Cognitive Impairment in Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative movement disorder that is classically characterized by the motor symptoms of bradykinesia, muscle rigidity, resting tremor, and, in later stages, postural instability. It affects between 4.1 and 4.6 million people worldwide and is poised to double in prevalence in the next 20 years (Dorsey et al. 2007). This anticipated expansion is due to greater worldwide life expectancy, increased survival of affected individuals, and increasing diagnosis of previously unrecog­nized cases. Untreated, most patients become severely disabled or die 10 to 14 years after disease onset (Poewe and Wenning 1996). While medical and surgical therapies have substantially improved motor disability, there is an increasing recognition that nonmotor symptoms contribute greatly to disability and quality of life (Hely et al. 2005). These nonmotor manifesta­tions include sensory, psychiatric, autonomic, and cognitive disturbances. This  post will focus on cognitive impairment (CI) in PD.

Although James Parkinson originally reported that intellectual func­tion is preserved in the “shaking palsy” (Parkinson 1817), CI is now rec­ognized as a common and very problematic complication of PD (Emre et al. 2007). CI encompasses a spectrum of cognitive disturbance ranging from CI with no dementia (CIND) to frank PD-related dementia (PDD). CIND has been reported in 19% of newly diagnosed, untreated patients with PD, a twofold increase over similarly aged adults (Aarsland, Bron- nick, et al. 2009). In a prospective study of newly diagnosed PD patients, 57% developed CIND by 3-5 years and a further 10% were diagnosed with dementia (Williams-Gray et al. 2007). PD patients with CIND have increased risk of developing dementia (Janvin et al. 2006), analogous to the increased risk of Alzheimer’s dementia in non-PD patients with mild cognitive impairment (Petersen et al. 2001). Dementia is more common in patients with PD compared to age-matched controls, with studies report­ing a five- to sixfold increased risk (Aarsland et al. 2001; Hobson and Meara 2004). The point prevalence of PDD among PD patients in community based studies has been estimated to be between 25% and 30% (Aarsland et al. 2003; Buter et al. 2008; Riedel et al. 2008) . Prospective longitudi­nal studies of CI in PD have consistently demonstrated that PD patients are at high risk for dementia. Large, often community-based, studies in Norway, Germany, Australia, and the United Kingdom have reported high cumulative prevalence and incidence of PDD (Table 1 ).

Thus, development of dementia is to be expected in the vast major­ity of patients with PD, even more frequent than some motor complica­tions, such as dyskinesias (Muller et al. 2007). Of particular concern, the presence of dementia in PD is associated with nursing home placement (Aarsland et al. 2000), greater disability (Weintraub et al. 2004), greater caregiver distress (Aarsland et al. 1999), and mortality (Buter et al. 2008). Thus, it is important for the clinician to recognize CI as an important com­plication of PD, to treat it, and for the research community to assist in the development of better treatments.

The DSM-IV diagnostic criteria for dementia require the presence of impairment in multiple cognitive domains and that these cognitive impair­ments are associated with significant impairment in social or occupational functioning (American Psychiatric Association 2000) . These impairments must represent a decline from previous levels of performance or function­ing. We will use these criteria for our discussion of dementia in PD. In addi­tion, per current criteria (discussed further below [Emre et al. 2007]), PDD will refer specifically to patients who fulfilled criteria for motor PD one year prior to the development of dementia. In many PD patients with CI, the CI it is not sufficiently severe to compromise daily function. These patients will be classified as “cognitive impairment with no dementia” (CIND). CIND is also referred to in the PD literature as mild CI (MCI), but this term may cause confusion with the MCI observed in prodromal Alzheimer’s disease patients and thus for the sake of this review we will use the term CIND. PD patients with normal cognition are referred to as PD, nondemented (PDND).

