Cognitive Changes with Parkinson Disease: The Good News and Not So Good News

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Cognitive Changes with Parkinson Disease The
Good News and Not So Good News

• James B. Leverenz, M.D.
• Neurology and Psychiatry and Behavioral Sciences
• University of Washington School of Medicine
• VA Northwest Network Mental Illness and
  Parkinsons Disease Research, Education, and
  Clinical Centers
• Washington Parkinson Disease Registry

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Overview

• Parkinson disease
• History, epidemiology, and neuropathology
• Cognitive Change in PD
• clinical characteristics and diagnosis
• neuropathology
• PDD treatment options
• EXPRESS study and other AChEis

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Clinical Symptoms in Parkinson Disease

• Tremor (resting)
• Rigidity
• Bradykinesia
• Postural instability

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Prevalence of PD
Dorsey et al, Neurology, 68384-6, 2007.
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Pathology in Parkinson Disease

• Neuronal loss and Lewy body inclusions in the
  substantia nigra, locus ceruleus, basal forebrain
  and cerebral cortex
• Clinical history of parkinsonism

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Lewy Body Inclusions

• Characteristic inclusions in substantia nigra
  neurons of patients with Parkinson disease
• Immunoreactive for neurofilaments, ubiquitin and
  alpha-synuclein, but not tau (NFT are tau and
  ubiquitin positive)
• In substantia nigra it is cytoplasmic, round,
  eosinophilic with clear halo
• In cortex less distinct appearance, best
  visualized with alpha-synuclein
  immunohistochemistry

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Pathology in Parkinson Disease
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Pathology in Parkinson Disease
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Pathology in Parkinson Disease
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Pathology in Parkinson DiseaseImproved
Detection of LB Pathology

• Alpha-synuclein (SNCA) mutations in familial PD
• SNCA immunoreactivity in all LBs
• classic brainstem LB
• cortical LB
• Lewy neurites

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SNCA Pathology in the Substantia Nigra
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SNCA Pathology in the Cerebral Cortex
Cerebral Cortex
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LRP Staging in PD
Braak H et al, J Neurology, 2002
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Cognitive Change and Parkinson Disease
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Definitions

• Dementia (DSM IV)
• Multiple cognitive deficits including memory plus
• aphasia, apraxia, agnosia, or a disturbance in
  executive functioning
• Sufficiently severe to cause impairment in
  occupational or social functioning
• Represent a decline from a previously higher
  level of functioning

Diagnostic and Statistical Manual, Fourth
Edition, Text Revised (DSM-IV-TR), 2000.
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Definitions

• Mild Cognitive Impairment (MCI)
• Evidence of a memory impairment
• can include non-memory components
• Preservation of general cognitive and functional
  abilities
• Absence of diagnosed dementia

Peterson RC et al, Mild Cognitive Impairment.
Arch Neurol, 1999.
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Impact and Burden of Cognitive Impairment in PD

• Cognitive and behavioral symptoms in PD patients
  are greatest contributors to caregiver distress1
• Risk of mortality increased when PD patients
  develop dementia2
• Considerable unmet medical need
• Increased burden for patients and families

1. Aarsland D, et al. Int J Geriatr Psychiatry.
199914866-874. 2. Hughes TA, et al. Acta
Neurol Scand. 2004110118-123.
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Prevalence of PDD

• Prevalence of PD
• Approximately 50,000 additional cases diagnosed
  each year1
• 500,000 to 1.5 million Americans are currently
  believed to have PD1
• Prevalence of PDD,
• prevalence of dementia is up to 40 in patients
  with PD1
• 78 of a population-based, representative cohort
  of patients with PD developed dementia during an
  8-year study period2
• Risk of developing dementia is 4 to 6 times
  higher with PD compared with age-matched
  controls3,4

• 1. Cummings JL. J Geriatr Psychiatry Neurol.
  1988124-36., 2. Hughes TA, et al. Neurology.
  2000541596-1602.
• 3. Aarsland D, et al. Arch Neurol.
  200360387-392., 4. Aarsland D, et al.
  Neurology. 200156730-736.

