CL-1

Parkinson’s Disease Dementia (PDD)A Clinical Perspective

Howard Feldman, MDCM, FRCP (C)Professor and Head

Division of NeurologyDirector-Clinic for Alzheimer Disease and Related Dementias

University of British Columbia Vancouver, British Columbia, Canada

CL-2

Overview of Parkinson’s Disease Dementia

Clinical presentation and definition of PDDDisease burden and need for treatmentDiagnostic differentiation from other dementia

syndromes and diagnostic criteria Identification and diagnosis in routine

clinical practice

CL-3

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)

CL-4

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

CL-5

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

CL-6

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

10-4

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

Pro

toco

l_P

DD

2311

EX

PR

ES

S S

ec 9

.5 A

ppen

dix

227

DV

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

CL-8

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

Pro

toco

l_P

DD

2311

EX

PR

ES

S S

ec 9

.5 A

ppen

dix

227

DV

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

Pro

toco

l_P

DD

2311

EX

PR

ES

S S

ec 9

.5 A

ppen

dix

227

DV

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

Step 3 – Supportive prospective positive criteria PD

CL-10

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.

13-6

CL-11

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¶

15-10

† 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.

CL-12

The Clinical Phenomenology of PDDand Contrast With AD

CL-13

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

CL-14

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.

CL-15

Behavioral Profiling in PD and PDD

Changes in personality frequentDepressive 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

CL-16

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.

CL-17

Diagnosing PDD

The DSM criteria

CL-18

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

1

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

CL-19

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)

1

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

CL-20

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

10-4

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

CL-21

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.

CL-22

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