLD from
non-depressed elderly, irrespective of the amount of VRF burden.
In this study, automated segmentation methods were used to
compare the total brain and regional WML burden found on MRI
between 83 older depressed adults and 32 age-matched controls.
While whole brain volumes, white matter, gray matter and WMLs
did not differ between groups, the prevalence of WMLs in seven
regions of the brain was significantly greater in the depressed
group than in the comparison group. The regions identified were (i)
the right superior longitudinal fasciculus; (ii) the right superior
longitudinal fasciculus; (iii) a second region in the right superior
longitudinal fasciculus; (iv) left superior longitudinal fasciculus;
(v) left uncinate fasciculus/frontal operculum; (vi) right extreme
capsule; and (vii) right inferior longitudinal fasciculus. This study
is unique in evaluating the white matter tracts and suggests more
detailed tractography analysis may ultimately be useful to help
delineate which neural circuits and connecting tracts are critical to
the vascular model of LLD.
5.2.1.1. Relationship with clinical and cognitive features. While a
prospective study failed to show that WMLs were predictive of
mild levels of depressive symptoms longitudinally (Versluis et al.,
2006), the aetiological significance of WMLs in LLD, as well as LoD,
is underscored by reports that they may predate the onset of
depression (Nebes et al., 2002; Teodorczuk et al., 2007), and may
predict progress over time in those with depression (Godin et al.,
2008). Indeed, recent prospective data from the Leukoaraiosis and
Disability in the Elderly (LADIS) multi-centre study has shown that
in several hundred people, more severe white matter changes at
baseline predicted both depressive episodes and depressive
symptoms at both two and three year follow-up periods
(Teodorczuk et al., 2010). Additionally subcortical disease appears
to have an important role in long-term outcome of LLD, with
reports that severity of subcortical gray matter hyperintensities at
baseline is associated with scores on the Montgomery-Asberg
Depression Rating Scale over a follow-up period of 64 months in
older adults with depression (Steffens and McQuoid, 2005).
In addition to being associated with later ages of depression
onset and cerebrovascular disease, WMLs also appear to be
associated with cognitive decline. For example, one early study
incorporating follow-up (Hickie et al., 1997b) showed that older
age at onset of depression and extent of WMLs on MRI played a
significant role in progressive cognitive decline and the develop-
ment of probable dementia syndromes, as well as the need for
institutional care (Hickie et al., 1997b). Specific associations have
been demonstrated with memory impairments, executive dys-
function and impaired processing speed (Hickie et al., 1995; Kohler
et al., 2010b; Kramer-Ginsberg et al., 1999; Potter et al., 2007).
Kramer-Ginsberg et al. (1999) found that depressed elderly with
moderate to severe WMLs in the deep white matter performed
significantly worse than both depressed patients without such
lesions as well as healthy controls (both with and without
moderate to severe deep white matter hyperintensities) on tests of
memory and executive function. Interestingly no significant
associations were observed for hyperintensities in periventricular
or subcortical grey areas. Sheline et al. (2008) examined the
functional significance of WMLs by correlating the lesion burden in
seven subcortical regions (mentioned previously) with perfor-
mance on a comprehensive battery of neuropsychological tests.
Among the depressed patients, three regions were significantly
and negatively correlated with executive function including (1)
right superior longitudinal fasciculus (2) left superior longitudinal
fasciculus and (3) left uncinate fasciculus. However, no significant
correlations were found within the control group. As these areas
support cortical regions critical for higher level thinking skills (i.e.
executive functions) and emotional processing, such lesion
locations may increase susceptibility to depression, expressed
functionally as cognitive deficits (Sheline et al., 2008). More
recently WMLs in both the deep white matter and periventricular
areas have been associated with continuing cognitive impairments
in older adults with depression. Using the modified Fazekas criteria
for assessing WML, Sheline et al. (2010) found that elderly (>60
years) patients with MD were more likely to perform poorly on
neuropsychological tests of executive function, processing speed,
episodic memory, language and working memory if they had
greater WML burden. Furthermore, severity of cognitive im-
pairment, as well as Fazekas scores were predictors of outcome
after 12 weeks of antidepressant (sertraline) therapy. By contrast,
other studies have shown that neither cortisol levels nor cerebral
atrophy are associated with such impairments (Kohler et al.,
2010b). Taken together these findings emphasize the role of
cerebrovascular disease in conferring vulnerability as well as
perpetuating LLD. Possibly confluence of WMLs confers a worse
prognosis than the presence of punctate lesions (Sachdev et al.,
2006); furthermore the association between specific WML location
and cognitive deficits suggests that disruption to fronto-subcorti-
cal connections may be relatively more important for the cognitive
impairments seen in LLD than lesions in the subcortical grey
matter, which presumably represent structural damage in these
areas. Such structural damage is likely to alter the function of the
subcortical region affected, possibly producing the particular
clinical features of depression such as anhedonia and apathy
(Sheline et al., 2010; Taylor et al., 2005a).
Of significance, WMLs are also related to functional disability.
Data from the LADIS study, a longitudinal cohort study investigat-
ing the relationship between white matter disease and subsequent
depression and disability in older adults, suggests that greater
baseline WMLs independently predict functional decline and
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
disability in this group (Inzitari et al., 2007). In older adults with
severe depressive disorders, the extent of WMLs predicts the long-
term disability experienced by these patients (Hickie et al., 1997b),
and after controlling for age, gender, depression severity and
medical comorbidity, subcortical WMLs have been found to be
significantly associated with impairments in instrumental activi-
ties of daily living (Steffens et al., 2002a). Of interest is the recent
data emerging from the LADIS study, which suggests that in older
adults with WMLs, the relationship with incident depression over
the longer term is somewhat attenuated as the levels of functional
disability increase (Teodorczuk et al., 2010). The authors suggest
that, over the longer term, a potential secondary pathway emerges,
whereby WMLs lead to functional impairments, which then go on
to amplify depressive symptoms, leading to further functional
impairments (Teodorczuk et al., 2010).
Early reports showed that increasing severity of WMLs were
associated with decreased response to treatment (Hickie et al.,
1995; O’Brien et al., 1998; Simpson et al., 1997). Additionally some
studies have implicated regional specificity in the relationship
between WMLs and treatment response. Patankar et al. (2007)
found that basal ganglia hyperintensities were associated with
failure to respond to antidepressant monotherapy. This mirrors
research linking subcortical gray matter hyperintensities with
failure to respond to ECT (Steffens et al., 2001). More recent work
has found that depressed elders who failed to respond to 12 weeks
of escitalopram therapy exhibited significantly greater WML
burden compared with both normal controls and those depressed
elders who did experience remission of depression (Gunning-
Dixon et al., 2010). There have been conflicting reports (Salloway
et al., 2002; Sneed et al., 2007), however it is possible that use of
visual rating scales may have contributed to the difference in
results; in particular a recent double-blind, placebo controlled trial
of citalopram in patients aged 75 years or older found that only
executive function deficits predicted response to the antidepres-
sant and no significant relationship existed between WML load and
treatment response (Sneed et al., 2007). The authors raised the
interesting point that, given the high rate of lesion load in their
sample combined with the average age of participants (79.6 years),
MRI based diagnoses of ‘vascular’ depression may only be useful in
younger populations where increasing WML load is likely to be
relatively specific (Sneed et al., 2007). Perhaps intertwined with
treatment responsiveness, it appears that lesion burden confers
increased risk for illness course or chronicity of depression. For
instance, an early cohort study found that on follow-up (6 months–
2 years), only 24% of a small group (n = 37) of older adults with
severe depression were in remission, whilst in 19% of patients, the
depression had not improved or had become worse (Hickie et al.,
1997b). Increased WML load has also been associated with a more
chronic course of depression (Heiden et al., 2005; Lavretsky et al.,
2008).
There also seems to be an important link between WML and
factors associated with homocysteine metabolism in patients with
depression. For instance, in a clinical sample of 47 older patients
with MD, low vitamin B12 levels (but not folate) were predictive of
more extensive WMLs on imaging (Hickie et al., 2005a). Total
plasma homocysteine levels have also been independently related
to deep WMLs in healthy men aged 60–64 years (Sachdev et al.,
2004). On the other hand, although the extent of WMLs was
positively correlated with plasma homocysteine concentration, the
association between higher plasma homocysteine and depression
remained even after controlling for WMLs, suggesting that the
relationship may not simply be due to vascular disease (Chen et al.,
2005). Thus consideration of a multifactorial approach that takes
into account the complex relationship between VRFs, dietary
factors, and structural brain changes is likely to be paramount to
primary and secondary intervention approaches.
115
5.2.2. Microstructural findings
As discussed above, the strategic location of WMLs may be a key
component in conferring vulnerability and/or perpetuating de-
pressive syndromes in later-life (Dalby et al., 2010; Sheline et al.,
2008). However, given the association between ageing and white
matter integrity, more subtle and diffuse white matter compro-
mise such as microstructural disturbance, could play a role in the
disorder. This has been assessed using diffusion tensor imaging
(DTI), a variation of MRI that measures the magnitude and
orientation of diffusion of water in tissues (Gunning-Dixon et al.,
2009). Diffusion occurs equally in all directions if no barriers to
diffusion exist (isotropy). Barriers include myelin sheaths, cell
membranes and white matter fibre tracts, and, when present, tend
to cause diffusion to follow the long axis of the barrier (anisotropy).
Thus fractional anisotropy (FA), which is a measure of the strength
of the directional dependence of diffusion and tissue disruption,
allows for a quantification of brain tissue microstructure.
DTI studies in LLD utilising a region of interest protocol have
consistently found widespread reduced FA primarily in frontal
(Alexopoulos et al., 2009; Bae et al., 2006; Nobuhara et al., 2006;
Taylor et al., 2004; Yang et al., 2007) but also temporal (Nobuhara
et al., 2006; Yang et al., 2007) regions. Furthermore a more recent
technique, an automated ‘tract-based spatial statistics’ procedure
that potentially improves DTI analysis and interpretation, also
demonstrated lower FA in frontal, temporal and midbrain regions
(Colloby et al., 2011). One study has demonstrated diffuse
abnormalities throughout the whole brain (Yuan et al., 2007).
The role of WMLs contributing to the observed reduced FA values
was investigated by Shimony et al. (2009), who excluded WMLs
from the DTI analysis by segmentation techniques. They found that
even ‘‘normal appearing’’ white matter displayed diffuse micro-
structural damage in LLD. The authors concluded that WMLs
represent the ‘tip of the iceberg’, implying that their presence
indicates that even normal appearing white matter is undergoing
microstructural change.
5.2.2.1. Relationship with clinical and cognitive features. DTI abnor-
malities in multiple frontostriatal–limbic regions have been
correlated with cognitive impairments in LLD, including proces-
sing speed (Shimony et al., 2009) and poor response inhibition on
the ‘Stroop’ task (Alexopoulos et al., 2002b; Murphy et al., 2007).
Furthermore, reduced FA of the right and left frontal white matter
regions lateral to the ACC has been associated with failure to
respond to a 12 week course of citalopram (Alexopoulos et al.,
2002b), and reduced FA of the corpus callosum, left superior corona
radiata and right inferior longitudinal fasciculum with failure to
respond to 12 weeks of escitalopram (Alexopoulos et al., 2010).
Contradicting these results, failure to remit to 12 weeks of
sertraline was found to be associated with higher FA values in the
ACC and superior frontal gyrus in a LLD group (Taylor et al., 2008a).
These results are unexpected given these regions have previously
been found to demonstrate depression-related DTI abnormalities.
Possibly, methodological differences (voxel based analysis versus
region of interest approaches) may play a role, however the
authors suggest that in some instances of LLD, impaired functional
connectivity may be secondary to structural changes, and these
may be responsive to the neurotrophic effects of antidepressants,
whereas in other cases functional connectivity deficits occur in the
face of intact structural connections. In this case, poorer response
to antidepressants may be expected (Taylor et al., 2008a).
6. Macromolecular findings
As detailed so far, white matter and volumetric abnormalities
at a macro- and micro-structural level in frontostriatal and
limbic circuitry are implicated in aetiological models of LLD.
116 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
Complementing these findings, alternative imaging modalities
have started to provide further insights into possible in vivo and
molecular changes. In particular, magnetization transfer imaging
(MTI), producing the magnetization transfer ratio (MTR), and
magnetic resonance spectroscopy (MRS) have begun to enhance
our understanding of LLD by providing information regarding the
biophysical and biochemical characteristics of particular brain
regions (see Fig. 1b).
6.1. Magnetization transfer ratio
MTI allows the examination of the macromolecular structure of
cerebral white matter based on the interaction of the normally
observed tissue water signal and protons contained in large
macromolecules (mainly myelin) (Hoptman et al., 2006). Water in
biological tissues falls into two classes: ‘bound’ water (i.e. water
associated with macromolecules), and ‘free’ water (i.e. water that
is free to move about within biological compartment restraints).
These two forms of tissue water produce different magnetic
resonance signal characteristics so may be separated out for
analysis. Two images are acquired: a control acquisition, which is
like a usual MRI study, and a MT acquisition (an ‘off-resonance’
radiofrequency pulse that interacts only with the bound water and
cancelling it out). As ‘free’ water is the predominant component of
the MRI signal due to the broad distribution of the ‘bound’ water
signal across a wide range of frequencies, the MTR, the difference in
signal intensity between the two images, reflects the concentration
of macromolecules in the tissue as well as their chemistry (see
Hoptman et al., 2006). There are few studies utilising MTR in the
examination of LLD. Kumar et al. (2004) examined normal
appearing white matter and subcortical regions in eight patients
with LLD and eight healthy age-matched controls. Significantly
lower MTRs were noted in the depressed group, located in the genu
and splenium of the corpus callosum, the right caudate nucleus
and putamen and the occipital white matter. A more recent study
(Gunning-Dixon et al., 2008) found that LLD is characterized by
reduced MTRs in multiple left sided frontostriatal and limbic
regions, including the white matter lateral to the lentiform nuclei,
dorsomedial and dorsolateral prefrontal, dorsal anterior cingulate,
periamygdalar, subcallosal, lentiform, insular and posterior
cingulate regions. Additional regions associated with decreased
MTR in the left hemisphere include the thalamus, splenium of the
corpus callosum, inferior parietal, precuneus and middle occipital
regions. Use of MTI in disorders characterized by damaged myelin
and axonal loss such as multiple sclerosis has demonstrated a
range of MTR abnormalities, suggesting that lower MTRs reflect
compromised myelin integrity and axonal damage (Filippi and
Agosta, 2007). Finding such markers of myelin damage in the white
matter and subcortical nuclei of patients with LLD dovetails with
the ‘tip of the iceberg’ concept; and suggests that the pathophysi-
ological changes underpinning LLD may be more widespread than
initially recognised. Moreover changes in the macromolecular pool
of the white matter may be related to metabolic changes (Wyckoff
et al., 2003).
