Neuropathology of Neurodegenerative Diseases
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1 Neuropathology of Neurodegenerative Diseases Melissa E. Murray, PhD XXVI INTERNATIONAL GRAL CONGRESS January 25, 2013 The authors have no relevant disclosures MFMER slide-1
2 Neurodegeneration Progressive loss of selective populations of vulnerable neurons, versus Static neuronal loss Selective vulnerability Classification Clinical Anatomical Molecular 2012 MFMER slide-2
3 Objectives Describe the molecular classification of neurodegenerative disorders Describe differences between typical and atypical Alzheimer s disease (AD) cases Discuss multi-proteinopathies (i.e. co-existing neuropathologies) Mayo Clinic Jacksonville brain bank series 2012 MFMER slide-3
4 Molecular classification of neurodegenerative disorders Amyloidoses Alzheimer s disease (aβ) Creutzfeldt-Jakob disease (prion protein) Tauopathies 4R (progressive supranuclear palsy and corticobasal degeneration) 3R (Pick s disease) Synucleinopathies Lewy body disease TDP-43 proteinopathy Frontotemporal lobar degeneration Amyotrophic lateral sclerosis Trinucleotide repeat disorders Huntington s disease Spinal cerebellar ataxia Unclassified Proteinopathies C9ORF72 hexanucleotide repeat Multiple systems atrophy 2012 MFMER slide-4
5 Methods Query the Mayo Clinic Jacksonville brain bank (n=3549) Cases were included if they had significant AD, tau, α-synuclein, or TDP-43 pathology Proportion of cases with multi-proteinopathies (> 2) Age Sex Brain weight 2012 MFMER slide-5
6 Demographics 1 Diagnosis n. (%) Age, yrs. Males (%) AD 1507 (42) 81 (74-86) 677 (43) CJD 27 (1) 70 (61-76) 9 (33) PSP 962 (27) 78 (70-84) 523 (54) CBD 139 (4) 69 (65-76) 65 (47) PiD 22 (1) 70 (66-74) 10 (45) LBD 549 (15) 78 (72-83) 383 (70) MSA 113 (3) 66 (60-72) 67 (59) FTLD 161 (4) 70 (61-79) 92 (57) HpScl 17 (0.5) 87 (81-92) 10 (59) ALS 74 (2) 65 (55-74) 35 (47) 2012 MFMER slide-6
7 Creutzfeldt-Jakob disease (prion protein) Rapidly progressive dementing disorder Macroscopic findings Normal brain weight (~ 1200 grams) No significant cortical or cerebellar atrophy No ventricular enlargement Normal pigment in substantia nigra Microscopic findings Spongiform encephalopathy in cortex, basal ganglia, thalamus and cerebellum PrP pre-amyloid deposits in cortex Not visible using thioflavin S fluorescent microscopy H&E PrP Pyknotic neuron Prion protein deposits Spongiform vacuolation 2012 MFMER slide-7
8 Tauopathies Tau gene A Alternative splicing of pre-mrna generated from a single tau gene 4R PSP CBD 3R Pick s Tau 3 repeat protein isoforms (3R tau) 2+ Tau 4 repeat protein isoforms (4R tau) MFMER slide-8
9 Progressive supranuclear palsy (4R tau) Atypical parkinsonism Macroscopic findings Significant atrophy of the subthalamic nucleus, superior cerebellar peduncle, and discoloration of dentate nucleus Pigment loss often observed in substantia nigra Superior cerebellar peduncle Subthalamic nucleus Subthalamic nucleus Neuromelanin loss 2012 MFMER slide-9
10 Progressive supranuclear palsy (4R tau) Microscopic findings Neuronal loss and gliosis 4R tau neuronal and glial inclusions Globose NFT in substantia nigra Gliosis in subthalamic nucleus H&E Tau Globose tangle Gliosis Tufted astrocyte NFT NFT Tufted astrocyte 2012 MFMER slide-10
