Psychiatric Aspects of Parkinson's

Disease
Uwe Ehrt, Dag Aarsland
Disclosures

Curr Opin Psychiatry. 2005;18(3):335-341.

Abstract
Purpose of Review: Recently, there has been much interest and rapid progress in understanding the
neuropsychiatry of Parkinson's disease. This paper reviews the most important papers published during 2004 on
dementia and cognitive impairment, depression and psychosis in Parkinson's disease.

Recent Findings: Many new studies of cognitive impairment and dementia in Parkinson's disease have been
published during 2004. Cognitive impairment has been demonstrated even during the first 12 years after onset
of disease. Whereas executive and attentional impairment is typical, learning deficits occur early in some
patients. Both functional and structural imaging suggest that in addition to fronto-subcortical deficits, temporal
and parietal changes occur early as well. In the first large placebo-controlled trial, the cholinesterase inhibitor
rivastigmine improved cognition, daily functioning and psychiatric symptoms without worsening of parkinsonism.
The frequency and characteristics of depression, anxiety and hallucinations have been explored in several
studies. Unfortunately, there is still little scientific evidence available to guide the treatment of these important
aspects of Parkinson's disease, and adequately designed clinical trials are needed. Although subthalamic
stimulation, in addition to improvement of movement, is frequently associated with some affective and cognitive
improvement, permanent and significant worsening may occur in some. Future studies should aim at identifying
at-risk patients, as well as identifying the optimal pharmacological and stimulation treatments for individual
patients.

Summary: These findings provide a deeper understanding of the neurobiological substrate of cognitive
impairment and dementia in Parkinson's disease, and provide new information regarding the assessment and
management of dementia and other neuropsychiatric aspects of Parkinson's disease.

Introduction
In addition to the motor symptoms characteristic of Parkinson's disease, neuropsychiatric symptoms are common
and have important clinical consequences for the quality of life of patients, caregiver burden, and course of
disease. Assessment, investigation and treatment of the neuropsychiatric aspects of Parkinson's disease are
important to improve quality of life of patients and their caregivers, as well as to provide insights into the basic
neurobiology of neuropsychiatric disorders occurring in the context of neurological disease. In the recent past,
there has been much interest and rapid progress in understanding the neuropsychiatry of Parkinson's disease.
This paper reviews the most important papers published during 2004 on dementia and cognitive impairment,
depression and psychosis in this disease.

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Cognitive Impairment and Dementia

Next P

Dementia and cognitive impairment are common in Parkinson's disease and have
important clinical consequences.[1] In a prospective, community-based study,
Hobson et al. .[2*] found that the relative risk of developing dementia in
Parkinson's disease is five times that of controls, thus confirming previous
studies.[3] The close relationship between extrapyramidal and cognitive
disturbances was further demonstrated in another prospective community-based
study.[4*] Elderly subjects with mild parkinsonian signs but without Parkinson's
disease or dementia had a higher risk of developing dementia than those without
parkinsonian signs.
Few adequately designed studies of the course of cognitive function in
Parkinson's disease exist. In a large-scale longitudinal study of an unselected
cohort without dementia at baseline, the overall annual decline on Mini-Mental
State Examination (MMSE) during 8 years was one point. However, marked
variation was found, and those who were diagnosed with dementia declined at a
similar rate to patients with Alzheimer's disease (2.5 points per year). On the
other hand, a small subgroup without dementia had a negligible decline similar to
healthy control subjects.[5*] Dujardinet al .[6*] found that at time of diagnosis of
Parkinson's disease, executive dysfunction and memory impairment predicted
mild cognitive impairment 3 years later. Interestingly, using single photon
emission computed tomography, perfusion deficits associated with subsequent
cognitive decline were found in posterior cortical regions, supporting the
hypothesis that both fronto-subcortical and temporo-parietal changes contribute
to cognitive impairment even in early Parkinson's disease.

