AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Parkinson disease (Parkinson's disease, PD) is a disabling, progressive condition that is predominantly thought of as a movement disorder. 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 overall incidence of cognitive impairment in PD increases with age from 2.7% per year at age 55-64 years to almost 14% per year in the 70-79 year age group. The prevalence of dementia in PD ranges from 20-40%, with the disease conferring a 2-6 fold increased risk compared with control populations. In the affected age group, comorbidity with other neurodegenerative disorders, particularly Alzheimer disease (AD) and cerebrovascular disease, is common. The relatively high prevalence of depression in patients with PD is another confounder in the diagnosis of Parkinson disease dementia (PDD).

The clinical manifestations of PDD are generally distinguishable from what are termed cortical dementias; however, these disorders largely overlap other disorders that manifest the typical subcortical pattern.

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 direct and indirect loops affecting nigral, pallidal, and thalamic structures. Different areas of the caudate project to different areas of the prefrontal cortex. Damage to the pathways connecting the structures or damage to the structures themselves can elicit the frontal-like cognitive deficits that characterize cognitive dysfunction in Parkinson disease (Parkinson's disease, 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).

Pathologic substrates in Parkinson disease dementia (PDD) include neuronal loss, basal forebrain degeneration, neurofibrillary tangles, neuritic plaques, and Lewy bodies. The neuronal loss is most notable in the substantia nigra and the striatum. At the molecular level, alpha-synuclein is the principal pathologic protein, being found in the Lewy bodies and Lewy neurites of both PD, PDD, and dementia with Lewy bodies (another dementia with a large degree of clinical and pathologic overlap with PDD).

Frequency

United States

Frequency of dementia in Parkinson disease (Parkinson's disease, PD) is variable with most estimates, ranging from 20-40%, and has wide ranging affects on quality of life and survival.

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 1,145/100,000 in patients >80 y). Approximately 41.3% of these patients had dementia. The frequency of dementia increases with age (approximately 3% of patients aged 50-59 y and almost 14% of patients aged 70-79 years 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.

Risk factors for development of dementia include age, lower education, male gender, presence of hallucinations, depression, sleep disturbance, and disease duration.

International

In a prospective longitudinal study in Leeds, United Kingdom, survival analysis showed that the cumulative incidence of dementia in a Parkinson disease (Parkinson's disease, 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 Parkinson disease (Parkinson's disease, PD) and dementia than in those with PD without dementia.

Race

Parkinson disease 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 Parkinson disease, with or without dementia, approximately twice as often as women do.

Age

The age of onset of Parkinson disease (Parkinson's disease, 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  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The development of dementia in patients with Parkinson disease (Parkinson's disease, PD) is associated with the following factors:
• • Male gender
  • 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
  • Fluctuations in cognition
  • 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 within 12 months of the onset of motor features is generally not supportive of a diagnosis of PD. It suggests dementia with parkinsonian features, most notably Dementia with Lewy bodies (see Differentials). However, the line separating these 2 conditions is becoming less and less clear from a clinical, molecular, and pathologic viewpoint.

Physical

A distinctive clinical phenotype for Parkinson disease dementia (Parkinson's disease dementia, PDD) has not been established. Patients with Parkinson disease (PD) exhibit a spectrum of cognitive abnormalities, ranging from impairment in specific cognitive domains to severe dementia. Difficulties in describing the clinical phenotype of PDD are in part due early studies using tests that were confounded by the motor slowing associated with PD.

• Mild cognitive changes on detailed neuropsychological tests are almost ubiquitous. The most common difficulty in patients with PD is in the domain of executive function or a mild subcortical dementia characterized by deficits in word list generation, shifting sets, problem solving skills, and a retrieval type memory deficit.  
• Disorders of executive function
• • This is the core early deficit in disorders of the basal ganglia. Interruption of the striatal-pallidothalamic-dorsolateral circuit is likely the anatomic basis of executive dysfunction in PD and other movement disorders. 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
• • Visuospatial deficits are reported in PD; however, many studies suggest that these deficits are not an integral part of the disorder. Neuropsychological testing reveals deficits resulting in difficulty with line orientation, block design, and picture arrangement. These deficits are known to increase with advancing age in PD patients.
  • 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 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
• • Aphasia is uncommon in PD; however, speech disorders affecting articulation are prevalent. This can manifest as reiterative disorders and dysarthria.
  • "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. Those patients with more severe dementia are more likely to have concomitant Alzheimer's or Lewy body dementia pathology.
  • 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.
  • 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 Parkinson disease are sporadic (ie, do not occur in geographic, racial, ethnic, or genetic clusters).
• A minority of patients have familial inheritance.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Alzheimer disease
Creutzfeldt-Jakob disease  
Multiple system atrophy
Progressive supranuclear palsy
Frontotemporal dementia with parkinsonism

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No specific tests are used for Parkinson disease dementia.
• Although findings are not useful for diagnostic purposes, associations with specific APOE e alleles have been variably found. Studies evaluating the role of the APOE4 allele have been inconclusive; a more recent and rigorously designed study found no association between APOE4 and Parkinson disease dementia.

