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Kehagia 2013 Cognitive Impairment in PD The Dual Syndrome Hypothesis
Kehagia 2013 Cognitive Impairment in PD The Dual Syndrome Hypothesis
Abstract Introduction
Research into the heterogeneous nature of cognitive impair-
ment documented in patients with Parkinson’s disease (PD) Parsing the heterogeneous nature of cognitive impair-
has focused on disentangling deficits that vary between in- ment in Parkinson’s disease (PD) into ontologically
dividuals, evolve and respond differentially to pharmacolog- meaningful deficits entails establishing clear cognitive,
ical treatments, and relate differentially to PD dementia anatomical and neurochemical definitions for these def-
(PDD). We summarise studies conducted in our laboratory icits as independent and/or hierarchically related entities.
over the last 2 decades, outlining the incremental develop- In essence, our task has been that of interpreting neuro-
ment of our hypotheses, the starting point for which is our psychological variation between and within individual
early work on executive deficits mirroring fronto-striatal dys- patients and groups, at a single or multiple time points,
function. We present subsequent findings linking these def- employing pharmacological manipulations, neuroimag-
icits to a model of dopaminergic function that conforms to ing and analyses of genotypic variation to delineate the
an inverted curvilinear function. We review studies that in- nature of each of these deficits.
vestigated the range of dopamine-independent attentional The diversity of progressive neurodegeneration in PD
and visuospatial memory deficits seen in PD, demonstrating is secondary to the intracellular fibrillisation of !-synu-
that abnormalities in these domains more accurately predict clein, which is its major pathological hallmark, and ad-
PDD. We conclude with an exposition of the dual syndrome ditional neuropathological features may include vascular
hypothesis, which distinguishes between dopaminergically disease, Lewy bodies, neurofibrillary tangles and amy-
loid plaques more commonly seen in dementia. This im- coeruleus [3–5], dorsal raphé nuclei [6, 7] and cholinergic
pacts on the major neurotransmitter systems at uneven brainstem nuclei, particularly the basal nucleus of
rates and asymmetrically between individuals, rendering Meynert [8] (fig. 1).
analyses of cognitive impairment patterns particularly The evolution and heterogeneity of cognitive impair-
challenging: early nigrostriatal degeneration causes pro- ment in PD mirrors the complexity of the disease pro-
gressive loss of dopamine neurotransmission in a dorsal cess, in terms of the variable as well as the interacting
to ventral gradient within the basal ganglia [1], unevenly compromise of the catecholaminergic and cholinergic
affecting different fronto-striatal ‘loops’ [2] at different systems. Mild cognitive impairment (MCI) in the form
stages of the disease in all patients. Parallel deficits in the of executive and working memory deficits similar to
mesocorticolimbic dopamine systems originating in the those seen in frontal lobe-damaged patients is present in
midbrain also develop. Beyond causing pronounced do- up to 50% of cases; however, PD dementia (PDD), a dis-
paminergic disturbance, PD also detrimentally affects tinctive pattern of rapid cognitive decline leading to
the noradrenergic, serotoninergic and cholinergic sys- aphasia, apraxia and agnosia (thus resembling deficits
tems, by causing degeneration respectively of the locus seen in patients with temporal lobe damage and cortical
COPY
THIS
dementia), is only seen in perhaps as many as 10% of shown to be sensitive to frontal lobe lesions [23]. The tests
cases [9]. Indeed, PDD represents a superordinate aspect included the Stockings of Cambridge (SoC) test of plan-
of clinical heterogeneity due to its detrimental implica- ning (derived from the ToL test), intra-/extra-dimension-
tions for patient mortality and quality of life [10]. In this al (ED) set shifting, which is a test of shifting aptitude
review, we chart our progress over the last 2 decades us- between stimulus exemplars and higher-order perceptual
ing a quasi-chronological approach culminating in the dimensions, and the self-ordered Spatial Working Mem-
dual syndrome hypothesis, which captures the evolu- ory task of the Cambridge Neuropsychological Test Au-
tion in our understanding of cognitive dysfunction in tomated Battery (CANTAB; fig. 2) [24]. These studies re-
PD. vealed planning and spatial working memory deficits as
a function of disease severity in the PD groups, which
paralleled those seen in patients with frontal lobe exci-
Dopaminergic Amelioration of Executive Deficits sions.