Relationship Between Parkinson's Disease and Dementia With

Lewy Bodies
Recently, there has been much interest in the relationship between Parkinson's
disease with dementia (PDD) and dementia with Lewy bodies (DLB), both
syndromes characterized by parkinsonism and dementia.[7] The clinical
presentation and brain changes are remarkably similar in DLB and PDD, but
there are subtle differences, which suggest that the disease mechanisms may
differ.[8] Mosimann et al .[9*] showed significant impairment of visual perception in
PDD, in particular in those with hallucinations. The pattern was similar to that of
DLB, but different from that of Alzheimer's disease patients. Imaging studies have
shown that although there is a loss of striatal dopamine transporters in both DLB

and PDD, there are regional differences: the characteristic rostrocaudal (caudateputamen) gradient in Parkinson's disease is flattened in DLB.[10,11*] However, the
regional pattern of cortical atrophy does not seem to differ between DLB and
PDD, both syndromes having widespread atrophy of frontal, temporal, parietal
and even occipital lobes.[12*]
Recent studies have identified several gene loci involved in the development of
Parkinson's disease.[13]In rare families, point mutations in the alpha-synuclein
gene give rise to autosomal dominant Parkinson's disease. While parkinsonism is
usually the presenting feature in familial Parkinson's disease, in some individuals
dementia is the presenting feature, and these cases show extensive cortical
Lewy body pathology. Thus, at least in some cases, Parkinson's disease and
DLB are genetically closely related. There is some indication of a 'dose-effect':
mutations, duplication or triplication of the a -synuclein gene lead to increasing
levels of a -synuclein expression, and a corresponding increased severity of
disease with regard to earlier onset and development of dementia and other
neuropsychiatric features.[14]
Conversely, there is no familial aggregation of Parkinson's disease and
Alzheimer's disease, suggesting that there are no major shared genetic
contributions to the causes of Parkinson's disease and Alzheimer's
disease.[15*] The genetic contribution to dementia in Parkinson's disease and
between Parkinson's disease and DLB is still unknown.

Mild Cognitive Impairment in Parkinson's Disease

Cognitive impairment occurs even in non-demented and early-stage Parkinson's
disease patients. Typically, impairment of executive, visuospatial and memory
functions has been reported, probably secondary to disturbance of frontosubcortical circuits.[16] Several recent studies replicated and extended the
previous literature. In the first community-based study to date reporting the
cognitive functioning of an incidence cohort with a mean duration of Parkinson's
disease of less than 2 years, Foltynie and co-workers[17**] found cognitive
impairment in 36%. In support of findings in a previous study,[18] they reported a
differential cognitive profile already at this early stage of disease: one subgroup
had an amnestic type, another a fronto-striatal deficit, and a third group had more
global cognitive impairment.[17**] This is consistent with functional[6*] and structural
imaging studies reporting frontal[12,19*] and hippocampal atrophy in non-demented
Parkinson's disease patients.[19*,20]

The study of speed of information processing (bradyphrenia) in Parkinson's

disease has been complicated by confounding by motor and high-order cognitive
demands. Using visual inspection time, which is not confounded by such
demands, cognitive slowing was shown in Parkinson's disease,[21]consistent with
a previous study.[22] No relation with levodopa treatment was found, suggesting
that other neurochemical systems, for example the cholinergic system, are
involved in information speed. This hypothesis was supported by the
improvement in reaction time after treatment with rivastigmine.[23**]
As in PDD, basic perceptual and semantic visual processing was found to be
impaired in early Parkinson's disease.[24] In addition, recent studies showed
deficits in decoding emotional stimuli,[25]verbal fluency[26] and other executive
subcomponents.[27] The differential contribution of fronto-subcortical and
hippocampal pathologies to the early cognitive deficits in Parkinson's disease
was recently shown in an elegant study from Finland.[19*] Using magnetic
resonance imaging, they found an association between hippocampal atrophy and
memory impairment, and between prefrontal atrophy and attentional impairment
in early, non-medicated, non-demented patients with Parkinson's disease.[19*]

