Dementia in Parkinson disease - Parkinson's Dementia

Dementia in Parkinson disease

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, clinico-pathological studies identified a dementia syndrome with a substrate comprising widely distributed cortical and subcortical Lewy bodies, now referred to as dementia with Lewy bodies (McKeith et al 1996). Dementia in association with Parkinson disease or Lewy bodies has emerged as a relatively common and important clinical problem.

Dementia in Parkinson disease

Peter Hedera

Former authors: Christopher Clark, Guila Glosser (original authors), and Douglas Galasko

Last reviewed: December 29, 2006


ICD codes

- ICD-9:
Parkinson disease: 332.0
Dementia in conditions classified elsewhere: 294.1

- ICD-10:
Parkinson disease: G20
Dementia in Parkinson disease: F02.3

Synonyms:
Dementia associated with Parkinson disease; Dementia in Parkinson disease; Dementia with parkinsonism


HISTORICAL NOTE AND NOMENCLATURE

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, clinico-pathological studies identified a dementia syndrome with a substrate comprising widely distributed cortical and subcortical Lewy bodies, now referred to as dementia with Lewy bodies (McKeith et al 1996). Dementia in association with Parkinson disease or Lewy bodies has emerged as a relatively common and important clinical problem.


CLINICAL MANIFESTATIONS

Clinical concepts and problems.

On sensitive psychometric tests, virtually all patients with Parkinson disease are impaired relative to age-comparable controls, even early in the course of disease. This most likely reflects weakening of dopaminergic input to cognitive circuits that include the basal ganglia. Cognitive deficits are usually mild and of uncertain clinical significance. Examining 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. Speech and motor disturbances may impair the speed and quality of responses. 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 dementia in Parkinson disease is not straightforward. Alzheimer disease, the most common type of dementia, is considered to be an 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 as the disease progresses. In Parkinson disease with dementia and dementia with Lewy bodies, there may be a pattern indicating subcortical dementia. This concept comes from studies of progressive supranuclear palsy and Huntington disease, conditions with prominent subcortical pathology. Patients have relatively good memory performance but prominent psychomotor slowing (bradyphrenia) and difficulty with tasks involving abstraction, reasoning, and cognitive shifts (Cummings 1986). 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 with dementia or dementia with Lewy bodies, the brain pathology often includes cortical pathology such as Alzheimer disease lesions or Lewy bodies (Jellinger 1996), producing a more complex or cortical pattern of dementia. The concept of subcortical dementia nevertheless provides a framework for understanding cognitive changes in Parkinson disease with 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. 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 permits different patterns of cognitive loss, for example, subcortical dementia or multifocal deficits due to vascular lesions, and avoids the issue of detecting and interpreting functional impairment (Cummings and Benson 1992). Dementia is diagnosed when there are deficits in three 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 dementia in Parkinson disease.

Three main categories of symptoms occur in Parkinson disease with dementia and dementia with Lewy bodies: cognitive, motor, and behavioral. Cognitive decline typically begins and progresses gradually. Episodes of cognitive clouding are common in patients with Parkinson disease with dementia and dementia with Lewy bodies. The episodes may arise spontaneously or they can be preempted by medications, infections, dehydration, or electrolyte upset. In dementia with Lewy bodies, fluctuation of cognitive performance has been incorporated into diagnostic criteria. The motor symptoms of parkinsonism in Parkinson disease with dementia are usually severe. In dementia with Lewy bodies, by contrast, the motor symptoms may be mild or sometimes absent. Behavioral symptoms in these disorders include hallucinations, delusions, and depression. Agitation and sleep disturbances are common in severe 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's institutionalization.

Several clinical risk factors for dementia in Parkinson disease include advancing age and late age at the onset of Parkinson disease (especially after 70 years), as well as severe motor findings. 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 duration of Parkinson disease does not increase the risk of dementia, independent of age and severity. Patients with akinetic Parkinson disease, prominent postural instability and gait disorder have increased risk of dementia when compared to a subgroup of patients with tremor dominant Parkinson disease (Burn et al 2003).