11 Corticobasal degeneration (4R tau) Heterogeneous clinical presentations Asymmetric apraxia Progressive aphasia Frontal lobe dementia Macroscopic findings Variable degree of cortical & basal ganglia atrophy Loss of pigment in substantia nigra Parasagittal atrophy 2012 MFMER slide-11
12 Corticobasal degeneration (4R tau) Heterogeneous clinical presentations Asymmetric apraxia Progressive aphasia Frontal lobe dementia Macroscopic findings Variable degree of cortical & basal ganglia atrophy Loss of pigment in substantia nigra Corpus callosum atrophy Nigral loss 2012 MFMER slide-12
13 Corticobasal degeneration (4R tau) Microscopic findings Superficial spongiosis Ballooned neurons are usually numerous Tau-immunoreactive neuronal lesions - pretangles White matter pathology Glial tau - astrocytic plaques, oligodendroglial coiled bodies, numerous neuropil threads H&E Superficial spongiosis GFAP & Tau Astrocytic plaque H&E Balloon neurons Tau Gallayas NFT Oligodendroglial coiled bodies 2012 MFMER slide-13
14 Pick s disease (3R tau) Frontotemporal dementia with behavioral abnormalities or non-fluent aphasia, and semantic dementia Macroscopic findings Severe cortical knifeedge atrophy Severe hippocampal pathology, affecting CA1 and the dentate fascia. knife-edge atrophy 2012 MFMER slide-14
15 Pick s disease (3R tau) H&E Microscopic findings Pick bodies tau positive neuronal inclusions Gallyas negative Pick cells (ballooned neurons) neurofilament positive swollen neurons Pick bodies H&E Pick bodies Neurofilament Pick cells 2012 MFMER slide-15
16 Lewy body disease (α-synuclein) Parkinson s disease & Dementia with Lewy bodies Macroscopic findings Normal brain weight, unless significant AD pathology No significant cortical or cerebellar atrophy No ventricular enlargement Loss of pigment in substantia nigra and locus coeruleus Discoloration of the basal ganglia and substantia nigra Nigral loss Locus coeruleus loss 2012 MFMER slide-16
17 Lewy body disease (α-synuclein) Microscopic findings Lewy related pathology Neuronal inclusion Lewy body Neuritic Lewy dots Neuronophagia with phagocytic macrophages Neuronal loss in nucleus basalis of Meynert H&E H&E neuronophagia Lewy body α-synuclein α-synuclein Lewy body 2012 MFMER slide-17
18 Multiple systems atrophy (α-synuclein) Cerebellar ataxia (MSA-C) or parkinsonian presentation (MSA-P) Macroscopic findings Severe degeneration of the posterior putamen and lateral substantia nigra (MSA-P) Discoloration of the pons and cerebellar white matter (MSA-C) Striatonigral degeneration 2012 MFMER slide-18
19 Multiple systems atrophy (α-synuclein) α-synuclein Microscopic findings Neuronal inclusions Neuritic processes Glial cytoplasmic inclusions and neurites NCI NCI 2012 MFMER slide-19
20 Frontotemporal lobar degeneration (TDP-43) Frontal behavioral syndrome, progressive amnestic syndrome, progressive nonfluent aphasia, semantic (anomia) dementia, progressive apraxic syndrome Macroscopic findings Frontal & temporal atrophy, sparing peri-rolandic Atrophy of caudate, amygdala, & hippocampus common Cortical atrophy 2012 MFMER slide-20
21 Frontotemporal lobar degeneration (TDP-43) H&E H&E Microscopic findings Cortical superficial spongiosis Gliosis in gray & white matter No Alzheimer plaques or tangles Caudate atrophy & spongiosis is common TDP-43 Status spongiosis NCI 2012 MFMER slide-21
