Dementia and Healthy Ageing : is the pathology any different? Professor David Mann, Professor of Neuropathology, University of Manchester, Hope Hospital, Salford
DEMENTIA Loss of connectivity within association neocortex and hippocampus Multiple causes, Mostly neurodegenerative Some vascular/infective/toxic/traumatic/tumour
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
ALZHEIMER S DISEASE CLINICAL Amnesia Aphasia Visuospatial disorder Apraxia RADIOLOGICAL Cerebral atrophy Ventricular dilatation Reduced tracer uptake in posterior parietal cortex
GROSS PATHOLOGY OF ALZHEIMER S DISEASE NORMAL AD CEREBRAL ATROPHY VENTRICULAR DILATATION DECREASED BRAIN WEIGHT
HISTOPATHOLOGY classic lesions Silver Senile Plaque Neurofibrillary Tangle IHC β-amyloid tau
β-amyloid and tau
PIN1 CHANGES (Granulovacuolar Degeneration) Hippocampus Mostly CA2 and CA1 Pyramidal cells c
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
GROSS PATHOLOGY NORMAL PD/LBD Loss of cells from substantia nigra
LEWY BODY DEMENTIA H&E Lewy bodies in substantia nigra α-syn Lewy bodies in cerebral cortex
CEREBROVASCULAR DISEASE (Cerebral Amyloid Angiopathy) H&E Congo red Thioflavin S A immunostain
AFFECTS OF CAA Increased risk of cerebral infarction Increased risk of cerebral haemorrhage
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
ARTERIOSCLEROSIS Thickening of vessel wall Dilatation of perivascular spaces Common cause of multi-infarct (vascular) dementia
WHITE MATTER LESIONS Vascular dementia AD White matter lesions are radiologically present in 50-70% cases of AD
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
Neuron Aβ Neprilysin etc 1 Microglia and Astrocytes 1 Absorption into blood (LDL-R-1 mediated) 1 2 3 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
Longitudinal Ageing Study 34 cases (14M, 20F) come to post mortem Mean age 83.8 years, range 72-94 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)
CLINICAL DIAGNOSIS VaD 6% MSA 3% AD 20% NORMAL 71%
PLAQUE (CERAD) SCORE CERAD score C in prob/definite AD C 37% 0 17% A 23% B 23%
Allele frequency APOE ALLELE AND PLAQUE SCORE 0.45 0.4 0.35 0.3 0.25 0.2 0.15 APOE ε4 0.1 0.05 0 0/A B C CERAD score APOE ε2
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%
Number of cases PIN1 (GVD) PATHOLOGY 25 20 AD 15 Long Cohort 10 5 0 0-4 5-8 9-12 13-16 17-20 PIN 1 Score
PIN1 (GVD) PATHOLOGY and BRAAK STAGE
CEREBROVASCULAR CHANGES 10-12 16% 0-3 0% 7-9 21% 4-6 63%
NEUROPATHOLOGY DLB 7% MILD AD/PD 3% CVD 13% PROB AD 27% MSA 3% INCIP AD 47%
BIOMARKERS (1) Imaging MRI/PET (FDG or amyloid)
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
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
BIOMARKERS (3) PET Imaging in Parkinson s Disease Diagnosis Normal Subject Early Parkinson s Disease Advanced Parkinson s Disease
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) 40 30 20 10 0 PD (38) DLB (15) PSP (12) MSA (8)Controls (16) Pathological diagnosis (no.) Oligomeric, phosphorylated α-synuclein increased in MSA
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?
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