About 40% to 50% of patients with Parkinson disease experience chronic dysthymia and depression at some point (Cummings 1992). Aspects 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 levels of dopamine metabolites. Depression in Parkinson disease may result from impaired meso-cortico-limbic dopaminergic pathways, serotoninergic pathways, or frontal lobe dysfunction.

Hallucinations occur in about one third of patients with Parkinson disease (Sanchez-Ramos et al 1996). Patients hallucinate in both "on" and "off" states. They react variably to the visions: 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).

Psychometric features of Parkinson disease-dementia. Nondemented 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 decrements in nondemented 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. Impairment of memory, leading to deficits on tasks involving delayed recall, appears to distinguish Parkinson disease with dementia from Parkinson disease (Zakzanis and Freedman 1999).

Although groups of patients with Parkinson disease with dementia and Alzheimer disease may show different profiles of cognitive impairment, there is much overlap. Individual patients with Parkinson disease may not necessarily demonstrate a distinctive profile. Structural and biochemical changes in the brain of patients with Parkinson disease with dementia are heterogeneous, affecting cortical regions as well as nigrostriatal pathways, and may include Alzheimer disease pathology.

Memory deficits in Parkinson disease with 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 savings, the delayed recall score as a percentage of the immediate recall score, which is typically low in Alzheimer disease. Patients with Parkinson disease with 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 savings (Stern et al 1993). Some studies, however, fail to find differences in memory impairment in Parkinson disease with dementia compared to Alzheimer disease (Kuzis et al 1999).

Patients with Parkinson disease with dementia typically show deficits on tests of executive function, visuospatial abilities, and verbal fluency (generating words that belong to a category). Other aspects of cognition, such as language ability, 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, the subject sorts a deck of cards according to three 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 eliminate other aspects of striato-frontal impairment, and detect deficits in Parkinson disease and Parkinson disease with 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 with 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).


Dementia with Lewy bodies.

Consensus criteria for dementia with Lewy bodies were proposed in 1996 (McKeith et al 1996). Dementia with Lewy bodies is a primary degenerative dementia with onset in later adult life. The consensus criteria require onset of dementia before Parkinsonism, or allow Parkinson disease to precede dementia by less than 12 months. Other than the required 1-year rule, clinical features of Parkinson disease with 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 with dementia, it highlights the problem of diagnosing dementia with Lewy bodies in the setting of dementia. In patients with Parkinson disease with dementia, by contrast, the initial Parkinson disease has usually pre-existed for many years, making the connection to Lewy bodies obvious. Probable dementia with Lewy bodies is diagnosed if there are two or more core features from the triad of Parkinsonism, fluctuation, and visual hallucinations. Possible dementia with Lewy bodies is diagnosed when only one core feature is present. Each core feature can arise in demented patients for reasons beside Lewy bodies, and the clinician must judge whether the symptoms suggest dementia with Lewy bodies or another condition. Dementia with Lewy bodies often closely resembles Alzheimer disease, and many patients with dementia with Lewy bodies have enough Alzheimer disease pathology to meet its diagnostic criteria.

Symptoms of dementia with Lewy bodies arise gradually, usually between age 60 and 90, overlapping with the age of onset in Alzheimer disease (McKeith et al 1996). Dementia with Lewy bodies is more common in men than women. The clinical course of dementia with Lewy bodies is usually steadily progressive, but may fluctuate. Early in the course, deficits in memory and language may be less prominent than in Alzheimer disease with more marked impairment of visual-spatial abilities, speed of cognitive processing, and problem-solving (Galasko et al 1996; Shimomura et al 1998). This is consistent with frontal-subcortical dysfunction. It may be difficult to detect in brief mental status testing or in severe stages of dementia when brain dysfunction is more global.

