Curr Psychiatry Rep (2012) 14:280–288
DOI 10.1007/s11920-012-0278-7
GERIATRIC DISORDERS (DC STEFFENS, SECTION EDITOR)
Depression and Cognitive Impairment in Older Adults
Sara L. Weisenbach & Laurie A. Boore & Helen C. Kales
Published online: 24 May 2012
# Springer Science+Business Media, LLC 2012
Abstract Late life depression (LLD) is a heterogeneous
illness with high rates of treatment resistance. Cognitive
impairment is common in the context of LLD, and LLD
may be a prodromal symptom and/or potentially a risk factor
for dementia. This manuscript reviews the most recent re-
search into the cognitive deficits associated with LLD and
risk of conversion to dementia in the context of LLD. We
discuss potential moderators and mediators of cognitive
deficits in LLD, including demographic and clinical varia-
bles, in addition to brain structure and function. Potential
interventions for cognitive symptoms of LLD are reviewed.
We conclude with a discussion of the broader implications
of what is now known about LLD, and how this might be
applied toward improved prognosis and models for effective
treatment.
S. L. Weisenbach (*)
Department of Psychiatry,
University of Michigan Medical School,
2101 Commonwealth Boulevard, Suite C,
Ann Arbor, MI 48105, USA
e-mail: sarawrig@med.umich.edu
L. A. Boore : H. C. Kales
Department of Psychiatry,
University of Michigan Medical School,
4250 Plymouth Road,
Ann Arbor, MI 48109, USA
S. L. Weisenbach : H. C. Kales
Geriatric Research, Education, and Clinical Center,
VA Ann Arbor Healthcare System,
Ann Arbor, USA
H. C. Kales
Center for Clinical Management Research,
VA Ann Arbor Healthcare System,
Ann Arbor, USA
Keywords Late life depression . LLD . Elderly . Cognition .
Dementia . Neuropsychological abnormalities . Mechanisms
of cognitive deficits . Interventions for cognitive impairment .
Treatment resistance
Introduction
Individuals with late life depression (LLD) frequently pres-
ent with comorbid cognitive symptoms. While cognitive
deficits are common among patients with LLD, there is a
great deal of cognitive symptom heterogeneity, with some
patients displaying performance that is equivalent to con-
trols, and others exhibiting substantial deficits that may
meet criteria for mild cognitive impairment (MCI) or de-
mentia [1, 2]. Since the development of the vascular depres-
sion hypothesis 15 years ago [3], there has been increasing
interest in:
1. The specific neuropsychological deficits accompanying
LLD
2. The mechanisms of cognitive deficits in LLD and their
related structural and functional abnormalities
3. The possibility of treatment interventions for these cog-
nitive deficits
In terms of the underlying neuropsychological deficits
observed, previous studies have demonstrated that, while
LLD patients perform more poorly than controls across a
variety of cognitive measures, processing speed and execu-
tive dysfunction are particularly deficient [4–6]. While
memory decrements are observed, they may be secondary
to executive dysfunction [6]. Cognitive deficits are known
to persist even following remission of active depression
symptoms [7], and for some patients, may signal the beginning
Curr Psychiatry Rep (2012) 14:280–288
stages of a neurodegenerative process (see Wright and
Persad [8]).
With the advent of more refined technologies for the de-
tection of early, developing neural dysfunction, we have
learned more about how brain structure and function relate
to the cognitive deficits observed in LLD. Researchers now
have the capability to investigate white matter integrity
through not only quantification of white matter lesions, but
also to evaluate the disruption of white matter pathways using
diffusion tensor and magnetic transfer resonance imaging.
Examination of how atrophy of specific structures, such as
the hippocampus, relates to cognitive decline in LLD contin-
ues to be of relevance. There has also been increasing utiliza-
tion of functional MRI (fMRI) in samples of LLD patients;
both with regard to activation to task and functional connec-
tivity. Through such seminal work, the field is gaining a better
understanding of the mechanisms of cognitive deficits and
prediction of cognitive decline among patients with LLD.
