Neuropathology of Neurodegenerative Disorders Prof. Jillian Kril
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1 Neurodegenerative disorders to be discussed Alzheimer s disease Lewy body diseases Frontotemporal dementia and other tauopathies Huntington s disease Motor Neuron Disease 2 Neuropathology of neurodegeneration Macroscopic f eatures of disease Extent and severity of atrophy Microscopic f eatures Diagnostic criteria 3 The screen versions of these slides have full details of copyright and acknowledgements 1
2 Ageing Cohort effect Atrophy White matter only ~2mL/y Neuron loss % of cerebral volume cortex white matter age at death (yr) No loss from hippocampus, entorhinal and superior temporal cortices male female Ref 1 Accumulation of plaques and tangles 4 Age-associated accumulation of plaques and tangles 100 Plaques 100 Tangles % total cases % total cases Age Category Age Category Data from Ref 2 5 Age-associated accumulation of plaques and tangles 100 Plaques Stage A&B Stage C 100 Tangles Stage I-IV Stage V-VI % total cases % total cases Age Category Age Category Data from Ref 2 6 The screen versions of these slides have full details of copyright and acknowledgements 2
3 Neurodegenerative disorders Alzheimer s disease Lewy body diseases Frontotemporal dementia and other tauopathies Huntington s disease Motor Neuron Disease 7 AD: Macroscopic pathology 8 AD: Macroscopic pathology 9 The screen versions of these slides have full details of copyright and acknowledgements 3
4 Determination of Regional Volumes 3mm coronal slices Cortical surfaces painted Volumes determined by point count technique 10 Volume loss Neuron loss Total CA1 Neuron Number Control AD Hippocampal volume (ml) Data from Ref 3 11 Regional atrophy in AD Data from Ref 4 12 The screen versions of these slides have full details of copyright and acknowledgements 4
5 AD: Neuropathological Diagnosis Neurofibrillary tangles Ab plaques 13 Diffuse AD: Plaques Neuritic Compact Ag Ab Ab Courtesy C Shepherd 14 CERAD criteria Age-associated accumulation of plaques Sparse Moderate Frequent <50y AD AD AD 50-75y possible AD possible AD possible AD >75y not AD probable AD AD Ref 5 15 The screen versions of these slides have full details of copyright and acknowledgements 5
6 AD: Neurofibrillary tangles Progression of NFTs pre-tangle early mature ghost 16 AD: Neurofibrillary tangles Spread of NFTs SUB Entorhinal cortex * * * * CA2-3 CA4 CA1 * * ** * * * transentorhinal entorhinal CA1 neocortex Ref 6 17 Braak staging of NFTs Region-specific accumulation of NFTs I Not AD { II III Possible AD { IV V AD { VI Entorhinal CA1 Cortex The screen versions of these slides have full details of copyright and acknowledgements 6
7 NIA- Reagan Institute Criteria Probability High Intermediate Low Plaques Frequent Moderate Infrequent NFTs B&B stage Cortical V-VI Limbic III-IV Few I-II Ref 197 Cholinergic neuron loss in AD Nucleus Basalis of Meynert (NbM) AC NbM OC 40-80% cell loss Relates to dementia severity Relates to cortical atrophy Lost due to NFTs 20 Neuron loss in AD Entorhinal cortex 48% early Hippocampal CA1 69% Superior temporal cortex >50% Locus coeruleus ~65% Raphe nuclei 25-70% Nucleus Basalis of Meynert 56% 21 The screen versions of these slides have full details of copyright and acknowledgements 7
8 Neuron loss in AD Due to NFT formation Entorhinal cortex? Hippocampal CA1 Superior temporal cortex no no Locus coeruleus? Raphe nuclei Nucleus Basalis of Meynert no yes 22 Neurodegenerative disorders Alzheimer s disease Lewy body diseases Frontotemporal dementia and other tauopathies Huntington s disease Motor Neuron Disease 23 Lewy body diseases H&E PD Normal α-synuclein 24 The screen versions of these slides have full details of copyright and acknowledgements 8
9 LBD: Neuropathological diagnosis Brainstem Lew y bodies (=PD) Limbic Frequent (5+) in cingulate Present in parahippocampus Neocortical Limbic LBs plus Frequent (5+) in temporal neocortex HE HE a sy n 25 Spread of Lewy bodies Braak Staging Stage I & II III & IV V & VI Region Medulla Olfactory Midbrain, Pons, NbM Neocortices Ref 8 26 Spread of Lewy bodies Braak Staging Stage Region I & II III & IV Medulla Olfactory Midbrain, Pons, NbM Preclinical disease Parkinson s disease V & VI Neocortices PD with dementia Ref 8 27 The screen versions of these slides have full details of copyright and acknowledgements 9
10 Regional atrophy in DLB 28 DLB: Other Pathology Plaques Ag Lew y neurites CA2 Ub 29 Neurodegenerative disorders Alzheimer s disease Lewy body diseases Frontotemporal dementia and other tauopathies Huntington s disease Motor Neuron Disease 30 The screen versions of these slides have full details of copyright and acknowledgements 10