Motor features of Parkinsonism occur in 25% to 90% of cases of dementia with Lewy bodies (Galasko et al 1996; McKeith et al 1996; Louis et al 1997). This range is broad because of different approaches used to assess Parkinsonism, and variable inclusion of patients with Parkinsonism that follow neuroleptic exposure or Parkinson disease that preceded dementia. In patients where dementia preceded or coincided with Parkinsonism, the Parkinsonian features resemble those of idiopathic Parkinson disease but are milder and usually symmetrical. Rest tremor is uncommon in dementia with Lewy bodies, noted in 10% to 25% of patients. Studies that do not restrict the order of onset of symptoms and include patients with Parkinson disease with dementia find severe Parkinsonism (Louis et al 1997).

Fluctuation refers to marked variation in alertness, cognitive function, or daily living performance. Patients may show marked daytime somnolence and may shift rapidly between impaired and less impaired cognition; these variations may be over minutes to days. It has been noted in 80% or more cases of dementia with Lewy bodies in the Newcastle group series (McKeith et al 1996; McKeith et al 2000). Investigators at other centers find fluctuation difficult to assess reliably (Mega et al 1996; Verghese et al 1999), and report lower frequencies in dementia with Lewy bodies. Fluctuation is difficult to quantify in the history, and novel rating scales and measures have been suggested (Walker et al 2000). When lucidity waxes and wanes over days, infection, electrolyte upset or medication reactions that may cause delirium should be assessed.

Visual hallucinations occur in 40% to 75% of patients with dementia with Lewy bodies, compared to 5% to 20% in pure Alzheimer disease (Galasko et al 1996; McKeith et al 1996). They may recur over days, weeks, or even longer. As in Parkinson disease with dementia, the visions are typically well-formed, vivid images of people or animals, and may incorporate bright colors and dramatic settings. In dementia with Lewy bodies, hallucinations arise spontaneously. Typically, they occur early in the course and can be a heralding symptom of the disease. Another important clue is the persistence of visual hallucinations, even after a prolonged period of follow up (Ballard et al 2001). Hallucinations in older patients should prompt a search for factors such as delirium, medication toxicity, stroke, or sensory impairment, especially vision impairment. These rarely produce hallucinations that are formed and recurrent.

Uncommon or less specific features are assigned supporting statuses and are not essential to diagnose dementia with Lewy bodies. They include repeated falls, syncope, transient loss of consciousness, neuroleptic sensitivity, systematized delusions, REM sleep behavior disorder, and nonvisual hallucinations. Exposure to dopamine-blocking neuroleptics, even newer agents such as risperidone, may lead to marked impairment of movement and cognition, abrupt clinical decline, and even death in dementia with Lewy bodies (McKeith et al 1992; Baskys 2004). For behavioral management in dementia with Lewy bodies, low-potency agents or atypical neuroleptics are preferred. REM sleep behavior disorder may occur in dementia with Lewy bodies (Boeve et al 2001; Ferman et al 2002). Patients have vivid dreams and appear to act out verbally or physically, for example, by shouting, punching, kicking, crawling, or running while in bed. Polysomnography shows loss of generalized muscle atonia or prominent phasic muscle twitching during REM sleep.

Several studies, including 2 that were prospective, have analyzed the diagnostic accuracy of proposed clinical criteria of probable dementia with Lewy bodies. In general, these studies have suggested high specificity (McKeith et al 2000; Lopez et al 2002), and the presence of identified fluctuations, REM sleep disorder, and neuroleptic sensitivity are highly predictive of dementia with Lewy bodies (McKeith et al 2004). Sensitivity of diagnostic criteria varies considerably, and 2 prospective studies reported sensitivity from 23% to 83% (McKeith et al 2000; Lopez et al 2002). Similarly, most of the retrospective studies have found high specificity for probable dementia with Lewy bodies but lower sensitivity (Litvan et al 2003). Alzheimer disease is one of the main alternatives in the differential diagnosis, and subjects with a high degree of overlapping neurofibrillary pathology had a lower diagnostic accuracy for the diagnosis of dementia with Lewy bodies because of smaller frequency of visual hallucinations and extrapyramidal signs (Merdes et al 2003).