There is also an emerging body of literature on interven-
tions targeting the cognitive symptoms of LLD, although
this is an area in which we are likely to see more growth as
we gain a better understanding of the mechanisms implicat-
ed in cognitive dysfunction in LLD. This manuscript will
provide a review of the most recent research (studies pub-
lished in the last year) into the cognitive deficits observed in
LLD, potential mechanisms underlying these deficits, and
interventions designed to minimize cognitive decline. It
concludes with a discussion of the limitations of the litera-
ture to date and suggestions for future research.
Underlying Neuropsychological Abnormalities
Patients with LLD, and even those with dysthymic disorder
and subsyndromal depressive symptoms, tend to display a
“subcortical profile” on neuropsychological testing including:
1. Poor learning and recall, but good cued recall and
recognition on memory testing
2. Poor executive functions, processing speed, and verbal
fluency
3. Intact visuospatial skills and orientation [9, 10]
Elderkin-Thompson and colleagues [10] assessed 112
unmedicated older adult outpatients with late-onset major
depressive disorder (MDD) and 138 healthy comparison
subjects. MDD patients had a poorer performance than
controls on indices of executive function, attention, and
processing speed, as well as on measures of verbal learning
and verbal and nonverbal recall. However, there were no
group differences in recognition or retention, implicit learn-
ing, or language fluency. The authors concluded that this
pattern of performance (i.e., normal retention and recogni-
tion, but deficient learning and recall) is suggestive of an
281
intact medial temporal explicit memory system for encoding
and consolidation, but poor executive functioning. Impor-
tantly, intact executive functioning is required for efficient
learning of new stimuli, such as through the creation of
semantic categories on recall memory.
Executive dysfunction has been associated with poor per-
formance in instrumental activities of daily living (IADLs)
among LLD patients [11]. Execution of many IADLs requires
problem-solving abilities. A study of 2,812 older adults par-
ticipating in a cognitive training program demonstrated that
depressive symptoms were associated with poor ability to
problem-solve everyday tasks, and that this relationship was
mediated by learning and memory and reasoning abilities (one
aspect of executive functioning). It is important to note that
learning and memory abilities were measured using total
recall of verbal material, which, as previously described,
involves an executive functioning component [12].
Despite known neurobiological substrates of LLD, some
investigators have raised the question as to whether subop-
timal effort might play a role in the cognitive deficits ob-
served among LLD patients. A recent study by Benitez and
colleagues [13] assessed 40 veteran outpatients with a diag-
nosis of MDD, in addition to 140 patients classified as being
mildly or severely depressed according to the Geriatric
Depression Scale (GDS [14]) relative to 58 nondepressed
controls and 168 patients classified as normal on the GDS.
All veterans were administered the Test of Memory Malin-
gering (TOMM [15]; a measure of effort) and the Repeat-
able Battery for the Assessment of Neuropsychological
Status (RBANS [16]). The LLD group had a poorer perfor-
mance than controls across all RBANS indices except
Visuospatial/Constructional. When patients who had failed
the TOMM (i.e., 47 nondepressed controls, 64 depressed)
were removed from analysis; however, the overall perfor-
mance was only marginally significantly different between
the two groups. As the authors note, it is important to
recognize that executive functioning was not assessed in
this study. Further, LLD patients who met criteria for MCI
were excluded from the study, likely resulting in a sample of
LLD patients with minimal cognitive impairment, and not
necessarily comparable to most of the samples of LLD
patients studied, many of whom putatively included patients
with MCI. Thus, although poor effort may contribute to
findings of cognitive deficits among LLD patients, it is
likely not the primary factor.
Clinical and Demographic Predictors of Cognitive Deficits
in LLD
Identifying predictors of cognitive deficits or decline among
patients with LLD is crucial for the development of more
individualized treatment regimens and better determination
of illness prognosis. Toward this end, a number of recent
282
studies have investigated how variability in symptom presen-
tation or course of illness predicts cognitive outcomes.
