Introduction. Clinical manifestations

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1 Dementia in Parkinson disease Martin R Farlow MD ( Dr. Farlow of Indiana University received research grant support from AbbVie, Accera, Biogen, Eisai, Eli Lilly, Genentech, Roche, Lundbeck, Novartis, Suven Life Sciences Ltd, and Boehringer Ingelheim; fees from Accera, Allergan, AstraZeneca, Avanir, Axovant, AZ Therapies, Eli Lilly and Company, FORUM Pharmaceuticals, INC Research, KCRN Research, Kyowa Kirin Pharma, Longeveron, Medavante, Merck, Medtronic, Proclara, Neurotrope Biosciences, Novartis, Sanofi-Aventis, Stemedica Cell Technologies Inc., Takeda, United Neuroscience Inc., and vtv Therapeutics for consultancy, or advisory board/dsmb membership; and licensing fees from Elan. ) Originally released January 25, 1995; last updated May 31, 2016; expires May 31, 2019 Introduction This article includes discussion of dementia in Parkinson disease, dementia associated with Parkinson disease, dementia in Parkinson disease, and dementia with parkinsonism. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Parkinson disease dementia is clinically distinct from other forms of dementia, including Alzheimer dementia and vascular dementia. Although it shares many of the pathologic features of dementia with Lewy bodies, it remains a separate and distinct entity. Understanding the distinguishing features of Parkinson disease dementia is helpful for screening patients, offering evidence-based treatments, and providing valuable information to patients and their caregivers. Key points Parkinson disease dementia is a clinically distinct entity, separate from dementia with Lewy bodies, Alzheimer disease, vascular dementia, and other forms of neurodegenerative disease. Longitudinal studies have shown that the risk of Parkinson disease dementia increases with age, akinetic/postural instability forms of Parkinson disease, early hallucinations, early executive dysfunction, and duration of disease (63% after 12 years and 83% after 20 years). Attention (particularly fluctuations), visuospatial construction, and executive function are more impaired in Parkinson disease dementia compared with Alzheimer disease. In general, short-term memory and language are less impaired compared to Alzheimer disease. Patients with Parkinson disease dementia have a cholinergic deficit thought to be greater than that in Alzheimer disease patients. Cholinesterase inhibitors are approved as a treatment for Parkinson disease dementia and have shown benefit in terms of both cognitive function and behavioral function (including reduction in visual hallucinations). Historical note and terminology James Parkinson first described the shaking palsy, emphasizing the classic motor symptoms of Parkinson disease. Friedreich Lewy has commented on the mental impairment in many patients with parkinsonism, but cognitive performance and dementia in Parkinson disease have only received systematic study since the 1970s. In the late 1980s, clinicopathological studies identified a dementia syndrome with a substrate comprising widely distributed cortical and subcortical Lewy bodies, then referred to as dementia with Lewy bodies (McKeith et al 1996). Clinically, physicians began to separate dementia with Lewy bodies from dementia associated with Parkinson disease (also known as Parkinson disease dementia) based on different historical presentations and manifestations. The original hypothesis, which still holds true to today, is that dementia with Lewy bodies and Parkinson disease dementia are likely in the same spectrum of Lewy body disorders (McKeith and Burn 2000; Lippa et al 2007). This article primarily discusses Parkinson disease dementia, but references dementia with Lewy bodies in places when needed to better clarify the distinction between these 2 entities. Clinical manifestations Presentation and course

2 Clinical concepts and problems. On sensitive psychometric tests, virtually all patients with Parkinson disease are impaired relative to age-matched controls, even early in the course of disease. This most likely reflects weakening of dopaminergic input to cognitive circuits that include the basal ganglia. In early stages of Parkinson disease, cognitive deficits are mild and of uncertain clinical significance. Mild cognitive impairment in Parkinson disease patients is prevalent, can predispose to Parkinson disease dementia, and has defined diagnostic criteria (Litvan et al 2012). Despite this, evaluating cognition and interpreting performance in patients with Parkinson disease can be tricky because noncognitive factors may come into play. Depressed mood, confusion, hallucination, and agitation may affect motivation and attention and consequent performance on cognitive testing. Speech and motor disturbances may impair the speed and quality of responses. Cognitive performance may vary in patients who fluctuate on dopaminergic medications. In the "off" state, patients may be severely akinetic, rigid, and hypophonic, whereas at a peak dose in the "on" state, dyskinesias may impede performance. The issue of diagnosing Parkinson disease dementia is not straightforward. Alzheimer disease, the most common type of dementia, is considered to be the archetypal cortical dementia. Decline in memory acquisition is the earliest and most prominent feature, whereas deficits in language, calculation, constructional tasks, and problem-solving develop later as the illness progresses. Parkinson disease has traditionally been regarded primarily as a motor disorder, but cognitive impairment and dementia are common associated features. A common substrate in these disorders may be dysfunction of prefrontal brain regions with major anatomic and neurochemical connections to the basal ganglia. In Parkinson disease dementia or dementia with Lewy bodies, the brain pathology often includes subcortical (and some cortical) pathology, but may also include Alzheimer disease amyloid plaques and neurofibrillary tangles, producing a more complex or cortical pattern of dementia (Jellinger 1996). New criteria for Alzheimer disease that allow for earlier diagnosis when cognitive impairment