6.2. Magnetic resonance spectroscopy
Taken together, results from these few studies suggest that LLD
may encompass disruptions in neuronal membrane structure, as
well as neuronal loss, glial dysfunction and possible dysregulation
in the second messenger system. The pattern of biochemical
abnormalities may be significant, findings of altered mI and cho/Cr
in the absence of NAA/Cr disturbance emphasizes the potential
importance of the glial compartment (Kumar et al., 2002).
Additionally, research using Phosphorus (31P) MRS, which is used
to quantify concentrations of metabolites including high energy
phosphate containing molecules and provides a measure of
bioenergetic changes, suggests altered energy metabolism in
LLD (Forester et al., 2009), and points to mitochondrial dysfunction
as playing a potential role in the pathophysiology of LLD.
This technique permits in vivo neurochemical evaluation of the
brain. Different molecules have unique magnetic resonance signals
that can be quantified by taking the area under the signal curve
(Hoptman et al., 2006); as values are not absolute, they are typically
reported as ratios to a standard metabolite. Nearly all studies of LLD
have employed 1H NMR (proton spectroscopy), which measures
compounds such as choline (cho), N-acetyl aspartate (NAA),
myoinositol (mI) and creatine (Cr). The cho signal is likely a
composite signal with contributions from free choline, phosphocho-
line and glycerophosphocholine (Kumar et al., 2002); as these
choline-containing metabolic compounds are essential constituents
of the cell membrane, as well as second messenger transmitters, cho
ratios are thought to reflect membrane turnover, degree of
myelination and cell density (Miller, 1991). Thus increased cho/Cr
seen in the frontal white matter may reflect altered neuronal
membrane structure (Kumar et al., 2002). mI is involved in
phosphoinositol cycling, thus plays an important role in the second
messenger systems (Ross, 1991); it is also considered a marker of
glial cells. Increases in the mI/Cr may therefore represent
disruptions in the receptor-second messenger system complex
(Kumar et al., 2002) or glial dysfunction. Finally NAA is located
predominantly in neurons, therefore it acts as a marker of neuronal
viability and density; NAA has also been demonstrated to be
expressed by oligodendrocytes, thus suggesting that reduced NAA/
Cr may not only represent neuronal loss but also disruption in the
formation and maintenance of myelin (Venkatraman et al., 2009).
Early studies demonstrated raised levels of cho in a large voxel in the
subcortical region (including the caudate, internal capsule and parts
of the temporal lobe) in LLD compared with controls; the increased
cho/Cr normalised after treatment with nefazodone (Charles et al.,
1994). Biochemical abnormalities may be more apparent in frontal
white matter. For instance, significantly increased ratios of mI/Cr
and cho/Cr were found in the left dorsolateral frontal lobe white
matter in a LLD group compared with controls (Kumar et al., 2002).
No significant differences were noted in the anterior cingulate grey
matter bilaterally. In the only known study to stratify the depressed
group by age of onset of depression, Murata et al. (2001) found that
compared with EoD, LoD was associated with poorer cognition and
more severe depression, as well as increased WMLs, which in turn
were associated with decreasing levels of NAA/Cr in the white
matter of the frontal lobes. Interestingly no difference in cho/Cr was
reported. Extending these findings, LLD has been associated with
significantly lower NAA/Cr in the left frontal white matter and
higher cho/Cr and mI/Cr in the left basal ganglia compared with
controls. Moreover the mI/Cr correlated with global cognitive
function in the LLD group but antidepressant therapy had no
significant effect on MRS biochemical ratios (Chen et al., 2009).
Contrasting previous work, Venkatraman et al. (2009) examined
biochemical disturbances in remitted LLD, and found reductions in
total NAA, cho and Cr in the medial PFC (anterior cingulate),
accompanied by elevations in NAA and mI in the left medial
temporal lobe (amygdala). These findings are interesting for two
reasons: firstly they are somewhat conflicting with results of studies
in acute LLD, demonstrating biochemical changes including reduced
cho signal in the anterior cingulate. These data therefore point to the
possibility of both state and trait neurochemical markers of
depression (Venkatraman et al., 2009). Secondly, the results indicate
that even with resolution of acute depression, underlying biochem-
ical abnormalities thought to reflect neuronal and glial changes
remain. These findings support the neuropsychological data cited
above, which displays persistence of deficits despite symptom
resolution (Box 3).
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
Box 3. Structural neuroimaging studies.
 Volumetric MRI studies show increased ventricular size and
reductions in prefrontal, hippocampal, amygdala and stria-
tal (including caudate) volumes in patients with LLD
 Volumetric changes in LLD appear to be associated with
clinical/cognitive features and medication effects
 White matter lesions are more frequent and severe in LLD,
supporting the ‘vascular’ depression model
 While white matter lesions may disrupt fronto-subcortical
circuitry critical for mood and emotional circuits, both lesion
location and lesion volume may be important for the ex-
pression of clinical features and cognitive impairment and
for influencing treatment response
 Even in the absence of white matter lesions, DTI studies
show microstructural changes are evident in patients with
LLD and relate to cognitive and clinical features
 Emerging MTI and MRS studies suggest widespread mac-
romolecular changes and in vivo biochemical abnormalities
may be implicated in LLD pathophysiology
7. Functional neuroimaging studies
Functional neuroimaging studies conducted in MD have
enabled more sophisticated heuristic frameworks for modelling
MD circuitry than that offered by structural imaging alone
(Krishnan and Nestler, 2010). Functional imaging has encom-
passed a range of methods including positron emission tomogra-
phy (PET), single photon emission computed tomography (SPECT)
and functional magnetic resonance imaging (fMRI), typically
conducted at rest or within a treatment, emotion-activation or
cognitive-induction paradigm. More recently, resting state fMRI
has also been employed as well as magnetoencephalography
(MEG), although to-date few studies using these techniques have
been published in LLD specifically. A limitation of this body of
literature is the considerable variability in study designs, the
heterogeneity of participant samples (e.g. medicated versus
untreated, variable age of onset, comorbid VRFs) as well as the
various approaches taken in analysing data. Nonetheless, these
techniques provide further elucidation of the specific brain regions
and neural networks involved in depression (see Figure 1b) and
antidepressant treatment mechanisms, as well as providing
diagnostic clarification and treatment guidance from a pathophys-
iological perspective.
Major advances in the use of radioligands have allowed for
specific investigations into regional cerebral blood flow (rCBF) and
cerebral metabolism (CM). They have allowed for the direct
examination of relevant neurotransmitter systems notably 5-HT,
which has long been linked to the pathophysiology of mood
disorders. Many studies in the 1990s quantified rCBF or CM resting
state abnormalities in LLD samples. The majority of studies
consistently reported global or topographical reductions in frontal
(PFC, ACC) or subcortical (caudate) regions, with the topographical
reductions most conspicuous in older and more severely depressed
patients. Metabolic reductions were often corrected with antide-
pressant medication (Drevets, 1998; see Nobler et al., 1999b;
Soares and Mann, 1997). While similar reductions have been
demonstrated in younger samples, Soares and Mann (1997) and
Nobler et al. (1999b) suggest that the greater extent and
topography of deficits in older depressed patients may relate to
an interaction between normal aging processes and depression
pathophysiology. The basis of this interaction may relate to
changes in cerebral vasculature associated with normal ageing in
combination with the proposed relationship between ischemic
vascular changes and depression.
117
7.1. Positron emission tomography (PET)
PET involves the use of radionuclides that produce positrons,
which in turn emit photons during the process of decay. These
photons can be sensed by radiation detectors and in conjunction
with computer reconstruction are used to produce three-dimen-
sional tomographic images of the brain. Unlike SPECT, PET allows
for absolute quantification of perfusion or metabolic rate as well as
high temporal and spatial resolution (D’haenen, 2001; Nobler et al.,
1999b; Soares and Mann, 1997).
In terms of investigating cerebral changes in depression, PET
has also offered a methodology by which direct examination of
serotonergic functioning is possible. This has occurred in the
context of increasing interest in the interaction between cognitive
decline and mood dysregulation, influence of age- and disease-
related processes on the serotonergic system (Meltzer et al., 1998)
as well as the integration of neuropharmacological and anatomical
information (Soares and Mann, 1997). While the majority of
studies have focused on younger samples, such studies have
generally indicated decreased 5-HT transporter density and
binding sites in depressed patients relative to healthy controls
(see Nobler et al., 1999a). The development of radioligands such as
altanserin and [11C]WAY-100635 have enabled targeted investi-
gation of pre- and post-synaptic serotonergic function. Studies
using [18F]altanserin PET have, however, produced inconsistent
results. For instance, one study showed no significant difference in
5-HT2A binding potential between 11 patients with LLD and a
control group across 12 brain regions (Meltzer et al., 1999). By
contrast, Sheline et al. (2004) showed significantly reduced (i.e.
39%) hippocampal receptor binding in a group of 16 patients with
LLD, relative to controls. No significant differences were found
between early- and late-onset sub-groups. In terms of the 5-HT1A
receptor, Meltzer et al. (2004) demonstrated significantly reduced
binding potential in the dorsal raphe nucleus in 16 depressed
elderly patients compared to 17 healthy controls.
More recent PET studies using various ligands including
[18F]
fluorodeoxyglucose (FDG), [18F]setoperone as well as
[18F]
altanserin have provided some further understanding of
changes in cerebral activation in LLD more specifically, although
sample sizes are typically small. For example, de Asis et al. (2001)
used a high sensitivity [15O]H2O (8 mCi) slow bolus rCBF imaging
technique to demonstrate bilateral rCBF deficits in the dorsal
anterior cingulate and hippocampus in six patients with severe
depression compared to five controls, both at rest and during a
word generation task. In a sample of 19 patients with LLD, Smith
et al. (2004) found that relative to controls, the depressed sample
had increased glucose metabolism bilaterally in frontal and post-
central cortices, as well as in the left middle frontal and middle
temporal cortices, inferior parietal lobule, occipital cortex and
cerebellum. Additionally, Smith et al. (2009a) measured cerebral
glucose metabolism using FDG-PET, and reported cerebral glucose
hypermetabolism in anterior and posterior cortical regions in the
context of cerebral atrophy in 16 depressed older adults with
moderate to severe depression relative to 13 control subjects. Also
using FDG-PET, other investigators have shown that in compari-
son to control subjects, treatment-resistant LoD is associated with
decreased metabolism in the anterior cingulate, temporal and
parietal regions, as well as increased metabolism in other regions
including the dorsal frontal region and basal ganglia (Fujimoto
et al., 2008). Furthermore, an earlier study by Kumar et al. (1993)
demonstrated a pattern of regional cerebral metabolic changes in
eight participants with LLD, which was comparable in magnitude
to the pattern seen in a group of eight participants with AD.
Changes were characterized by widespread decrements in major
neocortical, paralimbic and subcortical regions relative to healthy
controls.
118 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
7.1.1. Associations with clinical features
As noted in a recent review by Smith et al. (2009a), the available
data linking perfusion or metabolism abnormalities with clinical
features and treatment efficacy in LLD is limited, although has been
reviewed elsewhere (for example, see Nobler et al., 1999a,b, 2000).
Examples of reported associations between clinical features and
physiological measures include symptom severity, sleep quality
and treatment responsiveness. For example, in the empirical study
by Smith et al. (2009a) described above, greater cerebral
metabolism in anterior and posterior cortical regions relative to
controls was also associated with more severe symptoms of
depression and anxiety. Meltzer et al. (2004) investigation of 5-
HT1A receptor binding in 16 depressed older adults (described
above) further demonstrated a positive association between the
magnitude of the binding potential measured in the dorsal raphe
nucleus and the severity of depression. This latter somewhat
paradoxical finding may reflect a failure of adaptive mechanisms in
patients with more severe depression. A failure to induce adaptive
changes was also postulated to underlie differences in cerebral
glucose metabolism alterations over a treatment course of six
weeks between middle-aged SSRI treatment responders and non-
responders, as reported by Mayberg et al. (2000).
7.1.2. Medication and treatment effects
PET studies have perhaps been most elegantly employed to
elucidate the efficacy of various treatment paradigms in terms of
affective and cognitive symptom remission as well as alterations in
neural circuitry. An example of this application is the recent study
by Diaconescu et al. (2010), who further clarified the effect of SSRI
treatment in LLD in an exploration of the functional networks
associated with affective and cognitive improvement following
eight weeks of treatment with citalopram. Sixteen older depressed
patients with a mean age of onset of 60 years underwent FDG-PET
as well as psychiatric evaluation and neuropsychological assess-
ment. Consistent with expectations, PET results demonstrated
decreased cerebral glucose metabolism in the anterior cingulate,
middle temporal gyrus, precuneus, amygdala and parahippocam-
pal gyrus; as well as increased glucose metabolism in the putamen,
occipital cortex and cerebellum. Further analyses of correlations
between treatment-related changes in glucose metabolism and
clinical symptom (i.e. affective/cognitive) improvement also
identified distinct functional networks. Specifically, a subcorti-
cal-limbic-frontal network was associated with improved depres-
sion and anxiety symptoms, whilst a separate medial temporal-
parietal-frontal network was associated with cognitive improve-
ments (i.e. verbal fluency, verbal learning and memory). Mayberg
et al. (2000) also utilised FDG-PET to investigate the time course of
cerebral metabolic changes associated with SSRI (fluoxetine)
treatment, albeit in a mid-life sample of 10 depressed males.
Results indicated a significant change in cerebral glucose metabo-
lism after one week of treatment, with both increases and decreases
seen in the subcortical, limbic–paralimbic and (to a lesser extent)
cortical regions. A second follow-up after six weeks of fluoxetine
treatment generally indicated a reciprocal pattern of cortical
metabolic increases and limbic–paralimbic decreases. Three pat-
terns of change over time were identified, including (a) comparable
changes in glucose metabolism at one and six week scans; (b)
reversal of the one week pattern of changes at the six week scan; and,
(c) unique changes evident only at six weeks. The pattern of reversal
was thought to suggest a process of adaptation to sustain serotonin
reuptake inhibition in specific regions over time.
Antidepressant medication may also mediate 5-HT binding
potential, as demonstrated in a study by Sheline et al. (2004),
whereby six untreated patients showed reduced hippocampal 5-
HT2A receptor binding in comparison to 10 previously treated
depressed patients. The authors postulated that this difference
may reflect a compensatory up-regulation of the 5-HT2A receptor
as a result of prior pharmacotherapy. Further investigations
include D’haenen’s (2001) account of two PET studies showing
decreased 5-HT2A receptor binding following tricyclic treatment.
Using SSRIs, however, increased receptor binding has been
reported. Specifically, reduced 5-HT1A binding potential in the
dorsal raphe nucleus may predict time to remission following
paroxetine treatment (Meltzer et al., 2004).