Hall and colleagues [1] measured how specific symptom
clusters on the GDS (dysphoria, apathy, meaninglessness,
and cognitive impairment) predicted performance on a num-
ber of neuropsychological domains among 272 patients with
Alzheimer’s disease and 356 controls. Although subjects with
MDD or significant depressive symptoms were excluded, the
cognitive impairment subscale was related to poorer executive
functioning and memory recall, while the apathy subscale was
negatively associated with a measure of attention and psycho-
motor speed. These relationships were stronger for women
than for men, and among women, the meaninglessness sub-
scale additionally predicted verbal fluency performance.
Sleep disturbance in LLD patients may also predict cog-
nitive functioning. Among 44 patients with significant
symptoms of depression (18 meeting MDD criteria), greater
duration of nocturnal awakenings was associated with poorer
performance in verbal and visual learning and response inhi-
bition, and poor sleep efficiency was associated with poorer
problem-solving, in addition to performance in the other
aforementioned domains, even after controlling for depression
severity and sleep apnea [17].
The course of LLD may also itself predict cognitive func-
tioning over time. A study of 281 participants enrolled in the
Longitudinal Aging Study Amsterdam with significant symp-
toms of depression at baseline were assessed with a cognitive
screening battery. Depressive symptoms were re-assessed
every 5 months for 6 years, and subjects were divided into
those with a remitting, those with a fluctuating, and those with
a chronic course of LLD. Findings demonstrated an indepen-
dent association of processing speed with a chronic course of
depressive symptoms, in comparison to individuals showing
a remitting or fluctuating course, even after controlling for
vascular risk factors [18].
Cognitive problems can persist following remission of
LLD, however, and variability in clinical presentation of cog-
nitive symptoms may suggest particular pathophysiological
processes potentially underlying LLD. Yeh and colleagues [2]
compared 130 patients with remitted LLD with 100 controls
on a comprehensive battery of cognitive tasks. Reduced per-
formance on measures of information processing speed and
memory were independently associated with remitted LLD,
after controlling for age, education level, and sex. In addition,
among the LLD group, 28.5% met criteria for amnestic MCI
(aMCI; memory score of≤1.5 SD below same-age peers), and
23.8% for non-amnestic MCI (naMCI; performance in at least
one nonmemory domain that is≤1.5 SD below same-age
peers). Those with aMCI were more likely to have a late-
onset depression and ventricular atrophy, while those with
naMCI had a greater degree of vascular burden.
Interestingly, cognitive symptoms during LLD may also
predict remission of depression symptoms. In one study of
Curr Psychiatry Rep (2012) 14:280–288
70 older adults with MDD, performance on a measure of
semantic fluency positively predicted remission of symp-
toms over 12 weeks of treatment with escitalopram [19].
Semantic fluency is a specific executive function, and these
findings are consistent with a prior study of executive dys-
function predicting poor remission rates in LLD [20].
Depression as a Prodromal Symptom and/or Risk Factor
for Dementia
With some exceptions, there is increasing agreement among
epidemiological studies that for a subset of older adults,
depression can represent the first symptom of a neurodegen-
erative process (see Wright and Persad [8] for a review). A
meta-analysis of studies examining the risk of progressing to
dementia when symptoms of depression are noted during
old age yielded a relative risk of 1.16 to 3.50 [21]. Whether
lifetime history of depression is an actual risk for developing
dementia later in the clinical course is less clear, with some
studies supporting depression as a predictor of later dementia
(see Wright and Persad [8] for a review). A recent longitudinal
study by Chan and colleagues [22] suggests that depression in
the context of MCI is an independent risk factor for progres-
sion to dementia. Three hundred and twenty-one community-
dwelling Chinese older adults studied were assessed over a
2-year period, and results demonstrated that of all neuropsy-
chiatric symptoms assessed at baseline, only depression was
demonstrated to be a risk factor for progression to dementia,
with an odds ratio of 2.40. Another multi-site study of 6,376
postmenopausal women without cognitive impairment at
baseline identified a nearly two-fold greater risk of MCI and
incident dementia during approximately 5.5 years’ follow-up
among women with a history of depressive symptoms (prior
to baseline), after adjustment for demographic, lifestyle, and
vascular risk factors, assessment center, hormone therapy
assignment, baseline cognition, and antidepressant therapy.
