CN-1 Neuropathology of Parkinson's Disease Dementia

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  • 10/18/10 14:27
  • 10/18/10 14:27
  • 10/18/10 14:27 Key point:

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  • 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. 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. 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. Alzheimer’s Disease — Pathology Silver stain: plaques and tangles Silver stain: neuritic plaques Neurofibrillary tangles
  • 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. 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. 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 stage CERAD plaque ratings 0 - I II III IV - V None Sparse Moderate Frequent Number of subjects Number of subjects 0 2 6 8 10 12 4 14 0 5 15 20 10 25
  • 8. Neuropathology of Parkinson’s Disease
    • Substantia nigra pathology
      • Lewy body inclusions
      • Neuronal loss
  • 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. Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex Substantia nigra Cerebral cortex
  • 11. Braak Staging of Lewy Bodies Braak H, et al. J Neurology . 2002;249(suppl 3):1432-1459.
  • 12. What Is the Neuropathologic Basis of Dementia in Parkinson’s Disease?
  • 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. Neuropathology of PDD Cortical LB Pathology Correlates With Dementia 1-15 DV Cortical LBs 88 PD Braak, 2005 LBs in entorhinal cortex and Brodmann 24 22 PDD Kovari, 2003 Cortical LBs 13 PDD Apaydin, 2002 Cortical LBs 22 PDD vs 20 PD only Hurtig, 2000 Frontal cortical LBs 45 PDD Mattila, 2000 Cortical LBs 44 PDD Mattila, 1998 Cortical LBs 11 PDD Kosaka, 1998 Primary correlate of dementia Population Author, yr
  • 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. 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. 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. 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. 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. 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. Is the Cholinergic System Dysfunctional in Parkinson’s Disease with Dementia?
  • 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. Two Distinct Disorders With a Common Cholinergic Deficit
  • 24. Neurochemistry of PDD and AD Cholinergic System † AChE total/AChE 10S form. ‡ Included PD/PDD together.    PET (AChE activity) Bohnen, 2003  ‡  ‡ N/A Neurochem (ChAT) Mattila, 2001  N/A  Neurochem (ChAT) Tiraboschi, 2000  /  †  /  N/A Neurochem (AChE) Ruberg, 1986    Neurochem (ChAT) Perry, 1985 PDD PD AD Disease subgroups Technique Author
  • 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. Correlation Coefficients Between Individual Cognitive Tests and Cortical AChE Activities in the Combined PDD and PD Groups Bohnen NI, et al. J Neurol. 2006;253:242-247. Rs = 0.57 ( p < 0.005) WAIS-III Digit Span Rs = 0.44 ( p < 0.05) Trail Making Test B-A Rs = 0.46 ( p < 0.05) Stroop Color Word Test Rs = 0.43 ( p < 0.05) Judgment of Line Orientation Test Rs = 0.20 ns California Verbal Learning Test-LTM Rs = 0.13 ns California Verbal Learning Test-STM Correlation coefficient (significance) Cognitive test
  • 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. 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