In the context of treatment effects, PET has also been used to
illustrate Mayberg’s (1997) attribution of sleep and other somatic/
vegetative disturbances to dysregulation of a ventral compartment
comprising paralimbic cortical, subcortical and brainstem regions
within a limbic-cortical model of depression. According to
Mayberg’s review, various PET paradigms in depressed patients
as well as post-fluoxetine treatment have indicated that depressive
illness is associated with increased ventral paralimbic activity,
while improved mood and particularly remission of sleep and
vegetative disturbances correlates with ventral paralimbic sup-
pression in fluoxetine-responders. Additionally, PET has been
utilised in sleep deprivation studies, which have examined
whether acute sleep deprivation (particularly in conjunction with
antidepressant treatment) can be used as a therapeutic strategy to
improve depressive symptoms, possibly by recruiting dopaminer-
gic and serotonergic systems, which, in turn, promote neurogen-
esis (Wu et al., 2008). Initial applications of this paradigm within
the LLD literature were promising. For example, in a sample of six
elderly depressed patients, Smith et al. (1999) reported a
significant decrease in depression severity after total sleep
deprivation, after recovery and after antidepressant treatment,
effects which coincided with decreases in cerebral glucose
metabolism in the right anterior cingulate and medial frontal
gyrus following sleep deprivation. The decrease in metabolism in
the anterior cingulate persisted after recovery sleep and after two
weeks of paroxetine treatment. These promising results were
confirmed in subsequent studies by this group (Smith et al., 2002)
although a more recent large randomised controlled trial (RCT) (of
sleep deprivation, paroxetine and placebo) failed to corroborate
these findings, suggesting that there were no differences in clinical
response or remission after controlling for baseline depression
severity (Reynolds et al., 2005). A PET sub-study involving 16 of
these patients (Smith et al., 2009b) further indicated a lack of
evidence for an accelerated response to antidepressant treatment
in combination with sleep deprivation.
Addressing the depression–dementia interface, the Pittsburgh B
([11C] 6-OH-BTA-1) (PiB) ligand may offer the opportunity to
examine the presence of b-amyloid pathology in those patients
with LLD who have preclinical forms of dementia or in those with
cognitive impairment. This compound has shown high tracer
retention in cortical areas in patients with clinical diagnoses of
probable AD and low retention in age-matched controls. In a small
clinical sample of nine patients with remitted MD, Butters et al.
(2008) showed that in those meeting criteria for MCI, 50%
demonstrated PiB retention levels similar to those observed in
AD, while another three patients with MCI showed intermediate
levels of PiB retention. More recently, the 2-(1-(6-[(2-[18F]fluor-
oethyl)(methyl)-amino]-2-naphthyl)radiethylidene) malononi-
trile ([18F]FDDNP) radioligand has also been utilised to
investigate amyloid and tau distribution in critical brain regions
in individuals with LLD. Kumar et al. (2011) reported significantly
higher [18F]FDDNP binding overall and specifically in the posterior
cingulate and lateral temporal regions in 20 LLD patients compared
to 19 healthy controls matched for age, sex and level of education.
Importantly, the authors noted that [18F]FDDNP has previously
been shown to discriminate between those with AD and healthy
controls, and has demonstrated a progression in binding from MCI
patients to those with dementia. These findings from the LLD
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
sample provided further evidence of a pathophysiological pathway
mediated by amyloid and tau distribution that may predispose
older adults to mood and associated cognitive/behavioural
syndromes. Further larger studies utilising these compounds are
now needed in order to determine their prognostic value for
determining longitudinal dementia risk.
7.1.3. Summary of PET studies
In summary, while PET imaging has been widely utilised to
study cerebral activation in LLD, studies have typically included
small sample sizes, and have largely focused on the serotonergic
system as a key source of pathophysiology. Such studies have
suggested reduced serotonergic binding in frontal (PFC and ACC),
hippocampal and brainstem (dorsal raphe nucleus) regions and
some have reported hypermetabolism in similar (e.g. prefrontal) or
other regions such as the basal ganglia, temporal and parieto-
occipital regions. While few clinical features have been studied in
detail, several studies suggest that depressive symptom severity
relates to cerebral metabolism alterations. PET has also been
utilised to explicate the efficacy of antidepressant treatment, with
additional exploration of other features of medication effects such
as the time course of cerebral metabolism changes and associa-
tions with affective/cognitive symptom improvement. The litera-
ture pertaining to effects of sleep deprivation and treatment
responsivity is more disparate possibly due to the small sample
sizes typically studied.
Ultimately, continued development of new PET biomarkers will
afford the opportunity to investigate the pathogenesis of depres-
sion from new perspectives. One ligand with promise for
examining the vascular and inflammatory mechanisms that are
likely to relevant to aetiology is the [11C](R)-PK11195 ligand. This
ligand displays up-regulation of peripheral benzodiazepine
binding sites, which provides a cellular marker for microglial
activation, thus representing a measure of inflammatory activity
(Banati and Hickie, 2009). Initial studies utilising this ligand in
multiple sclerosis displayed increased binding in association with
focal white matter pathology as well as in grey matter (Banati et al.,
2000). The PK11195 ligand has since been utilised across a range of
disorders including AD (Edison et al., 2008), MCI (Okello et al.,
2009), Parkinson’s disease (Gerhard et al., 2006a) and progressive
supranuclear palsy (Gerhard et al., 2006b). However, to-date, no
known studies have utilised this ligand to measure potential
inflammatory activity that may be critical to the pathogenesis of
LLD generally, or LoD more specifically.
7.2. Single photon emission computed tomography (SPECT)
Similar to PET, SPECT utilises radioligands (typically hexam-
ethyl-propylene amine oxime [HMPAO]) for brain imaging. SPECT
yields lower resolution images in comparison to PET; however it is
significantly less expensive and therefore utilised more frequently
in research trials.
Resting state studies attempting to quantify changes in rCBF in
MD have generally indicated regional reductions in the frontal and
temporal lobes as well as subcortical areas (e.g. caudate). In older
samples specifically, Upadhyaya et al. (1990) examined 18 patients
aged over 66 years as well as 12 controls using HMPAO SPECT.
Their data suggested global deficits as well as regional reductions
in the frontal, temporal and parietal regions. These regional
reductions were also reported by Lesser et al. (1994) who used
HMPAO SPECT to assess 39 non-medicated patients aged over 50
years in comparison with 20 age-matched controls, and by
Ebmeier et al. (1998) in 39 patients relative to controls. The latter
group of patients was divided by age of onset with results
indicating that reductions in bilateral temporoparietal cortex
perfusion were associated with LoD. Awata et al. (1998) further
119
showed significant regional reductions in 18 older patients relative
to age-matched controls, with the greatest decrements observed in
the anterior cingulate, superior frontal and superior temporal gyri
and the caudate nucleus. Similarly, Curran et al. (1993) demon-
strated reductions in frontal and temporal cortices as well as the
anterior cingulate, caudate and thalamus in 12 older medicated
male patients; although the authors noted a possible interaction
effect of continuing antidepressant or benzodiazepine treatment.
More recently, reductions in frontal, temporal and parieto-
occipital regions were reported in 25 depressed patients older
than 55 years relative to healthy controls (Ishizaki et al., 2008).
Overall, this data yields reasonably consistent support for cortical
rCBF reductions across frontal, temporal and parietal areas as well
as reduced rCBF in the basal ganglia.
7.2.1. Associations with clinical features
Findings have been inconsistent regarding the relationship
between clinical features and cerebral activation in depressed
elderly. This may be due to the heterogeneity of clinical variables
investigated and reported in the literature. In terms of baseline
clinical parameters (e.g. age, age at onset, gender, number of
episodes, depression severity or global cognition scores), no
significant correlations were reported in a sample of 18 older
patients with on average mild depressive symptoms (Awata et al.,
1998). Likewise, Navarro et al. (2001) did not find correlations with
clinical features in a sample of 30 patients with more severe
depressive symptoms. Despite these findings, however, some data
suggests a relationship between rCBF and treatment responsive-
ness. For instance, the former study reported robust and extensive
reductions in anterior cerebral regions in a sub-group with
refractory depression relative to a non-refractory group and to
controls, indicating that the nature of hypoperfusion, particularly
in the anterior cingulate and prefrontal regions, may be related to
refractoriness and chronicity of depression. Furthermore, left
anterior frontal abnormalities associated with acute depression
have been shown to normalise with remission, as seen at 12-
month follow-up (Navarro et al., 2002).
There may be some prognostic value in SPECT abnormalities as
illustrated by a study by Ritchie et al. (1999) where the finding of
greater reductions in rCBF in patients with dementia and
depression was paralleled by clinical differences between the
groups over time. That is, in the two years prior to dementia
diagnosis, fewer affective and reactive symptoms and greater
psychomotor change was apparent. Finally, some data from
middle-aged samples suggests that atypical depression may
manifest with differential HMPAO tracer uptake compared to
typical depression (Pagani et al., 2007). Such results underscore the
importance of considering disease heterogeneity when analysing
neurobiological findings and highlight the need to consider the
presenting clinical and aetiological symptom complex.
7.2.2. Medication effects
To our knowledge, only a small number of studies have utilised
SPECT to examine the effects of antidepressant treatment
specifically in elderly depressed samples. For example, Ishizaki
et al. (2008) examined 25 depressed older adults and demonstrat-
ed that after 14 weeks of fluoxetine treatment, significant rCBF
improvements were apparent in areas that were reduced at
baseline including the left DLPFC, precentral regions and right
parieto-occipital regions. In an earlier study, Nobler et al. (2000)
utilised the planar 133Xenon inhalation technique to assess global
CBF in 20 older depressed patients treated with antidepressant
medication over six to nine weeks. This RCT of TCA (nortriptyline)
and SSRI (sertraline) treatments was not associated with global
CBF changes, although notably the sample size was very small
(n = 6 and 5 respectively). However, treatment responders showed
120 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
significantly greater regional CBF reductions in selective prefrontal
and anterior temporal regions compared to non-responders, and
the magnitude of change correlated with the extent of clinical
improvement on the Hamilton Depression Rating Scale. Other
studies have also investigated differences in rCBF between
antidepressant responders and non-responders, though these
have included general adult samples rather than older adults
specifically. For example, in 65 middle-aged depressed patients,
Joe et al. (2006) noted that a sample of 35 citalopram responders
initially demonstrated increased perfusion in the left frontal and
insula regions, right posterior cingulate and inferior frontal cortex,
the latter of which persisted four weeks later. By contrast, 30 non-
responders showed a significant rCBF increase in the left posterior
cingulate and putamen. A group-by-time analysis demonstrated
significantly different changes in rCBF in the two groups indicating
opposite directed courses, with responders showing a decrease and
non-responders showing an increase in the posterior cingulate, left
inferior frontal gyrus and left putamen. It was postulated that the
posterior cingulate region may be implicated in the pathophysiol-
ogy of depression and may have predictive value for treatment.
Using a similar methodology, Brockmann et al. (2009) studied 93
middle-aged depressed adults. In this sample, initial responders
also demonstrated significantly higher rCBF in prefrontal, tempo-
ral, and insula cortex regions in comparison to non-responders.
However, these differences did not persist after four weeks.
Overall, these studies demonstrate that SPECT has some capacity to
differentiate between treatment responders and non-responders,
whereby responders show higher perfusion in key cortical and
possibly also, basal ganglia regions.
7.2.3. Relationship to cognition
Regional decrements in frontal and temporal cortices as well as
the anterior cingulate, caudate and thalamus in male depressed
patients have been associated with impairment of performance on
Part B of the Trailmaking Test, a set-shifting and visuomotor task
(Curran et al., 1993). Also using SPECT, Hickie et al. demonstrated
that reductions in striatal rCBF are related to performance on a
reaction time task, particularly when the task is associated with a
more complex choice- as opposed to simple-reaction time
requirement (Hickie et al., 1999). Using an MRI and SPECT co-
registration method with a region of interest analysis, Hickie et al.
(2007a) later demonstrated that such striatal changes are not only
associated with increasing task complexity but are also associated
with performance on the Trailmaking test (postulated to reflect
fronto-subcortical functioning) as well as with WML load. While
few studies have examined the predictive longitudinal utility of
SPECT, some data suggests that LLD may intensify the decrements
in brain function occurring with neurodegenerative processes.
Specifically, Ritchie et al. (1999) reported greater reductions in left
temporal rCBF in elderly people who had both depression and
dementia, compared to those with dementia alone.
7.2.4. Summary of SPECT studies
Overall, studies utilising SPECT have generally reported
decreased rCBF in frontal, temporal and subcortical (e.g. caudate)
regions in samples of older adults with LLD, relative to healthy,
non-depressed controls. Data regarding relationships to clinical
features has been sparse and to-date has been inconsistent. Some
studies in middle-aged samples suggest that antidepressant
treatment is associated with improved rCBF in key cortical regions,
although data in LLD specifically is lacking. Few studies have
examined the relationship between SPECT-defined rCBF changes
and cognitive dysfunction, although in those that have data
suggests that changes in the striatum do relate to performance on
tasks thought to reflect fronto-subcortical functioning. Further
studies are required in order to determine whether SPECT changes
have prognostic utility in terms of longitudinal course or
progression to dementia.
7.3. Functional magnetic resonance imaging (fMRI)
Functional MRI (fMRI) elicits patterns of blood oxygen level
dependent (BOLD) activation during periods of rest, activity or
cognitive functioning. BOLD is an MRI marker of deoxyhaemoglo-
bin and reflects changes in cerebral blood flow and oxygenation.
These haemodynamic alterations resulting from neural activity
manifest as changes in BOLD signal intensity, with areas of higher
BOLD signal intensity reflective of increased concentration of
oxygenated haemoglobin in the particular brain region. Relative to
other functional imaging techniques (e.g. magnetic resonance
spectroscopy, electroencephalography, nuclear neuroimaging),
fMRI is less invasive, has less radiation exposure, has higher
spatial resolution and is more widely available.
7.3.1. Behavioural and cognitive paradigms
To-date, studies utilising fMRI have largely focussed on the PFC
(Ebmeier et al., 2006) and have utilised emotion-based paradigms.
Surprisingly, few of these studies have been conducted in older
and/or LoD samples.
Using an emotional paradigm, Brassen et al. (2008) examined
13 older antidepressant naı̈ve female patients with LoD and 13
controls. They employed an emotional evaluation task of positive,
negative and neutral words in association with fMRI and showed
that although there were no performance differences between
groups, the depressed group showed decreased BOLD activation in
the ventromedial PFC in response to negative words, compared to
positive stimuli, relative to control participants. Follow-up data
after seven months for this sample showed that the attenuated
response had normalised and was associated with a significant
improvement in depressive symptoms. In a study specifically
examining executive functioning in LoD, Wang et al. (2008b)
employed an emotional odd-ball paradigm in 12 older patients
with current MD, 15 patients with remitted MD and 20 controls.