Current symptoms of depression (at baseline) were related to
the development of MCI, but not to dementia [23]. Thus,
some recent studies with large samples provide rather con-
vincing evidence that history of depression, at least later in
life, is a risk factor for cognitive decline and dementia, among
individuals with and without baseline cognitive impairment.
The Mechanisms of Cognitive Deficits in LLD
and their Related Structural and Functional
Abnormalities
Vascular Burden
It is now generally accepted among investigators of LLD
that a relationship exists between cerebrovascular dysfunc-
tion and geriatric depression, such that areas of ischemia,
Curr Psychiatry Rep (2012) 14:280–288
particularly in fronto-striatal pathways, place older adults at
greater risk of experiencing depressive symptoms [24, 25].
For instance, a recent study of 1,655 patients with MCI
revealed that those with neuropsychiatric features, including
depression, were more likely to have cerebrovascular dis-
ease [26]. As such, there is growing interest in identifying
individuals at risk of cerebrovascular compromise, in the
hopes that early intervention may circumvent future depres-
sive episodes, and incident dementia as well as other com-
plications resulting from vascular effects. One such known
risk factor is hypertension. A study by Hajjar and colleagues
[27] studied 4,700 subjects over 12 years and found that
hypertension at baseline increased the risk of concurrent
impairments in mobility, cognition, and mood, which in turn
increased the risk of disability and mortality. This study
measured cognition with one brief measure that incorporates
executive functioning, processing speed, and attention, al-
though there is growing interest into whether vascular bur-
den has an impact on specific cognitive domains, but not
others. For example, Schneider and colleagues [28] studied
94 community-dwelling LLD patients and found that after
controlling for depression severity, cardiovascular risk fac-
tors were associated with cognitive control and attention,
but not memory or verbal fluency.
Diffusion tensor imaging is a newer tool that can be used
to study the integrity of white matter pathways by mapping
diffusion of water molecules along axonal projections. In a
study of 36 older adult patients with history of depression
and 25 controls, executive dysfunction was associated with
reduced white matter integrity of the anterior thalamic radi-
ation and the uncinate fasciculus. Slow processing speed
was related to the reduced white matter integrity of the
genu of the corpus callosum, while poor episodic mem-
ory was correlated with reduced white matter integrity of
the anterior thalamic radiation, the body and genu of the
corpus callosum, and the fornix [29]. Together, these
studies suggest that cerebrovascular compromise is common
among patients with LLD and is associated with cognitive
performance.
Gray Matter Volume Loss
There have been many studies of gray matter volume loss in
LLD, with investigations demonstrating gray matter volume
reductions in the frontal, temporal, and parietal regions, as
well as subcortical structures, relative to controls [30–34].
These studies have typically used voxel-based morphometry
and region of interest approaches. A recent study by Lim
and colleagues [35] measured cortical thickness, which is
reported to be more selective than earlier methods for detect-
ing atrophy, to investigate gray matter changes in LLD [36].
Drug-naïve patients with a history of late-onset depression
(n048) were compared with healthy controls (n047), and
283
were found to have decreased cortical thickness in the
rostral anterior cingulate, the medial orbitofrontal cortex,
the dorsolateral prefrontal cortex, the superior and middle
temporal cortex, and the posterior cingulate cortex, in addi-
tion to reduced hippocampal volume (HV). Further, among
the LLD patients, memory performance was associated with
cortical thickness in a number of regions, including the
medial temporal cortex (known to be critical to intact mem-
ory function), while executive functioning performance was
associated with the thickness of several frontal regions, in
addition to the insula. HV was associated with verbal flu-
ency performance.