in a single domain is accompanied by supportive biomarkers, and recognition that Alzheimer disease may begin with other deficits in executive or verbal functioning as well as amnesia, may also secondarily complicate diagnosis of Parkinson disease dementia (Knopman et al 2011; McKhann et al 2011). The concept of subcortical dementia nevertheless provides a framework for understanding cognitive changes in Parkinson disease dementia. Other complications arise when defining dementia in patients with Parkinson disease. The Diagnostic and Statistical Manual Revision IV criteria for dementia require cognitive decline of sufficient extent to interfere with social or occupational abilities (American Psychiatric Association 2000). In patients with advanced Parkinson disease, severe motor impairment may physically prevent patients from performing many daily activities in the absence of cognitive impairment. The clinician must judge whether functional deficits result from cognitive or motor problems, or both. Another approach to dementia classification recognizes the different patterns of cognitive loss. For example, subcortical dementia is defined as multifocal deficits as associated with vascular lesions, and avoids the issue of detecting and interpreting functional impairment (Cummings and Benson 1992). Dementia is diagnosed when there are deficits in 3 or more of the following areas: language, memory, visuospatial skills, personality, and complex cognitive abilities that include abstraction, judgment, and calculation. This approach depends critically on cutoffs for test scores and can over-diagnose dementia if patients score poorly on tests for reasons such as depression or low education. Clinical characteristics of Parkinson disease dementia. Three main categories of symptoms occur in Parkinson disease dementia: cognitive, motor, and behavioral. Cognitive decline typically begins and progresses gradually. Episodes of cognitive clouding are common in patients with Parkinson disease dementia. The episodes may arise spontaneously or they can be precipitated by medications, infections, dehydration, or electrolyte upset. The motor symptoms of parkinsonism in Parkinson disease dementia are usually severe. Behavioral symptoms in this disorder include hallucinations, delusions, depression, and REM sleep behavior disorder. Agitation is also common in more severe stages of this dementia. Although behavioral symptoms can result from medication side effects or concurrent medical illness, they usually lack an external cause. These symptoms often lead to the patient being institutionalized. Several clinical risk factors for Parkinson disease dementia include advanced age and late age at the onset of Parkinson disease (especially after 70 years), as well as severe motor findings (Possin and Kaufer 2010). Additional risk factors include coexisting depression, low verbal fluency, early executive dysfunction, and early onset of hallucinations (Katzen and Levin 1998; Giladi et al 2000; Aarsland et al 2003a). The risk of dementia does increase with the duration of Parkinson disease, being 60% after 12 years of follow up of 233 Parkinson disease patients and present in 83% of surviving patients followed up 20 years after diagnosis in a longitudinal study (Buter et al 2008; Reid et al 2011). Patients with akinetic Parkinson disease and postural instability and gait disorder have increased risk of dementia

3 when compared to a subgroup of patients with tremor dominant Parkinson disease (Burn et al 2003). About 30% to 40% of patients with Parkinson disease experience chronic dysthymia or depression at some point, which have a major impact on quality of life (Cummings 1992; Poewe 2007; Reijnders et al 2008). Features of motor impairment such as monotonous voice, masked facies, and poverty of movement may mimic depression. More specific symptoms include feelings of worthlessness, guilt, and loss of appetite. Depression in Parkinson disease does not correlate with dopaminergic deficiency; depressive symptoms are weakly related to the severity of motor dysfunction or to CSF reduced levels of dopamine metabolites. Depression in Parkinson disease may result from impaired mesocortico-limbic dopaminergic pathways or serotoninergic pathways, or be associated with frontal lobe dysfunction. Visual hallucinations of either simple or complex form are the most common psychotic symptoms in Parkinson disease dementia (Giladi and Treves 2000). Visual hallucinations have been shown to be specific for Lewy body pathology (Parkinson disease dementia and dementia with Lewy bodies) and occur rarely in progressive supranuclear palsy and multiple systems atrophy (Williams et al 2008). The incidence of visual hallucinations in Parkinson disease dementia is reported to be over 50% and similar to that reported in dementia with Lewy bodies (Diederich et al 2009). In a 20-year longitudinal follow-up study, 74% of patients with Parkinson disease eventually developed visual hallucinations, and a Kaplan-Meier plot shows that visual hallucinations and dementia develop concurrently in this cohort (Hely et al 2008). Patients hallucinate in both "on" and "off" states, and the hallucinations may recur over days, weeks, or even longer. In Parkinson disease dementia, the visual hallucinations are typically well-formed, vivid images of people or animals, and may incorporate bright colors and dramatic settings. They react variably to the visual hallucinations: some are not disturbed and may recognize the images as unreal whereas others find the visions threatening or distressing, and may incorporate them into delusional beliefs. Risk factors include old age, sleep disturbance, treatment with L-dopa, and cognitive impairment. Age and dementia appear to be the strongest risk factors; the dose of L-dopa is not necessarily higher in patients with hallucinations compared to those without (Sanchez-Ramos et al 1996). If lowering the dose of L- dopa eliminates hallucinations, this usually occurs rapidly over a day or two. Delusions are uncommon in Parkinson disease. When present, they are usually associated with hallucinations and dementia (Aarsland et al 