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Parkinson’s Disease Dementia (PDD)A Clinical Perspective

Howard Feldman, MDCM, FRCP (C)

Professor and HeadDivision of Neurology

Director-Clinic for Alzheimer Disease and Related Dementias University of British Columbia

Vancouver, British Columbia, Canada

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Overview of Parkinson’s Disease Dementia

Clinical presentation and definition of PDD

Disease burden and need for treatment

Diagnostic differentiation from other dementia syndromes and diagnostic criteria

Identification and diagnosis in routine clinical practice

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Case Presentation

63-yr old male, retired bus driver 10-yr history of PD (fulfilling UK Brain Bank Criteria) Initial presentation: R sided resting tremor, rigidity and

bradykinesia Motor symptoms initially improved with

l-dopa 300 mg/day Wearing-off dyskinesia and motor fluctuations after a

number of years of L- dopa treatment Dopamine agonist (bromocriptine) and entacapone

initiated 8 yr into illness gradual cognitive decline and recurrent

visual hallucinations (animals and children in the house)

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Case Presentation

Behaviorally less motivated, excessive daytime sleepiness, inattentive and forgetful especially for recent events and conversations

Thought process slower, trouble navigating in his own home

Less involved in activities at home, increased assistance needed in ADL

Dopaminergic medication decreased, hallucinations became less frequent, but motor symptoms worsened

Additional hx of sleep disorder elicited– Suggestive REM sleep behavioral disorder 10 yr prior

to motor symptom onset

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Examination Findings

PE: Stooped posture Cooperative; intermittently drowsy MMSE 21/30: time (-3), poor recall (-3), poor visual construction (-

1) and difficulties with serial 7’s (-2 ). Bradymimia; hypophonic speech Marked bradykinesia bilaterally, increased axial rigidity, cogwheel

rigidity in all extremities Gait: Small steps, festinating, severe start hesitation, postural

instability and retropulsion

Total UPDRS score 55, motor part III score 27 Hoehn and Yahr stage 3

Diagnosis: Parkinson’s disease dementia

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Parkinson’s Disease Dementia

PDD is a cognitive, and neuropsychiatric disorder that occurs in patients with Parkinson’s disease

Core of diagnosis is Idiopathic Parkinson’s disease

PDD follows a PD diagnosis

– Cognitive decline at least 1 yr after PD

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CL-7Idiopathic PD Based on UK Parkinson’s Disease Society Brain Bank Criteria

Step 1—Diagnosis of Parkinsonian syndrome

Bradykinesia and ≥ 1 of the following:

– Muscular rigidity

– 4 to 6 Hz rest tremor

– Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction

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Hughes AJ, et al. J Neurol Neurosurg Psychiatry. 1992;55:181-184.

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History of repeated strokes with stepwise progression of parkinsonian features

History of repeated head injury

History of definite encephalitis

Oculogyric crises

Neuroleptic treatment at onset of symptoms

Sustained remission

Strictly unilateral features after 3 yr

Supranuclear gaze palsy

Cerebellar signs

Early severe autonomic involvement

Early severe dementia with disturbances of memory, language, and praxis

Babinski sign

Presence of cerebral tumor or NPH on imaging study

Negative response to large doses of levodopa

MPTP exposure

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Hughes AJ, et al. J Neurol Neurosurg Psychiatry. 1992;55:181-184.

Step 2 – Exclusion criteria

Idiopathic PD Based on UK Parkinson’s Disease Society Brain Bank Criteria

CL-9Idiopathic PD Based on UK Parkinson’s Disease Society Brain Bank Criteria

≥ 3 required for diagnosis of definite Parkinson’s disease – Unilateral onset– Rest tremor present– Progressive disorder– Persistent asymmetry affecting side of onset most– Excellent response (70% to 100%) to levodopa– Severe levodopa-induced chorea– Levodopa response for ≥ 5 yr– Clinical course of ≥ 10 yr

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Hughes AJ, et al. J Neurol Neurosurg Psychiatry. 1992;55:181-184.

Step 3 – Supportive prospective positive criteria PD

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Prevalence of PDD

Prevalence of PD

– 500,000 Americans currently believed to have PD†

– Approximately 50,000 additional cases diagnosed each year†

Prevalence of PDD

– Cross-sectional prevalence of dementia ranges from 24%† to 40%‡ in patients with PD§

Risk of developing dementia is 4 to 6 times higher with PD compared with age-matched controls||,¶

† Parkinson’s Disease Backgrounder: NINDS. http://www.ninds.nih.gov/disorders/parkinsons_disease/parkinsons_disease_backgrounder.htm ‡ Cummings JL. Int J Geriatr Psychiatry. 1988;1:24-36; § Aarsland D, et al. Mov Disord. 2005;20:1255-1263.|| Hughes TA, et al. Neurology. 2000;54:1596-1602; ¶ Aarsland D, et al. Neurology. 2001;56:730-796.