There has been a particular interest in studying the role of
the hippocampus in the cognitive decline observed among
LLD patients. In one study of 36 older adults with a history
of depression relative to 25 controls, right HV was nega-
tively related to episodic memory, but not to executive
functioning or processing speed [29]. Steffens and col-
leagues [37] demonstrated a greater decrease in left HV
among 90 LLD patients, relative to 72 controls over 2 years.
Reduction in HV bilaterally during the 2-year period among
LLD patients was associated with a subsequent decline in
performance on the MMSE, with no significant associations
demonstrated for controls. One source of controversy, how-
ever, concerns whether HV decreases are a state effect,
rather than a permanent trait of patients with LLD, even
after achieving remission. While the latter study did not
address the question of remission, it is assumed that a
number of patients in the study achieved remission over
the 2-year period, and depression severity was used as a
covariate in analyses. A smaller study by Hou and col-
leagues [38] measured HV at baseline and (on average)
at a 21-month follow-up among 14 patients with remit-
ted LLD (who had had one previous episode of late-
onset depression) and 10 healthy controls. While bilat-
eral HV was smaller at baseline among the remitted
LLD patients, right HV volume increased at follow-up,
and this increase was related to improved performance
on a brief measure of executive functioning, processing
speed, and attention. At the same time, decrease in left
HV volume was related to a decline in MMSE score.
Both of these studies assessed only group differences.
However, the findings imply intra-individual variability
with the LLD samples. For some individuals, HV may
actually improve following remission and antidepressant
therapy, perhaps through neurotrophic effects of antide-
pressant therapy, and relationships with brain-derived
neurotrophic factor (BDNF), which is known to mediate
age-related hippocampal atrophy and memory impair-
ment [39]. For others who are in the beginning stages
of a neurodegenerative process, HV may decline over
time, potentially associated with conversion to dementia
[40].
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fMRI Challenge
There have been a handful of studies utilizing BOLD fMRI
in LLD patients to examine abnormalities in neural function
in response to tasks. The specific tasks employed across
studies have varied, but have generally sought to engage
circuitry important to emotion processing and executive
functioning. While the sample sizes employed have typical-
ly been quite small, findings have demonstrated abnormal
patterns of activation in fronto-striatal and fronto-limbic
pathways, relative to controls [41–43]. To date, only one
known study has followed subjects longitudinally over a
period of years, to assess whether baseline activation differ-
ences predict the course of cognitive symptoms in depres-
sion. Wang and colleagues [44] found that among 23 LLD
patients, those with decreased activation in the anterior
cingulate cortex, hippocampus, inferior frontal cortex, and
insula were more likely to show persistent cognitive impair-
ment following 2-year follow-up. These regions have been
implicated in executive functioning, and abnormalities in
these areas have also been associated with the development
of dementia.
Historically, fMRI studies have been conducted separate-
ly from anatomical studies, so that the relationship that
structural integrity disruption might have to the functional
abnormalities observed has been unclear. However, a recent
study by Aizenstein and colleagues [45] examined whether
white matter hyperintensity (WMH) burden is associated
with BOLD response to an affective processing task in 33
LLD patients, relative to 27 nondepressed controls. While
the two groups demonstrated similar normalized WMH
volumes, WMH burden in LLD patients (but not controls)
predicted greater BOLD response in the rostral anterior
cingulate during face emotion processing. These findings
suggest that white matter compromise in LLD might have
an impact on circuitry important for emotion processing.