PDD has an insidious onset and progression but the time to onset and rate of progression vary significantly between patients (Aarsland et al. 2004; Williams-Gray et al. 2007). CIND is present in some patients at time of PD diagnosis (Aarsland, Bronnick, et al. 2009). CIND may be a prodrome to frank dementia in some patients, although it is not currently clear whether all patients with CIND will progress to PDD (Janvin et al. 2006). In a lon­gitudinal study, the annual decline of the Mini-Mental State Examination (MMSE) score was 2.3 points in PDD patients compared to less than 1 point in PDND patients and healthy control subjects (Aarsland et al. 2004).

Cognitive Features

PDD is associated with a variety of cognitive deficits including the domains of executive function, attention, visuospatial function, and memory.

Generally the profile for cognitive domain impairment is different in PDD than observed in other dementias such as AD, although these differences are less obvious in severe dementia due to the eventual impairments in almost all cognitive domains. In PDD and PD-CIND, executive dysfunc­tion and attention are perhaps the most consistently reported deficits, while memory and language dysfunction are much less prominent in PDD than in AD (Watson and Leverenz 2010). For example, in a large study of 488 PDD patients and 488 AD patients, the neuropsychological profile accurately predicted 75% of the diagnoses. While both groups demonstrated memory impairment, the AD group performed significantly worse on memory mea­sures. The tests with the greatest discrimination between the two groups were a measure of orientation (dependent on memory), in which the AD group performed most poorly, and a measure of attention, in which the PDD group showed the greatest deficits (Bronnick et al. 2007). Executive function, high-level cognitive skills involved in regulating behavior and monitoring other cognitive processes, is also reported to be frequently impaired cogni­tive domain among PD patients with CI (Caviness et al. 2007). Patients with PD also perform more poorly on visuospatial tasks. Memory impairment, although less severe than in AD, is a frequent feature of PDD. However, in PDD and CIND, memory recall is reportedly more impaired than memory recognition, unlike AD in which both are impaired (Emre et al. 2007; Watson and Leverenz 2010).

There is some heterogeneity of the neuropsychological profile in PDD and subtypes of dysexecutive, amnestic, and mixed CI have been pro­posed (Lewis et al. 2005). Subtypes have also been reported in PD-CIND including amnestic, single-domain nonamnestic, and mild multidomain impairment (Janvin et al. 2006). The pathophysiologic significance of this variability in neuropsychological profile is not clear, but certainly raises the possibility of differing underlying pathologies (Leverenz et al. 2009).

Behavioral Features

PDD is associated with several behavioral changes including depres­sion, apathy, hallucinations, and delusions. These neurobehavioral symp­toms predominate in later disease, are difficult to treat, and are associated with reduced quality of life (Aarsland et al. 1999, 2007; Hely et al. 2005; Schrag, Jahanshahi, and Quinn 2000). Often overlooked in PD, depressive symptoms can be confused with motor findings (psychomotor retardation mistaken for bradykinesia and masked facies) and somatic complaints (fatigue and sleep disturbance are common to both disorders). In addi­tion, demented patients may have increased difficulty articulating their mood-related symptoms. Depressed PD patients demonstrate diminished global cognitive performance and specifically have shown impairment in the cognitive domains of naming and verbal memory (Fernandez et al. 2009). Executive functions have also been shown to be impaired in depressed nondemented PD patients (Santangelo et al. 2009). It is unclear whether the primary cause of poor performance was depression, intrinsic CIND, or a third factor (such as common neuropathology) causing both CI and depression. It is unknown whether these mood changes are the result of coping with a chronic, debilitating illness or whether they may be inherent changes due to underlying PD neuropathology. PDD and PD- CIND patients should be screened for depression and, when appropriate, treated both pharmacologically and behaviorally.