Differentiation of dementia with Lewy bodies and dementia with Parkinson disease 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 dementia with Parkinson disease did not reveal any significant differences in most of 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).


CLINICAL VIGNETTE

No information was provided by the author.


ETIOLOGY

It is not known why specific neurons degenerate in Parkinson disease. Hypotheses concerning etiological factors in Parkinson disease include an interplay between genetic and environmental factors (Duvoisin 1999). The major pathological changes that underlie dementia in Parkinson disease patients may have additional different etiologies.


PATHOGENESIS AND PATHOPHYSIOLOGY

Several structural changes in the brain may underlie dementia in Parkinson disease. 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).

Loss of dopaminergic neurons in the substantia nigra is the major pathology associated with Parkinson disease. Some demented patients with Parkinson disease had neuropathological changes restricted to cell loss within the substantia nigra, especially within the medial part of the substantia nigra (Rinne et al 1989). The reported proportion of these patients varies considerably from only rare cases (Jellinger 1996) to 40% to 50% of all demented patients (Hughes et al 1993). Damage to subcortical cholinergic and aminergic neurons that project to the cortex could contribute to dementia in Parkinson disease. 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 lesions. Prominent pathologic changes with widespread Lewy neurites and Lewy bodies have recently been reported in the fasciculus and central medial nuclei of the rostral intralaminar group in the thalamus in patients with Parkinson disease and 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).

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.

Cortical and limbic Lewy bodies have emerged as one of the major cause of dementia in Parkinson disease 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). Immunohistochemistry staining with antibodies against alpha-synuclein is more sensitive for visualization of Lewy bodies and Lewy neurites (Gomez-Tortosa et al 2000). The presence of cortical Lewy bodies and Lewy neurites in the frontal cortex is associated with dementia in Parkinson disease, 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 tangles, which may suggest an interaction between these 2 pathological processes (Apaydin et al 2002). The co-occurrence of neocortical Lewy bodies and Alzheimer lesions may have additive effects on the degree of cognitive impairment (Hansen and Samuel 1997; Matilla 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 with 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).

Neurochemical deficits in the dopaminergic, monaminergic, and cholinergic systems have been documented in Parkinson disease with dementia and dementia with Lewy bodies. Degeneration of cholinergic neurons in Lewy body dementia may even exceed the cholinergic deficit associated with Alzheimer disease (Tiraboschi et al 2002). Brain changes associated with dementia with Lewy bodies, such as decreased cholinergic function (Perry et al 1994) or visual-perceptual upset due to occipital lobe dysfunction, may predispose to hallucinations.

Genetic factors may predispose to the Alzheimer disease pathology often found in Parkinson disease with dementia and dementia with Lewy bodies. The frequency of the apolipoprotein E 4 allele, a risk factor for Alzheimer disease, is significantly higher in Parkinson disease with dementia relative to Parkinson disease patients without dementia or age-matched controls (Arai et al 1994). It is also increased in patients with dementia with Lewy bodies who had significant accompanying Alzheimer disease pathology at autopsy, but not in those with pure dementia with Lewy bodies (Singleton et al 2002).

Mutations in the gene encoding alpha-synuclein 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). Mutations in the alpha-synuclein gene are only a rare cause of dementia with Lewy bodies (Zarranzz et al 2004). However, cortical and nigral Lewy bodies and Lewy neurites strongly stain with antibodies against alpha-synuclein. The aggregation of alpha-synuclein to form fibrillary structures is a common pathway in Lewy body formation in general (Baba et al 1998). Even though few familial cases of dementia with Lewy bodies have been reported (Tsuang et al 2002), no mutations in the alpha-synuclein gene have been found in dementia with Lewy bodies. Abnormal expression of a wild type of alpha-synuclein may contribute to the aggregation of alpha-synuclein fibrils (Rockestein et al 2001).