Mirrors Fronto-Striatal Function Critically, we [22, 25] demonstrated specific beneficial
effects of dopaminergic medication on planning and spa-
Early research into the cognitive impairment patterns tial working memory, but not visual recognition memory
caused by PD revealed deficits across the cognition spec- (fig. 3), visuospatial paired associates learning (PAL; a de-
trum, in terms of visuospatial memory and learning [11– layed cued recall test) or ED set shifting, more clearly de-
14] and, prototypically, executive function including fining earlier findings of general cognitive amelioration
planning, problem solving and attentional shifting, on as a result of dopaminergic pharmacotherapy [26, 27] as
tests such as the Wisconsin Card Sorting Test and Tower specific improvements in executive function mirroring
of London (ToL) [15–20]. The PD dysexecutive syndrome fronto-striatal enhancement. These findings heralded a
exhibits similarities to the effects of frontal lobe damage, range of studies employing short-term withdrawal from
and its conceptualisation as a fronto-striatal deficit is well levodopa (L-DOPA), the dopamine precursor included in
exemplified by our early studies [21, 22], comparing the most therapeutic regimes. These studies extended dem-
performance of unmedicated and medicated PD patients onstrations of dopaminergic enhancement to other tasks
at different disease stages on a test battery previously sensitive to fronto-striatal dysfunction, including task
20
0.4
10 0.2
0 0
2 3 4 5 2 3 4 5
a Difficulty (moves) b Difficulty (moves)
40 100
SWM Recognition memory
Between-search errors
30 90
Percentage correct
Lack of effect
20 80
10 70
0 60
2 3 4 6 8 Sim. 0 4 8 16
c Difficulty (boxes) d Delay (s)
Fig. 3. Effects of L-DOPA medication withdrawal in PD. Significant impairments are observed in ToL perfor-
mance, as measured by latency (a) and accuracy (b; see also fig. 2) and self-ordered spatial working memory
(SWM) performance (c; see also fig. 2), but not in visual recognition memory (d), which is impaired relative to
age and IQ-matched controls. Sim. = Simultaneous matching. Reproduced from Lange et al. [25], with permis-
sion from the publishers.
switching in the face of stimulus interference [28, 29] and Dopaminergic ‘Overdosing’ Leads to Impulsivity
verbal working memory at the manipulation rather than
the retrieval phase of the task [30]. On this verbal work- Withdrawal studies were instrumental in revealing
ing memory paradigm, we found that impaired but not the role of dopamine neurotransmission in the fronto-
cognitively intact PD patients demonstrated specific re- striatal circuitry in forms of cognitive impairment in PD
ductions in dorsal fronto-striatal blood oxygenation lev- by demonstrating not only benefits, but also pernicious
el-dependent signal change using functional magnetic effects, of dopaminergic medication. Such effects were re-
resonance imaging (fMRI) [31], further emphasizing the ported initially by Gotham et al. [32] in terms of deterio-
case that these deficits have a locus within a dopaminer- ration in conditional learning, alongside improvements
gic fronto-striatal network. in alternating fluency. In one of the earliest findings in
support of a putative dopaminergic ‘overdosing’ theory,
Swainson et al. [33] found that medicated PD patients
showed a non-perseverative reversal deficit during prob- Given the tripartite division of the main midbrain do-
abilistic reversal learning similar to that seen in a group pamine pathways into the nigrostriatal, mesolimbic and
of frontal and temporal lobe lesion patients. In contrast, mesocortical systems, it would appear reasonable to as-
the L-DOPA withdrawn PD group surprisingly revealed sume that the mesocortical projection is additionally im-