Treatment
In addition to morphological changes related to dementia in Parkinson's disease,
such as Alzheimer-related changes and cortical Lewy bodies, neurochemical
deficits, in particular dopaminergic and cholinergic deficits, have been implicated
in the pathophysiology of cognitive impairment and dementia in the disease. [28,
29]
Although there is some indication that levodopa treatment can improve
cognition, the results are inconsistent and the issue is complex. The effect
depends both on the choice of tests as well as duration of disease and whether
there are motor fluctuations.[30] In a double-blind trial, the dopamine agonists
pramipexole and pergolide did not improve cognition in non-demented
Parkinson's disease patients.[31]
On the other hand, a sizeable literature supports the hypothesis that cholinergic
drugs may improve cognition as well as hallucinations.[32, 33] Emre et al .[23**] report
the first large, multicentre comparison of a cholinesterase inhibitor (rivastigmine)
in a double-blind, randomized placebo-controlled trial of patients with PDD.
Patients receiving rivastigmine responded better on the two primary outcome
measures, Alzheimer's Disease Assessment Scale Cognitive Subscale and
Clinical Global Impression of Change, as well as on all secondary outcome
measures, including Neuropsychiatric Inventory, activities of daily living,
executive functions and MMSE. The differences were moderate, however. More

patients in the rivastigmine group (17%) dropped out due to adverse events than
in the placebo group (8%), most commonly due to nausea. Objective assessment
of parkinsonism did not differ between the groups, although subjective worsening
of tremor was reported more often in the rivastigmine (1.7%) than the placebo
(none) arms.
A cross-sectional study[34*] reported for the first time an association between
elevated homocysteine and depression and cognitive impairment in Parkinson's
disease. Although there are many possible explanations for this finding, it cannot
be excluded that there is a causal effect, and thus lowering homocysteine may
prevent depression and cognitive decline in Parkinson's disease. In addition to
drug treatment, cognitive training may have a beneficial effect in cognitively
impaired subjects. In one of the first studies exploring the effect of cognitive
training in Parkinson's disease, Sinforiani et al .[35] included 20 Parkinson's
disease patients with mild cognitive impairment in a 6-week program consisting of
twelve 1-h sessions utilizing a computer-based training program. After completion
of the 12-week programme improvement was noted on three of the 10
neuropsychological tests. Interestingly, the improvement remained stable for 6
months. Although interesting, the interpretation of the study is difficult due to the
lack of a control group.[35]

Neuropsychiatric Complications of Subthalamic Deep Brain

Stimulation for Parkinson's Disease
EHRs: Which Do Physicians Like and Why

View Report >

Surgical therapies for Parkinson's disease are frequently complicated by

neuropsychiatric symptoms. In their review, Burn and Troster[36] reported that
depression, hypomania and apathy are not uncommon after subthalamic nucleus
(STN) deep brain stimulation (DBS). In a 3-year follow-up study of 77 Parkinson's
disease patients,[37*] marked psychopathology was reported in a considerable
proportion of patients: severe depression requiring hospitalization in one patient;
four suicide attempts and one suicide; hypomania during the first three months in
five patients; impulsive aggressive behaviour in two; and four patients suffered
from psychosis.

Although there are indications of cognitive impairment after STN DBS, the studies
have been difficult to interpret due to inconsistent results and methodological
limitations.[38] The most consistent finding is a reduction in verbal fluency.
Recently, one study,[39*] using a control group, reported mild impairment of
attention, language and memory, and significant impairment in one patient. Longterm studies have reported no change in global cognition after 1 [40] and
3[37*] years, suggesting that the effects of STN DBS on cognition are limited.
However, in individual patients, permanent and significant cognitive decline and
severe psychiatric complications may occur.[37*] Thus, careful management of
previous history and of pharmacological and stimulation treatments are required.
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