Resting State Functional Connectivity
fMRI is frequently used to understand the neural circuitry
underlying performance in specific kinds of tasks, as well as
abnormalities among patient groups when specific neural
circuitry is challenged. More recently, resting state fMRI has
gained popularity as a tool that can be used to understand
the functional connectivity of brain regions at baseline. It
has been shown that when no task is being performed in the
scanner, spontaneous low frequency fluctuations (SLFs) in
the BOLD signal occur at frequencies<0.01 Hz. SLFs are
related to anatomically and functionally plausible networks
showing stable functional relationships between brain
regions [46–48]. Functional connectivity analysis is appeal-
ing in the context of understanding disrupted networks
among patients with LLD. Unlike task-based studies, where
Curr Psychiatry Rep (2012) 14:280–288
regional activations have been shown to change following
treatment of LLD [42, 43, 49], abnormalities in SLFs among
LLD patients appear to:
1. Be stable over time
2. Remain abnormal following successful treatment of de-
pressive symptoms
3. Be similarly found among patients with remitted LLD
[41, 50]
There have been two recent functional connectivity stud-
ies among LLD patients. The first was a study of 11 LLD
patients with high comorbid anxiety (i.e., Hamilton Anxiety
Rating Scale [51] score of≥15 and a total Brief Symptom
Inventory [52] anxiety subscale score of≥1) and 8 LLD
patients with low anxiety. The DMN includes regions that
in healthy individuals have been found to be active when the
brain is at rest, and less engaged while working on a cogni-
tive task [53]. Using the posterior cingulate as a seed region
(i.e., the region from which to draw correlations with acti-
vation in other regions), results demonstrated higher func-
tional connectivity, among highly anxious patients relative
to mildly anxious patients, with posterior regions of the
DMN [54•]). The authors hypothesized that increased con-
nectivity in posterior regions of the DMN suggests that LLD
patients with high levels of anxiety might markedly scan
themselves and their surroundings, remaining vigilant to pos-
sible threats. They further suggested that decreased connec-
tivity with frontal regions might relate to utilization of fewer
techniques to regulate emotion [54•].
While the cerebellum has not historically been studied in
LLD, it has been shown that there are pathways to frontal
and limbic regions that are important to emotion and cogni-
tion (see Stoodley [55] for a review). In a study of 11
patients with LLD and 18 healthy controls, seeds were
placed in four cerebellar regions previously shown to be
important to executive, DMN, affective-limbic, and motor
networks. Findings demonstrated that LLD patients had
altered connectivity among all four of these networks and
the cerebral regions related to these functions. Findings
further suggested altered connectivity between the cerebel-
lum and cortical areas that may be independently associated
with cognition and emotion processing respectively. The
authors argue that including the cerebellum in the model
of LLD may lead to the development of alternative treat-
ments for LLD, such as neurostimulation of cerebellar
regions [56].
Two studies investigating the relationship between de-
pressive symptoms and memory performance among 15
patients with aMCI and 20 age-matched controls provide
further support for the separation of pathways in LLD me-
diating cognitive and affective symptoms respectively. In
the first study, using the hippocampus as a seed region,
poorer memory performance was associated with decreased
Curr Psychiatry Rep (2012) 14:280–288
hippocampal functional networks, including in the left medial
prefrontal and superior frontal gyrus and posterior cingulate
cortex (network functionally positively correlated with the
hippocampus) and with bilateral inferior parietal cortices and
the right dorsolateral prefrontal cortex (network functionally
anticorrelated with the hippocampus). In contrast, negative
relationships were found between scores on the GDS and
connectivity of the hippocampus with positively correlated
hippocampal networks. There was additionally an interaction
between depression symptom severity and memory perfor-
mance in connectivity with the bilateral posterior cingulate
cortex, the superior frontal gyrus, the medial prefrontal corti-
ces, and the left middle temporal gyrus [57].
The second study used the amygdala as a seed region,
finding a positive relationship between memory perfor-
mance and connectivity with prefrontal cortical regions
bilaterally, and the middle occipital gyrus, the right inferior
parietal cortex, and the left middle temporal gyrus. GDS
scores were positively correlated with connectivity with the
bilateral posterior cingulate and middle temporal gyrus, and
the left dorsolateral prefrontal cortex. There were interactive
effects of the GDS and memory performance in the bilateral
posterior cingulate, the middle temporal gyrus, and the left
dorsolateral prefrontal cortex [58••]. Findings from both of
these studies further support independent networks associat-
ed with emotion and memory, in addition to the interactive
effects of depressive symptoms and memory functions [58••].