unimpaired performance in the form of intact reversal plicated in aspects of cognitive impairment in PD, espe-
learning (fig. 4). In a replication of this result, Cools et al. cially in fronto-striatal deficits of working memory and
[28] demonstrated reversal deficits alongside improve- planning, consistent with preclinical evidence on the role
ments in task switching in patients tested on their normal of dopamine in normal cognitive function [41]. For in-
dopaminergic regime, and the opposite pattern following stance, improvements in spatial working memory and
withdrawal. These findings were extended to the Cam- planning conferred by L-DOPA are associated with de-
bridge Gambling Task, which is sensitive to orbitofrontal creased regional cerebral blood flow in the right dorsolat-
damage and where L-DOPA led to increased impulsive, eral PFC [42], suggesting that L-DOPA may enhance PFC
delay-averse behaviour in PD patients which was absent efficiency in PD. However, the locus of this enhancement
when the same patients were withdrawn from medication could well be in the caudate nucleus rather than the PFC
[29]. Both probabilistic reversal learning and the Cam- itself, with a consequent improvement of functioning
bridge Gambling Task rely on ventral fronto-striatal cir- arising due to dopaminergic enhancement within the
cuitry: the former is associated with blood oxygenation fronto-striatal ‘loops’ linking the cortex and striatum,
level-dependent signal change in the ventral striatum and rather than any isolated cortical or subcortical site.
inferior frontal cortex [34], and the latter with increases Moreover, instead of an obvious loss of cortical dopa-
in regional cerebral blood flow in the orbitofrontal cortex mine, 18F-fluorodopa positron emission tomography
[35]. Thus, considering the uneven gradient of dopamine (PET) studies have shown what appears to be a compen-
loss across the corticostriatal ‘loops’ in early PD, we hy- satory up-regulation in prefrontal cortical dopamine me-
pothesised that dopaminergic medication restores neu- tabolism in early (unilateral, Hoehn and Yahr stage I)
rotransmission in severely affected dorsal circuits, impli- compared to later (bilateral) stage PD [43, 44], possibly
cated in executive deficits of planning and working mem- reflecting the reciprocal relationship it often bears to the
ory, but putatively ‘overdoses’ relatively less affected activity of subcortical (mainly striatal) dopamine sys-
ventral circuits implicated in reward processing and tems [45, 46]. This up-regulation clearly complicates
Optimal
ing of typical forms of behaviour associated
with each loop after withdrawal of dopami-
nergic medication. Note on the extreme left,
tasks such as task set switching and spatial Too
working memory are mildly improved by low
dopamine medication. By contrast, on
gambling and reversal learning, tasks asso-
ciated with ventral frontal mediation, L- Motor Dorsolateral/ Lateral/ Inferotemporal
DOPA withdrawal significantly impairs b prefrontal orbitofrontal
performance. Reproduced with permission
from Swainson et al. [33] and the publishers.
analyses of the role of PFC dopamine in parkinsonian viduals, Val homozygosity compared with heterozygos-
cognition and could conceivably even mask impairments ity confers greater COMT efficiency, or more effective
stemming from striatal dopamine loss. Presumably, how- catabolic methylation of dopamine, thereby reducing
ever, a reduction in PFC dopamine levels eventually con- PFC dopamine levels. By contrast, Met homozygocity
tributes to the emergent cognitive deficit pattern as the renders COMT less efficient, leading to increased PFC
disease progresses from unilateral to bilateral and more dopamine levels (and putatively, enhanced PFC activity).