1999a). Certainly, hallucinations in older patients should prompt a search for factors such as delirium, medication toxicity, stroke, or sensory impairment, especially visual impairment; however, these conditions rarely produce hallucinations that are formed and recurrent. Psychometric features of Parkinson disease dementia. Non-demented patients with Parkinson disease show subtle deficits on specific cognitive tests relative to age-matched controls. These include tests dependent on psychomotor speed, visuospatial abilities, and executive function (Lees and Smith 1983). A few studies have found more widespread deficits, also affecting areas such as naming and memory (Goldman et al 1998). Age may influence the pattern because studies that reported broader deficits usually assessed older patients. The extent of deficits in non-demented Parkinson disease patients relative to controls is small. There is a continuum of cognitive impairment in Parkinson disease, and it is difficult to assign absolute cutoff points for dementia. Patients with Parkinson disease dementia typically show deficits on tests of executive function, attention, visuospatial abilities, constructional abilities, and some impairment of memory (Emre 2003; Aarsland et al 2007; Emre et al 2007). Other aspects of cognition, such as language ability, praxis, orientation, long-term memory, and calculation, are relatively preserved. Brief cognitive tests such as the Mini-Mental State Examination do not adequately assess executive function. More detailed tasks that tap into frontal abilities require the patient to sustain attention, strategize in order to solve problems, shift cognitive set, ignore distractions, and respond to feedback. For example, in the Wisconsin Card Sorting Test, a test of frontal lobe function, the subject sorts a deck of cards according to 3 types of sorting rules. The examiner changes the rule periodically; the patient must work out the new sorting rule and shift set accordingly. Patients with Parkinson disease make sorting errors and perseverate. Many neuropsychological paradigms have been used to illuminate other aspects of striatofrontal impairment and detect deficits in Parkinson disease and Parkinson disease dementia (Taylor et al 1986; Zakzanis and Freedman 1999). Although visuospatial processing is impaired in cortical dementia, it is often disproportionally affected in Parkinson disease dementia. Patients have deficits on tasks involving drawing, arranging objects into spatial patterns, mentally manipulating or rotating images, and visuospatial perception and attention (Levin 1990; Aarsland et al 2007; Emre et al 2007). The Montreal Cognitive Assessment (MoCA), which tests executive function, has been validated as more sensitive than the MMSE in detecting and differentiating Parkinson disease dementia (Hoops et al 2009). Of additional diagnostic value is fluctuation of cognitive function in Parkinson disease dementia. Several scales for assessment of cognitive fluctuation are available, and as fluctuations become more frequent and longer, the degree of Parkinson disease dementia becomes more

4 severe and shows a clinical verisimilitude to that of dementia with Lewy bodies (Walker et al 2000; Varanese et al 2010). Although groups of patients with Parkinson disease dementia and Alzheimer disease may show different profiles of cognitive impairment, there may be considerable overlap in individual patients. Structural and biochemical changes in the brain of patients with Parkinson disease dementia often affect both cortical regions as well as nigrostriatal pathways, and may include Alzheimer disease pathology. Though severity or neuropathological stage is typically less than what should be present to correlate with a given clinical stage. Memory deficits in Parkinson disease dementia may differ from those in Alzheimer disease. In Alzheimer disease, both initial acquisition and delayed recall of a set of stimuli are impaired. Delayed recall is usually impaired out of proportion to the extent of initial acquisition. This can be expressed in terms of the delayed recall score as a percentage of the immediate recall score, which is typically low in Alzheimer disease. Patients with Parkinson disease dementia may have difficulty acquiring and encoding new information (poor immediate recall), but they may retain items that were well-learned, leading to a higher percentage of retention (Stern et al 1993). Some studies, however, fail to find differences in memory impairment in Parkinson disease dementia compared to Alzheimer disease (Kuzis et al 1999). Clinical diagnostic criteria does conclude that visual and verbal memory are impaired in Parkinson disease dementia, but not to the extent that it is affected in Alzheimer dementia (Noe et al 2004; Emre et al 2007). There is a distinct pattern to the cognitive impairment in Parkinson disease dementia compared to Alzheimer dementia. In general, the following functions are worse in Parkinson disease dementia than in Alzheimer disease: attention (greater impairment plus increased fluctuations), executive function, and visuospatial construction. Typically memory (as above) and language function are not as impaired in Parkinson disease dementia compared to Alzheimer dementia (Emre et al 2007). Parkinson disease dementia criteria. Clinical diagnostic criteria for Parkinson disease dementia were established in 2007 (Dubois et al 2007; Emre et al 2007). Core features include a diagnosis of Parkinson disease and a dementia syndrome leading to impairment in more than 1 cognitive domain, deficits impairing daily life, and a decline from premorbid functioning. Other cognitive and behavioral features, some of which are described above, are also defined as well as exclusionary criteria and features that lead to diagnostic uncertainty. Finally, criteria for the diagnosis of possible and probable Parkinson disease dementia are defined. As a point of comparison, consensus criteria for dementia with Lewy bodies were proposed in 1996 and later revised (McKeith et al 1996; McKeith et al 2005). Dementia with Lewy bodies is a primary degenerative dementia with onset in later adult life that requires