Depressed patients demonstrated reduced BOLD activation in
regions involved in executive functions (i.e. right middle frontal
gyrus, cingulate and inferior parietal areas) relative to controls.
Reduced activity in the middle frontal gyrus appeared to be state-
dependent, as attenuated activity persisted in remitted partici-
pants only in the anterior portion of the posterior cingulate and
inferior parietal regions. Consistent with this observation of
posterior cingulate and parietal areas being implicated in the
pathophysiology of the disorder, Woo et al. (2009) recently
investigated the impact of depressive symptoms on the role of the
posteromedial cortex in an active memory task. Sixty-two older
participants with sub-threshold depressive symptoms underwent
fMRI scanning whilst completing a face-name associative memory
encoding task incorporating both ‘familiar’ and ‘novel’ conditions.
Data indicated a cluster within the posteromedial cortex whereby
reduced BOLD activation during encoding was associated with
depressive symptom severity, history and anxiolytic use. Since this
sample did not include cases of clinical depression, however,
further studies in clinical samples would be required to enhance
the relevance of these findings with respect to neurobiological
models of LLD. One recent study by Aizenstein et al. (2011)
attempted to do this by relating the characteristic structural
changes of LLD (namely white matter hyperintensities) with
functional neuroanatomical models of depression. Not only was
greater activity in the subgenual cingulate observed in depressed
elderly compared with healthy controls in response to a facial
expression affective reactivity task, but also task-related
activity was positively correlated with the burden of white matter
disease. The depressed group also showed a significantly greater
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
interaction between WML and fMRI activity effect than controls.
This data supports the notion that WMLs disrupt key regions
required for the control of limbic activity.
While the striatum has been implicated in various structural
volumetric investigations, as well as in research using PET and
SPECT (as described in Sections 6.1 and 6.2 above), few fMRI
studies have specifically sought to probe the frontostriatal circuitry
in MD generally or in LLD specifically. However, some investigators
have attempted this task using motor sequencing paradigms,
which assess implicit sequence learning, a cognitive function that
has been shown across many disease groups to be sensitive to
frontostriatal dysfunction. One fMRI study conducted by Aizen-
stein et al. (2005) utilised an implicit learning task in 11 elderly
patients with MD and 12 matched controls. This study reported no
difference between groups in striatal activation during this task.
However, the groups did differ in BOLD activation during an
explicit learning task, where increased striatal activation and
decreased prefrontal cortex activation were evident in the
depressed group. In a later study of 13 elderly males with LLD
and 13 controls, Aizenstein et al. (2009) again reported decreased
prefrontal activation, as well as reduced functional connectivity
between dorsolateral PFC and dorsal anterior cingulate regions, in
the depressed group during an executive-control task involving
response inhibition. More recently, Naismith et al. (2010b) also
employed a motor sequencing task with fMRI in an older depressed
sample of 22 patients and controls. While this data supported that
of Aizenstein et al. (2005) in demonstrating no between group-
effects in striatal activity, patients with MD did show performance
decrements in implicit sequence learning (Naismith et al., 2006), a
finding which appeared to relate to increased activation of the
DLPFC (middle frontal gyrus). This data highlights the need to
consider the broader neural networks when evaluating fronto-
subcortical circuitry in MD, and that different components of the
network may underpin dissociable cognitive and clinical phenom-
ena.
Data from the above studies is in accordance with that found by
Rostami et al. (2009), where there was no evidence of striatal
activation in a goal-directed implicit learning task despite
significant learning-related activity in prefrontal, precentral and
occipital regions. In this regard, it has been suggested that the basal
ganglia are more integral to the performance (i.e. reaction time)
component and general demands of implicit learning tasks, rather
than being responsible for the specific learning component, which
may be mediated by a more distributed network including the
frontal and cerebellar regions (Exner et al., 2002). Certainly, our
prior work has suggested that the striatum likely underpins some
of the functional changes associated with slowed reaction time
(Hickie et al., 1999, 2007a; Naismith et al., 2002). However, in MD,
it is possible that more diffuse network changes mediate tasks that
contain a greater cognitive load. Thus, although the striatum may
be critical to the pathophysiology of MD, broader cortical–
subcortical network dysfunction may be necessary to impede
more complex cognitive performance tasks. In this regard,
evidence from other areas of cognitive neuroscience suggests that
successful acquisition of implicit learning sequences may depend
initially on cortical and cerebellar involvement, while the basal
ganglia may be more integral to the maintenance of learning (see
review by Forkstam and Petersson, 2005). An alternative explana-
tion for the lack of striatal change in association with reduced
implicit learning is that the topographical components of the
striatum may need to be further detailed. That is, perhaps there are
altered patterns of activation that are only evident in specific
components of the network. Moreover, since there is some
evidence to suggest that some striatal regions show reduced
activity during task completion, while others show increased
activity, a ‘cancelling out’ may occur when activity is measured
121
across the entire striatum (Balleine and O’Doherty, 2010). An
additional consideration is the dynamic interaction between the
frontal and striatal regions in mediating performance. Ongoing
cognitive paradigms that seek to inform our knowledge of how
functions are partitioned within this region (Owen, 2000) may help
to further delineate the conditions upon which the broader fronto-
subcortical networks are involved in symptom expression and
cognitive dysfunction. Similarly, studies may need to increasingly
focus on homogenous samples including those with LoD or
melancholia, where both subtypes have been associated with
distinct cognitive profiles (Exner et al., 2009; Naismith et al., 2003).
7.3.2. Summary of fMRI studies
Overall, there has been a relative dearth of fMRI studies that
have specifically sought to examine the neurobiological circuitry
implicated in LLD. Of those that exist, it seems that reduced PFC
activation may underpin emotion-specific effects (i.e. negative
emotions) and may relate to depressive ‘state’ phenomena. Other
posterior circuitry changes have also been reported, even in the
remitted state and in those with sub-threshold symptomatology.
Reductions in posterior regions have also been associated with
memory encoding. A small but concise set of studies has
specifically attempted to probe the frontostriatal circuits, and
has demonstrated that frontal, as opposed to striatal mechanistic
changes likely underpin implicit sequence learning deficits,
although there are some circumstances in which increased striatal
activity may be required. Further studies in this area may be able to
delineate specific neural network correlates of various phenotypic
expressions and may also elucidate the threshold upon which such
network dysfunction begins to manifest (e.g. task complexity,
effortful tasks, treatment responsiveness).
7.4. Resting state fMRI
Resting state fMRI is an emerging novel technique for
determining functional connectivity between brain regions and
networks. It examines the level of co-activation between the
functional time series of anatomically separated brain regions
during rest. Studies show that even at rest, there is a high level of
connectivity suggestive of communication between motor, func-
tional (i.e. visual and auditory), emotion and cognitive networks
(see review by van den Heuval and Hulshoff Pol, 2010). To-date,
there is a paucity of studies utilising this technique in MD and even
less in LLD, although many are currently in progress. In addition to
functional connectivity analysis, a new technique known as
assessment of regional homogeneity has recently been reported
within this developing area. Yuan et al. (2008) described this
technique as a means of exploring the time series of the regional
BOLD signal, rather than its density across larger areas. Abnormal
regional homogeneity may therefore reflect changes in the
temporal aspects of neural activity in particular regions of interest.
In the first known application of this resting state fMRI technique
in MD (Yuan et al., 2008), 18 patients with remitted LoD and 14
controls showed that those with LoD demonstrated an atypical
pattern of neural activation, characterized by decreased regional
homogeneity over the frontal, temporal and parietal lobes, and
increased homogeneity in the putamen, frontal and parietal lobes.
Of interest, regional homogeneity in fronto-subcortical areas
(superior frontal gyrus and putamen) was negatively associated
with performance on both Parts A and B of the Trailmaking Test
(reflecting visuomotor speed and mental flexibility/set-shifting) in
the depression sample, suggesting that this technique may further
aid in understanding the pathophysiology of executive function in
LLD. Using a somewhat different approach focusing on the caudate
as the ‘seed’ region of interest, Kenny et al. (2010) utilised resting
state fMRI in a sample of 33 subjects, 16 of whom had a recent
122 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
Box 4. Functional neuroimaging studies.
 Have enabled more sophisticated modelling of MD patho-
physiology and treatment mechanisms
 PET ligands have identified alterations in serotonergic bind-
ing in various regions including frontal, hippocampal, basal
ganglia and brainstem regions
 SPECT studies have generally reported decreased regional
cerebral blood flow in frontal, temporal and subcortical
regions in LLD, where relationships between decreased rCBF
and some clinical features such as psychomotor speed have
emerged
 fMRI data in LLD is relatively sparse but thus far indicates
prefrontal and posterior circuitry changes in relation to
cognitive and emotional tasks
 Resting state fMRI and MEG are emerging techniques for
investigating functional connectivity in LLD
 Variability in study designs, heterogeneity of samples and
data analyses should be considered
depressive episode. This study found that the connectivity
between the caudate and frontal regions was more diverse in
the depressed, compared to the control group (Box 4).
8. Neuropathology
Neuropathological studies, although few, provide a glimpse of
the cellular changes that may underlie the metabolic and
structural changes noted so far (see Fig. 1b). However, for cortical
regions, it appears that such changes may differ according to age.
While previous studies involving younger samples have shown a
reduction in astrocyte and oligodendrocyte density in the ACC, OFC
and DLPFC (Cotter et al., 2005; Rajkowska et al., 1999), no
significant differences in glial density in the DLPFC (Rajkowska
et al., 2005b) or OFC (Khundakar et al., 2009) have been found in
LLD. By contrast, LLD has been associated with a significantly
decreased packing density of pyramidal neurons in the OFC,
specifically cortical layers IIIc and V (Rajkowska et al., 2005a).
Although examination of the DLPFC has shown no significant
differences between subjects with LLD and controls in the neuron
density (Van Otterloo et al., 2009), morphometric analysis of the
DLPFC has revealed reduced pyramidal neuronal size (Khundakar
et al., 2009), particularly in cortical layer V. These changes were not
associated with any alterations in the glial population or non-
pyramidal neurons. In the DLPFC and OFC, cortical layers III and V
contain pyramidal neurons that project to the striatum. Accord-
ingly, neuronal density has been reported to be decreased in the
striatum in LLD, with specific reductions in the dorsolateral and
ventromedial aspects of the caudate nucleus. No differences were
evident in those with EoD compared to LoD and the authors did not
find alterations in glial density (Khundakar et al., 2011).
In the hippocampus, Stockmeier et al. (2004) reported a 35%
increase in both glial and neuronal density in the brains of 21 older
patients (mean age 57.4 years, range 30–87) with MD when
compared to controls, with a significant decrease in neuronal soma
size. The authors suggested that the differential pattern in the
hippocampus compared with other frontal structures may be due
to altered neuropil, including a loss of dendritic branching and glial
processes. This may be related to the reduction in neurotrophic
factors implicated in the pathophysiology of depression. No known
studies have found any significant differences between late and
early-onset depression groups with regard to neuronal pathology
(Khundakar et al., 2009; Rajkowska et al., 2005a), suggesting that
reductions in neuronal density may represent a final common
pathway for differing trajectories of illness. Smaller but
Box 5. Neuropathological studies.
 Few studies exist and unlike studies in younger patients,
those with LLD show no specific glial density alterations in
the ACC, DLPFC or OFC
 For cortical regions, decreased density of pyramidal neurons
has been found in the OFC, while reductions in pyramidal
neuron size have been found in the DLPFC
 For subcortical regions, decreased neuronal density is evi-
dent in the caudate nucleus, and decreased glial density has
been found in the amygdala
 Increases in hippocampal neuronal and glial density have
also been found
 No known studies have examined the microglia specifically
non-significant reductions have been reported in the entorhinal
cortex (Bowley et al., 2002).
Two studies have reported a reduction in glial density and in the
glia/neuron ratio in the amygdala of patients with MD (Bowley
et al., 2002; Hamidi et al., 2004). Although neither study was
specifically focused on LLD, all specimens came from subjects aged
between 59 and 90 years (mean age of 77.7 years). Interestingly it
appears that the changes in glial density in the amygdala are due to
reductions in the density of oligodendrocytes (Hamidi et al., 2004).
Oligodendrocytes are well known for their role in myelination;
satellite oligodendrocytes, a population located next to neuronal
cell bodies, appear to function in the metabolism of synaptic
glutamate (D’Amelio et al., 1990), additionally they appear to be
sensitive to excess levels of glutamate as well as ischaemic injury
(Dewar et al., 2003). Taken together with structural neuroimaging
data suggesting shape alterations in the core nuclei of amygdalae
of subjects with LLD (Tamburo et al., 2009), this suggests that
glutamatergic toxicity may play a role in LLD pathophysiology.
It has been postulated that consideration of neuronal and glial
cell pathology in MD must be considered dynamically. That is, glial
pathology may be most prominent early in the disease, whereas
neurons may become affected in later stages, possibly due to an
excess in extracellular glutamate and glial dysfunction (Rajkowska
and Miguel-Hidalgo, 2007). Indeed, a recent meta-analysis
supported this view using the glial marker protein S100B, found
in serum. This study showed that S100B was more pronounced in
older subjects compared to younger subjects, though there was no
relationship with duration of illness or age of onset (Schroeter
et al., 2011). Overall, studies to-date have been somewhat limited
in terms of the range of glial cells and processes they can examine
and no known studies have examined the microglia. Further
clinicopathological work in LLD is still required, and in particular
needs to provide detailed characterisation of the clinical and
cognitive profile of patients. Such work may also help to elucidate
the unique contributions of illness-specific (e.g. inflammatory,
glucocorticoid) processes, as well as those associated with
concomitant cerebrovascular and emerging neurodegenerative
disease and underlying changes in glial cell, particularly microglia
functioning (Box 5).
9. Genetics
Increasingly, there is recognition of the interactions between
genetic variations and specific environmental factors that bias
brain development towards illness vulnerability or resilience. A
number of genetic polymorphisms have been identified as having
potential importance in the aetiology, management and outcome
of LLD (see Fig. 1a). To-date, these include genes that are
considered to be important for neuronal plasticity and survival,
serotonin transmission, lipid transport and systemic vascular risk.
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
However interpretation of the literature to-date is challenging due
to the complexity of methodology, with issues in the measurement
of environment, the diagnosis of depression and study design,
among others (for review, see Lotrich, 2011).
