1. CN-1 Neuropathology of Parkinson’s Disease Dementia James B. Leverenz, MD Associate Professor Neurology and Psychiatry and Behavioral Sciences University of Washington School of Medicine UW Alzheimer’s Disease Research Center VA Northwest Network Mental Illness and Parkinson’s Disease Research, Education, and Clinical Centers

2. CN-2 Overview—Neuropathology of PDD  Dementia in elderly PD patients is primarily due to Lewy body pathology, and not just coexistent AD – Review of AD pathology – Review of PD pathology – Neuropathologic changes in PDD  PDD is associated with severe deficits in the cholinergic system – Biochemical and neuroimaging data – Neuropsychologic data

3. CN-3 Abbreviations and Terminology  PD – Parkinson’s Disease without dementia  PDD – Parkinson’s Disease with dementia  AD – Alzheimer’s Disease  LBP – Lewy Body Pathology – “classic” Lewy body inclusions – alpha-synuclein immuno-positive inclusions and neurites  CERAD – Consortium to Establish a Registry for Alzheimer’s Disease

4. CN-4 Silver stain: plaques and tangles Alzheimer’s Disease—Pathology Silver stain: neuritic plaques Neurofibrillary tangles

5. CN-5 Pathological Criteria for AD  Staging of AD pathologic change – Neuritic plaques (CERAD, absent to frequent) – Neurofibrillary tangles (Braak staging, I - VI)  For pathological diagnosis of AD † – Integrate CERAD and Braak staging evaluating “likelihood” AD changes led to dementia High - CERAD frequent/Braak V or VI Intermediate - CERAD moderate/Braak III or IV Low - CERAD sparse/Braak I or II † Neurobiol Aging. 1997;18(4 suppl):S1-2.

6. CN-6 AD Pathologic Change in Non-Demented Elderly  Knopman et al (JNEN 2003) † – 39 longitudinally followed non-demented cases Mean age 85 years (74 - 95) – AD pathologic change 38 Braak stage I or greater, 4 Braak stage IV or V 37 with sparse or absent neuritic plaques, ~50% with moderate to frequent diffuse plaques – “...cut off points...Braak stage ≥ IV...neuritic plaques ≥ moderate...” † Knopman et al. J Neurol Pathol Exp Neurol. 2003;62:1087-1095.

7. CN-7 AD Pathologic Change in the Elderly Knopman et al. J Neuropathol Exp Neurol. 2003;62:1087-1095. Diffuse plaques Cored plaques Neuritic plaques Braak and Braak stageCERAD plaque ratings 0 - IIIIIIIV - V NoneSparseModerateFrequent Number of subjects 0 2 6 8 10 12 4 14 0 5 15 20 10 25

8. CN-8 Neuropathology of Parkinson’s Disease Substantia nigra pathology Lewy body inclusionsNeuronal loss

9. CN-9 Improved Detection of Lewy Body Pathology  Alpha-synuclein mutations in familial PD  Alpha-synuclein immunoreactivity in all Lewy bodies – Classic brainstem Lewy bodies – Cortical Lewy bodies – Lewy neurites

10. CN-10 Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex Cerebral cortexSubstantia nigra

11. CN-11 Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459. Braak Staging of Lewy Bodies

12. CN-12 What Is the Neuropathologic Basis of Dementia in Parkinson’s Disease?

13. CN-13 Neuropathology of PDD AD Pathologic Change “…contrary to published reports, most patients with parkinsonism who exhibit dementia do not have concomitant Alzheimer’s disease…Some pathogenetic mechanism must be sought to account for this increasingly common cause of cognitive decline in the sufferers of Parkinson’s disease.” —Ball M. Can J Neuro Sci. 1984;11(1 suppl):180-184.

14. CN-14 Neuropathology of PDD Cortical LB Pathology Correlates With Dementia Author, yrPopulationPrimary correlate of dementia Kosaka, 199811 PDDCortical LBs Mattila, 199844 PDDCortical LBs Mattila, 200045 PDDFrontal cortical LBs Hurtig, 200022 PDD vs 20 PD only Cortical LBs Apaydin, 200213 PDDCortical LBs Kovari, 200322 PDDLBs in entorhinal cortex and Brodmann 24 Braak, 200588 PDCortical LBs 1-15\ DV

15. CN-15 Neuropathology of PDD AD 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

16. CN-16 Neuropathology of PDD AD Pathologic Change  Apaydin et al (Arch Neurol, 2002) – Clinical 13 PDD cases (mean age 78.1yr, range 64 - 89) – Pathology 12 with diffuse or transitional Lewy body pathology – 1 case with intermediate likelihood of AD (Braak stage IV, CERAD plaque stage B) 1 case with PSP (no LBP) Apaydin H, et al. Arch Neurol. 2002;59:102-112.