EPIDEMIOLOGY

Parkinson disease rises in prevalence with age and affects 1% to 2% of people 80 years old and over. The prevalence of dementia in Parkinson disease depends critically on methods of assessment and clinical definitions. Recent studies suggest a range of 20% to 40% (Mayeux et al 1992; Aarsland et al 1996). Because patients with Parkinson disease with dementia have high rates of mortality and institutionalization, they tend to be under-represented in epidemiological surveys. A recent 8-year prospective study has found a 78.2% prevalence of dementia in patients diagnosed with Parkinson disease (Aarsland et al 2003a).

Incidence studies indicated 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).

The presence of mild parkinsonian signs can also predict the development of dementia in elderly (Louis et al 2004). Older age at onset of Parkinson disease, hallucinations before the baseline and akinetic-dominant subtype of Parkinson disease strongly influence the likelihood of developing dementia, but sex, race, and smoking history are not consistent risk factors (Aarsland et al 2003a).

Dementia with Lewy bodies may represent up to 20% of all dementia cases. The frequency of dementia with Lewy bodies pathology in consecutive autopsy series from centers that study dementia is of interest despite drawbacks such as clinical referral bias and various rates of autopsy. In large autopsy series, Lewy bodies are found in 15% to 25% of demented older patients (Kalra et al 1996). This frequency of 15% to 20% greatly exceeds the prevalence of Parkinson disease in the elderly. Almost equal distribution of cortical Lewy bodies has been noted in 1 autopsy study, suggesting a high prevalence of preclinical cases (Esiri et al 2001). Clinical studies have reported a similar frequency of cases of dementia with Lewy bodies with estimated prevalence of 5.5%, accounting for 2% of all dementia cases (Stevens et al 2002; Rahkonen et al 2003).

Also see the clinical summary: Epidemiology of movement disorders.


PREVENTION

Parkinson disease or 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 with 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, fronto-temporal dementia linked to chromosome 17, striatonigral degeneration, cortico basal degeneration, Hallervorden-Spatz disease, 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.

Dementia in Parkinson disease and Lewy body dementia can be separated based on the temporary relationship between the onset of extrapyramidal signs and dementia with an arbitrary rule of 1 year, where the onset of cognitive decline within the first year of the development of parkinsonism is classified as dementia with Lewy bodies (McKeith et al 1996; McKeith et al 2000).


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 re-assessed. 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 neuro-imaging study, CT or MRI, is obtained in most patients, to search for a structural factor, such as stroke or tumor, that could contribute to dementia. Detailed neuropsychological testing is not essential, but may be helpful in cases of mild dementia.

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 2004a). 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 2004b; O'Brien et al 2004).


PROGNOSIS AND COMPLICATIONS

After dementia develops in a patient with Parkinson disease with 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. 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 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).


MANAGEMENT

No medical treatment can reverse the dementia process in patients with Parkinson disease. Interventions and medications are aimed at control of target symptoms (Burns and McKeith 2003).


General issues in treatment of dementia in Parkinson disease.

The management of Parkinson disease with dementia and dementia with Lewy bodies should include the patient, caregiver, and social and physical environment. 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 with dementia, dopamine replacement may be associated with visual hallucinations or agitation whereas medications with anticholinergic actions may cause confusion. Medications should be closely monitored and titrated to maintain an appropriate balance between efficacy and side effects. When L-dopa is titrated carefully, it will continue to improve motor function in Parkinson disease with dementia. It does not improve cognitive function substantially, although some patients may show increased speed of thought or nonspecific arousal. Although patients with dementia with Lewy bodies may show a lesser motor response to L-dopa compared to patients with Parkinson disease, 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 with dementia may require treatment with psychotherapy, antidepressant medications, and occasionally electro-convulsive therapy. Tricyclic antidepressants are efficacious in patients with Parkinson disease (Cummings 1992), but anticholinergic actions and orthostatic hypotension may limit their use in Parkinson disease with dementia. These side effects are somewhat less likely with nortriptyline and desimipramine. 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 often also temporarily improves motor function (Faber and Trimble 1991).