9.1. Brain-derived neurotrophic factor gene (BDNF)
As previously mentioned, BDNF is the most abundant
neurotrophin in the brain, and of critical importance for neuronal
plasticity and survival (Duman et al., 2006). BDNF also regulates
the mesolimbic dopaminergic pathway and nucleus accumbens
that are involved in the identification and response to emotional
environmental stimuli (Berton et al., 2006). In non-geriatric
samples there is increasing evidence to suggest that the BDNF
genotype mediates the response to social stressors (Aguilera et al.,
2009). BDNF has been implicated in the pathogenesis of depres-
sion, and appears to be an important mediator of therapeutic
response to antidepressants (Duman et al., 2006). The BDNF gene
has been mapped to chromosome 11; a single nucleotide
polymorphism (G/A), resulting in an amino acid switch from
valine to methionine at position 66 of the coding exon of the BDNF
gene (Maisonpierre et al., 1991). The BDNF val66met polymor-
phism (met allele) reduces the activity-dependant secretion of
BDNF that is important for hippocampal based synaptic plasticity,
learning and memory (see Egan et al., 2003).
In an older community dwelling cohort with no depression,
impairments in processing speed and delayed recall as well as
reduced performance on tests of general intelligence were
significantly associated with the met allele (Miyajima et al.,
2008). The met allele has been associated with increased risk of LLD
in both inpatient and outpatient samples, however no association
with severity of depression or age of onset has been demonstrated
(Hwang et al., 2006; Taylor et al., 2007), and not all studies have
replicated this result (Surtees et al., 2006). The met allele may be
associated with increased incidence of depression after stroke
(Kim et al., 2008), and is associated with significantly greater
WMLs in older adults, independent of diagnosis of depression
(Taylor et al., 2008b). Additionally both serum and plasma
concentrations of BDNF have been demonstrated to be significant-
ly lower in older adults with LoD compared with healthy age-
matched controls (Diniz et al., 2010b; Shi et al., 2010). The use of
peripheral BDNF as a biomarker for affective disorders has many
methodological issues (Gass and Hellweg, 2010) including
whether peripheral BDNF actually provides an accurate represen-
tation as to cerebral BDNF concentrations. However both animal
and human studies have correlated BDNF serum levels with
cortical BDNF expression (for review see Gass and Hellweg, 2010),
attesting to serum levels as an adequate proxy.
The literature to-date regarding BDNF in LLD has been most
informative regarding treatment responsiveness. Specifically, the
met allele has been found to be associated with increased odds of
remission at six months in depressed elders (Taylor et al., 2010a); a
relationship that was noted to be independent of WMLs and
perceived social support. Similarly BDNF met carriers were more
likely to achieve remission than val/val homozygotes after 12
weeks of treatment with escitalopram (Alexopoulos et al., 2010). In
the same group, microstructural abnormalities in the corpus
callosum, left superior corona radiata and right inferior longitudi-
nal fasciculum were correlated with failure to achieve remission.
However there was no significant interaction between val66met
status and microstructural abnormalities in predicting remission.
It has been postulated that polymorphisms in the BDNF gene
impact on early cerebral development leading to permanent
changes in cellular development and plasticity (Egan et al., 2003),
thus placing carriers preferentially at risk of depression in the
context of further neurobiological or psychosocial risks (Taylor
123
et al., 2008b). Such models are certainly immensely complex and
need to incorporate multi-faceted data points. In younger
euthymic samples the met allele has been associated with smaller
hippocampal volumes (Bueller et al., 2006; Pezawas et al., 2004),
and cognitive changes, particularly delayed memory (Egan et al.,
2003). Two recent studies in a clinical population have produced
conflicting results. Benjamin et al. (2010), investigating a large
sample of patients with LLD, found no significant relationships
between BDNF genotype and hippocampal structure, memory or
working memory. In contrast, Kanellopoulos et al. (2011)
demonstrated that depressed val/val homozygotes had larger
hippocampal volumes than non-depressed controls with the same
genotype. This data highlights the need to consider the broader
gene–environment associations in large community and/or
genetically informed (e.g. twin) studies, whereby the interactions
between gene expression, risk and protective factors and complex
illness trajectories can be examined. A recent study has attempted
to unravel some of these connections; Gatt et al. (2009) used path
modelling in a non-clinical sample to investigate the relationship
between the BDNF val66met polymorphism and early life stress,
and its effects on brain structure, cognition and the phenomenol-
ogy of depression. In those with the met allele, increased exposure
to early life stress resulted in reductions of the volume of
hippocampal gray matter as well as its lateral prefrontal
projections, higher levels of neuroticism and elevated body
arousal. In turn, reductions of hippocampal volume were
associated with elevated levels of depressive symptoms, which
were themselves associated with declines in working memory;
similarly a pathway from elevated arousal to heightened neuroti-
cism to increased depression was demonstrated. Further longitu-
dinal studies examining the effect of gene–environment
interactions on brain structure and function, as well as the role
that social connection and support may play are now required.
9.2. Serotonin transporter gene (5HTTLPR)
Polymorphisms in the promoter region of the serotonin
transporter gene (5HTTLPR) may be important in LLD, as the gene
product is critical for serotonergic neurotransmission, mainly via
uptake of serotonin. Polymorphisms of 5HTTLPR, which most
commonly include a 44 base pair insertion (L allele) or deletion (S
allele), affect gene expression rather than changing the structure of
the serotonin transporter protein (Heils et al., 1995). The S allele is
inefficient in transcribing the serotonin transporter in neurons
(Heils et al., 1995), with the L allele associated with increased
serotonin reuptake. Generally the literature suggests that the S
genotype confers increased risk for depression in younger adults,
via interactions with ‘‘stress’’ (Caspi et al., 2010, 2003; Kendler
et al., 2005b), although this relationship is by no means universal,
as evidenced by some large studies with negative findings (see
Risch et al., 2009). With regard to older adults, in a study
examining those with LoD, no significant association was found
between the S allele and depression in the whole sample. However
there did appear to be gender differences, with the S allele being
associated with depression development in men, and recurrent
depression in women (Steffens et al., 2002c). A prominent question
relates to the nature of the stressor in the relationship (Lotrich
et al., 2011). Much of the early work has found that the S/S
genotype interacts with severe childhood stress and trauma to
increase the risk of depression in adult life (Caspi et al., 2003). By
extension this increased risk then passes into old age as recurrent
episodes of depression leading to an increased risk for LLD
(Luijendijk et al., 2008). However the role of acute stressors is less
clear. Increased medical burden in older adults, considered a
specific stressor, appears to interact with the S/S genotype to
increase the risk for depression (Kim et al., 2009) whereas the
124 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
relationship between psychosocial stress and 5HTTLPR polymor-
phisms is less obvious (Surtees et al., 2006). It has been suggested
that individuals with the S/S genotype are more sensitive to the
depressogenic effects of acute stressful life events (e.g. divorce/
separation, major financial problems, serious illness/injury, job
loss) because they have an increased sensitivity to the impact of
mild stressors (Kendler et al., 2005a).
CVD, a common form of stress in older adults, is associated with
somewhat contradictory findings. The L/L genotype has been
associated with greater platelet activation, which is thought to
increase the risk of thrombus development, as well as increased
depression in older adults with a low cardiovascular burden
(Whyte et al., 2001). Moreover the L/L genotype has been
demonstrated to be associated with increased cardiac events
post coronary artery bypass grafting (Phillips-Bute et al., 2008).
Thus the presence of the L allele appears to increase the risk for
exposure to adverse cardiovascular events, thus negating its
‘‘positive’’ effect (Lotrich et al., 2011). However there are
conflicting results, as the S allele has also been related to
increased risk for further vascular disease post myocardial
infarction, a relationship that appears to be mediated in part by
depressive symptoms (Nakatani et al., 2005). Further complicat-
ing the literature regarding the relationship between the S and L
alleles and vascular disease is the finding that heterozygosity (i.e.
the S/L genotype) was associated with increased risk for higher
cholesterol levels, as well as heart disease in healthy older male
samples (Comings et al., 1999).
Of relevance to the pathophysiological link between the
serotonin transporter gene and neurobiological changes in LLD,
a number of studies have investigated the relationship between
5HTTLPR polymorphisms, structural brain changes and risk for
cerebrovascular disease. With regard to structural brain changes in
depression, some studies have shown that the 5HTTLPR genotype
relates to hippocampal volumes although there have been some
inconsistencies, which may possibly relate to the aetiological path
to depression including age of illness onset. Data from adult MD
samples has shown that L/L homozygotes with depression have
smaller hippocampal volumes than L/L control participants (Frodl
et al., 2004). Within depressed samples, hippocampal volumes
have also been found to be smaller in L/L, compared to S/S
homozygotes (Frodl et al., 2008), although this has not been a
consistent finding (Hickie et al., 2007b). Upon specifically
examining these relationships in LLD, Taylor et al. (2005b)
reported that among L/L homozygotes, those with LoD had
significantly smaller right hippocampal volumes than those with
EoD and controls. Hickie et al. (2007b) reported that in a sample of
47 older patients with moderate to severe depression, the presence
of at least one S allele was associated with smaller caudate nucleus
volumes. However, there was no relationship between the S allele
and aetiological factors such as age of onset, summed VRFs,
duration of depression episode or years of illness. Given the data
highlighting the links between 5HTTLPR polymorphisms and
vascular disease, the relationships with white matter changes in
LLD are important. Alexopoulos et al. (2009) reported that
depressed S allele carriers had lower DTI-measured FA (that is,
microstructural white matter change) than L allele homozygotes in
fronto-limbic brain areas; and, extending findings related to
heterozygosity, the S/L genotype has been associated with
increased total and WML volumes in a sample of older adults
with depression (Steffens et al., 2008).
The possible role of the HPA axis underpinning the relationship
between stress, S/S genotype and depression is suggested by some
studies in non-clinical samples. Alexander et al. (2009) showed
that the L/S genotype was associated with HPA axis hyperreactivity
in a stressful situation, when the individual had previously been
exposed to multiple stressful life events. Although there was no
direct association between the S allele and hippocampal volume in
a healthy sample of older adults, there was a significant interaction
between waking cortisol levels and the S allele on reduced
hippocampal volume and delayed memory function (O’Hara and
Hallmayer, 2007). At somewhat of a tangent to this work,
amygdala hyperactivation to negative stimuli may also be
heightened in the presence of the S allele (Munafo et al., 2008).
Moreover the S/S genotype has been associated with reduced gray
matter in the amygdala and perigenual cingulate (Pezawas et al.,
2005). Given the amygdala’s role in modulating glucocorticoid
release (Savitz and Drevets, 2009), this body of work highlights the
potential importance of the HPA axis, mediating the interaction of
stress and 5HTTLPR polymorphisms on risk for depression.
While few studies have examined the potential prognostic
relevance of 5HTTLPR polymorphisms, there is some data
suggesting that, together with white matter change, presence of
the S allele may be linked to remission. More specifically, lower
remission rates after treatment with SSRI antidepressants were
seen in those with the S/S genotype (Alexopoulos et al., 2009). This
data is consistent with earlier work by the same group, which had
shown that presence of the S allele was associated with poorer
response to the noradrenergic and specific serotonergic antide-
pressant, mirtazapine; possibly related to poor tolerability rather
than reduced efficacy of this agent (Murphy et al., 2004).
9.3. Apolipoprotein E gene (Apoe)
The apolipoprotein E gene (Apoe) encodes a lipid transport
protein that is involved in the maintenance and repair of neuronal
cells (Yuan et al., 2010). There are three alleles: e2, e3 and e4, with
data suggesting that the e4 allele is less efficient. A considerable
body of literature has indicated that the e4 allele is a risk factor for
AD, with about 65% of individuals with non-related sporadic AD
and up to 80% of familial AD sufferers carrying this allele,
compared with only 20% in healthy control populations (Farrer
et al., 1997). Despite clear evidence of an association, the
mechanism for the association between e4 and AD remains
unclear, although it may be mediated by the role played by e4 in
the redistribution of lipids between cells in the central nervous
system (CNS), which are important in neuronal repair and
maintenance of synaptic-dendritic connections (Mahley et al.,
2006).
Studies that have sought to examine whether the e4 allele is
relevant to the pathogenesis of LLD have generally produced
inconsistent results. For instance, some data has suggested that the
e4 allele is more common in individuals suffering from LoD as
compared with EoD (Krishnan et al., 1996). However these results
have not been replicated in more recent research (Hickie et al.,
2001a; Steffens et al., 2003).
Other investigations have focused on the link between the e4
allele and volumetric changes in LLD; these have primarily focused
on the hippocampus, alterations of which are implicated very early
in the course of AD. The e4 allele has been associated with
reductions of hippocampal volume in some (Kim et al., 2002), but
not all (Hickie et al., 2005b) studies. It has been suggested that the
e4 allele may mediate hippocampal shape alterations in the region
of the CA1 subfield (Qiu et al., 2009). A small longitudinal study in
depressed, non-demented elders (n = 45) found that the e4 allele
was associated with more rapid hippocampal volume loss on the
right over two years (Kim et al., 2002). Other studies examining
more extensive brain regions in 37 patients with remitted LoD
found that in comparison to non e4 carriers, those with an e4 allele
had smaller volumes of the medial and middle frontal gyrus and
left inferior occipital gyrus although there were no differences in
neuropsychological performance between these groups (Yuan
et al., 2010). The lack of relationship between Apoe4 and cognitive
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
decline in older patients with MD replicates earlier work (Hickie
et al., 2001a; Naismith et al., 2003). However more recently,
depressed e4 carriers were shown to have greater cognitive decline
than those without the e4 allele (Corsentino et al., 2009; Niti et al.,
2009). These findings have been recently extended to show that
the e4 allele moderates the relationship between hippocampal
volume and cognitive decline, such that smaller hippocampal
volumes in depressed e4 allele carriers, have greater cognitive
decline (Sachs-Ericsson et al., 2011).
Although the precise mechanism by which the Apoe4 genotype
may be pertinent to the structural brain changes in LLD is
unknown, there is some data suggesting that the expression of
Apoe4 may relate to cerebrovascular disease. Replicating a
suggested link between cerebrovascular disease and Apoe
genotype (Nebes et al., 2001), Steffens et al. (2003) found a
significant association between the e4 allele and the volume of
gray matter hyperintensities in elderly depressed patients.
Despite these structural associations, however, the e4 allele
was not found to be associated with the development of dementia
in a longitudinal study of depressed older adults (Steffens et al.,
2007). Additionally, the Apoe4 allele does not appear to relate to
concomitant cerebrovascular disease in LoD (Traykov et al., 2007),
suggesting it plays a unique and differential role in cognitive
decline.
As has been observed with the serotonin transporter gene, some
data suggests that Apoe genotype may play a role in antidepressant
response in LLD. A double-blind 8-week randomised controlled
trial involving 246 patients over the age of 65 years with MD,
examined the effect of Apoe genotype on response to mirtazapine
or paroxetine. Interestingly, those patients with the e4 allele
showed a rapid onset of mirtazapine action whereas those on
paroxetine were slow to respond (Murphy et al., 2003).