Apathy is also very common in PD and, while frequently associated with depression, it can occur independently (Oguru et al. 2009). In a four- year population based, longitudinal study, greater than 60% of PD patients reported apathy (Pedersen et al. 2009), as measured by the Neuropsychi­atric Inventory (Cummings et al. 1994). Dementia and depression were both found to be risk factors for apathy (Pedersen et al. 2009). Apathy has also been linked to frontal and visuo-constructional deficits ( Santan- gelo et al. 2009), suggesting a cognitive underpinning of this symptom. It is clinically important to differentiate apathy from depression as the pharmacologic and behavioral management can differ. For example, anti­depressants have been shown to improve depression in PD, while acetyl­cholinesterase inhibitors may improve apathy (Devos et al. 2008; Figiel and Sadowsky 2008).

Psychotic symptoms are common in PD; in particular, visual halluci­nations are reported in up to 74% of 20-year PD survivors (Hely et al. 2008)   .  In contrast, less than 10% of autopsy-confirmed AD patients, with­out coexistent Lewy bodies, suffer from hallucinations, indicating an asso­ciation between hallucinations and Lewy body pathology (Tsuang et al. 2009)   .  Visual hallucinations are much more common than auditory, olfac­tory, or tactile hallucinations, although all forms may occur (Diederich et al. 2009). Visual hallucinations in PD patients are often well formed, taking the shape of people, animals, or objects. They can be adverse effects of dopaminergic treatment, particularly dopamine agonists (Goetz et al. 2001)   , but also result from the underlying disease (Fenelon, Goetz, and Karenberg 2006, . Delusions appear to be less common than hallucina­tions in PD and, when present, often co-occur with hallucinations and CI (Marsh et al. 2004; Kulisevsky et al. 2008). Delusions are often of a para­noid or jealous nature and are associated with increased caregiver burden (Marsh et al. 2004).

PD patients can suffer from a wide variety of sleep disturbances; among these, rapid eye movement sleep behavior disorder (RBD) may be particularly associated PD and other disorders associated with Lewy body pathology (Boeve et al. 2003). RBD is characterized by loss of normal muscle atonia during REM sleep resulting in complex, sometimes violent, movements. Several studies have suggested an association between RBD and PD-CIND with the majority of PD-CIND patients also suffering from RBD (Gagnon et al. 2009; Vendette et al. 2007); notably, another group has not confirmed this association (Yoritaka et al. 2009).

Risk Factors

In addition to CIND and RBD (discussed above), several other risk fac­tors have been identified for development of PDD. Older age has been consistently associated with increased risk for dementia in PD (Aarsland et al. 2001; Riedel et al. 2008; Hely et al. 2008; Williams-Gray et al. 2007). This association with age may result from an increased susceptibility to dementia, an increased risk of co-morbid dementia from other causes such as AD or cerebrovascular disease, or likely both. Greater disease sever­ity and longer duration of disease, factors correlated with each other and with age, are also linked to development of dementia (Aarsland et al. 2001; Riedel et al. 2008). Lower education attainment has been reported among PDD patients (Riedel et al. 2008). Other clinical features associated with the development of PDD are a nontremor-predominant motor phenotype, poor pentagon copying, and impaired semantic fluency (Williams-Gray et al. 2007 ).

Diagnostic Criteria

In the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), PDD is categorized as dementia due to a general medical condition and defines dementia in terms of functional impairment due to CI (American Psychiatric Association 2000). More specific criteria were proposed by the Movement Dis­orders Society (MDS) Task Force in 2007 (Emre et al. 2007) (see Table 2).

The core features include the development of dementia in the con­text of already established motor PD, as determined by the UK Parkin­son’s Disease Society Brain Bank criteria (Gibb and Lees 1988) . The CI must be a decline from premorbid performance and affect two or more of the following four cognitive domains: attention, executive function, visuo-constructive ability, and memory. CI must be sufficiently severe

