Psychiatric Aspects of Parkinson's Disease

Uwe Ehrt; Dag Aarsland

Disclosures

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

In This Article

Cognitive Impairment and Dementia

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*] Dujardin et 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 (caudate-putamen) 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 fronto-subcortical 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

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. Long-term 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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