神经退行性疾病讲座

1、CN-1Neuropathology ofParkinsons Disease Dementia James B. Leverenz, MDAssociate ProfessorNeurology and Psychiatry and Behavioral SciencesUniversity of Washington School of Medicine UW Alzheimers Disease Research CenterVA Northwest Network Mental Illness and Parkinsons Disease Research, Education, an

2、d Clinical CentersCN-2OverviewNeuropathology of PDDu Dementia in elderly PD patients is primarily due to Lewy body pathology, and not just coexistent AD Review of AD pathologyReview of PD pathologyNeuropathologic changes in PDDu PDD is associated with severe deficits in the cholinergic systemBiochem

3、ical and neuroimaging dataNeuropsychologic dataCN-3Abbreviations and Terminology uPD Parkinsons Disease without dementiauPDD Parkinsons Disease with dementiauAD Alzheimers DiseaseuLBP Lewy Body Pathology“classic” Lewy body inclusionsalpha-synuclein immuno-positive inclusions and neuritesuCERAD Conso

4、rtium to Establish a Registry for Alzheimers DiseaseCN-4Silver stain: plaques and tanglesAlzheimers DiseasePathologySilver stain:neuritic plaquesNeurofibrillarytanglesCN-5Pathological Criteria for ADuStaging of AD pathologic changeNeuritic plaques (CERAD, absent to frequent)Neurofibrillary tangles (

5、Braak staging, I - VI)uFor pathological diagnosis of ADIntegrate CERAD and Braak staging evaluating “likelihood” AD changes led to dementiaHigh - CERAD frequent/Braak V or VIIntermediate - CERAD moderate/Braak III or IVLow - CERAD sparse/Braak I or II Neurobiol Aging. 1997;18(4 suppl):S1-2. CN-6AD P

6、athologic Change in Non-Demented ElderlyuKnopman et al (JNEN 2003)39 longitudinally followed non-demented casesMean age 85 years (74 - 95)AD pathologic change38 Braak stage I or greater, 4 Braak stage IV or V37 with sparse or absent neuritic plaques, 50% with moderate to frequent diffuse plaques“.cu

7、t off points .Braak stage IV .neuritic plaques moderate.” Knopman et al. J Neurol Pathol Exp Neurol. 2003;62:1087-1095.CN-7AD Pathologic Change in the ElderlyKnopman et al. J Neuropathol Exp Neurol. 2003;62:1087-1095.Diffuse plaquesCored plaquesNeuritic plaquesBraak and Braak stageCERAD plaque ratin

8、gs0 - IIIIIIIV - VNoneSparseModerate FrequentNumber of subjectsNumber of subjects026810124140515201025CN-8Neuropathology of Parkinsons DiseaseSubstantia nigra pathologyLewy body inclusionsNeuronal lossCN-9Improved Detection of Lewy Body PathologyuAlpha-synuclein mutations in familial PD uAlpha-synuc

9、lein immunoreactivity in all Lewy bodiesClassic brainstem Lewy bodiesCortical Lewy bodiesLewy neuritesCN-10Alpha-Synuclein Pathology in the Substantia Nigra and NeocortexCerebral cortex Substantia nigra CN-11Braak H, et al. J Neurology. 2002;249(suppl 3):1432-1459.Braak Staging of Lewy BodiesCN-12Wh

10、at Is the Neuropathologic Basis of Dementia in Parkinsons Disease?CN-13Neuropathology of PDDAD Pathologic Change“contrary to published reports, most patients with parkinsonism who exhibit dementia do not have concomitant Alzheimers diseaseSome pathogenetic mechanism must be sought to account for thi

11、s increasingly common cause of cognitive decline in the sufferers of Parkinsons disease.”Ball M. Can J Neuro Sci. 1984;11(1 suppl):180-184.CN-14Neuropathology of PDDCortical LB Pathology Correlates With DementiaAuthor, yrPopulationPrimary correlate of dementia Kosaka, 199811 PDDCortical LBsMattila,