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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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Williams-Gray CH et al, Brain, 1787-98, 2007.
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• 66 of PD patients showed evidence of cognitive
  change
• 10 developed dementia during 3.5 year follow up
• ? more mixed cognitive profile

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BGPCC and UW Experience

• BGPCC Neuropsychological testing
• UW PD Biomarker study

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BGPCC and UW Experience

• BGPCC
• WA APDA pilot project (Martha Glisky)
• Logical memory, verbal fluency (animals, FAS),
  trails A, trails A-B, Boston naming, Judgement of
  line orientation, WASI vocab, WASI matrix
  reasoning
• 68 non-demented patients

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BGPCC - Principle Components Analysis
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BGPCC - Principle Components Analysis
Attention/working memory
Memory
Visuospatial
Verbal Fluency
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BGPCC - Performance on Core Testing
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BGPCC and UW Experience

• UW PD Biomarker Study
• Core tests available logical memory, trails
  A-B
• 34 non-demented patients

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UW PDB - Performance on Core Testing
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BGPCC and UW Experience

• Mixed cognitive impairment common in PD patients
  without dementia
• Four core domains
• attention/executive function
• memory
• visuospatial
• verbal fluency
• Clinical and biological significance our next
  step

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What Is the Neuropathologic Basis of Cognitive
Change in Parkinson Disease?(is it just
Alzheimers disease?)
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Neuropathology of PDDCortical LB Pathology
Correlates With Dementia
1-15\ DV
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Neuropathology of PDDAD Pathologic Change

• Case selection
• Treatment-responsive PD precedes dementia
• Neuropathology
• Alpha-synuclein immunohistochemistry
• Up-to-date criteria for AD diagnosis
• Braak IV to VI and CERAD plaque stage B or C

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SummaryNeuropathology of PDDAD Pathologic
Change

• Total of 110 cases with PDD studied
• DSM III or III-R criteria for dementia diagnosis
• Age in late 70s at death
• Neocortical LB pathology correlates with
  dementia
• Only 7 (6) cases fulfilled pathologic
  criteriafor AD

Aarsland D, et al. Ann Neurol. 200558773-776.
Apaydin H, et al. Arch Neurol. 200259102-112.
Braak H, et al. Neurology. 2005641404-1410.
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Parkinson Disease Dementia Demographics AD
Comparison Group
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Parkinson Disease Dementia Parkinsonism
B Bradykinesia T Tremor R Rigidity G
Postural / Gait PI Postural Instability
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PDD vs AD Alone
Neuropsychology Memory

plt0.05
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PDD vs AD Alone
Neuropsychology Attention
plt0.05
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Parkinsons Disease Dementia Summary and
Comparison to AD
B Bradykinesia T Tremor R Rigidity G
Postural / Gait PI Postural Instability
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Formed Visual Hallucinations
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Parkinson Disease Dementia Neuropathology
Neurites only
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PDD in a Community-Based, Autopsy-Confirmed
Dementia Sample

• Diffuse Lewy body/ASN pathology
• Limited AD pathology
• Unique clinical and genetic characteristics
• Clinical diagnosis highly predictive

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SummaryNeuropathology of PDDAD Pathologic
Change

• Clinical diagnosis highly predictive of Lewy body
  pathology
• Significant AD pathology is relatively uncommon
  in clinically diagnosed PDD cases
• Dementia in PD patients is
• primarily due to Lewy body pathology
• and not coexistent AD

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Treatment Options for Cognitive Change in PD
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Cholinergic Activity in PDD and AD
Distinct Disorders with Common Cholinergic
Deficit
Cholinergic Deficit
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Is There a Cholinergic Deficit in the PD with
dementia ?
Bohnen, Arch Neurol, 601745-8, 2003.
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Cholinesterase Inhibitors
H
C
3

C
H
Acetylcholine
O
3
N
H
C
3
O
C
H
3
Rivastigmine Mechanism AChE/BuChE-I
O
N
Donepezil Mechanism AChE-I
Galantamine Mechanism AChE-I
Physicians Desk Reference 2003, 57th ed.
Montvale, NJ Medical Economics Company November
2002
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AChEi for PDD ?
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EXPRESS StudyObjective and Study Design

• Objective
• Evaluate the efficacy and safety of EXELON in
  patients with mild to moderate PDD
• Study design
• 24-wk, double-blind, randomized,
  placebo-controlled, parallel-group, multicenter
  study and an additional 24-wk open-label study
• 541 patients with mild to moderate PDD enrolled
  from 12 countries in Europe and Canada
• Randomized 21 (3-12 mg/day EXELONplacebo)