Behavior.

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.

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 with dementia with minimal worsening motor function (Factor et al 1994). However, regular hematological monitoring is required because of potential toxicity. Because clozapine has some anticholinergic activity, higher doses may lead to confusion or worsen cognition.

Olanzapine, a newer atypical antipsychotic agent, has a similar pharmacologic profile to clozapine, but does not require hematological monitoring. In patients with Parkinson disease with dementia, olanzapine appears to be effective for psychotic symptoms without worsening Parkinsonism. However, drowsiness may be a limiting factor (Aarsland et al 1999b). In dementia with Lewy bodies, behavioral improvement has been reported with olanzapine although confusion and sedation are common side effects (Walker et al 1999). Quetiapine, a new atypical antipsychotic agent, has virtually no anticholinergic activity, making it an excellent theoretical choice (Fernandez et al 2002; Takahashi et al 2003).

Cholinesterase inhibitors have been shown to significantly improve hallucinations and psychosis in demented patients with Parkinson disease and dementia with Lewy bodies. Clinical trials reporting the efficacy of this class of medication are reviewed in the next paragraph.


Cognitive symptoms.

There are marked cholinergic deficits in the brains of patients with dementia with Lewy bodies, and emerging evidence suggests that cholinesterase inhibitors may be more effective for dementia with Parkinson disease and dementia with Lewy bodies than for Alzheimer disease (Samuel et al 2000). Both placebo-controlled and open label studies of cholinesterase inhibitors have been demonstrated improvement in cognitive fluctuations, apathy and visual hallucinations. Open label studies with rivastigmine (Reading et al 2001) and donepezil (Bergman and Lerner 2000;(Fabbrini et al 2002) have suggested improvement of both cognitive and noncognitive symptoms without impairment of extrapyramidal signs. Significant improvements have been reported in the Neuropsychiatric Inventory total score in a double-blind, placebo-controlled trial with rivastigmine in 120 patients with dementia with Lewy bodies (McKeith et al 2004).

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 dementia with Lewy bodies, and patients need to be monitored for orthostatic hypotension and diarrhea. Possible worsening or parkinsonism has also been occasionally noted (Leroi et al 2004).

Cholinesterase inhibitors should not be discontinued without gradual taper as sudden decline in cognition has been reported in these patients (Minett et al 2003). Most of these studies have relatively low numbers of patients enrolled with a limited duration of the follow-up period. Further multicenter, double-blind placebo-controlled studies are in progress to better assess the efficacy of cholinesterase inhibitors in dementia due to Parkinson disease or Lewy bodies.


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 with 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.


ASSOCIATED DISORDERS

Alzheimer disease

Dementia with Lewy bodies

Diffuse Lewy body disease

Lewy body variant of Alzheimer Disease

Parkinson disease with cortical Lewy bodies


RELATED SUMMARIES

Advanced Parkinson disease

Affective disorders in neurologic disease

Epidemiology of movement disorders

Parkinson disease

Sleep disorders associated with parkinsonism


DIFFERENTIAL DIAGNOSIS

progressive supranuclear palsy

fronto-temporal dementia linked to chromosome 17

striatonigral degeneration

cortico basal degeneration

Hallervorden-Spatz disease

Parkinson-dementia complex of Guam

Creutzfeldt-Jakob disease

Huntington disease

Alzheimer disease


DEMOGRAPHICS

For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary.



AGE

45-64 years

65+ years



POPULATION

None selectively affected.



OCCUPATION

None selectively affected.



SEX

male>female, >1:1



FAMILY HISTORY

family history may be obtained



HEREDITY

heredity may be a factor

autosomal dominant


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**References especially recommended by the author or editor for general reading.

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Disclosures:

Dr. Hedera has no relevant financial relationships to disclose.