Interventions for Cognitive Decline in LLD
The advent of medications to symptomatically treat cogni-
tive impairment, such as acetylcholinesterase inhibitors and
excitatory amino acid receptor antagonists, has been met
with a great deal of enthusiasm by patients and physicians.
These medications are not disease-modifying, however,
have relatively modest effects, and generally only slow
progression of the illness for a limited period of time (see
Delrieu et al. [59] for review). In more recent years, there
has been a growing interest in intervening in cognitive de-
cline earlier, in the hope of preventing further decline and
conversion to dementia.
There have been two known studies published in the last
year that have provided potential avenues for treatment of
cognitive decline in the context of LLD. The first study
tested the efficacy of a combined psychoeducation and
computerized cognitive training on subsequent cognition
among 41 patients with a lifetime history of MDD (with
currently normal to mild symptoms). Patients were assigned
to treatment (n024) or wait-list control (n020). The inter-
vention lasted for 10 weeks and utilized a group format of
less than 10 patients. Patients assigned to the treatment
group displayed improved performance following treatment
285
on tests of visual memory and verbal memory retention, but
not executive functioning, relative to wait-list controls [60].
A second study of registry data between 1995 and 2005
included 37,658 patients with a diagnosis of depression who
were exposed to antidepressants after discharge from a
psychiatric hospital found a decreased rate of dementia
and Alzheimer’s disease during periods of two or more
prescriptions of older antidepressants, compared with a pe-
riod of one prescription of older antidepressants. During
periods of continued use of SSRIs or newer non-SSRIs,
the rate of dementia did not decrease [61]. The mechanisms
underlying these findings are unclear, but this is clearly a
target for further study.
Finally, while there have been no known studies pub-
lished in the last year, it would be remiss not to mention
problem-solving therapy (PST), as it has been shown to be
effective for treatment of patients with LLD and comorbid
executive dysfunction. PST trains patients to become more
effective problem solvers and to increase engagement in
pleasurable activities, and has been modified for patients
with LLD [62]. While PST does not directly improve cog-
nitive symptoms associated with LLD, it provides mecha-
nisms for patients to compensate for executive dysfunction
and has been shown to reduce depressive symptoms and
disability in patients with comorbid LLD and executive
functioning declines [63–65].
Conclusion
In the last year, research into the sequelae and mechanisms
of LLD has further elucidated the specific cognitive deficits
associated with LLD and suggested which patients are at
greatest risk of further cognitive decline and conversion to
dementia. Newer tools for detecting variability in anatomi-
cal and functional neural pathways, and how disruptions in
normal cerebral connectivity might relate to cognition and
other symptom presentation are likely to burgeon in the
future. To date, neuroimaging research into LLD has been
limited by small sample sizes, which decreases the power to
detect inter-individual variability in this heterogeneous ill-
ness. Few studies have been conducted longitudinally; thus,
the extent to which samples are composed of individuals in
the early stages of a neurodegenerative process is unclear.
There is also a great deal of variability in the kinds of
patients being recruited for studies of LLD. For example,
some samples are composed of those with both early and
late onset illness, which likely have distinct etiologies, ge-
netic influences and potentially different prognoses [66, 67].
Variability in the medication status of patients and the pres-
ence of an active illness state are also confounds that are
rarely addressed, and oftentimes difficult to address, in older
cohorts. Collecting large, well-defined samples of patients
286
with LLD will likely require multi-site investigations and
the utilization of tools that can be widely applied. This is
critical toward developing more individualized treatments
for LLD, which to date has been a difficult-to-treat illness,
often with a poor prognosis. Ultimately, it is the integration
of behavioral and neuropsychological measures, which pres-
ent greater variability, together with more direct measures of
neural function and structure, potentially with links to spe-
cific etiologies (e.g., genetic, vascular, endocrine, environ-
mental), that will provide a systems-level understanding of
the pathophysiology of LLD.
Disclosure Drs Weisenbach and Kales reported no potential conflicts
of interest relevant to this article.
Dr Boore has had travel/accommodation expenses reimbursed by
the American Association for Geriatric Psychiatry.
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