onset of dementia before parkinsonism, or allows Parkinson disease to precede dementia by less than 12 months. Other than the required 1-year rule, clinical features of Parkinson disease dementia and dementia with Lewy bodies strongly overlap (McKeith et al 2004). Although this sets an artificial boundary between dementia with Lewy bodies and Parkinson disease dementia, it highlights the problem of diagnosing dementia with Lewy bodies in the setting of dementia. In patients with Parkinson disease dementia, by contrast, the initial Parkinson disease has usually preexisted for many years, making the connection to Lewy bodies obvious. Differentiation of dementia with Lewy bodies and Parkinson disease dementia remain problematic, as their clinical distinction is based on an arbitrary difference between the onset of motor and cognitive symptoms. There is a need to refine diagnostic criteria for both entities (Aarsland et al 2004). Direct comparisons of cognitive impairment in dementia with Lewy bodies and Parkinson disease dementia have not revealed any significant differences in most studies (Horimoto et al 2003; Noe et al 2004), even though a tendency toward more pronounced deficit in the executive functions has been associated with dementia with Lewy bodies (Aarsland et al 2003b). Prognosis and complications After dementia develops in a patient with Parkinson disease dementia, the course accelerates (Mayeux et al 1992). Patients are vulnerable to complications of severe Parkinson disease, compounded by the presence of dementia. Injury from falls, poor nutrition and aspiration, progressive loss of gait, poor judgment and agitation due to impaired cognition, susceptibility to infections, and medication toxicity all hasten morbidity and mortality. In a large study of Parkinson disease patients evaluated for 20 years after initial diagnosis, falls were present in 87%, dementia was present in 83%, freezing in 81%, dysarthria in 81%, hallucinations in 74%, choking in 48%, and daytime sleepiness in 20% (Hely et al 2008). The presence of dementia in patients with Parkinson disease is associated with earlier nursing home placement (Aarsland et al 2000) and a 2-fold increase of mortality (Levy et al 2002). In dementia with Lewy bodies, the average survival from the onset of dementia until death is similar to that reported in Alzheimer disease and

5 ranges from 2years to 12 years. However, some patients with dementia with Lewy bodies have a more aggressive disease course, suggesting a clinical heterogeneity of this entity (Lopez et al 2000). Clinical vignette A 70-year-old male with idiopathic Parkinson disease diagnosed 8 years ago returned to clinic for his annual follow-up. He was accompanied by his wife, who stated that the patient had fluctuating attention and occasionally seemed spaced-out. He mentioned a problem with rabbits getting into the house as he had seen a family of them living in the bedroom. He had more difficulty staying engaged and playing the correct cards when he and his wife played euchre with their friends every other week. Finally, he required help with bathing as he had difficulty adjusting the water temperature knobs, finding the soap, and applying it properly; this was out of proportion to his motor deficits, which had been relatively stable over the past year. The patient did not have any major changes to his other medical comorbidities and had no changes to his medications. He had imaging of his brain to evaluate for vascular dementia, but the scan did not show significant vascular lesions. Additionally a geriatric depression scale score did not reveal active depressive symptoms. After extensive discussion with the patient and his wife, the patient was diagnosed with probable Parkinson disease dementia based on the published diagnostic criteria (Emre et al 2007). Biological basis Etiology and pathogenesis It is not known why specific neurons degenerate in Parkinson disease. Hypotheses concerning etiologic factors in Parkinson disease include interplay between genetic and environmental factors (Duvoisin 1999). The major pathological changes that underlie Parkinson disease dementia patients may have additional different etiologies. Several structural changes in the brain may underlie Parkinson disease dementia. They may be divided into 3 categories: pathologic changes limited to subcortical structures, cortical and limbic system Lewy bodies, and coexisting Alzheimer disease pathology (Apaydin et al 2002; Emre 2003). Damage to subcortical cholinergic and aminergic neurons that project to the cortex could contribute to Parkinson disease dementia. These include the medial substantia nigra (a source of dopamine), the locus ceruleus with major noradrenergic projections, and the nucleus basalis (a key site of origin of cholinergic projections). The nucleus basalis may show damage even in the absence of Alzheimer disease pathology. Prominent pathologic changes with widespread Lewy neurites and Lewy bodies have been reported in the fasciculus and central medial nuclei of the rostral intralaminar group in the thalamus in patients with Parkinson disease dementia. These thalamic nuclei are part of the limbic loop, and their degeneration may contribute to the cognitive decline in patients with Parkinson disease (Rub et al 2002). Neurochemical deficits in the dopaminergic, monoaminergic, and cholinergic systems have been documented in Parkinson disease dementia and dementia with Lewy bodies (Farlow and Cummings 2008). Degeneration of cholinergic neurons in dementia with Lewy bodies likely exceeds the cholinergic deficit associated with Alzheimer disease (Tiraboschi et al 2002). However, amyloid changes in Parkinson disease dementia and mild cognitive impairment may be closer to that of normal controls (Petrou et al 2015). Brain changes associated with dementia with Lewy bodies, such as decreased cholinergic function or visual-perceptual upset due to occipital lobe dysfunction, may predispose to hallucinations (Perry et al 1994). Decreased cholinergic inputs likely result in difficulty with memory and attention; these cholinergic changes may be a necessary step in the development of cognitive decline in Parkinson disease dementia (Klein et al 2010). Additionally, it has been proposed that deficits in other neurotransmitters (dopamine and other monoamines) lead to deficits in executive function, attention, and depression (Emre 2003). Cortical and limbic Lewy bodies have emerged as 1 of the major cause of Parkinson disease dementia and dementia with Lewy bodies (McKeith et al 1996; McKeith et al 2000). Distribution of Lewy bodies can be restricted to the brainstem or can involve the limbic system and the cortex (Churchyard and Lees 1997). The presence of cortical Lewy bodies and Lewy neurites in the frontal cortex is associated with Parkinson disease dementia, independent of the degree of Alzheimer type of pathology (Hurtig et al 2000). Furthermore, the burden of Lewy bodies correlates with the density of amyloid plaques and neurofibrillary