9.4. Genes implicated in systemic vascular risk
In light of the considerable wealth of data linking LLD, and
more specifically LoD, with cerebrovascular disease, there has
been relevant interest in those genes that appear to predict
systemic vascular risk. One that has received attention is the
MTHFR gene, which encodes the enzyme 5-methylenetetrahy-
drofolate reductase. This enzyme is associated with the metabo-
lism of homocysteine, utilising B12 and folic acid as co-factors. A
relatively common polymorphism (C677T) produces an enzyme
with reduced activity leading to increased homocysteine levels. A
large number of studies have linked the C677T mutation and/or
homocysteine levels with cardiovascular and cerebrovascular
disease as well as to WMLs. Studies examining the presence of this
genotype in LLD have noted an increased prevalence in compari-
son to controls (Almeida et al., 2008) and have noted it to be
associated with later ages of onset (Hickie et al., 2001a). Some
neuropsychological data has also linked the C677T genotype with
slowed processing speed in older depressed samples (Naismith
et al., 2002, 2003). However, a recent analysis of data from the
NCODE study found no association between MTHFR genotype and
neurocognitive performance (specifically MMSE, and tests of
processing speed, delayed recall and executive function) in older
adults with MD (Hong et al., 2009). Despite this, an interaction
between age and genotype was discovered, such that the TT
genotype was associated with increased WML volume compared
with the CC genotype for a given age. Since homocysteine levels
may be particularly linked to WMLs even in those with small
vessel disease (Wong et al., 2006), the influence of this genotype
may be particularly relevant to processes mediated by subcortical
structures (Naismith et al., 2002), which are in turn especially
vulnerable to ischaemia (Kumral et al., 1999; Steffens et al.,
1999b).
125
Box 6. Genetic research in late-life depression.
 The serotonin transporter gene may be implicated in depres-
sion onset, basal ganglia changes, vascular risk, WMLs and
treatment responsiveness
 The Apoe4 allele may be linked to hippocampal volume loss
and later depression onsets
 BDNF polymorphisms may be associated with risk for LLD
and response to treatment responsiveness
 The MTHFR gene mutation is integral to homocysteine
metabolism, relates to cardiovascular risk and has been
associated with later ages of depression onset and slowed
psychomotor speed
More recent studies have begun to focus on other genotypes
that are relevant to cardiovascular health. Of these, genes that are
seemingly integral to blood pressure regulation have been of
interest including the renin-angiotensin system genes, angiotensin
II receptor vascular types I and II (AGTR1 and AGTR2). Early studies
in this area have suggested that there may indeed be a link with
WMLs, particularly in progression of WMLs in men (Taylor et al.,
2010b), as well as with LLD outcomes (Kondo et al., 2007) (Box 6).
10. The role of inflammation
Despite the multitude of evidence relating to structural and
metabolic abnormalities in LLD, the pathophysiological mecha-
nisms underpinning such changes are poorly understood. Recently,
prolonged and exaggerated immune responses have been postu-
lated to promote such changes in neurobiological circuitry that
predispose to LLD or facilitate metabolic changes that mediate
depression (Alexopoulos and Morimoto, 2011). The role of the
inflammatory system and immune activation in the aetiology of
MD was suggested well over a decade ago (Hickie et al., 1990b;
Maes, 1995). There is now ample evidence demonstrating a
relationship between pro-inflammatory cytokines, such as the
interleukins and interferons and MD specifically (Dantzer et al.,
2008; Thomas et al., 2005). Commonly studied cytokines include
interleukin (IL)-1, IL-6, tumour necrosis factor alpha (TNFa) and
CRP. These intracellular signalling polypeptides, produced by
macrophages, monocytes and other immune activated cells, play a
central role in the regulation of the immune response. Increased
levels of pro-inflammatory cytokines have been found in older
adults (Krabbe et al., 2004); such an age-related ‘‘pro-inflamma-
tory state’’ has been suggested to be associated in part with high
levels of VRFs and morbidity (Ferrucci et al., 2005).
Although holistic examination of the role of immunological
and/or inflammatory responses cannot be tested entirely, the
results of studies to-date investigating inflammatory markers in
LLD are less consistent than in younger or mixed populations. After
adjusting for common confounders, one study (Penninx et al.,
2003) found CRP to be elevated in depression. This cross-sectional
community study also demonstrated raised IL-6 and TNFa levels to
be associated with depressed mood; moreover if two or all three
markers were elevated, the odds ratio of MD was 2.45 compared
with those with no elevation in markers. However a number of
other studies did not find any association with raised levels of CRP
and depression in older adults (Almeida et al., 2007; Bremmer
et al., 2008; Forti et al., 2010; Kop et al., 2002; Pan et al., 2008;
Steptoe et al., 2003; Thomas et al., 2005; Tiemeier et al., 2003).
Interestingly, in a large cross-sectional community study of men
aged over 70 years, raised levels of CRP were not associated with
clinical significant depressive symptoms once confounders had
been adjusted for, but the risk of depression was increased in men
carrying a genetic polymorphism resulting in lower serum
126 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
concentrations of CRP (Almeida et al., 2009). Four studies reported
elevation of IL-6 in depressed subjects (Bremmer et al., 2008;
Dentino et al., 1999; Penninx et al., 2003; Tiemeier et al., 2003);
with another four studies not finding any significant difference in
the levels of IL-6 between depressed and controls subjects
(Empana et al., 2005; Forti et al., 2010; Pan et al., 2008; Steptoe
et al., 2003).
Only two studies have investigated the association between
depression and IL-1b, both reported an increase in the depressed
group, independent of confounders (Diniz et al., 2010a; Thomas
et al., 2005). These two studies compared IL-1b levels in EoD and
LoD. In the study by Diniz et al. (2010a), the mean IL-1b level was
raised in the EoD group compared with the LoD group, but the
difference only approached significance. One explanation for
higher levels in EoD group may be ‘‘a cumulative increase in
inflammatory response’’ related to the increased rates of recur-
rence seen in this group (i.e. mean of 3.0 episodes in EoD compared
to 1.1 in LoD) (Diniz et al., 2010a). Thomas et al. (2005) did not
report any difference in IL-1b between their EoD and LoD subjects,
or any correlation between IL-1b and age of depression onset.
These contrasting findings suggest that further research is required
in order to delineate the contribution of inflammatory changes in
those disorders emerging later in life.
Although cross-sectional approaches have failed to yield
consistent results, two longitudinal studies have demonstrated
an association between the development of depression in
community dwelling older adults and pro-inflammatory markers.
In a population-based cohort of 85 years old, participants who did
not report depressive symptoms at baseline had cytokine levels
determined by ex vivo whole blood stimulation with bacterial
lipopolysaccharide (LPS) (this method reflects the capacity of the
innate immune system) (van den Biggelaar et al., 2007). High
circulating levels of CRP at baseline predicted accelerated increase
of depressive symptoms; additionally higher IL-1b and lower IL-
1ra production after LPS challenge was associated with the
development of self-reported depressive symptoms over a 5-year
period. On the other hand, in a population-based cohort of older
adults asymptomatic at baseline, only levels of IL-1ra predicted the
development of significant depressive symptomatology 6 years
later (Milaneschi et al., 2009). Those in the two highest quartiles of
IL-1ra at baseline had a 2.3- and 2.8-fold increased risk of
depression compared with those in the lowest two quartiles. IL-1ra
is an antagonist of IL-1ra and IL-1b, and represents a marker of
immune activation. It is produced in large quantities in the liver
under the same circumstances that lead to the production of IL-1ra
and IL-1b, and may be considered a more reliable indicator of
inflammation than IL-1, as it remains in the circulation for longer
periods (Granowitz et al., 1991). The contradictory findings of both
reduced IL-1ra production after LPS challenge and increased
circulating IL-1ra levels being associated with increased risk of
depression may result from the differing methods of cytokine
measurement, and suggests that on one hand risk for depression
may depend on the ability to produce IL-1ra to an immune
challenge, conversely, high circulating levels of IL-1ra indicate a
state of immune activation, which increases depression risk. In any
case it would appear that the IL-1 signalling network has a role in
the development of depressive symptoms in older adults.
Whilst the accumulation of VRFs as well as other inflammatory
conditions may contribute to increasing levels of pro-inflammato-
ry cytokines, stress, particularly psychological stress, is likely to be
important. In fact increasing inflammatory markers may be a key
mechanism in the development of depression in the face of
increased stress. In a longitudinal community study, chronically
stressed older caregivers were demonstrated to have a four-fold
increased rate of increase of IL-6 levels compared to non-stressed
older adults (Kiecolt-Glaser et al., 2003). Chronic stress, and more
particularly caregiving burden, is associated with depression in
older adults (Marin et al., 2011). Furthermore it appears that such
depressed and stressed older adults may then be primed to
respond to undergo an exaggerated inflammatory response to
further stressors and challenges (Gouin et al., 2008).
Despite the associations between stress and VRFs and increas-
ing levels of peripherally circulating pro-inflammatory factors, it is
not clear whether peripheral elevations in inflammatory factors
are positively associated with cerebral levels, or how raised
cytokine levels contribute to depressed mood. Although the blood
brain barrier is relatively impermeable to cytokines, saturable
transport mechanisms exist that allow limited penetration of IL-1b
and TNFa (Banks et al., 1991). Additionally, peripherally circulat-
ing cytokines may influence cerebral processes via the vagus nerve
(Maier and Watkins, 1998), and pro-inflammatory cytokines may
be able to enhance permeability at vascular sites (de Vries et al.,
1996). Recent findings suggest that peripheral cytokine elevations
are reflected in the brain; post-mortem microarray mRNA
expression analysis, carried out in the BA10 region of brains from
individuals with melancholic depression as well as controls,
demonstrated altered expression of a number of genes, particularly
up-regulation of the expression of pro- and anti-inflammatory
cytokines (Shelton et al., 2011). The CNS immune system therefore,
although protected in some degree by the blood brain barrier, has
some link to the periphery. Microglia, the primary immune defence
cells in the CNS (Allen and Barres, 2009), exist in both quiescent
and primed states (Kreutzberg, 1996). Primed microglia may be
rapidly activated by stimulation with an antigen, and secrete
cytokines and growth factors, as well as stimulate an activation
cascade, that allows recruitment of other glial cells, particularly
astrocytes, and secretion of more cytokines and neurotrophic
factors to bring about repair and facilitate homeostasis. As
mentioned above, the age-related pro-inflammatory state is
associated with increased numbers of activated microglia as well
as increased production of pro-inflammatory cytokines (Sparkman
and Johnson, 2008).
The role of glia in the neurobiology of depression is increasingly
a focus of research (see review by Paradise et al., in press).
Increases in glial fibrillary acidic protein (GFAP), an astrocytic
marker, have been discovered in cortical layer one of the DLPFC in
persons with LLD (Davis et al., 2002). Furthermore in younger
people with depression, levels of GFAP in the PFC were significantly
lower compared to controls (Si et al., 2004), whilst there was no
significant difference in the level of GFAP between depressed and
control subjects older than 60 years at time of death. One
explanation for these findings may be that early in the course of
depression an imbalance in toxic (glucocorticoid/glutamate) and
trophic factors may lead to a reduction in glia, with resultant
neuronal damage and injury. Compensatory mechanisms later in
the course of depression then lead to gliosis and increased glial
density (Rajkowska, 2000), with levels becoming comparable with
older subjects without a history of depression. Alternatively,
differences in GFAP expression may result from differing
underlying pathophysiologies in EoD and LoD. Neuropathological
studies investigating the pathophysiology of WMLs have demon-
strated evidence of ischaemia in the white matter of the DLPFC but
not the ACC or occipital cortex (Thomas et al., 2003), and that all
deep WMLs in a depressed group of adults with LLD were
ischaemic in origin as compared with only one-third of WMLs in a
healthy aged matched control group (Thomas et al., 2002).
Moreover, compared with healthy age-matched controls, ischae-
mic lesions in depressed elders were significantly more likely in
the DLPFC than the ACC. Additionally up-regulation of the
intracellular adhesion molecule-1, a vascular marker of inflamma-
tion, in the grey and white matter of the DLPFC in subjects with LLD
(Thomas et al., 2000), suggests that cerebral ischaemia may induce
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
inflammatory changes. This is partially supported by the GFAP
findings in layer one of the DLPFC described above. Finally
microglial activation has been demonstrated in periventricular and
deep subcortical WMLs in ageing brains (Simpson et al., 2007),
with the response associated with periventricular lesions in
particular, possibly reflecting immune activation related to
disruption to the blood brain barrier. Taken together, these
findings suggest a mechanism by which vascular risk increases the
risk for LLD. Cerebrovascular disease, represented by WMLs, may
lead to localized microglial activation and the production of
inflammatory cytokines, thus priming the individual’s innate
immune response, which then responds in an exaggerated fashion
to future stressors – how this then culminates in the clinical
picture of depression remains unclear. Potential explanations
include altered tryptophan metabolism, leading to reduced
serotonin synthesis, via the activation of indoleamine 2,3-
dioxygenase by pro-inflammatory enzymes (Dantzer et al.,
2008), and excess glutamate, leading to excitotoxicity, due to
inflammatory mediator associated impaired expression of excit-
atory amino acid transporter on astrocytes (McNally et al., 2008).
Once delivered in the brain or alternatively once local
production is increased, pro-inflammatory cytokines exert their
effects in a number of ways. Animal studies have demonstrated
that cytokines potently activate the HPA axis (Dantzer et al.,
2008), via inducing glucocorticoid receptor resistance thus
reducing the ability of glucocorticoids to down-regulate cortico-
trophin releasing hormone, and resulting in a feed-forward
cascade in cortisol production. Moreover the induction of
glucocorticoid receptor resistance in circulating immune cells
would lead to failure of the inhibitory effect of glucocorticoids on
cytokine production and action, with a consequent intensified
pro-inflammatory state. Although studies in younger adults have
frequently reported hyperactivity of the HPA axis as well as high
cortisol levels (Holsboer, 2000), there are relatively few studies
examining the role of the HPA axis in LLD. Generally these studies
have demonstrated HPA axis hyperactivity and high cortisol
levels in depressed older adults (O’Brien et al., 2004), with
cortisol levels returning to normal with resolution of the
depressive episode. However there have been contradictory
findings of hypocortisolaemia in frail elderly with LLD (Morrison
et al., 2000), as well as those with chronic and recurrent
depression (Oldehinkel et al., 2001). More recent research has
demonstrated a U-shaped association between depression and
cortisol levels in older adults with LLD. Two population-based
studies of adults aged 65 and over have both found that LLD
symptoms are associated with both hyperactivity and hypoac-
tivity of the HPA axis (Bremmer et al., 2007; Penninx et al., 2007).
