INTRODUCTION — Cognitive dysfunction is common in Parkinson's disease (PD). When severe, dementia often surpasses the motor features of PD as a major cause of disability and mortality.
While PD can coexist with other common causes of dementia, such as Alzheimer's disease and vascular dementia, dementia is increasingly recognized as a common feature of Parkinson's disease itself. The clinical characteristics and course of dementia, its pathological features, and the most appropriate treatment are areas of current investigation. Clinical features can generally distinguish between PD and other movement disorders associated with dementia. However, whether PD dementia (PDD) and dementia with Lewy bodies (DLB) are distinct disorders, or whether they represent different presentations of the same disease, is an area of debate and investigation [1].
This topic will discuss Parkinson's disease dementia. Other aspects of Parkinson's disease and dementia with Lewy bodies are discussed separately. (See "Clinical manifestations of Parkinson's disease", see "Management of comorbid problems associated with Parkinson's disease", see "Pharmacologic treatment of Parkinson's disease", see "Epidemiology; pathology; and pathogenesis of dementia with Lewy bodies", see "Clinical features and diagnosis of dementia with Lewy bodies" and see "Prognosis and treatment of dementia with Lewy bodies").
EPIDEMIOLOGY — Dementia is a common feature of Parkinson's disease (PD). In community-based studies of PD, the prevalence of dementia has been found to be as high as 41 percent [2]. A meta-analysis of 27 studies largely drawn from academic centers found a mean prevalence of 40 percent; however, this study did not distinguish Parkinson's disease dementia (PDD) from dementia with Lewy bodies (DLB) [3]. In a review, using exacting criteria to identify 24 studies from the literature, 31 percent of 1767 PD patients were found to have dementia [4]. In the same study, PD dementia was found to account for 3.6 percent of all cases of dementia in the population.
Incidence rates may better describe the association of PD and dementia. In prospective cohort studies, incidence rates for dementia in patients with PD are consistently estimated at 95 to 107 per 1000 patient years, a rate almost five- to sixfold higher than controls [5,6]. In one eight-year follow-up study, the cumulative incidence of dementia in PD was found to be as high as 78 percent [7].
Older age, age at onset of PD 60 years, duration of PD, and severity of parkinsonism may impact the incidence of dementia in PD [2,5-10]:
In a community-based study, the prevalence of PD with dementia (PDD) in the general population was 787 per 100,000 for those 80 years, while the prevalence for those <50 years was zero [2].
In a population-based study, 37 percent of patients whose PD began after the age 70 years were demented, compared with 9 percent of patients whose symptoms had begun before 70 years [10]. After 5 years of follow-up, the prevalences had risen to 62 and 17 percent, respectively.
In a prospective follow-up study evaluating the effect of disease duration, a 26 percent prevalence of dementia was noted at baseline in 224 patients with a mean disease duration of 11.5 years [7]. The prevalence of dementia was 52 percent four years later, and 78 percent eight years later. The mean PD duration at the onset of dementia in this study was 14 years.
In a population-based study, the relative risk (RR) for dementia was 9.7 in elderly (72 years), high-severity (Unified Parkinson's Disease Rating Scale, UPDRS >24) PD patients, compared with young, low-severity patients [11]. Young, high-severity patients and elderly, low-severity patients were not at higher risk of dementia compared with the reference population, suggesting that age and PD severity interact to increase the risk of dementia.
However, even patients with mild PD may suffer from cognitive impairment that does not meet criteria for dementia (see "Cognitive features" below) [12-14]. Patients with subtle parkinsonian signs such as rigidity, but without a clinical diagnoses of PD, have been found to exhibit signs of amnestic mild cognitive impairment (MCI) [12]. In two studies of patients with a new diagnosis of PD, MCI was common, in 24 and 36 percent, respectively [13,14]. Older age and severity of motor parkinsonism correlated with cognitive impairment. The prognostic significance of these findings is not yet known.
There may also be genetic risk factors for the development of dementia in PD.
Siblings, but not parents, of patients with PDD were three times as likely to develop AD compared with normal subjects [15].
A rare hereditary syndrome of juvenile parkinsonism with dementia has been linked to a region on chromosome 1p and to a mutation in an ATPase gene [16].