Imaging Studies

• Structural imaging
• • CT scanning and MRI do not help establish the diagnosis.
  • As in PD without dementia, patients with dementia may show decreased width of the pars compacta, decreased signal in the putamen, or both.
• Positron emission tomography
• • PD is associated with decreased uptake and retention of 18F-dihydroxyphenylalanine (18F-DOPA) in the basal ganglia.
  • Reports of functional imaging in patients with PD and cognitive impairment have been few. Some have shown changes similar to those observed in AD (asymmetrical decreased 18fluorodeoxyglucose-positron emission tomography [18FDG-PET] uptake on the parietal and posterior temporal regions) and others have not.
  • Some studies of patients with PD and either dementia or depression have demonstrated marked deficits in prefrontal activation and hypoperfusion in the superior temporal regions. The latter is more impaired in patients with PD and dementia; the former, in patients with PD and depression.

Histologic Findings

Parkinson disease is characterized by the death of a heterogeneous cell population, including neuromelanin-laden dopaminergic neurons of the substantia nigra pars compacta, aminergic brain nuclei, cholinergic neurons, neurons in the hypothalamus, and small cortical neurons (particularly in the cingulate gyrus and the entorhinal cortex).

Lewy bodies are found in the brainstem, basal forebrain, and cortex. In the first 2 regions, Lewy bodies are large, eosinophilic, hyaline inclusion bodies with clear halos and targetlike appearances. Cortical Lewy bodies are smaller and have less distinct cores.

A greater degree of medial nigral cell loss can result in more severe cognitive impairment. The degree of cognitive impairment also correlates with the density of Lewy neurites in the cornu ammonis 2 field of the hippocampus. Lewy neurites are degenerating, ubiquitin-positive neuronal processes or neurites that are different from Lewy bodies.

Senile plaques and neurofibrillary tangles are found in the cortices of patients with severe dementia, most prominently in their hippocampi. Other changes often include granulovacuolar degeneration and cortical cell loss.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Although no specific therapy exists for dementia, the American Academy of Neurology recently evaluated the evidence regarding the use of cholinesterase inhibitors in Parkinson disease dementia (Parkinson's disease dementia, PDD). Based on their review, they suggested that rivastigmine and donepezil are probably effective in treating the dementia. The risk of potentially exacerbating motor symptoms may limit their widespread use.
• Aggressively treat concurrent mood disorders and psychoses. For mood disorders, tricyclic agents, specifically the secondary amines (eg, nortriptyline, desipramine), heterocyclic agents, or serotonin reuptake inhibitors (SSRIs) are indicated. For psychoses, atypical antipsychotics are preferred. Clozapine is the agent of choice, but its use may be limited because of adverse effects. Quetiapine has not been tried extensively. Olanzapine and risperidone worsen motor function.
• Focus treatment on managing the motor manifestations of Parkinson disease (Parkinson's disease, PD).
• Anticholinergic drugs used for the treatment of motor manifestations of PD may exacerbate memory impairment. When possible, avoid these medications.

For related information, see Medscape's CME activity, Simvastatin Linked to Reduced Incidence of Dementia, Parkinson's Disease.

Surgical Care

Surgical treatment of Parkinson disease (eg, thalamotomy, pallidotomy, thalamic or subthalamic stimulation) improves some of the motor features of the disease but has no effect on cognitive deficits.

Consultations

The treatment of patients with Parkinson disease and dementia is best accomplished using a team approach.

• Motor manifestations, especially those that develop late in the course of the disease, are best managed by neurologists or internists experienced in the treatment of patients with dementia disorders.
• A psychiatrist who is familiar with the psychopharmacologic issues of Parkinson disease treatment should be part of the team, particularly when a mood disorder or psychosis complicates the course of illness.
• Physical therapists should work with the patient to ensure optimal neuromuscular fitness.
• A nutritionist can help ensure adequate energy intake, particularly when low-protein diets are needed to avoid adverse effects of levodopa.