Bremmer et al. (2007) found in a European population-based
study that plasma cortisol levels were associated with MD in a U-
shaped fashion. Hypocortisolaemic depression was associated
with being female, recurrent depression, smoking and joint
disease, whilst hypercortisolaemic depression was associated
with older age, male sex, CVD and cognitive impairment
(although this last association was only of borderline signifi-
cance) (Bremmer et al., 2007). A community study, conducted in
Italy investigated the relationship between urinary cortisol and
depressive symptoms and had similar findings: individuals at
each end of the cortisol spectrum reported higher depressive
symptoms (Penninx et al., 2007). Moreover hypocortisolaemic
depression was associated with relatively lower depressive
severity but increased physical frailty. Neither study looked
specifically at the age at onset of depression; however the
association with chronicity and hypocortisolaemia on the one
hand and cardiovascular risk and hypercortisolaemia on the
other, further highlights the likelihood that LoD and EoD are
underpinned by differential mechanisms.
127
Box 7. Inflammatory research in late-life depression.
 Cross-sectional studies yield inconsistent results regarding
the association between CRP, IL-6 and LLD
 Some data linking IL-1b with LLD, with no clear link to LoD
specifically
 Longitudinal data shows baseline IL-1ra and IL-1ra predicts
increase of depressive symptoms over time, with mixed
results for CRP and IL-1b
 Glial fibrillary acidic protein may be increased in the DLPFC
and may be indicative of altered astrocytic activity
 Intracellular adhesion molecule-1 may be up-regulated and
may be indicative of vascular inflammatory activity
 Altered functioning of the HPA axis is supported by data
showing U-shaped curves for hypercortisolaemia and hypo-
cortisolaemia
Overall, the inflammation hypothesis of MD requires further
empirical examination. However, a convergence of data does
support some role for immunological changes in the pathogen-
esis of this disease, warranting efforts devoted to further
understanding the interaction between such factors and medical
comorbidity, ageing, and microglial responses, and the emer-
gence and/or perpetuation of depressive disorders. As recently
highlighted by Alexopoulos and Morimoto (2011), this model
certainly leads to testable hypotheses and data regarding the
mechanisms by which inflammatory responses may promote
depressive symptoms. In turn, this may allow greater opportu-
nities for specific interventions targeting the underlying
pathophysiology, and may even be suited for early intervention
approaches (Box 7).
11. Prognosis in late-life depression
The prognosis of LLD is typically poor and is characterized by
chronicity, mortality and increased risk for cognitive impairment
and progression to dementia (Djernes et al., 2011; Hickie et al.,
1997b; Reynolds et al., 2008; Schoevers et al., 2009). In a three year
cohort study, LoD was found to be associated with a high rate of
mortality and dementia. VRFs, including lower HDL, raised
erythrocyte sedimentation rate (ESR) and a higher score on the
Hachinski Index (a measure of ischaemic disease), were associated
with worse prognosis in this group (Baldwin et al., 2006).
Eleven longitudinal studies have investigated the prognosis of
LLD as related to the age at onset of first episode. Of these, six
found a difference in prognosis, in either direction when the
cohort was either divided into EoD and LoD (four studies) or age of
onset was analysed as a continuous variable. Two studies reported
LoD to have a worse prognosis: Alexopoulos et al. (1996) found
those with LoD had less chance of recovery at two years and, with
regard to short-term prognosis, Conwell et al. (1989) found
subjects with LoD had a longer hospital stay and worse symptoms
at discharge. In contrast, four studies found those with EoD had a
worse prognosis: Reynolds et al. (1998) found that those with EoD
took longer to achieve remission although no overall differences
were found between groups in rates of remission, relapse,
recovery or recurrence; Dew et al. (1997) reported earlier onset
of depressive disorder (as a continuous measure) predicted a
poorer treatment response and Brodaty et al. (1993) found EoD to
have a worse prognosis in the elderly (measured at one year and
two to four year follow-up periods, using a categorical ‘global
outcome’ scale). In the earliest study, Kay et al. (1955) also
reported EoD had a better prognosis in several domains, although
these latter findings are limited by the lack of valid diagnostic
criteria and omission of statistical tests to confirm differences
between groups.
128 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
The effect of age of onset of depression on prognosis and
treatment response is therefore uncertain. Age may have a
complex relationship with depression and is highly correlated
with a number of other known risk factors known to affect
prognosis. Elderly depressed patients with an early first onset of
depression are more likely to have had a greater lifetime number of
relapses and an overall longer duration of illness; both of these
factors are important predictors of poor prognosis. Alternatively,
patients presenting with depression for the first time in later-life
have an increased risk of physical comorbidities (Lavretsky et al.,
1998; Subramaniam and Mitchell, 2005; Tupler et al., 2002) and
physical comorbidity has been associated with a worse prognosis
(Iosifescu et al., 2003). Complicating the clinical picture is the
possibility of emerging neurodegenerative disease in some
patients, with prevalence rates for AD alone doubling every five
years after the age of 60 (Lobo et al., 2000; National Institute on
Aging, 1999). If VRFs are untreated, depressive symptoms may
become more chronic and cognitive decline may also continue.
Therefore the effect of age of onset on prognosis may be partially
mediated by the presence of early illness, physical comorbidities,
untreated VRFs and emerging incipient neurodegenerative disease.
12. Treatment approaches
12.1. Pharmacological treatments
While there have been a very large number of studies
investigating response to pharmacological treatments in middle-
aged persons, there is still a remarkably small number of studies
specifically focused on assessing interventions in older persons,
particularly those with LoD. Increasingly over the last two decades,
as much larger studies have moved to evaluate populations outside
specialist settings the differential between active treatments and
placebo response has declined. It is assumed that this has resulted
from the movement away from assessment of interventions
among a more severely ill group (who best fit a more traditional
‘neurobiological’ model) to much more heterogeneous (and less
persistently-ill) populations. The same phenomena may well
emerge among studies of older persons with depression, as both
preventive/early intervention studies (Christensen et al., 2011;
Cockayne et al., 2011; Walker et al., 2010) and broader communi-
ty-based studies are now underway.
Although drawing on the current data base, pharmacological
treatments appear to be effective for older persons with MD (Roose
and Schatzberg, 2005), with a Cochrane meta-analysis (Wilson
et al., 2001) of 17 studies demonstrating efficacy of SSRIs, TCAs and
monoamine inhibitors (MAOIs) over placebo in the treatment of
LLD; more recent data suggests response rates may be little better
than placebo (Nelson et al., 2008). Several comparator or ‘head-to-
head’ studies of different classes of antidepressant including SSRIs
to TCAs (Bondareff et al., 2000) and mirtazapine (a noradrenergic
and specific serotonergic antidepressant) to SSRI (Schatzberg et al.,
2002) have failed to consistently demonstrate the superior efficacy
of one class of antidepressants over another, although different
tolerability and side-effect profiles are seen between classes
(Mottram et al., 2006). Moreover, a recent large-scale general
practice-based review of treatment of depression in older persons
(Coupland et al., 2011; Hickie, 2011) indicates the extent to which
widespread prescribing of SSRIs are associated with important
side-effects (e.g. falls, hyponatraemia, agitation), and the extent to
which some classes may be associated with more significant risks
including increased risk to stroke, seizures, fracture and premature
death.
Compared to middle-aged patients, older persons may take
longer to respond to antidepressant medication, and unfortunately
as many as 50% of patients with LLD will not achieve remission
with the first treatment (Roose and Schatzberg, 2005), warranting
the need to consider alternative non-pharmacological options in
some sub-groups. A recent systematic review of treatment for
refractory depression in older adults found that lithium was the
only treatment with consistent evidence for an additional effect
(Cooper et al., 2011). This is indicative of the lack of focus on this
key patient group. Traditionally, other physical treatments,
notably ECT, have been preferentially used in older subjects with
severe and treatment-resistant depression. Such patients more
often present with psychotic features or disturbance of psycho-
motor function (psychomotor retardation or agitation) that do
predict a comparatively better response to ECT (Hickie et al.,
1990a). Interestingly, ECT has often been suggested as an
adjunctive treatment for other neurological and neurodegenera-
tive disorders including Parkinson’s disease and delirium (see
Popeo and Kellner, 2009). New direct brain stimulation models for
treatment-resistant depression (Mayberg et al., 2005) have been
directly modelled on the success of similar interventions for
patients with Parkinson’s disease.
Other data is largely limited to small non-randomised trials or
case studies. Nimodipine (a calcium channel blocker) augmenta-
tion in those with ‘vascular’ depression has demonstrated
encouraging results (Taragano et al., 2005), as has Aripiprazole
augmentation in SSRI non-remitters with LLD (Rutherford et al.,
2007). A trial of Galantamine, a cholinesterase inhibitor, augmen-
tation produced negative results (Holtzheimer et al., 2008).
Methylphenidate has been used in older adults and medically ill
patients for many years, despite no clear evidence of efficacy. A
recent review of clinical trials of methylphenidate in older adults
found that the data to support its use is of relatively poor quality,
but suggests that it may have efficacy for depressive symptoms,
fatigue, apathy and cognitive slowing in a variety of medically ill
populations (Hardy, 2009). Other agents that may show promise in
LLD are those that concurrently target the sleep–wake system,
whilst also possessing low side-effect profiles. In this regard, the
novel antidepressant Agomelatine, may show some promise for its
capacity to concurrently target melatonergic receptors (Hickie and
Rogers, 2011). However, no known studies to-date have examined
the efficacy of this agent for LLD.
Extensive research now suggests that the presence of VRFs,
small vessel vascular disease or cognitive dysfunction is a strong
predictor of impaired response to SSRI treatments, highlighting the
relevance of these variables for management plans (Sheline et al.,
2010). In general, WMLs, VRFs, executive dysfunction, depression
recurrence and later ages of illness onset are associated with
particularly poor treatment outcomes (Alexopoulos et al., 2008;
Hickie et al., 1997b; Potter and Steffens, 2007; Sheline et al., 2010).
However, some evidence suggests that better outcomes can be
achieved if treatment trials are prolonged or more complex
(Anstey and Brodaty, 1995; Driscoll et al., 2005). Unfortunately,
little attention has been paid to the role of other neurotransmitter
systems in LLD that may offer viable options for treatment targets,
and which may be better tailored to the underlying neurobiology
of the disease. A previous emphasis has been placed on
dopaminergic systems, particularly as it related to relief of anergia
and psychomotor retardation (Brown and Gershon, 1993). Hence,
the older literature emphasizes the use of stimulant medications
and antidepressants with evidence of increased dopaminergic
activity (e.g. Antleman and Chiodo, 1981). In more recent times
agents acting on glutamatergic or GABA systems have been
proposed (see review by Javitt et al., 2011). However, more human
data regarding the pathophysiological roles of these various
systems in depressive disorders is required (possibly through
magnetic resonance spectroscopy and/or neuropathological stud-
ies). The additional role of agents that focus on specific cognitive
features, including memory dysfunction (e.g. acetylcholine)
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
requires systematic evaluation in cohorts with such features. In
younger samples, there is certainly preliminary evidence suggest-
ing that agents targeting glutamate, GABA and dopamine may
demonstrate antidepressant efficacy (Berman et al., 2000; Zarate
et al., 2004), thereby warranting further evaluation in older, albeit
more complex samples.
Electroconvulsive therapy is an effective option in those with
psychomotor retardation, psychotic phenomena or severe disease
(Hickie et al., 1996). However, MRI-associated white or grey nuclei
changes predict a poorer response (Hickie et al., 1997b). Other
clinical predictors of poor response include anxiety, hopelessness,
limitations in physical function, chronicity of current episode,
social isolation, and poverty (Alexopoulos et al., 2008). Repetitive
transcranial magnetic stimulation (rTMS) is a low risk, non-
invasive approach that involves the stimulation of specific brain
regions via the passage of magnetic pulses through the skull, and
does not involve a general anaesthetic or seizure. A recent review
on the use of rTMS in MD found that although rTMS is more
effective than sham treatment for the treatment of depression, it
may be less effective than other conventional antidepressant
therapies (Loo and Mitchell, 2005). The literature is less clear on
the benefits of rTMS in LLD. Two small controlled studies in elderly
patients reported that rTMS produced no additional antidepres-
sant effects when compared with sham treatment (Mosimann
et al., 2004), and did not lead to improvement in depression
severity (Manes et al., 2001). However a case series of 49 older
adults who received high frequency rTMS delivered to the left
DLPFC as an adjuvant to pharmacotherapy, reported a modest but
statistically significant mean reduction in the Hamilton Depression
Rating Scale scores from baseline to the end of treatment (Milev
et al., 2009). The largest study to-date, a double-blinded RCT of
rTMS in geriatric patients with ‘vascular’ depression, demonstrated
the efficacy of rTMS of the left DLPFC compared with sham
treatment (Jorge et al., 2008). Both older age and smaller frontal
gray matter volumes were associated with poorer response to
rTMS although interestingly the burden of WMLs was not
associated with treatment response. These findings suggest that
rTMS may be an effective alternative treatment in LLD when
accompanied by cerebrovascular disease.
Recent years have witnessed an increasing interest in the role
that genetic polymorphisms may play in antidepressant response. In
middle-aged subjects, there is as yet no clear set of predictors of
response to pharmacological interventions (Licinio and Wong,
2011). Consistent with the more general treatment literature, there
is little evidence for any strong associations between specific
markers and treatment response in older persons, though some
associations have emerged, as outlined above. In a study of 246 older
outpatients treated with either paroxetine or mirtazapine, several
polymorphisms at the ABCB1 (i.e. ATP-binding cassette, subfamily B,
member 1 transporter (ABCB1); a gene that produces P-glycopro-
tein, which affects the transport of drugs out of cells) locus appeared
to predict treatment outcome in geriatric patients taking paroxetine
(which is a substrate for P-glycoprotein) (Sarginson et al., 2010).
However, these results were no longer significant after Bonferroni
correction. Similarly a reported finding of an association between
polymorphisms in the FK506 binding protein 5 (FKBP5; a gene that is
involved in the regulation of glucocorticoid receptor sensitivity, and
response to antidepressant therapy in MD), was not replicated in a
sample of 246 geriatric patients (aged 65 years and older) treated for
eight weeks in a double-blind randomised trial of mirtazapine and
paroxetine (Sarginson et al., 2009). Despite their implicated role in
pathogenesis, analysis of genetic polymorphisms of the 5HTTLPR
gene has also returned null findings with regard to outcome of
antidepressant treatment in LLD, though in most studies, the S allele
does appear to be associated with a slower treatment response (see
Gerretsen and Pollock, 2008 for review).