Both the epsilon 2 (e2) and epsilon 4 (e4) alleles of the apolipoprotein gene have been implicated as possible risk factors for PDD [17-19]. However, a meta-analysis of studies examining this association found a significant association of PDD and apolipoprotein e4 but not e2 [20]. The investigators cautioned against firm conclusions regarding the association because of potential publication bias and heterogeneity of source data. A subsequent publication reported that in a population in which strict criteria were used to exclude comorbid AD and other dementia types, there was no association between PDD and APOE genotype [21].
NEUROPATHOPHYSIOLOGY
Neuropathology — The anatomic and pathologic basis of Parkinson's disease dementia (PDD) is not fully understood. Magnetic resonance imaging (MRI) and neuropathologic studies demonstrate more prominent global brain atrophy in PD patients with dementia than those without [22-24]. Patients with PD without dementia have similar rates of brain atrophy as do controls. One MRI study found that these changes are most prominent in limbic and paralimbic structures, especially the anterior cingulate gyrus [23].
Neuropathologic staging in PD uses the observation that there is to some extent a relatively predictable neuroanatomic spread of Lewy body pathology. This is initially most prominent in the olfactory system and lower brainstem, then progresses to involve the midbrain structures. In later stages, other brain structures are involved, including the cortex. The neuropathologic stage of PD correlates with the severity of both motor parkinsonism and dementia [25].
In the past, dementia in PDD has been attributed to coexisting Alzheimer and vascular pathology. However, neuropathologic studies have found that the degree of Lewy body pathology (Lewy bodies and Lewy neurites) correlates better with cognitive decline and dementia than does the degree of Alzheimer pathology, which is relatively modest in these patients [26-28]. Studies correlating dementia with neuropathology in PD note a potential critical role for nuclei, which project diffusely to cortical and subcortical areas, limbic structures, and the neocortex [28]. Important exceptions are noted; some individuals have significant cognitive decline in the absence of cortical Lewy pathology, while others have normal cognitive function in the presence of widespread cortical pathology [25,29].
Whether the neuropathology of PDD differs from that seen in dementia with Lewy bodies (DLB), or whether both conditions exist on a continuum is not clear; there are few comparative neuropathologic studies [30,31]. Cortical Lewy bodies and Lewy neurites appear to substantially contribute to the pathologic substrate for dementia in both conditions [30,32,33]. One small study did find that neuronal loss in the substantia nigra was more significant in PDD than in DLB; other features including cortical Lewy pathology and Alzheimer pathology did not differ in PDD and DLB [34]. In contrast, an evaluation of brain pathology in 57 patients with DLB or PDD found that a longer duration of parkinsonism prior to dementia was associated with more pronounced cortical cholinergic deficits and less severe cortical Lewy body pathology [35].
Neurotransmitter systems — Cognitive dysfunction in PD is less a function of dopaminergic loss than are the motor symptoms [36]. Dopaminergic medication has mild, heterogeneous effects on cognitive performance and may improve short-term memory early in the disease but not in more advanced patients [37,38].
Cholinergic systems may be more important in the cognitive decline in PDD:
Loss of cholinergic neurons in the nucleus basalis of Meynert and decreased cholinergic activity in the cortex appears to be at least as significant in PDD as in AD [39-42]
Anticholinergic drugs often exacerbate cognitive deficits in PD patients
Cholinesterase inhibitors modestly improve cognitive function in PDD (see "Cholinesterase inhibitors" below)
CLINICAL FEATURES
Cognitive features — Early signs of cognitive impairment in patients with Parkinson's disease (PD) include executive dysfunction and visuospatial impairments [13]. Tests of face recognition, in particular, are impaired early in the course of PD [43]. Other measures of visuospatial function become impaired in more severe PD and are more impaired in those with, rather than without, dementia. All of these deficits may impair higher-level functioning well before patients meet criteria for dementia [44,45].
The prognostic significance of these early findings has not been as well defined for PD dementia (PDD) as they have for mild cognitive impairment (MCI) and Alzheimer's disease (AD) [46]. However, some studies suggest that early evidence of cognitive impairment in PD identifies a higher risk of future dementia [5,6].