severe impairment. Although dopamine transporters play a predominant
These hypotheses are difficult to test using conven- role in the regulation of striatal dopamine, their relative
tional methods, but an opportunity to do so arose from absence in the PFC renders COMT activity in this region
the discovery of the catechol-O-methyl-transferase the major means of regulating dopamine neurotrans-
(COMT) polymorphism, for which a single methionine mission. A much simplified summary of the consider-
(Met) to valine (Val) substitution at residue 158 confers able literature stimulated by the findings of Weinberger
up to fourfold increase in enzymatic efficiency as a func- and colleagues [47, 48] in healthy individuals and pa-
tion of the number of Val alleles carried. In healthy indi- tients with schizophrenia holds that, in general, COMT
1.0
Prefrontal function
Val/Val
SZ/ Early PD
0 control
–0.5 Disease
progression
–1.0
Met/Met
–1.5
–2.0
Val/Val Val/Met Met/Met b Dopamine level
a COMT genotype
ToL
The performance of patients with PD is 8.5 8.5
contrasted with that of patients with 8.0 8.0
schizophrenia (SZ). Cross-sectional anal- 7.5 7.5
ysis of ToL planning performance in pa-
tients relatively early (!1.6 years; d) and 7.0 7.0
Val/Val Val/Met Met/Met Val/Val Val/Met Met/Met
later (61.6 years; c) in the course of PD
(n = 425), stratified by COMT genotype. c COMT genotype d COMT genotype
Fisher’s test: p = 0.001
Reproduced from Williams-Gray et al.
[52], with permission from the publishers.
polymorphism confers superior performance on tasks formance that included the dorsolateral PFC, frontopolar
sensitive to prefrontal function, such as working memo- and parietal cortex [51].
ry, as a function of the number of Met alleles carried. Met These findings were expanded upon in a separate co-
homozygotes outperform Val homozygotes [47, 48] in a hort study of 425 patients [52] which confirmed the orig-
pattern that conforms to an inverted U-shaped function, inal finding of SoC impairment in those patients with
analogous to the Yerkes-Dodson principle [49]. These more Met alleles relatively early in the course of the dis-
findings bear obvious implications concerning those as- ease (!1.6 years), compared with those later in the course,
pects of parkinsonian cognition mirroring prefrontal where the relationship was actually reversed (fig. 6c).
dopamine neurotransmission and raised the possibility These findings are readily interpretable in terms of a do-
of adopting a neurogenetic approach to further investi- paminergic optimum titrated according to the hypothet-
gating these deficits. ical inverse U-shaped function which is exceeded in ear-
In collaboration with Weinberger’s group, and in the ly PD: Met homozygosity may actually have detrimental
context of the Cambridgeshire Parkinson’s Incidence effects on SoC planning at a time when PFC dopamine is
from GP to Neurologist (CamPaIGN) cohort study which up-regulated, placing Val homozygotes, unusually, at an
we elaborate on later, 288 PD patients stratified by COMT advantage. If valid, this hypothesis predicts improve-
polymorphism were assessed, focusing in particular on ments for Met homozygote patients as their disease pro-
the CANTAB SoC test [50]. Surprisingly, Met homozy- gresses and the initially up-regulated PFC dopaminergic
gosity was associated with impaired planning accuracy in system eventually becomes compromised. Indeed, at the
PD, an effect especially magnified in male patients and 5-year follow-up of 70 of these PD patients, the initially
those on dopaminergic medication. A subsequent fMRI disadvantaged Met homozygotes actually exhibited dif-
study confirmed that Met-homozygote patients showed ferential improvement in planning performance over this
hypoactivation in regions underpinning planning per- time span compared with Val homozygotes (in whom no
p value
Age >72 –0.42
years
–0.27
Fig. 7. Predictive power of clinico-patho- ≥25
logical variables for dementia in PD; pen-
–0.38
tagon copying and semantic verbal fluen-
cy from the MMSE were the best predic- ToL <10
–0.38
tors. Reproduced from Williams-Gray et Beck Depression score >7
al. [52], with permission from the publish-
ers. UPDRS = Unified Parkinson’s Disease
Rating Scale; NART = National Adult
Reading Test.
vals, indicating deficits during registration, following the first to assess the incidence of PD and parkinsonism,
long-term administration of anti-cholinergic medication and the extent and natural history of cognitive deficits in
in PD [67], as well as detrimental effects on memory the ensuing patient cohort [50]. We identified five sub-
caused by the muscarinic antagonist hyoscine (scopol- groups of patients at disease presentation, who were im-
amine) in a group of PD patients, but not in a matched paired on (i) ToL, indicating fronto-striatal deficits, (ii)
control group [68]. Treatment with another muscarinic visual pattern recognition memory, indicating temporal
antagonist, trihexiphenidyl, has also been associated with lobe dysfunction, (iii) both ToL and pattern recognition
PD impairments on a visual associative learning task of memory, as well as (iv) a cognitively preserved subgroup
transfer generalisation [69]. and (v) a group of patients who demonstrated marked
cognitive impairment and had an MMSE score !24, in-
dicating dementia.