6 tangles, which may suggest an interaction between these 2 pathological processes (Apaydin et al 2002). The cooccurrence of neocortical Lewy bodies and Alzheimer lesions may have additive effects on the degree of cognitive impairment (Hansen and Samuel 1997; Mattila et al 1998). However, Lewy body dementia patients with prominent hallucinations and delusion had a lower density of neurofibrillary tangles than patients with Alzheimer disease (Ballard et al 2004). The density of cortical Lewy bodies does not differ in patients diagnosed with Parkinson disease dementia and patients with dementia with Lewy bodies (Harding and Halliday 2001). The patients with hallucinations have significantly higher density of Lewy bodies in the temporal lobes (Harding and Halliday 2002). Braak and colleagues described a series of stages over which Parkinson disease evolves by reviewing autopsy studies in 168 patients (Braak et al 2003). The initial stages primarily involve brainstem and subcortical nuclei changes beginning in the dorsal motor nucleus and reticular zone, progressing to the caudal raphe nuclei, then to the midbrain (substantia nigra), the prosencephalic regions, and finally to the cortex. Subsequent studies by this same group also looked exclusively at the changes related to Parkinson disease dementia and showed that cognitive impairment was directly related to increasing neuropathological stage (Braak et al 2005; Braak et al 2006). Despite this work, there is little consensus on the pathological cascade that eventually leads to Parkinson disease dementia as there is not a direct correlation between pathology and clinical progression of disease (Emre 2003; McKeith 2007; Burke et al 2008). Overall, this work and the work of others indicates that Parkinson disease dementia is likely a combination of brainstem changes and diffuse subcortical (and cortical) accumulated pathology that leads to cognitive impairment through multiple mechanisms. Coexisting Alzheimer disease pathology is common and severe enough to warrant an independent diagnosis of Alzheimer disease in the majority of cases (Jellinger et al 2002). Even when the plaque and tangle burden is below the Alzheimer disease diagnostic threshold, these lesions probably still contribute to dementia. Several studies have shown that a majority with Parkinson disease dementia also have concomitant Alzheimer disease dementia-related changes in the brain (Emre 2003; Farlow and Cummings 2008). Data has shown that synergy between cortical Lewy bodies and amyloid-beta/tau pathologies are associated with Parkinson disease dementia, and the degree of amyloidbeta burden shows a direct relationship with progression to dementia (Compta et al 2014). Biomarker data has shown that the amyloid to tau index is lowest amongst Alzheimer disease patients but also decreased in Parkinson disease dementia and dementia with Lewy bodies patients compared to patients with Parkinson disease and controls. Additionally, the biomarker clusterin is elevated to the greatest degree in Parkinson disease dementia patients compared to other pathologies (Vranova et al 2014). Genetics. There are no clear genetic factors that predispose to Parkinson disease dementia. Apolipoprotein E4 allele has not been shown to predispose to Parkinson disease dementia as it does to Alzheimer disease (Farlow and Cummings 2008). That being said, several studies have found that ApoE4 does increase the risk of concomitant Alzheimer disease pathology and cognitive changes consistent with Alzheimer disease in Parkinson disease patients (Mata et al 2014; Monsell et al 2014). One study also found increased odds of hallucinations in Parkinson disease patients with ApoE4 (Monsell et al 2014). Mutations in the gene encoding alpha-synuclein (SCNA) occur in rare familial cases of early-onset autosomal dominant Parkinson disease patients who have diffusely distributed Lewy bodies in their brains at autopsy (Golbe 1999). SCNA gene duplications can lead to Parkinson disease and also the risk of developing Parkinson disease dementia (Farlow and Cummings 2008). Patients with the most common form of genetically acquired Parkinson disease leucine-rich repeat kinase 2 (LRRK2) do not show an increased risk of Parkinson disease dementia (Aarsland and Kurz 2010). Epidemiology" Parkinson disease rises in prevalence with age and affects 1% to 2% of people 80 years old and over. The prevalence of Parkinson disease dementia depends critically on methods of assessment and clinical definitions. Based on data, the prevalence of Parkinson disease dementia is approximately 30% in Parkinson disease patients, with 75% or more Parkinson disease patients developing Parkinson disease dementia prior to death. Longitudinal studies indicate consistently higher incidence of dementia in patients with Parkinson disease; 4-fold to 5-fold higher incidence has been found over a 5-year follow-up, and a relative risk was 1.7 over a 2-year follow-up (Marder et al 1995; Hobson and Meara 2004). Mild cognitive impairment in Parkinson disease is a strong predictor of conversion to dementia. A cohort study of patients with mild cognitive impairment in Parkinson disease showed an 11% conversion rate to dementia per year, and 91% had dementia at 16 years (Hobson and Meara 2015). The presence of mild parkinsonian signs can also predict the development of dementia in the elderly (Louis et al