Executive dysfunction is a hallmark feature of PDD. This syndrome consists of deficiencies in set shifting, attention, and planning [47]. In addition, visuospatial function appears disproportionately impaired in PDD compared with AD [43,48]. Memory deficits, while less prominent than in AD, do occur in PDD but appear to be related to retrieval of learned information, which is improved by cuing. Conspicuously absent in PDD is aphasia, apraxia, and severe memory loss, features that are more common in AD.
Comparison of neuropsychologic test profiles among patients with DLB, AD, and PDD revealed no differences between DLB and PDD [49,50]. AD patients were more likely to have significant impairment on memory testing, while patients with PDD and DLB were more likely to have visuoperceptive, visuoconstructive, and attentional deficits [49].
Neuropsychiatric features — Visual hallucinations are common in PD with and without dementia and can be identified in as many as 50 percent of patients [51,52]. The presence of visual hallucinations is strongly associated with cognitive dysfunction and to a lesser extent with rigidity and autonomic dysfunction [53]. A variety of antiparkinson's drugs, most notably anticholinergic agents, dopaminergic agents, and amantadine, can exacerbate visual hallucinations. In nondemented PD patients, those with hallucinations are more likely to develop dementia than are patients without this symptom [5,7,8,54].
Other manifestations of psychosis in PD include delusions, often paranoid and related to spousal infidelity and persecution. These also may be exacerbated by antiparkinsonian drugs. The neuropsychiatric features of PD are discussed in more detail separately. (See "Management of comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations).
PD patients with and without dementia are also subject to depression, anxiety, and sleep disorders [52]. Depression occurs in 30 to 40 percent and correlates poorly with degree of motor impairment [31]. Sleep disorders include sleep fragmentation, nightmares, and REM sleep behavior disorder. The latter is a parasomnia characterized by vivid dreams in REM sleep without the usual accompanying muscle atonia. This causes individuals to "act out" their dreams, especially when they are vivid or frightening. REM sleep behavior disorder occurs in 15 percent of patients with PD and may be even more common in patients with DLB [55]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on REM sleep disorder).
Cardinal motor features — Core motor features of Parkinson's disease include:
Brady- and akinesia
Rigidity
Resting tremor
Postural instability
Resting tremor is more specific to PD than are other parkinsonian features; however, PD patients with tremor as their predominant motor symptom are less likely to develop cognitive impairment than are those with more prominent postural instability and gait impairment [56,57]. Another characteristic of PD is the asymmetry of motor features early in the disease. (See "Clinical manifestations of Parkinson's disease").
Other features — Other signs of neurologic impairment are prevalent in patients with Parkinson's disease. These are summarized in the tables (show table 1 and show table 2) and discussed in more detail separately. (See "Clinical manifestations of Parkinson's disease").
Clinical course — Dementia typically occurs in the last half of the clinical course of PD, whereas it is often one of the presenting features of DLB. Similarly, hallucinations are a late-appearing consequence of PD or PDD but are seen early in the course of DLB and may be among the presenting features of the illness.
DIFFERENTIAL DIAGNOSIS — Parkinson's disease dementia (PDD) is one of a number of conditions that include dementia and parkinsonism as prominent features.
Dementia with Lewy bodies — The differentiation of PDD and Dementia with Lewy bodies (DLB) is somewhat arbitrary. In PDD, dementia occurs in the setting of well-established parkinsonism, while in DLB, dementia usually occurs before, at the same time, or very shortly after the development of parkinsonian signs. If parkinsonism is present for more than one year before the onset of dementia, it is officially classified as PDD. This arbitrary "one year rule" may be an artificial distinction; the length of time that parkinsonism precedes other symptoms in otherwise similar patients does not correlate with pathologic differences [58].
Other features that may help distinguish between PDD and DLB are a faster clinical decline and decreased levodopa responsivity for DLB compared with PDD [59]. Parkinsonian features are more likely to be bilaterally asymmetric and more severe in PDD according to most, although not all, studies [60]. Tremor is more common in PDD than DLB [61]. Significant fluctuations in cognition are common in DLB, but rarely occur in PDD.