17. CN-17 Neuropathology of PDD AD Pathologic Change  Braak et al (Neurology, 2005) – 88 clinical PD cases with autopsy confirmation of LBP (mean age 75.9 yr; range 60 - 89) – 79 with mild to severe cognitive impairment – MMSE score correlated with stage of LBP (using Braak’s staging of LBP) – Only 2 cases fulfilled criteria for AD pathologically (VI C and IV B) Braak H, et al. Neurology. 2005;64:1404-1410.

18. CN-18 PDD - AD Pathologic Change  Aarsland et al (Ann Neurol, 2005) – Community-based sample of PD (N = 245) – Longitudinal follow-up with cognitive evaluation – 22 autopsied cases (18 demented) – All with limbic or neocortical stage LBP Correlation of LB score to last MMSE – AD pathology limited (all Braak stage IV or less) No correlation of AD pathology and last MMSE Aarsland D, et al. Ann Neurol. 2005;58:773-776.

19. CN-19 Summary—Neuropathology of PDD AD 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 criteria for AD Aarsland D, et al. Ann Neurol. 2005;58:773-776. Apaydin H, et al. Arch Neurol. 2002;59:102-112. Braak H, et al. Neurology. 2005;64:1404-1410.

20. CN-20 Conclusion—Neuropathology of PDD AD Pathologic Change  Clinical diagnosis highly predictive of Lewy body pathology  Significant AD pathology is relatively rare in clinically diagnosed PDD cases Dementia in elderly PD patients is primarily due to Lewy body pathology and not just coexistent AD

21. CN-21 Is the Cholinergic System Dysfunctional in Parkinson’s Disease with Dementia?

22. CN-22 Neurochemistry of PDD and AD Cholinergic System  Cholinergic basal forebrain – Neuronal loss and Lewy body pathology in PD and PDD – Neuronal loss and neurofibrillary tangles in AD  Pedunculopontine (PPT) nucleus – Neuronal loss and Lewy body pathology in PD and PDD – Neuronal loss and neurofibrillary tangles in AD Jellinger K. J Neurol Neurosurg Psychiatry. 1988;51:540-543.

23. CN-23 Two Distinct Disorders With a Common Cholinergic Deficit

24. CN-24 AuthorTechnique Disease subgroups ADPDPDD Perry, 1985Neurochem (ChAT)  Ruberg, 1986Neurochem (AChE)N/A // /  † Tiraboschi, 2000Neurochem (ChAT)  N/A  Mattila, 2001Neurochem (ChAT)N/A  ‡ Bohnen, 2003PET (AChE activity)  † AChE total/AChE 10S form. ‡ Included PD/PDD together. Neurochemistry of PDD and AD Cholinergic System

25. CN-25 Percentage Reductions of Cerebral Acetylcholinesterase Activity in PD, PDD, and AD Alzheimer disease PD without dementia Parkinsonian dementia Mean cortex Amygdala Hippocampus Inferior temporal Superior temporal Parietal Frontal Region of the brain, % Percentage reductions of cerebral acetylcholinesterase (AChE) activity in the various patient groups compared with healthy control subjects. Bohnen NI, et al. Arch Neurol. 2003;60:1745-1748. 0–5–10–15–20–25–30 % reduction in AChE activity

26. CN-26 Correlation Coefficients Between Individual Cognitive Tests and Cortical AChE Activities in the Combined PDD and PD Groups Cognitive test Correlation coefficient (significance) California Verbal Learning Test-STMRs = 0.13 ns California Verbal Learning Test-LTMRs = 0.20 ns Judgment of Line Orientation TestRs = 0.43 (p < 0.05) Stroop Color Word TestRs = 0.46 (p < 0.05) Trail Making Test B-ARs = 0.44 (p < 0.05) WAIS-III Digit SpanRs = 0.57 (p < 0.005) Bohnen NI, et al. J Neurol. 2006;253:242-247.

27. CN-27 Neurochemistry of PDD and AD Cholinergic System  Cholinergic nuclei are pathologically involved in PDD  Reduced cortical cholinergic activity is more severe in PDD than in mild AD ‡  Cholinergic dysfunction in PDD is associated with decreased performance on tests of attentional and executive functioning § † Mattila, et al. Acta Neuropathol. 2001;32:397-402. ‡ Bohnen, et al. Arch Neurol. 2003;60:1745-1748. § Bohnen NI, et al. J Neurol. 2006;253:242-247.

28. CN-28 Conclusion  Clinical PDD is highly predictive of specific neuropathologic and neurochemical characteristics – Neuropathology Lewy body pathology Limited AD pathologic change – Biochemistry Profound loss of cholinergic function Cholinergic deficit associated with impairments in attentional and executive functions