Diet

Encourage patients to adopt a low-protein diet because such a diet may reduce fluctuations in dopamine levels.

Activity

Encourage patients to keep as active as possible. Recommend physical therapy to optimize motility.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Various medications are used to treat the movement disorders of PD, but these agents do not usually help the psychiatric symptoms of the disorder. In fact, they may worsen cognitive and psychiatric symptoms. Patients with PD dementia respond to cholinesterase inhibitors, but improvement observed in any dementing disorder, given the products available currently, is neither dramatic nor permanent.

Drug Category: Centrally acting acetylcholinesterase inhibitors

Used to palliate cholinergic deficiency.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

Patients with Parkinson disease must have regular follow-up care to ensure adequate treatment of motor and behavioral abnormalities. Once patients are stable on medications, provide follow-up care at least every 3-6 months and periodically adjust medication dosages as necessary.

In/Out Patient Meds

• Treatment of patients with Parkinson disease relies on the use of levodopa, dopamine agonists, monoamine oxidase type B (MAO-B) and catechol methyltransferase inhibitors, and anticholinergics.
• Patients with psychosis can be treated with atypical neuroleptics.
• SSRIs and tricyclics are useful for the treatment of patients with depressive symptoms. MAO-B inhibitors contraindicate the use of many of these agents. Before starting any medication, possible interactions must be considered. MAO-B inhibitors contraindicate the use of many of these agents. Before starting any medication, possible interactions must be considered.

Deterrence/Prevention

To date, no strategy, method, treatment, or therapy prevents Parkinson disease and dementia.

Complications

• Patients with Parkinson disease and dementia with associated hallucinations are at high risk of dying within a few years of placement in care facilities.
• Psychotic states can develop as adverse effects of treatment with levodopa or, to a lesser extent, dopamine agonists.

Prognosis

Patients with Parkinson disease and dementia have a poorer prognosis than patients with Parkinson disease without dementia.

Patient Education

For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education articles Parkinson Disease Dementia, Parkinson Disease, Dementia Medication Overview, and Alzheimer Disease.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Driving ability in patients with Parkinson disease must be assessed on an individual basis. Patients with prominent bradykinesia have difficulty moving the foot from the accelerator to the brake.
• Advise patients taking the non–ergot-derived dopamine agonists pramipexole and ropinirole not to drive or engage in hazardous activities because these medications produce sleep attacks.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Aarsland D, Zaccai J, Brayne C. A systematic review of prevalence studies of dementia in Parkinson's disease. Mov Disord. Oct 2005;20(10):1255-63. [Medline].
• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington DC: American Psychiatric Association; 2000.
• Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol. Aug 1993;50(8):873-80. [Medline].
• Cummings JL, Darkins A, Mendez M, Hill MA, Benson DF. Alzheimer's disease and Parkinson's disease: comparison of speech and language alterations. Neurology. May 1988;38(5):680-4. [Medline].
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• Ebmeier KP, Calder SA, Crawford JR, Stewart L, Besson JA, Mutch WJ. Clinical features predicting dementia in idiopathic Parkinson's disease: a follow-up study. Neurology. Aug 1990;40(8):1222-4. [Medline].
• Galvin JE, Pollack J, Morris JC. Clinical phenotype of Parkinson disease dementia. Neurology. Nov 14 2006;67(9):1605-11. [Medline].
• Goetz CG, Blasucci LM, Leurgans S, Pappert EJ. Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients. Neurology. Sep 26 2000;55(6):789-94. [Medline].
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• Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. Mar 13 2007;68(11):812-9. [Medline].
• Marder K, Tang MX, Cote L, Stern Y, Mayeux R. The frequency and associated risk factors for dementia in patients with Parkinson's disease. Arch Neurol. Jul 1995;52(7):695-701. [Medline].
• Mayeux R. Parkinson's disease: A review of cognitive and psychiatric disorders. Neuropsychiatr Neuropsychol Behav Neurol. 1990;3:3-14.
• Mayeux R, Denaro J, Hemenegildo N, Marder K, Tang MX, Cote LJ, et al. A population-based investigation of Parkinson's disease with and without dementia. Relationship to age and gender. Arch Neurol. May 1992;49(5):492-7. [Medline].
• Miyasaki JM. New practice parameters in Parkinson's disease. Nat Clin Pract Neurol. Dec 2006;2(12):638-9. [Medline].
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Article Last Updated: Aug 9, 2007