In one study, volumetric analysis of MRI scans found that patients with DLB had more pronounced cortical atrophy than did patients with Parkinson's disease dementia (PDD) despite having a similar severity of clinical dementia [89]. However, it seems unlikely that this observation is sufficiently sensitive and specific to aid in diagnosis of DLB versus PDD in individual patients [90].
Despite these observed clinical trends, no individual symptom characteristic or test finding reliably distinguishes the motor parkinsonism of PD versus DLB. It remains uncertain even whether these are distinct disorders. (See "Clinical features and diagnosis of dementia with Lewy bodies").
Progressive supranuclear palsy — Progressive supranuclear palsy (PSP) is a rare syndrome that can mimic PDD early on. Distinctive early features of this disorder include a vertical supranuclear gaze palsy and prominent postural instability with falls [62,63]. The response to levodopa is typically poor, but about 20 percent of patients may have some improvement with L-dopa in early stages of the disease [62]. Bradykinesia and rigidity are typically symmetric in onset [64]. Behavioral changes: apathy, disinhibition, dysphoria, and anxiety are common [65]. (See "Dementia syndromes", section on Progressive supranuclear palsy).
Multiple systems atrophy — An umbrella term for olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome, multiple systems atrophy (MSA) commonly presents with parkinsonism. Other features can include dysautonomia, cerebellar ataxia, and corticospinal tract deficits. The prominence of these manifestations and the symmetry of onset, absence of tremor, and poor response to levodopa suggest this diagnosis rather than PDD [66]. The dementia of MSA is much milder than that seen in PSP or CBD, probably reflecting less cortical involvement in that condition [67].
Corticobasal degeneration — Patients with this condition (CBD) can have asymmetric parkinsonism including bradykinesia, rigidity, and postural instability. More distinctive features can include ideomotor apraxia, alien limb phenomenon, aphasia, and loss of cortical sensory function [66]. Absence of tremor and lack of levodopa response are typical for CBD and help to distinguish it from PDD.
Alzheimer's disease — Parkinsonism may develop in late stages of Alzheimer's disease (AD). However, the relative timing of the appearance of dementia and parkinsonism is usually obvious, such that this feature, in itself, does not confuse AD and PDD.
Alternatively, AD may develop in a patient with PD, as the two disorders are not rare. This might be hard to distinguish from PDD early on, but the ultimate appearance of cortical dysfunction, such as aphasia or apraxia, or a profound amnesic syndrome usually suggests the presence of the second dementing condition. Prominent neuropsychiatric symptoms, however, suggest that the dementia is due to PDD rather than AD [54].
Cerebrovascular disease — Infarctions in multiple vascular territories affecting periventricular and subcortical white matter, basal ganglia, and brainstem can produce dementia and a vascular parkinsonism. An abrupt onset of symptoms, predominant involvement of the lower extremities, a stepwise course, vascular risk factors, focal neurologic signs, pseudobulbar palsy, and evidence of vascular disease on neuroimaging suggest this diagnosis. (See "Etiology; clinical manifestations; and diagnosis of vascular dementia").
Other considerations — When cognitive impairment occurs in the setting of Parkinson's disease, clinicians should consider possibilities other than dementia. Depression and other neuropsychiatric symptoms are common in PD and may contribute to cognitive impairment. Motor impairments of PD, particularly physical inactivity and bradyphrenia, may lead to the appearance of dementia. Similarly, patients with PD should be screened for causes of delirium that can lead to superimposed cognitive impairment, usually presenting more acutely and with altered sensorium.
Patients with Alzheimer's disease or other dementias may be treated with neuroleptic drugs associated with extrapyramidal side effects. Valproate also has been associated with a syndrome of reversible parkinsonism and cognitive decline. (See "Pharmacology of antiepileptic drugs", section on Valproate). Because medication effects can be prolonged, even for a year or more, after medication discontinuation, a complete history of medication use should be elicited [66].
DIAGNOSIS — The evaluation of a patient with dementia first establishes the presence of cognitive impairment and provides a measure of its severity. The mini mental state exam (MMSE) cannot be solely relied upon to detect disabling cognitive impairment in Parkinson's disease dementia (PDD) because it is not very sensitive to executive dysfunction, a key feature of PDD (see "Cognitive features" above). Neuropsychologic testing is more sensitive for defining cognitive impairments.