Contributions from Longitudinal Cohort Studies to In further studies on this patient cohort, we employed
Understanding Clinical Heterogeneity a data-driven approach using cluster analysis to separate
patients into groups characterised by internal cohesion
Most studies investigating the nature of cognitive and external isolation [71], as well as longitudinal assess-
dysfunction in PD employ prevalent cross-sectional co- ment [9] to assess the evolution of cognitive impairment.
horts of patients, usually screened for the presence of Both approaches identified a cluster of patients with mild
dementia using the Mini-Mental State Examination cognitive deficits and rapid disease progression, and an-
(MMSE) [70]. Such studies are thus inherently biased in other cluster of cognitively impaired patients with a non-
terms of patient selection, which limits their potential to tremor dominant, akinetic motor phenotype at presenta-
investigate more severe cognitive impairment in the tion with dopamine-unresponsive gait disturbance, po-
form of dementia. tentially indicating the impact of cholinergic deficits due
Large cohort studies have been instrumental in efforts to degeneration of the pedunculopontine nucleus [72].
to systematically address this aspect of cognitive hetero- The CamPaIGN study produced a striking finding of sig-
geneity. Using a community-based epidemiological ap- nificant clinical value given its prognostic implications: it
proach in a population of approximately 700,000 over a identified a patient phenotype indicative of early transi-
25-month incidence period, the CamPaIGN study was tion to PDD, which was older (172 years) at presentation
and performed poorly on two simple bedside tests of se- icit syndrome. We also showed that the H1/H1 MAPT
mantic fluency and copying overlapping pentagons from haplotype, but not COMT, independently predicted de-
the MMSE [9] (fig. 7). mentia onset.
Within the framework of the CamPaIGN study, and
in parallel to our neurogenetic investigations into COMT
polymorphism, we addressed genetic susceptibility fac- The Dual Syndrome Hypothesis
tors associated with cortical Lewy body pathology that
characterises PDD, namely !-synuclein and tau. Using Our approach to understanding the heterogeneity of
this candidate gene approach, Goris et al. [73] found a cognitive impairment in PD has employed a range of
robust association between the MAPT (microtubule-as- techniques in a large number of studies spanning 2 de-
sociated protein tau) gene and the rate of dementia in the cades. We have integrated these diverse findings along
incident cohort at the 3.5-year follow-up. In the Cam- with clinicopathological and diagnostic criteria in a com-
PaIGN cohort at the 5-year follow-up and an additional prehensive review [74], which permits a broad dichotomy
cross-sectional prevalent cohort, Williams-Gray et al. to be drawn between hypothetically independent but
[52] replicated the predictive utility of neuropsychologi- partially overlapping syndromes of MCI and dementia in
cal assessment of pentagon copying and semantic fluen- PD.
cy, reflecting temporal lobe function, but not phonemic The dual syndrome hypothesis differentiates between
fluency, sensitive to frontal lobe damage, in dementia. By two broad syndromes (fig. 8): (i) a profile of neuropsycho-
contrast, some of the ‘classic’ deficits within the fronto- logical deficit in non-demented PD patients with MCI
striatal cluster, for example, on SoC (i.e. ToL) planning, and a tremor-dominant phenotype on tests of planning,
were not predictive of progression to dementia, suggest- working memory and executive function reflecting fron-
ing at least two independent aspects of the cognitive def- to-striatal dysfunction, amenable to dopaminergic ame-
Disclosure Statement
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