Table 2

Features of Parkinson’s Disease Dementia

Core diagnostic features Diagnosis of Parkinson’s diseaseDementia of slow onset and progression developing greater than one year after onset of Parkinson’s disease and characterized byImpairment in at least one cognitive domainA decline from pre-morbid level of functionCognitive deficits sufficiently severe to impair daily functioningAssociated clinical features Cognitive FeaturesAttention impairedExecutive functions impairedVisuo-spatial processing impairedMemory impairedLanguage function largely intactBehavioral features 1 . ApathyPersonality changeMood changeHallucinationsDelusionsSomnolenceFeatures that make PDD diagnosis uncertain Co-morbid abnormalities that can contribute to cognitive dysfunction but are not sufficiently severe to cause dementiaUncertain time-course between onset of motor symptoms and dementiaFeatures suggesting alternative cause of cognitive impairment Cognitive symptoms arising in context of systemic disease, intoxication, or mood disorder.Clinical and imaging features suggestive of vascular dementia Source: Table adapted from Emre et al. 2007

to impair daily function (in social, occupational, or self-care domains) independent of functional impairments from motor or autonomic symp­toms. Supportive criteria include the presence of typical behavioral fea­tures (depression, apathy, anxiety, delusions, hallucinations, or excessive daytime somnolence) and absence of features suggesting alternative diagnoses. Criteria for probable and possible PDD were delineated. This assessment is based on history and clinical and cognitive examinations.

The MDS criteria specify that dementia must arise in the context of an established PD diagnosis (Hughes et al. 1993). This condition serves

to distinguish PDD from dementia with Lewy bodies (DLB) and other dementias (including Alzheimer’s dementia, AD). DLB is diagnosed when dementia either precedes or occurs within one year of onset of PD motor symptoms and when other core symptoms such as fluctuations and visual hallucinations are present (Emre et al. 2007; McKeith et al. 2005).

The MDS has subsequently proposed a two-tiered system for PDD diagnosis (Dubois et al. 2007). Level 1 is designed for clinicians without expertise in neuropsychological assessment who require simple, practi­cal diagnostic criteria and brief neuropsychological measures. A proposed algorithm for this level includes (1) diagnosis of PD by Queen, s Square Brain Bank criteria (Hughes et al. 1993); (2) PD onset at least one year prior to onset of dementia; (3) decline of global cognitive efficiency as evi­denced by MMSE (Folstein, Folstein, and McHugh 1975) score < 26; (4) CI severe enough to impair daily life (e.g., based on caregiver questionnaire or questioning patient about medication regimen); (5) impairment in two of the four cognitive domains most impacted in PDD: attention as assessed by months reversed (Shum et al. 1990) or serial sevens (Folstein, Folstein, and McHugh 1975), executive function as measured by phonological ver­bal fluency (Benton and Hamsher 1989), visuo-constructive function such as clock drawing (Sunderland et al. 1989) or MMSE pentagons (Folstein, Folstein, and McHugh 1975), or memory as demonstrated in three-word recall (Folstein, Folstein, and McHugh 1975) (see Table 2). There should be an absence of major depression, delirium, or other confounding cause of dementia. Level 2 involves extensive neuropsychological and behav­ioral testing and is appropriate when more detailed neuropsychological information is required because of diagnostic uncertainty in Level 1 or for research purposes.

Ancillary Diagnostic Evaluations

PDD must be distinguished from other forms of dementia because treat­ment and prognosis differ according to etiology. The American Academy of Neurology (AAN) recommends structural brain imaging, with either noncontrast computerized tomography (CT) or magnetic resonance imag­ing (MRI), to exclude structural lesions in demented patients (Knopman et al. 2001) . Neuroimaging studies have found structural lesions in 5% of demented patients without clinical history or signs suggesting those lesions (Chui and Zhang 1997). In particular, subdural hematoma, normal pressure hydrocephalus, and brain tumor should be detected and treated appropriately. Other findings, such as vascular lesions or lesions sugges­tive of a Parkinson-plus disorder, may alter the diagnosis and course of
medical treatment. MRI studies in PDD have shown whole brain and regional cortical atrophy, but these changes overlap with those seen in other dementias and, thus, offer only limited contribution in PDD diagno­sis (see Emre et al. 2007 for review)

The AAN also recommends screening demented patients for depres­sion, vitamin B12 deficiency, hypothyroidism, and, if clinically suspected, syphilis. While these disorders can cause or contribute to a dementia-like syndrome (Knopman et al. 2001), more often they are co-morbidities of an underlying dementing disease such as AD and PD. Appropriate treatment of these can improve cognitive function even in the context of another primary etiology of dementia such as PD.