Treatable causes of cognitive impairment and dementia should be excluded. In general, this evaluation includes a neuroimaging study (usually magnetic resonance imaging), and laboratory evaluations (eg, vitamin B12 level and thyroid function tests). This topic is discussed in more detail elsewhere. (See "Evaluation of cognitive impairment and dementia").
Because of the frequent comorbidity of depression in PD, screening for depression as an alternative cause or a contributor to cognitive impairment is recommended. The Beck Depression Inventory, Hamilton Depression Rating Scale, and the Montgomery Asberg Depression Rating scale have all had demonstrated utility in this setting [68-71].
There are no published clinical criteria for PDD as there are for dementia with Lewy bodies (DLB). The diagnosis of PDD is primarily based upon clinical history and examination, in which the diagnosis of dementia is made in the setting of established parkinsonism (of at least one year), and other diagnoses are excluded. There are no specific findings on either neuroimaging, neuropsychologic testing, or laboratory results that are useful in the positive diagnosis of PDD. While some neuropsychologic test features are more suggestive of PDD versus AD, their sensitivity and specificity is not defined, and at present there is little clinical imperative to make this distinction [67].
PROGNOSIS — Dementia in Parkinson's disease is associated with reduced patient and caregiver quality of life, reduced survival, increased risks of nursing home admission, and other neuropsychiatric symptoms [5,10,17,68,72-75]. Among a cohort of 180 patients with PD not demented at baseline, incident dementia was associated with a twofold increase in mortality over a mean four-year follow-up, even after controlling for severity of motor symptoms [73].
TREATMENT — The treatment of Parkinson's disease dementia (PDD) is symptomatic. No therapies have been shown to modify the course of the disease or influence prognosis.
Cholinesterase inhibitors — The treatment of dementia in PD centers on the use of cholinesterase inhibitors. Most studies of cholinesterase inhibitors in PDD have noted a mild to moderate benefit:
Rivastigmine was evaluated in a 24-week, double-blind, placebo-controlled study of 501 patients with mild to moderate PDD and was found to result in moderate improvement in dementia, mean improvement of 2.1 points on the Alzheimer's disease Assessment Scale-Cognitive Subscale (ADAS-cog) score compared with 0.7 point decline in the placebo-treated group [76]. Clinically meaningful improvements were seen in 20 and 14.5 percent in the treatment and placebo groups, respectively, while clinically meaningful worsening was observed in 13 and 23 percent. This suggests that overall, 15 percent of patients benefited from treatment [77].
A small double-blind crossover study of donepezil in 22 patients revealed only a nonsignificant trend toward improvement on the ADAS-cog in treated patients after 10 weeks of treatment; mini mental state exam (MMSE) scores were significantly better on treatment compared with placebo [78]. Another 14-patient, 10-week, double-blind crossover study also found improvement with treatment on MMSE [79]. An open-label study of donepezil that specifically utilized measures of executive function did note benefit in PDD [80].
Among other cholinesterase inhibitors, an open-label study suggested that galantamine is useful in treating PDD [81].
An additional potential benefit of cholinesterase inhibitor therapy in PDD is improvement in neuropsychiatric symptoms, such as hallucinations. This was seen in one trial and one open-label study [76,81]. However, increased dropouts due to worsened tremor, nausea, and vomiting were also reported [76,81]. (See "Treatment of behavioral symptoms related to dementia", section on Cholinesterase inhibitors).
Because of the presence of a modest benefit for acetylcholinesterase inhibitors, we suggest their use in PDD if the patient does not experience intolerable side effects. A more detailed discussion of the use of cholinesterase inhibitors in dementia is found separately. (See "Cholinesterase inhibitors in dementia"). When cholinesterase inhibitors are discontinued, they should not be abruptly terminated, if at all possible, but rather tapered to avoid sudden cognitive and behavioral worsening [82].
Psychosis — Visual hallucinations and other psychotic features can be treated with atypical antipsychotic agents. Some caution should be employed with these agents because of the risk of motor side effects in this population. Severe side effects, while not as common as in dementia with Lewy bodies, do occur in a substantial portion of patients with PDD [83]. (See "Clinical features and diagnosis of dementia with Lewy bodies", section on Neuroleptic sensitivity). Doses should be started at the lowest possible and titrated upward gradually.