129
12.2. Non-pharmacological treatments
Non-pharmacological approaches for treatment of depression
and cognition in LLD have been limited. This may reflect previous
consensus statements implying that psychotherapeutic interven-
tions may be less efficacious in older adults (NIH Consensus
Development Panel on Depression in Late Life, 1992) or the more
general practice bias against providing psychological interventions
to older persons with depression (Hickie et al., 2001b). However a
recent meta-analysis of psychotherapy and pharmacotherapy
trials in LLD demonstrated comparable effect sizes for both forms
of treatment (Pinquart et al., 2006) and expert guidelines have
generally recommended the use of both forms of treatment (see
review by Alexopoulos, 2011). Moreover, for elderly patients
suffering minor depression and dysthymia, psychotherapeutic
interventions displayed larger effects with regards to clinician-
rated depression than pharmacological strategies. Despite data
suggesting that antidepressants may demonstrate little superiority
over placebo (as reviewed above), as well as evidence that
psychological therapy has similar efficacy to medication in mild to
moderate depression (McCusker et al., 1998) in older people,
psychotherapeutic interventions are less frequently offered to this
age group (Baldwin and Wild, 2004). In fact, a combination of
pharmacological and non-pharmacological strategies may have
optimal benefits, as evidenced by a study comparing monotherapy
Cognitive Behavioural Therapy (CBT), desipramine (a TCA), or a
combination of the two. Although all three groups showed
improvement, the combination group demonstrated the greatest
improvement (Thompson et al., 2001).
The two most extensively researched non-pharmacological
treatments for LLD are CBT (Serfaty et al., 2009) and Interpersonal
therapy (IPT) (Reynolds et al., 1999). Briefly, CBT focuses on
challenging negative thoughts and changing the behaviours that
reinforce them. Dysfunctional patterns of thought and behaviour are
identified, and interventions include challenging unhelpful thinking,
reducing avoidant behaviour and introducing positive behaviour
patterns (Hepple, 2004). IPT, on the other hand, takes as its focus
disturbances in current relationships; a range of interventions to
improve communication and expression of emotion are employed in
order to reduce symptoms and improve levels of function (Hepple,
2004). Both therapies are best delivered in approximately 10–20
sessions. Recently there has been increased interest in briefer and
alternative psychotherapeutic interventions, such as problem
solving therapy (PST). This treatment trains patients to identify
problems that are affecting their wellbeing, and provides education
regarding how to select and then enact a plan for solving the problem
(Arean et al., 2010). It is based on the assumption that if patients are
better able to manage their lives, they will experience less stress and
a reduction in depressive symptoms. There is evidence to suggest
that PST has efficacy in older adults with LLD (Arean et al., 1993) and
may be particularly suited to those with executive dysfunction. For
instance, a recent RCT investigated the efficacy of PST for LLD with
concomitant executive dysfunction (Arean et al., 2010). Two hundred
and twenty one adults were randomly assigned to weekly sessions of
either supportive therapy or PST for 12 weeks. Although reductions
in depression severity were comparable between the two groups at
week six, by weeks nine to twelve PST was more effective in reducing
depressive symptoms and produced greater response and remission
rates than supportive therapy. Additionally, this form of therapy was
associated with reductions in disability that were sustained
(Alexopoulos et al., 2011). These results have important implications
for offering non-pharmacological strategies to those with cognitive
impairment and pharmacological treatment resistance.
Rather than address the depressive features directly, investi-
gators are now beginning to address other factors such as
disturbed sleep, disrupted circadian cycles and reduced physical
130 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
activity which are critically linked to LLD. Lieverse et al. (2011)
recently published a double-blind placebo-controlled RCT, which
examined the role of bright light therapy for improving depressive
symptoms. In a sample of 89 patients aged over 60 years, three
weeks of 1-h bright light was associated with improvement in
mood that was sustained for a further three weeks after treatment
cessation and which was associated with concomitant changes in
melatonin rise and salivary cortisol. These data suggest that
therapies directly addressing the sleep–wake system have signifi-
cant antidepressant effects. Exercise-based treatments have been
well evaluated in older adults, and look to be particularly effective
in the treatment and management of mood disturbance (Chodzko-
Zajko et al., 2009; Lautenschlager et al., 2004). Evidence suggests
that regular physical exercise (such as walking or jogging) may be
as effective in reducing depressive symptoms as antidepressant
therapy in depressed older adults (Blumenthal et al., 1999), though
beneficial effects of physical activity training appear to be
correlated with the intensity of the intervention, and ideally
should include aerobic, muscle strengthening and flexibility
exercises (Chodzko-Zajko et al., 2009). Importantly, these thera-
peutic effects may be sustainable, as demonstrated by Singh et al.
(2001) who reported persistently reduced depressive symptoms at
20-week and 26-month follow-up assessments in individuals who
participated in a 10-week supervised exercise program. Further-
more, exercise has also been associated with reduced rates of
relapse over a 10-month follow-up period, particularly if
individuals remained physically active over the follow-up period
(Babyak et al., 2000). It has been suggested that physical exercise
impacts on psychological well-being by improving psychosocial
constructs such as self-efficacy and functional independence, as
well as by mediating metabolic and other physiological processes
associated with depression and with ageing generally (Chodzko-
Zajko et al., 2009; Lautenschlager et al., 2004). While evidence has
thus far suggested an important role for physical exercise and
activity in managing depression in older adults, further RCTs are
needed to delineate its efficacy in specific groups such as those
with LoD and/or concomitant cerebrovascular disease. In addition,
generalised exercise programs may not be suitable for depressed
individuals with medical comorbidities and/or VRFs or those
whom have been sedentary for some time. These individuals may
initially require supervised and/or individually tailored exercise
programs to ensure safety and compliance.
Due to the high preponderance of cognitive impairment in LLD,
some investigators have sought to improve neuropsychological
functioning in this group using cognitive training techniques. One
recent study employing cognitive training demonstrated signifi-
cant improvements in learning and memory in older people with a
history of major depressive disorder and cognitive decline without
dementia (Naismith et al., 2011a). These improvements corre-
sponded with medium to large effect size changes (i.e. ÿ0.74 to
ÿ0.82), which was considered to be a clinically meaningful
improvement. However, there was no improvement in executive
functioning, which would be optimal if dysfunction in this domain
indeed relates to other aspects of daily functioning such as
disability. Certainly, across the area of neuropsychiatry and
neurodegenerative disease, these techniques are showing promise
as a way to slow cognitive decline (see review by Mowszowski
et al., 2010), and this form of treatment warrants further
investigation in LLD.
13. A focus on prevention for late-life depression?
It is proposed that future paradigms targeting early interven-
tion and management of both minor and major depression
occurring in later-life need to shift from purely diagnostic models
toward those which incorporate early screening and management
of underlying aetiological risk factors as well as factors which
perpetuate symptom persistence (Naismith et al., 2009a). To-date,
there have been few studies that actively seek to reduce the
incidence of LoD. A limited range of studies has focused on broad
interventions such as increased mental health literacy and folate
supplementation (Christensen et al., 2011). Increasingly, a focus on
providing targeted non-pharmacological, novel supplements (fish
oils, folate) or traditional antidepressants to populations who are
at risk due to either prior depressive symptoms or presence of VRFs
has emerged (Cockayne et al., 2011; Walker et al., 2010). Since data
suggests that even mild depressive symptoms are risk factors for
later illness, approaches that utilise clinical disease staging may
also provide more effective frameworks for tracking the trajecto-
ries of illness progression and providing optimal periods for
intervention delivery (Naismith et al., 2009a). Providing education
regarding modifiable risk factors for healthy brain ageing
(including VRFs) may be one way in which older age groups
may become more cognizant of the factors which contribute to
cognitive decline, depression and dementia, and may offer
potential for prevention. Data suggests that older ‘at risk’ people
can benefit from such educational programs in terms of knowledge
(Norrie et al., 2011), though it is unclear whether such programs
translate into altered behaviour.
Clearly, if the disability associated with persistent depression in
later-life (with related cognitive decline and risk to dementia) is to
be averted, effective new interventions (e.g. pharmacological, non-
pharmacological and physical) need to be developed. Clearer
differentiation of the underlying pathophysiological models is
required to develop personalised treatments that will target the
deficits arising from dysfunction in the underlying circuitry.
Clinical trials need to be stratified more carefully, with regards to
underlying MRI parameters, neuropsychological function and
other neurobiological makers. In particular, older patients need
to be more clearly differentiated with regards to actual age of onset
of depression (i.e. early-onset grown old, versus genuine late-
onset). Additionally, innovative health service models that target
the specific (behavioural, cognitive, physical) needs of older
persons need to be designed and evaluated. The development of
such models for younger patients (McGorry et al., 2007) has
already had a profound effect on clinical research directions in this
cohort and is an excellent template for these later-onset disorders.
14. Summary and future directions
To-date, neurobiological research in LLD has provided invalu-
able insights into the key pathophysiological factors that underpin
this clinical disorder. In particular, it is increasingly clear that there
is a need to focus attention on the pathways to depression that
emerges for the first time in later-life. These data strongly
implicate fronto-subcortical regions in the aetiology and perpetu-
ation of this disorder. This model only partially overlaps with other
neurobiological models that have been developed for younger
patients with depressive disorders. Specifically, the key role of
disruption of subcortical and hippocampal elements in older
patients (as compared with other areas of frontotemporal cortex) is
emphasized.
This review has also highlighted the pronounced role depres-
sion plays in the emergence of neurodegenerative disease. A
converging body of structural and functional neuroimaging
research implicates various aspects of PFC functioning in
neuropsychological and clinical symptoms while the basal ganglia
and hippocampus also appear to have specific clinical correlates.
More recent research has provided a preliminary insight into
potential changes in the synaptic complex, neurometabolite
changes, and astrocytic markers of disease, and although more
work is required, some data has linked HPA functioning,
 S.L. Naismith et al. / Progress in Neurobiology 98 (2012) 99–143
inflammatory and glial markers to depressive symptoms and
illness trajectories. Concurrently, research conducted largely in
clinical samples has begun to unravel likely gene candidates that
now need further examination and validation in larger genome-
wide association studies. Future models of LLD must synthesise
these findings into coherent testable frameworks within which the
interaction of these multi-layered systems can be examined.
Unfortunately, treatment options for patients with LLD are
under-evaluated. Consequently, we are still somewhat faced with
limited efficacy data that relate to this specific age and syndromal
group (Mottram et al., 2006; Nelson et al., 2008; Pinquart et al.,
2006; Taylor and Doraiswamy, 2004). The same issues that are
challenging for younger cohorts (i.e. separation of response
between active and non-specific treatments, emergence of new
side-effect profiles with new treatments) are emerging as larger
numbers of older patients with depression receive active treat-
ments. Since the focus to-date has been largely on modifying
monoamine systems (typically serotonergic) for LLD, future
research focusing on other critical neurotransmitters is now
warranted. Examination of the value of treatments in these critical
periods may be enhanced by greater reference to personalised
treatment approaches that investigate individual patterns of
heterogeneity and treatment responsiveness as well as the more
traditional approaches of pooling group data (Insel, 2009b).
Further development of targeted physical treatments (e.g. direct
and indirect brain stimulation techniques) is also deserving of
specific evaluation.
For older people, more emphasis must be placed on evaluating
the role of informational, psychological, behavioural and other
social interventions. This is particularly relevant given the large
number of role changes that older people encounter, as well as
factors such as grief and bereavement, onset of concurrent physical
health problems, lack of physical activity, changes in the sleep and
circadian system, increasing social isolation and the disability
directly attributable to other medical difficulties. Certainly, current
evidence suggests that psychosocial treatments are likely to have
superior benefits to medication in those with depression and
dementia (Banerjee et al., 2011). Similarly, in those with cognitive
decline and disability (Alexopoulos et al., 2011; Mowszowski et al.,
2010; Naismith et al., 2011a), psychological therapies show
promise.
Despite the significant advances made in identifying aetiolo-
gical contributors to LLD, the true challenge facing mental health
research is the capacity to translate this basic biomedical
knowledge into enhanced health outcomes (Insel, 2009b). Future
research must aim to evaluate whether such knowledge can be
successfully applied to early intervention paradigms for the late-
onset mood and psychiatric disorders. Knowledge of relevant risk
factors should provide pertinent opportunities for early interven-
tion paradigms (Naismith et al., 2009a), particularly since we are
now beginning to understand how experience and biology interact
over the life cycle. Emerging neuroimaging, neuropsychological
and other neurobiological markers for illness onset and progres-
sion characterize the field; compared with other neuropsychiatric
disorders, this is a major advantage in terms of predicting
longitudinal course and assessing response to treatments. Fur-
thermore, since this last decade has witnessed major advances in
the field of neuroplasticity, it now seems apparent that rapid
reorganization can occur in the brain in response to negative, as
well as positive stimuli (Mahncke et al., 2006). In this sense,
paradigms for LLD need to incorporate prevention of risk factors
that confer common pathways to depression and dementia as well
as promotion of those factors that lead to healthy brain ageing.
Research has not yet addressed how health interventions
should ideally incorporate the various trajectories to illness onset
including multiple lifestyle factors (e.g. diet, exercise, social
131
support, sleep and circadian systems) as well as the more
commonly associated medical and vascular risks. Similarly,
emerging research focusing on gene–environment interactions
must be incorporated as comprehensively into neurobiological
models of late-onset disorders as it is for early-onset disorders.
Primary and secondary prevention strategies must increasingly
focus on how such strategies directly prevent or alleviate
detrimental impacts on brain functioning (Naismith et al.,
2009a). Indeed, the ‘translational gap’ between knowledge and
clinical practice remains wide and must be addressed if we are to
see public health impact (Insel, 2009b). The use of e-health
technologies (and other self-care strategies) may also provide a
viable way for early screening and management of depression.
Current trials are underway to evaluate such approaches (Cock-
ayne et al., 2011). Similarly, large-scale prevention and early
intervention trials are urgently required if we are to reduce the
burden of depression on medical and cognitive outcomes.
Ultimately, it is clear that improved earlier identification and
management of depression will be associated with lower preva-
lence rates of dementia, and consequently, enhanced independent
living, less reliance on formal and informal caring systems, lower
levels of disability and decreased health care utilisation.
Conflict of interest
Professor Hickie has led projects for health professionals and
the community supported by governmental, community agency,
and drug industry partners (Wyeth, Eli Lily, Servier, Pfizer, Astra
Zeneca) for the identification and management of depression and
anxiety. He has served on advisory boards convened by the drug
industry in relation to specific antidepressants, including nefazo-
done, duloxetine and desvenlafaxine, and has participated in a
multicentre trial of agomelatine. He has participated in Servier-
sponsored educational programs related to circadian-based
therapies.
Acknowledgements
A/Professor Naismith is supported by a Career Development
Award from the National Health and Medical Research Council of
Australia (NHMRC). Professor Ian Hickie, Dr Louisa Norrie and Ms
Loren Mowszowski are supported by an NHMRC Australia
Fellowship awarded to Professor Hickie.
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