Parkinson’s Disease Dementia (PDD) A Clinical Perspective Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM Parkinson’s Disease Dementia (PDD) A Clinical Perspective Howard Feldman, MDCM, FRCP (C) Professor and Head Division of Neurology Director-Clinic for Alzheimer Disease and Related Dementias University of British Columbia Vancouver, British Columbia, Canada

Overview of Parkinson’s Disease Dementia Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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)

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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

Parkinson’s Disease Dementia Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 10-4 4/19/2017 1:54 AM 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

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 27 DV 4/19/2017 1:54 AM Idiopathic 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 Protocol_PDD2311EXPRESS Sec 9.5 Appendix 2 Hughes AJ, et al. J Neurol Neurosurg Psychiatry. 1992;55:181-184.

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 27 DV 4/19/2017 1:54 AM Idiopathic PD Based on UK Parkinson’s Disease Society Brain Bank Criteria Step 2 – Exclusion criteria 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 Protocol_PDD2311EXPRESS Sec 9.5 Appendix 2 Hughes AJ, et al. J Neurol Neurosurg Psychiatry. 1992;55:181-184.

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 27 DV 4/19/2017 1:54 AM Idiopathic PD Based on UK Parkinson’s Disease Society Brain Bank Criteria Step 3 – Supportive prospective positive criteria PD ≥ 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 Protocol_PDD2311EXPRESS Sec 9.5 Appendix 2 Hughes AJ, et al. J Neurol Neurosurg Psychiatry. 1992;55:181-184.

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 13-6 Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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.

Impact and Burden of PDD Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 15-10 4/19/2017 1:54 AM 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¶ † 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.

The Clinical Phenomenology of PDD and Contrast With AD Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM The Clinical Phenomenology of PDD and Contrast With AD

Cognitive Profile in PDD Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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

Cognitive Profile in AD Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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.

Behavioral Profiling in PD and PDD Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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

Behavioral Symptoms Presents a Significant Therapeutic Challenge Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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.

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM Diagnosing PDD The DSM criteria

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 1 4/19/2017 1:54 AM 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 Diagnostic & Statistical Manual of Mental Disorders – IV Text Revision. American Psychiatric Association. 1994

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 1 4/19/2017 1:54 AM 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) Diagnostic & Statistical Manual of Mental Disorders – IV Text Revision. American Psychiatric Association. 1994

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 10-4 4/19/2017 1:54 AM 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 † McKhann G, et al. Neurology. 1984;34:939-944. ‡ McKeith IG, et al. Neurology. 2005;65:1-10.

PDD Can be Diagnosed in Routine Clinical Practice Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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.

Parkinson’s Disease Dementia (PDD): A Clinical Perspective (CL) 4/19/2017 1:54 AM 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