22 Heterogeneity of TDP-43 (FTLD-TDP subtypes) Type A Type B Type C Cortex NCI, neurites, NII NCI neurites Hippocampus NCI & NII NCI (granular) NCI (Pick body-like) Clinical: Genetics: FTDbv, PNFA, CBS GRN FTD-MND C9ORF72 SD C9ORF72 Department of Neuroscience 2012 MFMER slide-22
23 Hippocampal sclerosis (HpScl) Slowly progressive amnestic syndrome H&E Macroscopic findings Hippocampal atrophy of CA1 & subiculum Microscopic findings Disproportionate neuronal loss compared to neurofibrillary tangle (NFT) accumulation in the hippocampus TDP-43 type dependent typically reflects coexisting pathology healthy Selective vulnerability (Dickson, Acta Neuropathol, 1994) 2012 MFMER slide-23
24 Hippocampal sclerosis (HpScl) Slowly progressive amnestic syndrome Macroscopic findings Hippocampal atrophy of CA1 & subiculum Microscopic findings Disproportionate neuronal loss compared to neurofibrillary tangle (NFT) accumulation in the hippocampus TDP-43 type dependent typically reflects coexisting pathology H&E 50 μm Neuronal loss and gliosis Phospho-tau Minimal tau pathology 2012 MFMER slide-24
25 Amyotrophic lateral sclerosis (TDP-43) Weakness, with muscle atrophy with fasciculations, spasticity (increased tendon reflexes; clonus), dysphagia & dysarthria Luxol fast blue Macroscopic findings Normal brain weight Subtle motor cortex atrophy can be observed Corticospinal tract (CST) degeneration common H&E Corticospinal tract degeneration Luxol fast blue Microscopic findings Neuronal loss of motor neurons Inclusion bodies TDP-43 - Lewy-like, skein-like, Bunina bodies foamy macrophages myelin loss 2012 MFMER slide-25
26 Amyotrophic lateral sclerosis (TDP-43) Weakness, with muscle atrophy with fasciculations, spasticity (increased tendon reflexes; clonus), dysphagia & dysarthria Macroscopic findings Normal brain weight Subtle motor cortex atrophy can be observed Corticospinal tract degeneration common Microscopic findings Neuronal loss of motor neurons Inclusion bodies Lewy-like Bunina bodies TDP-43 -skein-like H&E a Neuronophagia c Lewy-like inclusions b d Reactive astrocytosis Bunina bodies 2012 MFMER slide-26
27 TDP-43 in ALS TDP-43 in neurons (a-e) Redistribution to cytoplasm as early pathology ( preinclusions (f)) Glial TDP-43 inclusions (g, h & i) Department of Neuroscien 2012 MFMER slide-27 ce
28 C9ORF72 hexanucleotide repeat (unclassified) Heterogeneous clinical presentation; FTD, MND, AD Macroscopic Reflective of the primary diagnosis Microscopic Ubiquitin-positive, TDP- 43 negative cerebellar inclusions P62-positive inclusions often greater than TDP- 43 in hippocampus and cortex Ub Ub p62 Molecular layer p62 NCI NCI Cerebellar granule cell pathology (Murray et al., Acta Neuropath, 2011) (Bieniek et al., Acta Neuropath, 2012) 2012 MFMER slide-28
29 Alzheimer s disease (Aβ) Most common form of dementia Macroscopic findings Significant cortical atrophy Ventricular enlargement Pigment loss in locus coeruleus Microscopic findings Neuronal loss and gliosis Amyloid β deposits in cortex (extracellular) Neurofibrillary tau accumulation (intracellular) Cortical atrophy Bielschowsky Senile plaque Gallayas Neurofibrillary tangle 2012 MFMER slide-29
30 Amyloid precursor protein (APP) 2012 MFMER slide-30