7 2004). Sex, race, and smoking history are not consistent risk factors for the development of dementia in Parkinson disease (Aarsland et al 2003a; Aarsland and Kurz 2010). Other risk factors shown to increase the risk of development of Parkinson disease dementia include a nontremor predominant Parkinson disease (Compta et al 2014), cardiovascular autonomic dysfunction, REM sleep behavior disorder, color vision disturbance, and worse gait disturbance (Anang et al 2014). Prevention Parkinson disease and Parkinson disease dementia cannot be prevented at present. Future studies may identify drugs that will slow the progression of Parkinson disease, delay its onset, or prevent its occurrence. If so, the drugs may have a similar beneficial effect on Parkinson disease dementia. Similarly, strategies that delay the onset or slow the rate of progression of Alzheimer disease may decrease the rate of dementia in Parkinson disease. Differential diagnosis Evaluation of dementia includes looking for potentially reversible contributing factors such as medications, depression, loss of hearing or vision, metabolic upset, vitamin deficiency, and infection. Several uncommon degenerative disorders may cause dementia and parkinsonism, such as progressive supranuclear palsy, frontotemporal dementia linked to chromosome 17, striatonigral degeneration, corticobasal degeneration, pantothenate kinase-associated neurodegeneration, Parkinson-dementia complex of Guam, Creutzfeldt-Jakob disease, and Huntington disease. These conditions generally have additional neurologic features or atypical parkinsonism that fail to respond to L-dopa. More common considerations are Alzheimer disease (particularly in its severe stages), and Alzheimer disease patients with impaired basal ganglia function due to pharmacologic dopaminergic receptor blockade, usually due to neuroleptics, or strategically placed strokes (Ellis et al 1996). Patients with Alzheimer disease are sensitive to neuroleptics and may develop parkinsonism even after even low doses. Usually this reverses after neuroleptics are discontinued, but may take a month or longer. Persistent parkinsonism after neuroleptic withdrawal in a demented patient suggests dementia with Lewy bodies. Parkinsonism increases as dementia worsens in Alzheimer disease, and is thus particularly common in institutionalized patients with severe Alzheimer disease (Ellis et al 1996). In terminal Alzheimer disease, severe immobilization, loss of gait, and paraplegia in flexion often occur. Parkinsonian findings in a patient with Alzheimer disease may not reflect underlying Lewy bodies. As a rough guide, if parkinsonism first appears late in the course of dementia, when the Mini- Mental State Examination score falls below 10/30, Alzheimer disease is the likely diagnosis whereas parkinsonism arising earlier in the course of apparent Alzheimer disease suggests dementia with Lewy bodies. Parkinsonian signs in Alzheimer disease are typically bilateral and symmetrical, and resting tremor is rare. It can be a challenge to conduct and interpret the motor examination in demented patients. For example, apathy may lead to flat speech, resembling mild hypophonia and masked facies, apraxia or difficulty following commands may lead to slowed movements, and paratonia (gegenhalten) may be difficult to distinguish from true rigidity. Diagnostic workup Patients diagnosed with Parkinson disease and who develop dementia should undergo rigorous evaluation to identify potentially reversible or treatable factors mentioned above. If delirium is present, it should be treated, and the patient should be reassessed. Formal cognitive testing is necessary to document dementia, establish its severity, and provide a baseline to follow longitudinally. Information from an informant is important to document functional impairment and clarify details of the history. Blood tests should include levels of vitamin B12 and thyroid function. A neuroimaging study, CT or MRI, is obtained in most patients, to search for a structural factor, such as stroke or tumor, which could contribute to dementia. Detailed neuropsychological testing is not essential, but may be helpful in cases of mild dementia. EEG changes are nonspecific, but slowing in the temporal-occipital regions during rapid eye movement sleep may be predictive of development of dementia (Latreille et al 2016). There are no specific neuroimaging modalities that can accurately identify Parkinson disease dementia. A host of studies have used MRI to look for changes that may help differentiate Parkinson disease dementia from other disorders and control patients. In general, Alzheimer dementia patients generally show more atrophy in the mesial temporal lobe and hippocampus as compared to Parkinson disease dementia patients (Tam et al 2005). Parkinson disease dementia patients tend to have more posterior cortical and subcortical changes (Beyer et al 2007). One study found that Parkinson disease dementia patients tended to show more atrophy in the anterior caudate and ventricular

8 enlargement (Apostolova et al 2010). Functional imaging can be used to support the diagnosis of dementia with Lewy bodies, but it remains a research, rather than a routine clinical test. A pattern of hypometabolism affecting the occipital lobe but not temporoparietal regions may be seen on PET or SPECT studies in dementia with Lewy bodies (Lobotesis et al 2001; Gilman et al 2005). In vivo, assay of dopamine transporter and striatal monoamine terminals can also help in the differentiation of dementia with Lewy bodies and Alzheimer disease (Gilman et al 2004; O'Brien et al 2004). Biomarker analysis of cerebrospinal fluid may have the ability to discriminate Parkinson disease dementia patients from others. A panel of 9 spinal fluid biomarkers was able to differentiate Parkinson disease dementia from progressive supranuclear palsy, multiple system atrophy, and corticobasal syndrome patients (Magdalinou et al 2015). Additionally, a set of 5 spinal fluid biomarkers were able to identify patients with Parkinson disease