The pathological processes that underlie CI in PD are likely primar­ily related to the pathology linked to PD: Lewy bodies and Lewy-related neurites (Lewy Related Pathology, LRP). LRP is best detected utilizing immunohistochemistry for alpha-synuclein, the predominant protein component of this pathologic change of PD (Spillantini et al. 1997; Sch­neider et al. 2002). Pathologic studies using this technique to detect LRP in well-characterized PD patients who fulfilled criteria for PDD, that is, motor parkinsonism preceding dementia by one year or more, have found a high frequency of LRP in brainstem, limbic, and neocortical regions of the brain (Aarsland et al. 2005; Apaydin et al. 2002; Braak et al. 2005; Galvin, Pollack, and Morris 2006; Hurtig et al. 2000). All of these studies have found that the presence or severity of LRP in limbic and neocortical regions is associated with a clinical history of dementia in PD.

The contribution of other pathological processes such as Alzheimer’ s disease and vascular disease to dementia in PD are unclear. Some stud­ies have suggested that co-existent Alzheimer’s disease occurs in less than 10% of PDD patients at autopsy (Aarsland et al. 2005; Apaydin et al. 2002; Braak et al. 2005), while others have observed co-existent pathologic AD in 30 to 40% of PDD patients (Galvin, Pollack, and Morris 2006; Hurtig et al. 2000). Given the limited number of autopsy cases in each of these studies, fewer than 200 in total, it is not surprising that there is disagree­ment between these studies. One alternate method to examine this issue is to evaluate biomarkers linked to Alzheimer’ s disease pathology, specifi­cally cerebrospinal fluid (CSF) levels of Ap (senile plaques) and tau (neu­rofibrillary tangles). In AD multiple studies have consistently found that CSF levels of Ap are lower than normal and tau levels are elevated (Blen- now et al. 2010). At this point, it appears that CI in PD is associated with
lowered CSF Ap levels, similar to AD, but not elevated tau (Montine et al.

2010)    . These findings would appear to be most consistent with the neu­ropathological studies that have observed elevated Ap deposition in the brain of PDD patients, without significant coexistent tau deposition (i.e., neurofibrillary tangle) (Apaydin et al. 2002). Thus, the preponderance of clinical biomarker and neuropathologic data suggest that the majority of PD cases with CI do not have all the pathologic features of AD, but some AD-associated pathologic changes may play a role in the pathophysiol­ogy of CI in PD. Clinically, one can hypothesize that the subset of PD with predominant declarative short-term memory impairments might also have coexistent LRP and Alzheimer’s disease.

The contribution of vascular disease to CI in PD is even less well stud­ied. To the best of our knowledge there have been no systematic autopsy studies examining this issue. It is clear from autopsy studies in community- based autopsy samples that vascular disease is an important contributor to dementia in the general population (Sonnen et al. 2007; White et al. 2002). Given these findings it is likely that there are a subset of PD patients with CI who have both LRP and vascular pathology contributing to their deficits.

While the consensus appears to be that LRP drives the CI observed in PD, further research is necessary to further elucidate other potential contributors to CI in PD. This becomes particularly relevant as disease- specific treatments for Alzheimer’s disease and other neurodegenerative disorders become available.