31 Classification of atypical and typical AD Quantified NFT on 889 cases Hippocampus (Hp) CA1 & subiculum Neocortex Temporal, frontal, & parietal Developed a mathematical algorithm Quartile classification for the hippocampal and cortical NFT count Classification based on median values Thioflavin-S Neurofibrillary tangle Senile plaque (Murray et al., Lancet Neurol, 2011) 2012 MFMER slide-31
32 Hippocampal and cortical NFT Braak stage NFT stages I + II NFT stages III NFT stages VI Cortex Entorhinal cortex Hippocampus Phospho-tau stain on a coronal slice demonstrates stereotypic progression of neurofibrillary tangle (NFT) pathology (Braak & Tredici, Alzheimer s & Dementia, 2012) 2012 MFMER slide-32
33 NFT differences across AD subtypes Hippocampal NFT p<0.001 p<0.001 Cortical NFT p<0.001 p<0.001 As expected, hippocampal NFTs were lowest in HpSp AD, with Typical AD remained centered between, and LP AD showing the highest Surprisingly, cortical NFTs were significantly higher in HpSp AD and lower in LP AD Independent regions demonstrated the same significance pattern No differences in senile plaque counts were found (Murray et al., Lancet Neurol, 2011) 2012 MFMER slide-34
34 Tau immunohistochemistry (15%) Phospho-tau (early) and a conformational epitope marker (late) in mid-frontal Digital microscopy to measure % burden Verified thio-s findings Implicates early cortex involvement in HpSp 50% 28% 1.8% 0.41% (Janocko et al. Acta Neuropath 2012) 8.5% 0.10% 2012 MFMER slide-35
35 Amyloid-β immunohistochemistry Amyloid-β found to be lowest in HpSp and highest in LP mid-frontal cortex Conversely, the frequency of senile plaques in the basal ganglia were found to be higher in HpSp and lowest in LP 2.2% 4.7% (Janocko et al., Acta Neuropath, 2012) 5.2% 2012 MFMER slide-36
36 Demographic and Clinical characteristics Age, sex, and clinical presentation significantly differ amongst subtypes HpSp Typical LP p-value Number (% total of n=889) 97 (11%) 665 (75%) 127 (14%) Age at death, mean yr. (SD) 73 (10) 79 (9) 86 (6) <0.001 Females (% total of AD type) 36 (37%) 368 (55%) 87 (69%) <0.001 Education, mean yr. (SD) 15 (3) 14 (3) 14 (3) Age of onset, mean yr. (SD) 63 (10) 69 (10) 76 (7) <0.001 Disease duration, mean yr. (SD) 8 (3) 9 (4) 10 (4) Atypical clinical, % total 30% 17% 6% <0.001 An Analysis of Variance (ANOVA) or Chi-square was performed
37 Rate of clinical decline MMSE Typical HpSp Shorter duration MMSE HpSp Typical LP p-value LP Initial score 20 (15,25) 23 (15,26) 23 (18,28) 0.64 ǂ Final score 7 (2,13) 11 (6,16) 15 (8,19) ǂ Rate of decline 4.8 (8.3,3.1) 2.8 (4.4,1.5) 1.4 (2.8,0.8) ǂ Shown for each measure is median and interquartile range. Black line = moving average
38 Multiproteinopathy in AD subtypes Pathology TDP-43+ Lewy body disease Hippocampal sparing 13/97 (13%) 11/97 (11%) Typical 170/559 (30%) 172/665 (26%) Limbic predominant 30/100 (30%) 33/127 (26%) p-value Data was analyzed using Chi-square 2012 MFMER slide-39
39 Multiproteinopathies Protein number N (%) Age, years* Males (%)** Brain weight* Braak NFT stage* (79) 76 (69-83) 1505 (54) 1120 ( ) 3 (2-5) (20) 80 (74-86) 333 (48) 1080 ( ) 5 (4-6) 3 49 (1) 81 (78-84) 22 (45) 980 ( ) 6 (4-6) AD Tau TDP-43 α-syn Data assessed by ANOVA on Ranks, except for a Chi-square analysis of gender. * p<0.001, **p< MFMER slide-40