12、199844 PDDCortical LBsMattila, 200045 PDDFrontal cortical LBsHurtig, 200022 PDD vs 20 PD onlyCortical LBsApaydin, 2002 13 PDDCortical LBsKovari, 200322 PDDLBs in entorhinal cortex andBrodmann 24 Braak, 200588 PD Cortical LBs1-15DVCN-15Neuropathology of PDDAD Pathologic ChangeuCase selectionTreatment

13、-responsive PD precedes dementiauNeuropathologyAlpha-synuclein immunohistochemistryUp-to-date criteria for AD diagnosisBraak IV to VI and CERAD plaque stage B or CCN-16Neuropathology of PDDAD Pathologic ChangeuApaydin et al (Arch Neurol, 2002)Clinical13 PDD cases (mean age 78.1yr, range 64 - 89)Path

14、ology12 with diffuse or transitional Lewy body pathology1 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.CN-17Neuropathology of PDDAD Pathologic ChangeuBraak et al (Neurology, 2005)88 clinical PD ca

15、ses with autopsy confirmation of LBP (mean age 75.9 yr; range 60 - 89)79 with mild to severe cognitive impairmentMMSE score correlated with stage of LBP (using Braaks 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.CN-1

16、8PDD - AD Pathologic ChangeuAarsland et al (Ann Neurol, 2005)Community-based sample of PD (N = 245)Longitudinal follow-up with cognitive evaluation22 autopsied cases (18 demented)All with limbic or neocortical stage LBPCorrelation of LB score to last MMSEAD pathology limited (all Braak stage IV or l

17、ess)No correlation of AD pathology and last MMSEAarsland D, et al. Ann Neurol. 2005;58:773-776.CN-19SummaryNeuropathology of PDDAD Pathologic Change uTotal of 110 cases with PDD studieduDSM III or III-R criteria for dementia diagnosisuAge in late 70s at deathuNeocortical LB pathology correlates with

18、 dementiauOnly 7(6%) cases fulfilled pathologic criteriafor ADAarsland 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.CN-20ConclusionNeuropathology of PDDAD Pathologic ChangeuClinical diagnosis highly predictive of Le

19、wy body pathologyuSignificant AD pathology is relatively rare in clinically diagnosed PDD casesDementia in elderly PD patients is primarily due to Lewy body pathology and not just coexistent ADCN-21Is the Cholinergic System Dysfunctional in Parkinsons Disease with Dementia?CN-22Neurochemistry of PDD

20、 and AD Cholinergic SystemuCholinergic basal forebrainNeuronal loss and Lewy body pathology in PD and PDDNeuronal loss and neurofibrillary tangles in ADuPedunculopontine (PPT) nucleusNeuronal loss and Lewy body pathology in PD and PDDNeuronal loss and neurofibrillary tangles in ADJellinger K. J Neur

21、ol Neurosurg Psychiatry. 1988;51:540-543.CN-23Two Distinct Disorders With aCommon Cholinergic DeficitCN-24AuthorTechniqueDisease subgroupsADPDPDDPerry, 1985Neurochem (ChAT) Ruberg, 1986Neurochem (AChE)N/A / /Tiraboschi, 2000Neurochem (ChAT) N/AMattila, 2001Neurochem (ChAT)N/ABohnen, 2003PET (AChE ac

22、tivity) AChE total/AChE 10S form. Included PD/PDD together.Neurochemistry of PDD and AD Cholinergic SystemCN-25Percentage Reductions of Cerebral Acetylcholinesterase Activity inPD, PDD, and AD Alzheimer diseasePD without dementiaParkinsonian dementiaMean cortexAmygdalaHippocampusInferior temporalSup

23、erior temporalParietalFrontalRegion 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;60:1745-1748.051015202530% reduction in AChE activityCN-26Correlation Coe

24、fficients Between Individual Cognitive Tests and Cortical AChE Activities in the Combined PDD and PD GroupsCognitive testCorrelation coefficient(significance)California Verbal Learning Test-STMRs = 0.13 nsCalifornia Verbal Learning Test-LTMRs = 0.20 nsJudgment 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 = 0.5