Dementia and Healthy Ageing : is the pathology any different?

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1 Dementia and Healthy Ageing : is the pathology any different? Professor David Mann, Professor of Neuropathology, University of Manchester, Hope Hospital, Salford

2 DEMENTIA Loss of connectivity within association neocortex and hippocampus Multiple causes, Mostly neurodegenerative Some vascular/infective/toxic/traumatic/tumour

3 MAJOR CAUSES OF DEMENTIA Alzheimer s disease Parkinson s disease dementia and Lewy body dementia Cerebrovascular disease and multi-infarct dementia Frontotemporal dementia and related disorders Corticobasal Degeneration and Progressive Supranuclear Palsy Creutzfeldt-Jakob disease and related disorders Huntington s disease Motor Neurone Disease dementia

4 ALZHEIMER S DISEASE CLINICAL Amnesia Aphasia Visuospatial disorder Apraxia RADIOLOGICAL Cerebral atrophy Ventricular dilatation Reduced tracer uptake in posterior parietal cortex

5 GROSS PATHOLOGY OF ALZHEIMER S DISEASE NORMAL AD CEREBRAL ATROPHY VENTRICULAR DILATATION DECREASED BRAIN WEIGHT

6 HISTOPATHOLOGY classic lesions Silver Senile Plaque Neurofibrillary Tangle IHC β-amyloid tau

7 β-amyloid and tau

8 PIN1 CHANGES (Granulovacuolar Degeneration) Hippocampus Mostly CA2 and CA1 Pyramidal cells c

9 PARKINSON S DISEASE (Parkinson s disease dementia Lewy body dementia) Clinical Radiological Fluctuating cognitive decline Cerebral atrophy Delusions, hallucinations Bilateral loss of tracer Parkinsonism uptake from posterior cerebral cortex

10 GROSS PATHOLOGY NORMAL PD/LBD Loss of cells from substantia nigra

11 LEWY BODY DEMENTIA H&E Lewy bodies in substantia nigra α-syn Lewy bodies in cerebral cortex

12 CEREBROVASCULAR DISEASE (Cerebral Amyloid Angiopathy) H&E Congo red Thioflavin S A immunostain

13 AFFECTS OF CAA Increased risk of cerebral infarction Increased risk of cerebral haemorrhage

14 ATHEROSCLEROSIS Infarctions due to large vessel disease (atherosclerosis) are coincidental in Alzheimer s disease In absence of Alzheimer s disease may be sufficient to cause multi-infarct dementia

15 ARTERIOSCLEROSIS Thickening of vessel wall Dilatation of perivascular spaces Common cause of multi-infarct (vascular) dementia

16 WHITE MATTER LESIONS Vascular dementia AD White matter lesions are radiologically present in 50-70% cases of AD

17 Neuron Formation and elimination of Aβ from the Brain Aβ Neprilysin etc 1 Microglia and Astrocytes Diffusion of Aβ through brain parenchyma (Mouse studies). 2 Absorption into blood (LDL-R-1 mediated) 3 Clearance of Aβ along perivascular Interstital Fluid Drainage pathways 21 Blood Vessel Direction of Blood Flow

18 Neuron Aβ Neprilysin etc 1 Microglia and Astrocytes 1 Absorption into blood (LDL-R-1 mediated) Impaired diffusion of Aβ through brain parenchyma. Accumulation as plaques (A 42 ) Reduced clearance of Aβ along perivascular pathways by loss of vessel pulsations Impeded by cerebrovascular disease and retention of ECF in white matter with accumulation as CAA (A 40 ) Direction of Blood Flow

19 Longitudinal Ageing Study 34 cases (14M, 20F) come to post mortem Mean age 83.8 years, range years 30 cases, so far, assessed for:- Aβ (CERAD Mirra et al 1990), Tau (Braak stage, Braak and Braak 1991) PIN1/GVD (Dakson et al 2010) α -synuclein (Foulds et al 2010) Cerebrovascular disease (BDR 2010) APOE genotype (Wenham et al 1990)

20 CLINICAL DIAGNOSIS VaD 6% MSA 3% AD 20% NORMAL 71%

21 PLAQUE (CERAD) SCORE CERAD score C in prob/definite AD C 37% 0 17% A 23% B 23%

22 Allele frequency APOE ALLELE AND PLAQUE SCORE APOE ε /A B C CERAD score APOE ε2

23 BRAAK STAGEING Braak stages 5 and 6 are prob/definite AD 0 3% V-V1 20% I-II 17% II-III 20% III-IV 40%

24 Number of cases PIN1 (GVD) PATHOLOGY AD 15 Long Cohort PIN 1 Score

25 PIN1 (GVD) PATHOLOGY and BRAAK STAGE

26 CEREBROVASCULAR CHANGES % 0-3 0% % %

27 NEUROPATHOLOGY DLB 7% MILD AD/PD 3% CVD 13% PROB AD 27% MSA 3% INCIP AD 47%

28 BIOMARKERS (1) Imaging MRI/PET (FDG or amyloid)

29 BIOMARKERS (1) Disadvantages: 1. MRI/FDG - Non-specific, surrogate marker (cerebral atrophy, blood flow, glucose uptake) 2. Amyloid - Non-selective - amyloid in virtually all older subjects. Does not predict conversion normal/mci/ad

30 BIOMARKERS (2) Cerebrospinal fluid or serum/plasma AD CSF: Aβ42 and/or Ptau196 increased in AD vs controls BUT CSF: Aβ42 does not predict conversion ND/MCI/AD and Ptau raised in other tauopathies. PIN1 as possible biomarker Blood marker preferable

31 BIOMARKERS (3) PET Imaging in Parkinson s Disease Diagnosis Normal Subject Early Parkinson s Disease Advanced Parkinson s Disease

32 BIOMARKERS (4) Differentiation of PD/DLB from other parkinsonian disorders (eg PSP/CBD (tauopathy) and MSA (α-synuclein). Increased CSF α-synuclein (total or oligomeric forms) in PD vs controls. Oligomeric phospho synuclein ( g/ml) PD (38) DLB (15) PSP (12) MSA (8)Controls (16) Pathological diagnosis (no.) Oligomeric, phosphorylated α-synuclein increased in MSA

33 CONCLUSIONS In an elderly cohort: 83% show β-amyloid deposition 97% have tau pathology (60% AD/incipient AD). 90% have PIN1 changes (33% in AD range). 100 % show cerebrovascular disease Cognitively normal and AD cases lie on a continuum of pathological (β-amyloid, tau and PIN1) change AD is ultimate expression of biological ageing?

34 Acknowledgements The work of the Manchester Brain Bank is supported through the Alzheimer s Research Trust/Alzheimers Society, Brains for Dementia Research Initiative We thank DeNDRoN North West for assistance in sample collection Project 111 funding from People s Republic of China DMAM and SPB receive funding from Wellcome Trust/MRC Neurodegeneration Programme