40 Multi-proteinopathies Co-existing pathologies at autopsy are common Pure AD is relatively uncommon *n = 367 (22%) in our series when cases with vascular disease, etc. are removed TDP-43 AD α-syn Tau Proteinopathy Proteins number AD 1682 Pure AD * + Tau α-synuclein TDP α-synuclein + TDP α-synuclein TDP TDP Tau α-synuclein TDP TDP α-synuclein TDP TDP n 2012 MFMER slide-41
41 Summary There are several classifications schemes that can be used to classify neurodegenerative diseases, today s focus was on molecular classification. The number of both multiproteinopathies increases with age and shifts to a female predominance AD is prime example of a multiproteinopathy and can be classified based on the predominance of neurofibrillary tangles 2012 MFMER slide-42
42 Summary & Conclusion AD subtypes differ by gender, age, age of onset, disease duration, and cognitive decline Neuropathologic differences in AD subtypes is associated with quantitative differences in early and late tau, as well as amyloid burden Co-existing neuropathology is common finding and should be considered when inferring the cognitive correlates of neuropathologic accumulation Classification of neurodegenerative disease as single proteinopathies has its limitations, as many disorders are frequently found to have multiple proteins 2012 MFMER slide-43
43 Acknowledgements Grant support Mayo ADRC grant (P50 AG16574) Florida ADRC (P50 AG215711) Einstein Aging Study (P01 AG03949) Florida Alzheimer s Disease Initiative ADRC Pilot Program Fellowship Robert H. and Clarice Smith and Abigail vanburen AD Research Program Fellowship We thank the patients and their families who have donated brains to help further our knowledge in neurodegeneration. Dickson Lab: Nicholas Janocko Kevin Bieniek Amanda M. Liesinger Linda G. Rousseau Virginia R. Phillips John Gonzalez Monica Castanedes-Casey 2012 MFMER slide-44
44 Questions & Discussion 2012 MFMER slide-45
45 Structural MRI Voxel based morphometry (Whitwell et al., Lancet Neurol, 2012) 2012 MFMER slide-46
46 Multiple diagnoses AD Typical LP HpSp Not specified Tau 4R PSP CBD 3R - PiD 3R+4R - NFT Α-synuclein LBD BLBD TLBD DLBD MSA TDP-43 FTLD ALS HpScl Dx. n (%) Age, yrs Males (%) (48) 76 (68-82) 932 (54) (45) 78 (72-84) 831 (44) (7) 80 (75-85) 106 (45) (1) 83 (78-87) 11 (39) MFMER slide-47
47 Multiproteinopathy AD = 2 3R&4R tau + amyloid CAA = 1; if AD = 0 CJD = 1 3R tau = 1 4R tau = 1 Synuclein = 1 TDP43 = 1 HpScl = 1 Protein n (%) Age, yrs Males (%) (36) 73 (67-79) 764 (59) (42) 79 (72-84) 766 (50) (20) 81 (75-86) 324 (45) (2) 83 (80-88) 26 (41) MFMER slide-48
48 Multiproteinopathy in 1º AD Dx. n (%) Age, yrs Males (%) (54) 80 (73-86) 360 (44) (42) 81 (75-86) 293 (46) (4) 82 (80-89) 22 (38) 2012 MFMER slide-49
49 AD Typical LP HpSp Not specified Tau 4R PSP CBD 3R - PiD 3R+4R - NFT Α-synuclein LBD BLBD TLBD DLBD MSA TDP-43 FTLD ALS HpScl 2012 MFMER slide-50
50 Multi-proteinopathies Co-existing pathologies at autopsy is common Pure AD is relatively uncommon *n = 367 in our series when cases with vascular disease, etc. are removed AD TDP-43 α-syn Tau Proteinopathy Proteins number n (%) AD 1682 (47) Pure * Tau 2 87 α-synuclein TDP Tau + α-synuclein 3 4 Tau + TDP α-synuclein + TDP Tau + α-synuclein + TDP Tau 1125 α-synuclein 2 70 TDP α-synuclein + TDP α-synuclein 1125 TDP TDP MFMER slide-51
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