AUTHOR INFORMATION	Section 1 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Author: Jose G Merino, MD, Staff Clinician, Section of Stroke Diagnostics and Therapeutics, National Institute on Neurological Disorders and Stroke, National Institutes of Health Coauthor(s): Jose Luchsinger, MD, MPH, Assistant Professor, Department of Internal Medicine, Columbia University College of Physicians and Surgeons; Zhigao Huang, MD, PhD, Assistant Professor, Director of Parkinson Center, Department of Neurology, University of Florida Health Science Center Jacksonville

Jose G Merino, MD, is a member of the following medical societies: American Academy of Neurology, and American Stroke Association

Editor(s): Alan D Schmetzer, MD, Professor and Vice-Chair for Education, Director of Residency Training, Department of Psychiatry, Indiana University School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Iqbal Ahmed, MD, Program Director, General and Geriatric Psychiatry Residency Programs, Vice Chair for Education, Professor, Department of Psychiatry, John A Burns School of Medicine, University of Hawaii; Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry, Assistant Professor, Department of Medicine, Froedtert Hospital, Medical College of Wisconsin; and Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH; Faculty, Metropolitan College of Boston University, Boston, MA

Disclosure

	INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Parkinson disease (PD) is a disabling, progressive condition. In 1817, when James Parkinson originally described the "shaking palsy," he stated that cognitive changes are not evident until the later stages of the disease but that the disorder is often complicated by a spectrum of cognitive deficits that range from isolated cognitive impairment to severe dementia.

The true incidence and prevalence of dementia in PD are difficult to establish. In the affected age group, comorbidity with other neurodegenerative disorders, particularly Alzheimer disease (AD) and cerebrovascular disease, is common. In addition, those who have investigated this issue use different definitions of dementia.

The clinical and pathological features of PD and AD overlap. This may reflect a common pathogenic mechanism for neurodegeneration within specific vulnerable neuronal populations.

Pathophysiology: Cognitive deficits are due to the interruption of frontal-subcortical loops that facilitate cognition and that parallel the motor loop. Fibers from various areas of the cortex (eg, posterior parietal, premotor) converge on the striatum (particularly the head of the caudate) and project to the prefrontal cortex via nigral, pallidal, and thalamic structures. Different areas of the caudate project to different areas of the prefrontal cortex. Damage to any of the structures of the circuit can elicit the frontal-like cognitive deficits that characterize cognitive dysfunction in PD.

Dementia is likely due to a dopamine deficiency caused by nigral degeneration compounded by the loss of inputs from noradrenergic and cholinergic nuclei (locus coeruleus and nucleus basalis of Meynert, respectively).

The prevalence of AD pathology increases with age. AD changes are more common in the brains of patients with PD than in those of healthy controls, and prevalence of plaques and tangles in the cortex increases as the severity of PD dementia increases.

Frequency:

• In the US: Frequency of dementia in PD varies from 0-81%. This wide variation is due to methodological inconsistencies in the definitions of dementia and in the designs of the studies. The studies discussed in this article used the Diagnostic and Statistical Manual, Revised Third Edition (DSM-III-R) criteria for the definition of dementia.

  A community-based population study found the prevalence of PD to be 99.4 cases per 100,000 persons (2.3/100,000 in patients aged <50 y and 1145/100,000 in patients >80 y). Approximately 41.3% of these patients had dementia. The frequency of dementia increases with age (12.4% of patients aged 50-59 y and 68.7% of patients >80 y had dementia).

  In terms of coincident dementia, a prospective cohort study in New York City revealed that 19.2% of patients with PD developed dementia after 2 years of follow-up care. The relative risk for developing dementia with PD (vs patients without PD) was 1.7, with a 95% confidence interval (1.1-2.7) after adjusting for age, education, and sex.

• Internationally: In a prospective longitudinal study in Leeds, United Kingdom, survival analysis showed that the cumulative incidence of dementia in a PD cohort after 37 months was 19%. This translates into 47.6 cases per 1000 person-years of observation.

  A cohort study in Scotland observed 249 patients with PD for 3.5 years and found that 23.6% developed dementia.

  In Norway, prevalence of dementia in patients with PD is 27.7%.

Mortality/Morbidity:

• Mortality and morbidity may be higher in patients with PD and dementia than in those with PD without dementia.

Race:

• PD occurs throughout the world, and no clear evidence indicates that the risk of developing dementia differs among racial or ethnic groups.

Sex:

• Older men develop PD, with or without dementia, approximately twice as often as women do.

Age:

• The age of onset of PD is one of the strongest risk factors for the development of dementia.
  
  
  • Dementia is very rare, even with disease of long duration, when the age of onset is younger than 50 years.
    
    
  • Patients whose PD first arises at an advanced age are more likely to experience dementia, particularly if they are older than 70 years.

	CLINICAL	Section 3 of 10
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History:

• The development of dementia in patients with PD is associated with the following factors:

• Age older than 70 years

• Parkinson Disease Rating Scale (PDRS) score more than 25
  • The PDRS is a rating tool used to follow the longitudinal course of PD. It consists of 3 subsections: (1) mentation, behavior, and mood; (2) daily living activities; and (3) motor function.

  • A score of 25 signifies moderate impairment.