dementia from patients with Parkinson disease without dementia with an 80% accuracy (Berlyand et al 2016). Management No medical treatment can delay, stabilize, or reverse the biological processes underlying progressive dementia in Parkinson disease. However, treatment with cholinesterase inhibitors can lead to improvements in cognition and quality of life for both the patient and the caregiver, as well as allow for possible prolongation of home-based care. Other interventions and medications are aimed at control of target symptoms (Burn and McKeith 2003). Comprehensive reviews of literature have been done to examine the available evidence (Ballard et al 2011). Cognitive symptoms. There are marked cholinergic deficits in the brains of patients with Parkinson disease dementia, and evidence suggests that cholinesterase inhibitors are efficacious (van Laar et al 2011). Both placebocontrolled and open-label studies of cholinesterase inhibitors have shown improvement of cognitive fluctuations, apathy, and visual hallucinations. Open-label studies with rivastigmine (Reading et al 2001) and donepezil (Bergman and Lerner 2002; Fabbrini et al 2002) have suggested improvement of both cognitive and noncognitive symptoms without worsening extrapyramidal signs. A large double-blind, placebo-controlled study of rivastigmine in 541 patients with Parkinson disease dementia, with the dementia developing at least 2 years after onset of the Parkinson disease, was of 24 weeks' duration and found that those on rivastigmine were significantly improved in measures of cognition, global functioning, function in activities of daily living, and in behavior, particularly with regards to reduction in visual hallucinations. Adverse effects primarily involved gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Most adverse events occurred during the initial titration phase and were usually transient. There was increased tremor in 10% of treated patients, but this was usually mild and did not lead to discontinuing the medication. This study used capsules whereas the rivastigmine patch, which has fewer adverse effects, is most commonly used in clinical practice (Emre et al 2004). Further analysis in this trial showed that the subgroup with hallucinations had the most profound improvement in cognitive testing (Burn et al 2006). Increased MMSE and Clinician's Global Impression of Change scores, but no change in the Neuropsychiatric Inventory score, have been reported in a placebo-controlled trial with donepezil (Aarsland et al 2002). The incidence of significant side effects caused by peripheral cholinergic stimulation may be higher in patients with Parkinson disease, and patients need to be monitored for orthostatic hypotension and diarrhea. Possible worsening or parkinsonism and tremor has also been occasionally noted (Leroi et al 2004; Gurevich et al 2006; Almaraz et al 2009). In general, rivastigmine or the other cholinesterase inhibitors should not be discontinued without gradual taper as sudden decline in cognition has been reported in these patients (Minett et al 2003). Memantine has been studied in a number of small and intermediate sized trials with dementia with Parkinson disease. Results to date have been equivocal regarding cognitive or behavioral benefits in these populations and it remains unclear whether benefits outweigh potential adverse effects in these populations. A small 72 patient double-blind, placebo-controlled trial showed improved clinical global impression of change at 24 weeks in Parkinson disease dementia and dementia with Lewy bodies patients (Aarsland et al 2009). A subsequent 199 patient randomized, double-blind, placebo-controlled trial showed only a benefit in dementia with Lewy bodies patients but not in Parkinson disease dementia patients (Emre et al 2010). A meta-analysis of both memantine and cholinesterase inhibitors showed that only cholinesterase inhibitors improved cognition, but both cholinesterase inhibitors and memantine slightly improved clinicians' global impression of change (Wang et al 2015).

9 General issues in treatment of Parkinson disease dementia. The management of Parkinson disease dementia should include consideration of the patient, caregiver, and social and physical environments. Issues such as competence to work and drive, home safety, and the need for assistance at home should be evaluated. The caregiver should be educated about dementia and the strategies to support and maintain the patient. Community resources such as day care centers and support groups can provide substantial assistance. The patient's social and physical environment must be adapted to his or her disabilities and the daily routine should be kept simple and predictable. Factors such as inappropriate levels of stimulation or poor sleep may worsen cognitive functioning. The treating physician should look out for treatable or reversible causes of symptoms. The sudden onset or worsening of hallucinations, confusion, somnolence and agitation, or rapid cognitive or motor decline should prompt a thorough search for an underlying medical illness, metabolic or electrolyte upset, or side effects of medications. Motor dysfunction. In Parkinson disease dementia, there is risk that dopaminergic replacement therapies used as a standard of care may cause or worsen visual hallucinations or agitation whereas medications with anticholinergic actions may cause confusion. Such medications, which may be necessary for the practical management of patients, should be closely monitored and titrated to maintain an appropriate balance between efficacy and side effects. When L-dopa is titrated carefully, it may well continue to improve motor function in Parkinson disease dementia with minimal adverse effects. It does not improve cognitive function per se, although some patients may show increased speed of thought or nonspecific arousal. In untreated patients with worsening motor symptoms, a trial of such treatment is warranted. L-dopa may be less likely than newer dopamine receptor agonists to provoke hallucinations. Depression. Persistent depression in patients with Parkinson disease dementia may benefit from treatment with