While PDD and AD appear to have distinct neuropathology, both share a common cholinergic deficit. In AD, the deficit presumably arises from neurofibrillary tangle pathologic change in the cholinergic basal fore­brain, while in PDD the deficit is likely due to LRP in those same neural structures (Tiraboschi et al. 2000). Interestingly, Frederick Lewy’s original description of Lewy bodies was in the same cholinergic basal forebrain neurons, not in the dopaminergic substantia nigra. Given this, acetylcho­linesterase inhibitors (AChEi), originally designed to address the cholin­ergic deficiency in AD, can be rationally used in PDD.

To date only one large-scale placebo-controlled study has examined the use of AChEi in PDD (see Table 3). A 24-week study randomly assigned 541 patients with mild or moderate PDD to placebo or 3mg to 12mg daily oral doses of Rivastigmine (Emre et al. 2004). The primary outcome mea­sures were the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) (Rosen, Mohs, and Davis 1984) and Alzheimer) s Dis­ease Cooperative Study-Clinician’s Global Impression of Change (ADCS- CGIC) (Schneider et al. 1997). Secondary outcomes included other cognitive measures (MMSE, clock drawing, verbal fluency test, and a measure of attention), a behavior measure (neuropsychiatric inventory, NPI [Cum­mings et al. 1994]), and a metric for activities of daily living (ADL). In the 410 patients who completed the study, there was statistically significant improvement in all of the primary and secondary measures in patients treated with rivastigmine. There was clinically meaningful ADCS-CGIC improvement in 5% of patients on rivastigmine and worsening in 10% of patients on placebo, both favoring use of rivastigmine in PDD and similar to the benefit of this class of medications in AD. In an extension study, 273 patients (from both placebo and active drug groups) completed an addi­tional 24 weeks of open-label rivastigmine (Poewe et al. 2006). The group as a whole showed improvement in the ADAS-cog and subjects initially treated with placebo showed gains similar to the drug treatment group in the original study. Rivastigmine has also been shown to improve cognitive and behavior symptoms in DLB (McKeith et al. 2000).

Smaller studies using the other available AChEi medications done- pezil and galantamine have not consistently found positive cognitive or behavioral effects (Aarsland et al. 2002; Leroi et al. 2004; Ravina et al. 2005; Grace, Amick, and Friedman 2009). It is not clear if this indicates an actual difference in effectiveness between the different AChEi agents, or whether these studies were just too small to adequately detect the modest effects observed in the larger rivastigmine trial.

AChEi are associated with a number of adverse effects. In the study by Emre and colleagues (2004), patients treated with rivastigmine suffered nau­sea, vomiting, and tremor with greater frequency than those treated with placebo. Not surprisingly, there was also greater attrition in the rivastig- mine treated group. Another study using the same database reported that tremor exacerbation occurred only transiently during dose titration (Oertel et al. 2008). Transdermal rivastigmine has fewer gastrointestinal side effects (Winblad et al. 2007) and would appear to be a reasonable alternative to oral treatment of PDD, but the clinical effectiveness and side effect profile in PDD has not yet been specifically studied.

Memantine is an N-methyl D-aspartate receptor antagonist that is used to limit the potential negative effects of glutamate overactivity in neuro- degenerative disease. It has shown symptomatic benefit as mono-therapy in moderate to severe AD (McShane, Areosa Sastre, and Minakaran 2006) and also can be combined with an AChEi for a positive clinical effect in AD (Tariot et al. 2004). In a small (40 PDD cases) placebo-controlled
study combining PDD and DLB patients, memantine was associated with improved global clinical ratings, but other measures of cognition, behavior, and activities of daily living failed to demonstrate a benefit of treatment (Aarsland, Ballard et al. 2009). In another small study (N=25), memantine showed no benefit compared to placebo except that the memantine-treated group had greater deterioration after withdrawal of the drug (Leroi et al. 2009)   . In these studies, memantine was generally well tolerated with mild adverse events that were similar between treatment and placebo groups (Aarsland, Ballard et al. 2009; Leroi et al. 2009). These small studies are encouraging, but larger-scale studies are needed to better determine effi­cacy and tolerability.