• Depression

• Development of mania, agitation, disorientation, or psychosis when treated with levodopa

• Facial masking at presentation

• Exposure to psychological stress

• Presence of cardiovascular abnormalities

• Low socioeconomic status

• Low educational level

• Cognitive impairment and poor prognosis are more common when patients have bradykinesia and postural and gait disturbance. Tremor or other parkinsonian signs are not associated with dementia.

• The presence of dementia at the onset of illness does not support a diagnosis of PD. It suggests dementia with parkinsonian features (see Differentials).

Physical: Patients with PD exhibit a spectrum of cognitive abnormalities, ranging from impairment in specific cognitive domains to severe dementia. The presence of isolated cognitive deficits is not a preamble to dementing illness. The heterogeneous clinical picture suggests that multiple dementia syndromes in PD are associated with varying structural and biochemical pathologies.

• Mild cognitive changes on detailed neuropsychological tests are almost ubiquitous. Cognitive testing reveals deficits in several domains, including executive function, visuospatial abilities, memory, and language. The deficits have a frontal-subcortical pattern.

• Disorders of executive function

• This is the core early deficit in disorders of the basal ganglia. Difficulties in generating, maintaining, shifting, and blending of sets characterize executive-function disorders, which manifest as mental inflexibility.

• Nondemented patients with PD display decreased generation and maintenance of sets and slowness in shifting sets in new situations. They show no impairment when performing overlearned tasks, and they benefit from external cues and structure. Difficulty occurs when shifting attention to novel stimuli.

• Visuospatial difficulties

• This is a common deficit. Neuropsychological testing reveals a typical progression of deficits resulting in difficulty with line orientation, block design, and picture arrangement.

• The most severely impaired patients show deficits in non–familiar-face discrimination. Deficits are present even when motor impairment is absent.

• Memory deficits

• Frontal-subcortical systems are essential for organized recall of information. Damage to these systems leads to retrieval deficits in declarative memory and to abnormalities in procedural memory.

• Patients with PD and dementia experience immediate- and long-term memory impairment. Providing patients with retrieval cues can improve memory performance.

• Patients with PD and dementia tend to do better on recognition tasks than patients with AD.

• Patients with PD are disproportionately impaired in their ability to temporally order or sequence new information.

• Language abnormalities

• Language functions may be normal or nearly normal.

• "Tip of the tongue" phenomenon is common and consists of decreased naming and fluency.

• Patients with PD may have difficulty comprehending syntactically embedded questions. Their sentences tend to be grammatically simple.

• Patients with PD and dementia exhibit greater deficits in length of phrases, melody of speech, information content of spontaneous speech, and comprehension of verbal and written commands compared with patients who have PD without dementia.

• Dementia

• Based on clinical and neuropathologic criteria, Cummings has suggested that dementia in PD can take the following 3 forms:
  • Dementia can be mild and show the clinical features of classic subcortical dementia.

  • Dementia can be more severe, with cortical features, but still be neuropathologically different from AD.

  • Dementia can be the more severe form, characterized pathologically by changes in the basal ganglia and the cortex. The cortex changes resemble those observed in AD (ie, neurofibrillary tangles, senile plaques).

• Clearly defined criteria do not exist. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), dementia involves memory impairment; a decline in functional level; and one or more cognitive disturbances, including aphasia, apraxia, agnosia, and disturbance in executive function. Disturbance in executive function is the most common; apraxia and agnosia rarely occur. Language disturbances occur in PD but do not constitute full-blown aphasia. The criteria require evidence that the dementia is due to PD and that the deficits do not occur exclusively during the course of delirium.

• The features of dementia are frontal-subcortical and are most commonly mild to moderate in severity.

• Patients with dementia present with bradyphrenia (slowness of thought processes), memory retrieval deficits, impaired set shifting and maintenance, impaired problem solving, poor visuospatial function, decreased fluency, and other language abnormalities. They often have prominent mood disorders.

• Patients with PD who have both dementia and depression have more severe disabilities and experience faster cognitive decline.

• In some cases, the neuropsychological findings may resemble those of AD.

• Dementia is more common in patients with akinetic-rigid syndromes than in those with predominating tremors.

• Atypical neurological features of PD (eg, early occurrence of autonomic failure, symmetrical disease presentation, moderate response to dopamine agonists) are associated with more severe dementia.

• Psychiatric examination

• Patients with PD, even without dementia, respond slowly to questions and requests. They are usually dependent, fearful, indecisive, and passive. As the disease progresses, they become increasingly dependent upon spouses or caregivers.

• Hallucinations, illusions, delusions, agitation, and mania can occur as adverse effects of treatment with levodopa.

Causes:

• Most cases of PD are sporadic (ie, do not occur in geographic, racial, ethnic, or genetic clusters).

• A minority of patients have familial inheritance.

• The development of dementia may be associated with the presence of certain apolipoprotein E (ApoE) gene alleles (eg, e2, e4).

	DIFFERENTIALS	Section 4 of 10
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Depression
Huntington Disease Dementia
Vascular Dementia

Other Problems to be Considered:

Alzheimer disease
Creutzfeldt-Jakob disease
Lewy body dementia
Multiple system atrophy
Progressive supranuclear palsy