psychotherapy, antidepressant medications, and occasionally electroconvulsive therapy. Double-blind, placebocontrolled trials of various drugs in Parkinson disease with or without dementia have generally had large placebo effects, and efficacy has been equivocal (Weintraub et al 2005). Tricyclic antidepressants may be efficacious in patients with Parkinson disease (Cummings 1992), but anticholinergic actions and orthostatic hypotension may limit their use in Parkinson disease dementia. These side effects are somewhat less likely with nortriptyline and desipramine. In patients with agitated depression, the sedation of tricyclic antidepressants can be useful in promoting sleep. Newer antidepressants in the selective serotonin reuptake inhibitor class may be effective in treating depression, especially when withdrawal and apathy are prominent. Rarely, selective serotonin reuptake inhibitor administration may worsen motor function, but this is not an obstacle. Electroconvulsive therapy may be helpful when depression persists, especially when severe apathy is present; it has been reported to also temporarily improve motor function (Faber and Trimble 1991). Psychosis. Before resorting to medications for behavioral control, environmental or interpersonal factors should be sought. Adjuncts to behavior management include regular scheduling of activities and sleep, or using techniques such as distraction. There is no single type of medication that consistently reduces delusions, hallucinations, agitation, insomnia, or other behavioral changes associated with dementia. Because of the possibility of adverse side effects, medication should be initiated at low doses, increased slowly as tolerated, and decreased or discontinued if the behavior abates. For symptoms such as agitation and delusions, non-neuroleptic medications, such as trazodone or possibly valproate are worth a trial. Benzodiazepines such as alprazolam may be used on an intermittent or as needed basis to promote sleep or control agitation. More chronic use increases risk for sedation and falls, a particular danger in this population with impaired righting reflexes. High potency neuroleptics such as haloperidol may worsen parkinsonism, and can lead to marked deterioration in patients with dementia with Lewy bodies, therefore, atypical neuroleptics are preferable. Clozapine is an atypical antipsychotic with high affinity for D4 receptors, and weak affinity for D1 and D2. It is effective in controlling psychosis in Parkinson disease dementia with minimal worsening motor function (Factor et al 1994). However, regular hematological monitoring is required because of potential for bone marrow toxicity. Because clozapine has some anticholinergic activity, higher doses may lead to confusion or worsen cognition. These features have limited its use in clinical practice. Olanzapine, an atypical antipsychotic agent, has a similar pharmacologic profile to clozapine, but does not require hematological monitoring. In patients with Parkinson disease dementia, olanzapine appears to be effective for psychotic symptoms without worsening parkinsonism. However, drowsiness may be a limiting factor (Aarsland et al 1999b). Quetiapine, an atypical antipsychotic agent, has virtually no anticholinergic activity, making it an excellent theoretical choice (Fernandez et al 2002; Takahashi et al 2003).

10 Cholinesterase inhibitors have been shown to improve hallucinations and psychosis in demented patients with Parkinson disease. Several clinical trials have reported the efficacy of this class of medication. REM sleep behavior disorder. Movements of the extremities associated with vivid dreams may be fluctuating and severe, making or agitating or even causing insomnia in bed partners. Clonazepam 0.5 to 2 mg at night before bedtime is usually effective in suppressing symptoms. Special considerations Pregnancy Dementia in Parkinson disease almost always occurs beyond childbearing age. Anesthesia There are no studies specifically addressing the impact of anesthesia in patients with Parkinson disease dementia. Demented patients can experience prolonged confusion after emerging from general anesthesia. If possible, tranquilizers and sedatives should be minimized during the post-anesthesia recovery period. References cited Aarsland D, Andersen K, Larsen JP, Lolk A. Prevalence and Characteristics of Dementia in Parkinson Disease. An 8-Year Prospective Study. Arch Neurol 2003a;60: PMID Aarsland D, Ballard CG, Halliday G. Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity. J Geriatr Psychiatry Neurol 2004;17: PMID Aarsland D, Ballard C, Walker Z, et al. Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol 2009;8(7): PMID Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson disease. J Neurol Sci 2010; 289(1-2): PMID Aarsland D, Laake K, Larsen PJ, Janvin C. Donepezil for cognitive impairment in Parkinson's disease: a randomized controlled study. J Neurol Neurosurg Psychiatry 2002;72: PMID Aarsland D, Larsen JP, Cummings JL, Laake K. Prevalence and clinical correlates of psychotic symptoms in Parkinson disease: a community-based study. Arch Neurol 1999a;56: PMID Aarsland D, Larsen JP, Lim NG, Tandberg E. Olanzapine for psychosis in patients with Parkinson's disease with and without dementia. J Neuropsychiatry Clin Neurosci 1999b;11: PMID Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson's disease: a population-based, prospective study. J Am Geriatr Soc 2000;48: PMID Aarsland D, Litvan I, Salmon D, et al. Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease. J Neurol Neurosurg Psychiatry 2003b;74: PMID Almaraz A, Driver-Dunckley ED, Woodruff BK, et al. Efficacy of rivastigmine for cognitive symptoms in Parkinson disease with dementia. Neurologist 2009;15(4): PMID American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition. Washington DC: American Psychiatric Association, Anang JB, Gagnon JF, Bertrand JA, et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology 2014;83(14): PMID Apaydin H, Ahlskog JE, Parisi JE, Boeve BF, Dickson DW. Parkinson disease neuropathology: later- developing dementia and loss of levadopa response. Arch Neurol 2002;59: PMID