Among the atypical antipsychotic agents, clozapine has the best established utility, with an extremely low risk of exacerbating parkinsonism, but has a risk of fatal agranulocytosis, requiring rigorous monitoring of the white blood cell count [68,69]. Quetiapine is also effective and has a more acceptable side effect profile [84,85]. Olanzapine doesn't clearly improve psychosis and may worsen motor symptoms [68]. Older, so-called conventional antipsychotic agents are much more likely to exacerbate motor parkinsonism and should be avoided in PDD. This topic is discussed separately. (See "Management of comorbid problems associated with Parkinson's disease", section on Psychosis and hallucinations and see "Treatment of behavioral symptoms related to dementia").
Motor parkinsonism — Treatment of motor parkinsonian symptoms is similar in PD with and without dementia. However, patients with PDD may be particularly susceptible to the neuropsychiatric side effects of dopaminergic medications; these may be dose limiting and/or require concomitant use of antipsychotic agents. Anticholinergic agents frequently exacerbate cognitive impairment and are generally avoided in patients with PDD. Observational studies suggest that L-dopa does not adversely affect cognition [86]. (See "Pharmacologic treatment of Parkinson's disease", section on Symptomatic therapy).
Patients with PDD are generally excluded from consideration for deep brain stimulation (DBS) therapy because of poor outcomes. As an example, in a study of 41 patients evaluated after suboptimal response to DBS, 20 percent of these patients had preoperative dementia [87]. On the other hand, in PD patients with mild or no dementia, accumulated evidence suggests that bilateral subthalamic DBS can result in small declines in measures of executive function and a moderate decline in verbal fluency [88].
SUMMARY AND RECOMMENDATIONS — Cognitive dysfunction and dementia are common in Parkinson's disease (PD).
The risk of dementia in patients with PD increases with age of onset, age of the patient, duration, and severity of the illness. (See "Epidemiology" above).
Neuropathologic studies suggest that Lewy body pathology rather than coincident Alzheimer's or cerebrovascular disease is responsible for dementia in most patients with PDD (PD dementia). (See "Neuropathophysiology" above).
The cognitive dysfunction of PDD is distinct from Alzheimer's disease. With PDD, memory impairment is less prominent early on, while executive dysfunction and visual spatial impairments are features that may be apparent and functionally limiting before the patient meets criteria for dementia. (See "Cognitive features" above).
Other disorders that produce dementia and parkinsonism include dementia with Lewy bodies (DLB), progressive supranuclear palsy, multiple systems atrophy, and corticobasal degeneration. PDD is distinguished from DLB by the onset of dementia in the setting of well-established parkinsonism of at least one year's duration. (See "Differential diagnosis" above).
The diagnosis of PDD is made by the determination of dementia in a patient with typical, well-established PD of at least one year's duration. Neuropsychological testing may aid in the diagnosis of dementia; laboratory studies and neuroimaging are performed to exclude other conditions. The mini mental state exam (MMSE) cannot be solely relied upon to detect disabling cognitive impairment in PDD because it is not very sensitive to executive dysfunction. (See "Diagnosis" above).
We suggest the use of cholinesterase inhibitors in patients with PDD (Grade 2B). These appear to confer a modest benefit for cognition in patients with PDD; evidence for improved neuropsychiatric symptoms is less convincing. (See "Cholinesterase inhibitors" above).
Patients with PDD may be more susceptible to neuropsychiatric side effects of antiparkinson medications. This may be dose limiting. We suggest avoiding anticholinergic medications in patients with PDD. We recommend using low-dose quetiapine or clozapine for treatment of psychosis when necessary (Grade 1B). Clozapine requires rigorous white blood cell monitoring. We recommend avoiding the use of older, conventional antipsychotics, which are known to exacerbate motor parkinsonism. (See "Psychosis" above).
The treatment of motor parkinsonism is similar to that for the patient with PD without dementia. An exception is that dementia is a relative contraindication for deep brain stimulation therapy. (See "Treatment" above).
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