11 FTLD: Macroscopic pathology M M 31 FTLD: Macroscopic pathology M M FTD Control 32 Regional atrophy in FTLD Data from Ref 9 33 The screen versions of these slides have full details of copyright and acknowledgements 11
12 FTLD: Disease staging Control Stage 1 Stage 2 Stage 3 Stage 4 Ref Tauopathy: Distribution by stage T au + v e FT D* Tau v e FT D* CBD # PSP # N St ag e (2 3 %) 1 (1 1 %) 1 5 ( 62% ) St ag e 2 2 (1 8 %) 5 (3 8 %) 4 (4 4 %) 7 (2 9 %) St ag e 3 6 (5 5 %) 3 (2 3 %) 4 (4 4 %) 2 (8% ) St ag e 4 3 (2 7 %) 2 (1 5 %) 0 0 * Ref 10; # Ref Tauopathy: Distribution by stage Tau +ve FT D* Tau ve FT D* CBD # PSP# N Stage (23 %) 1 (11 %) 15 (62%) Stage 2 2 (18 %) 5 (38 %) 4 (44 %) 7 (29 %) Stage 3 6 (55 %) 3 (23 %) 4 (44 %) 2 (8 %) Stage 4 3 (27 %) 2 (15 %) 0 0 * Ref 10; # Ref The screen versions of these slides have full details of copyright and acknowledgements 12
13 FTLD: Neuropathological diagnosis Tau-positive 1. Intraneuronal - Pick s Disease 2. Extraneuronal - CBD, PSP Tau-negative 3. Ubiquitin-positive, tau-negative inclusions (FTLD-U or FTLD+MND) 4. Absence of inclusions (DLDH) Ref CBD 2 PSP 3 Ag Tau Ag Ub 37 FTLD: Neuron loss %control values Early (Stages 1 & 2) Late (Stages 3 & 4) Frontal cortex - layer III 77% * 58% *# Frontal cortex - layer V 81% * 60% *# Temporal cortex - layer III 63% * 48% * Temporal cortex - layer V 76% 56% * CA1 of hippocampus 81% 24% *# Astrocyte density 377% * 458% * Significantly different from *control and #early values Ref Neurodegenerative disorders Alzheimer s disease Lewy body diseases Frontotemporal dementia and other tauopathies Huntington s disease Motor Neuron Disease 39 The screen versions of these slides have full details of copyright and acknowledgements 13
14 Huntington s disease Autosomal dominant CAG-repeats in HD gene on chromosome 4 (others = SCA, DRPLA, Kennedy s disease) Age of onset related to number of repeats No. repeats Age of onset Normal Huntington s disease Middle age >60 Juvenile 40 Regional atrophy in HD Data from Ref HD: Macroscopic pathology 42 The screen versions of these slides have full details of copyright and acknowledgements 14
15 HD: Disease staging caudate putamen accumbens P C A P Ventricle C A Stage 1 Stage 2 Stage 3 Stage 4 Ref HD: Microscopic pathology Striatum Loss of medium spiny neurons Astrocytosis HD Severity related to stage Intranuclear inclusions of mutant protein Control 44 HD: Microscopic pathology Other Neocortex Entorhinal cortex Nucleus basalis Amygdala Severity related to stage 45 The screen versions of these slides have full details of copyright and acknowledgements 15
16 Neurodegenerative disorders Alzheimer s disease Lewy body diseases Frontotemporal dementia and other tauopathies Huntington s disease Motor Neuron Disease 46 Motor Neuron Disease Complex of disorders Motor neuron loss Inherited forms SOD1 (~20%) Juvenile forms Upper MN Brain stem MN Lower MN 47 Motor Neuron Diseases Upper MN Brainstem MN Lower MN ALS PMA Late (>50%) Late (~85%) PLS 48 The screen versions of these slides have full details of copyright and acknowledgements 16
17 ALS: Microscopic pathology Corticospinal tract Control Ant Horn ALS 49 ALS: Microscopic pathology 50 Conclusions Brain atrophy Anatomical distribution Severity of atrophy Atrophy ref lects neuron loss Unique microscopic f eatures Overlapping microscopic features Evolving neuropathological criteria 51 The screen versions of these slides have full details of copyright and acknowledgements 17
18 References 1 Double KL, et al. Neurobiol Aging 1996;17: Braak H, Braak E. Neurobiol Aging 1997;18: Kril JJ, et al. Neurosci Lett 2004;361: Halliday GM, et al. Neurobiol Aging 2003;24: Mirra SS, et al. Neurology 1991;41: Braak H, Braak E. Acta Neuropathol 1991;82: National Institute on Aging and Reagan Institute Working Group. Neurobiol Aging 1997;18(4S):S Braak H, et al. Neurobiol Aging 2003;24: Kril JJ, et al. J Neurol Sci 2005;232: Broe M, et al. Neurology 2003;60: Schofield EC, et al. Movement Dis 2005;20: McKhann GM, et al. Arch Neurol 2001;58: Kersaitis C, et al. Acta Neuropathol 2004;108: Halliday GM, et al. Exp Neurol 1998;154: Vonsattel J-P, et al. J Neuropathol Exp Neurol 1985;44: Acknowledgements Thank you to Glenda Halliday and Heidi Cartw right for the use of figurew ork and artw ork in this presentation The author s research is supported by the National Health and Medical Research Council of Australia The screen versions of these slides have full details of copyright and acknowledgements 18
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