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EXPRESS StudyConsistent Efficacy Results Across
Primary and Secondary Endpoints
Mean changes on efficacy measures at week 24.,
Positive values indicate improvements and
negative value deteriorations. OC analysis.,
ITT-RDO analysis. , Not performed for all sites
so only OC analyses were available.
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Most Frequent Discontinuations Due to AEs ( 1
in Any Group)
Core
Extension
Plc-EXELONN123n ()
EXE-EXELONN211n ()
PlaceboN179n ()
EXELONN362 n ()
127 (70.9)
303 (83.7)
Total patients with AE(s)
93 (75.6)
159 (75.4)
17 (13.8)
21 (10.0)
20 (11.2)
66 (18.2)
All AE discontinuations
1 (0.6)
13 (3.6)
Nausea
5 (4.1)
1 (0.5)
1 (0.6)
7 (1.9)
Vomiting
3 (2.4)
0
2 (1.6)
1 (0.5)
0
6 (1.7)
Tremor
2 (1.1)
4 (1.1)
Diarrhea
0
0
2 (1.6)
1 (0.5)
2 (1.1)
4 (1.1)
Hallucination
1 (0.8)
0
2 (1.1)
1 (0.3)
Anorexia
3 EXELON-treated and 2 placebo-treated patients
in the core study and 2 patients in Plc-EXELON
group had multiple AEs leading to discontinuation.
EXE-EXELON On EXELON in Core Study and
Extension Plc-EXELON On placebo in Core Study,
EXELON in Extension
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Safety ConclusionCore and Extension Studies

• Most frequent AEs in EXELON group were nausea,
  vomiting, and tremor
• Tremor was higher in the EXELON group (10) than
  in the placebo group (4)
• No increased incidence of cardiac or psychiatric
  AEs in the EXELON group compared to placebo
• Long-term treatment in PDD (core and open-label
  extension studies totaling 48 weeks) was not
  associated with any new safety concerns

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AChEi in PDD

• Aarsland et al, JNNP 2001
• crossover, donepezil
• Leroi et al, IJGP 2004
• placebo controlled, donepezil
• Ravina et al JNNP 2005
• crossover, donepezil
• Dubois et al AD/PD 2007
• Placebo controlled, donepezil
• Emre et al NEJM 2004
• placebo controlled, rivastigmine

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AChEi in PDD Subject

• Aarsland et al, JNNP 2001
• 14
• Leroi et al, IJGP 2004
• 16
• Ravina et al JNNP 2005
• 22
• Dubois et al AD/PD 2007
• 550
• Emre et al NEJM 2004
• 541

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AChEi in PDD results

• Aarsland et al, JNNP 2001
• MMSE/CIBIC, - NPI
• Leroi et al, IJGP 2004
• - MMSE/DRS, - BPRS
• Ravina et al JNNP 2005
• - ADAScog, MMSE, - BPRS
• Dubois et al AD/PD 2007
• CIBICp, /- ADAScog, - NPI and ADL
• Emre et al NEJM 2004
• ADAScog, CGIC, MMSE, ADL, NPI

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Cognitive Change in Parkinson Disease The Good
News and Not So Good News

• Good news
• this is NOT Alzheimers disease
• treatment is available
• were working hard to address this problem (e.g.
  Udall Center application, WPDR)
• Not So Good News
• this is not an uncommon problem in PD

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Co-Investigators/Collaborators
Cyrus Zabetian, MD, PhD Debby Tsuang, MD,
MSc Stennis Watson, PhD Steve Millard, PhD Ali
Samii, MD Mike Kim, MD Pamela McMillan, PhD Darcy
Vavrek, ND, MS Elaine Peskind, MD Murray A.
Raskind, MD Martha Glisky, PhD Jeff Shaw,
PsyD Monique Giroux, MD Alida Griffith, MD Pinky
Agarwal, MD BGPCC
Supported by the Department of Veterans Affairs,
NIA AG05136 and AG08419
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Co-Investigators/Collaborators

• Advocacy Groups
• APDA
• NWPF
• NWCC
• Private Donors
• Patients and families!

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Washington PD Registry (WPDR)

• Why?
• Rapid subject recruitment
• access to contact
• demographics (e.g., region for clinical trials)
• clinical dataset
• Foundation for larger center
• funding
• Patient/clinician education
• better access to clinical trials

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WPDR

• Please join the WPDR!
• 206-277-6080
• 1-800-329-8387 (ext 66080)
• wpdr_at_u.washington.edu