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Impact and Burden of PDD

Dementia and associated behavioral symptoms (ie, hallucinations) predict and decrease time to nursing home placement†,‡,§

Cognitive and behavioral symptoms in PD patients are greatest contributors to caregiver distress||

Risk of mortality increased when PD patients develop dementia¶

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† Aarsland D, et al. J Am Geriatr Soc. 2000;48:938-942; ‡ Goetz CG, et al. Neurology. 1993;43:2227-2229.§ Parashos SA, et al. Mayo Clin Proc. 2002;77:918-925; || Aarsland D, et al. Int J Geriatr Psychiatry. 1999;14:866-874; ¶ Hughes, et al. Acta Neurol Scand. 2004.

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The Clinical Phenomenology of PDDand Contrast With AD

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Cognitive Profile in PDD Impaired memory (retrieval > amnestic pattern)

– Benefit from external cues– Preserved recognition

Executive dysfunction– Concepts, problem solving, set shifting – Internally cued behavior

Attentional impairment– Reaction times and vigilance– Fluctuations

Visuospatial deficit– Visuospatial analysis and orientation – Tasks that require planning and sequencing

Bradyphrenia

Emre M, Lancet Neurology. 2003;2:229-237

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Cognitive Profile in AD

Language changes§

– Anomia,

– Information content in spontaneous speech,

– Impaired comprehension

Memory deficit (retrieval and retention)‡

Apraxia

Both PDD and AD have progressive functional decline

‡ Helkala EL, et al. Ann Neurol. 1988;24:214-217.§ Cummings JL, et al. Neurology. 1988;38:680-684.¶ Stern Y, et al. Arch Neurol. 1993;50:1040-1045.

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Behavioral Profiling in PD and PDD

Changes in personality frequent

Depressive symptoms common†

More frequent visual hallucinations in PDD‡

REM behavioral sleep disorder prior to PD (65%)§,||

† Aarsland D, et al. Int J Geriatr Psychiatry. 2001;16:184-191.‡ Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations in PD Brain. 2000;123:733-734.§ Schenck C, Bundlie S, Mahowald. Sleep. 2003;26:A 316, || Boeve B, et al. Neurology. 61:40-45

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Behavioral Symptoms Presents a Significant Therapeutic Challenge

Dopaminergic therapy– Exacerbating/ triggering psychotic symptoms

Neuroleptics (atypical)– Hypersensitivity to neuroleptics† – Complications of antipsychotics in elderly

(mortality rates)‡

– Worsening cognitive function§

– Worsening motor problems

† Aarsland D, et al. Nord J Psychiatry. 2003;57:94. SCNP Abstract: Poster 1.‡ http://www.fda.gov/cder/drug/advisory/antipsychotics.htm. Accessed April 4, 2006§ Ballard C, et al. BMJ. 2005.

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Diagnosing PDD

The DSM criteria

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Diagnosis of Dementia Based on DSM-IV Criteria for Dementia Due to Other Medical Conditions

Memory impairment One or more of the following cognitive disturbances

– Aphasia – Apraxia – Agnosia – Executive dysfunction

Significant impairment in social or occupational functioning and decline from previous level of functioning

Deficits do not occur exclusively during the course of a delirium

There is evidence that the disturbance is the direct consequence of condition other than AD or CVD

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Diagnostic & Statistical Manual of Mental Disorders – IV Text Revision. American Psychiatric Association. 1994

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Diagnosis of Dementia Based on DSM-IV Criteria for Dementia Due to PD 294.1

Presence of dementia judged to be direct pathophysiological consequence of PD

Occurs in patients with PD

Characterized by

– Cognitive and motor slowing

– Executive impairment

– Impairment in memory (retrieval)

There are a number of syndromes that have dementia, parkinsonian movement disorders and other neurological features (ie, PSP, OPCA, VaD)

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Diagnostic & Statistical Manual of Mental Disorders – IV Text Revision. American Psychiatric Association. 1994

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Parkinson’s Disease Dementia—Differentiation from Other Dementia Syndromes

Alzheimer’s disease (AD)†

– “Probable AD” by NINCDS-ADRDA criteria state that PD must be excluded for diagnosis

– Parkinsonism can develop with advancing AD, but is usually not prominent or full blown PD

Dementia with Lewy bodies (DLB)‡

– Parkinsonism and dementia temporal relationship

• Dementia occurs before, concurrently or within 1 year of the onset of parkinsonism

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† McKhann G, et al. Neurology. 1984;34:939-944.‡ McKeith IG, et al. Neurology. 2005;65:1-10.

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PDD Can be Diagnosed in Routine Clinical Practice

DSM criteria for dementia due to other medical conditions can be applied by physicians for diagnosis in routine clinical practice

These criteria do not require specific psychometric test scores

The temporal relationship between the onset of the dementia and the diagnosis of PD can be obtained from patient history (at least 1 year)

† McKeith I, et al. Neurology. 2005;65:1863-1872.

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Conclusion

PDD is a clinical disease with a unique progression– Begins with Parkinson’s disease – Motor signs present for years before onset

of dementia – Dementia syndrome characterized by memory,

executive, attentional, and functional deficits– Prominent neuropsychiatric symptoms with

psychotic features PDD can be identified and diagnosed in usual settings

of care Need for effective treatments

– There are no currently approved treatment options