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1 Neuropathology Shigeo Murayama Department of Neuropathology (Brain Bank) Tokyo Metropolitan Institute of Gerontology Today s Themes A. General consideration Hierarchy of the nervous system Dynamic Neuropathology Clinical manifestation - Neurology & Psychiatry Neuroimages: CT, MRI, SPECT & PET Pathology: Mophology, Biochemistry & Molecular genetics B. Category of disorders 1. Cerebrovascular disorders -thrombosis, embolism, aneurysm, lacuna 2. Infectious disorders 3. Developmental, perinatal & metabolic disorders 4. Demyelinating disorders -multiple sclerosis 5. Neuromuscular disorders 6. Degenerative disorders, hereditary & sporadic -amyotrophic lateral sclerosis 7. Aging and dementing disorders - Alzheimer disease Parkinson disease Hierarchy of the Nervous System Cerebrum Basal ganglia Thalamus Cerebellum Brain Stem Spinal Cord Peripheral Nerve Muscle Localization Level Dynamic Neuropathology Neurology & Psychiatry Signs and symptoms - behavior Neurophysiology - EEG, EMG, NCV, EP Laboratory medicine: blood, urine and CSF Neuroradiology CT scan - X-ray based MRI - NMR SPECT - radioisotope PET - positron Correlation with Neuropathology Neuropathology Morphology Routine staining: - hematoxylin and eosin Special staining: Nissl - mrna - neuron luxol fast blue - lipid - myelin silver staining Bodian neurofilament - axon Gallyas-Braak tau - tangle Methenamine beta amyloid - plaque Bielshowsky Immunohistochemsitry Ultrastructural study Protein biochemistry Molecular biology Cellular Pathology Immunohistochemistry amyloid β plaque τ, phosphorylated tangle α-synuclein, phosphorylated Lewy body ubiquitin glial-fibrillary acidic protein: astrocytes MHC class II (HLA-DR): microglia Factor VIII endotheil Ultrastructural study organella, abnormal accumulation 1

Brain Bank Official system (infrastructure) to provide human brain tissue for neuroscience research 1.

350 brain banks, NIH funded, connecting researcher A Gift of Hope movement 3.

Brain Donation for Next Generation movement 5. Australia A Gift of Hope movement 6.

Gerontology and Japanese Ministries of Education, Culture, Sports, Science, and Technology & Health, Labor and

2 Brain Bank Official system (infrastructure) to provide human brain tissue for neuroscience research 1. Dutch Brain Bank living will, official + private, providing tissue worldwide 2. U.S.A. 350 brain banks, NIH funded, connecting researcher A Gift of Hope movement 3. EC EC Brain Network 提供者証明書 ( 死亡の際は直ちに Brain-Net センターへ電話連絡を ) ドイツブレインネットドイツブレインネット剖検施設ネットワーク 4. U.K. Brain Donation for Next Generation movement 5. Australia A Gift of Hope movement 6. Brain Bank for Aging Research funded by Tokyo Metropolitan Geriatric Hospital, Tokyo Metropolitan Institute of Gerontology and Japanese Ministries of Education, Culture, Sports, Science, and Technology & Health, Labor and Welfare ( 裏面 ) (Brain-Net センターアドレス ) ( 提供者氏名 ) ( 提供者署名 ) 赤 : 独立した神経病理施設黄 : 病理施設下の神経病理部門 Gross Anatomy 1. To identify representative structures 2. Most important for accurate diagnosis 3. Requiring careful clinical and pathological correlation Brain Cutting Session 2

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6 脳血管障害脳動脈硬化脳底動脈血栓症動脈硬化生活習慣病生活習慣の改善で予防可能 6

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CJD Protocol Sequence study of prion gene

with anti-prion antibody hippocampus, processed

99% formic acid: 5 minutes Tissue processing

8 CJD Protocol Sequence study of prion gene Immunoblot of frozen brain Immunohistochemistry with anti-prion antibody hippocampus, processed as below 1-3mM HCl 121 o C 10 minutes atuoclave 99% formic acid: 5 minutes Tissue processing fixed in formalin :>1week processed in 99% formic acid: 1hr post-fixed in formalin overnight embedded in paraffin Immunoblot with anti-prion antibody (3F4) 8

Multiple sclerosis Inflammtory demyelination involoving the

space Three clinical types: relapsing-remittent secondary

responsible gene, translating into polyglutamine 2.

Selective neuronal degeneration Huntington disease: caudate

9 Multiple sclerosis Inflammtory demyelination involoving the central nervous system Multiple occurrence both in time and space Three clinical types: relapsing-remittent secondary progressive primary progressive Myelin Axon Myelin Axon Triplet repeat disease 1. Abnormal expansion of CAG repeats in the exons of the responsible gene, translating into polyglutamine 2. Accumulation of polyglutamine in the nucleus and cytoplasm 3. Selective neuronal degeneration Huntington disease: caudate nucleus SCA3/ MJD: pons, cerebellum spinal cord, basal ganglia DRPLA: dentate-rubllo-pallido-luysain atrophy Huntington Control 9

10 Amyotrophic lateral sclerosis 1. Progressive weakness and atrophy 2. Death due to respiratory failure 3. Intact intellectual function 4. A subgroup of familial case caused by mutation of superoxide dismutase 1 (SOD1), leading to the accumulation of ubiquitinated abnormal SOD1 Intraneuronal inclusion 10

Aging and Dementia Abnormal accumulation of posttranslated proteins β amyloid = Alzheimer disease (senile plaques) accompanying secondary tauopathy (tangles) hereditary

synucleinopathy - Parkinson s disease hereditary - α-synuclein gene, mutation, dupulicaion Parkin gene (ubiquitin ligase), LRRK2 sporadic - Lewy body disease multiple

phosphorylation of τ protein β & γ secretase cleaves amyloid precursor protein (APP) to form Aβ Vaccination of Aβ halted by complication of fatal encephalitis

11 Aging and Dementia Abnormal accumulation of posttranslated proteins β amyloid = Alzheimer disease (senile plaques) accompanying secondary tauopathy (tangles) hereditary - mutation in APP, PS1 & 2 sporadic - association with apoe4 τ = tauopathy hereditary - FTDP17- mutation in τ gene sporadic - Pick s disease α-synuclein = synucleinopathy - Parkinson s disease hereditary - α-synuclein gene, mutation, dupulicaion Parkin gene (ubiquitin ligase), LRRK2 sporadic - Lewy body disease multiple system atrophy Alzheimer s disease The most common cause of dementia Progressive cognitive decline Amyloid cascading hypothesis accumulation of β amyloid (Aβ) abnormal phosphorylation of τ protein β & γ secretase cleaves amyloid precursor protein (APP) to form Aβ Vaccination of Aβ halted by complication of fatal encephalitis Acetylcholine esterase inhibitor, transiently effective AD 70Y Averaged FDG-PET Images in Alzheimer s Disease 83Y Normal N=12 Mild AD HDRS>20 N=6 Moderate AD HDRS 10~20 N=7 Severe AD HDRS<10 N=6 11

12 軽度認知機能障害 : 初期アルツハイマー病疑 Comparison with 21 normals ANCOVA p<0.01 MCI 76 M Alzheimer disease Control 12

Immunization with Aβ 容量計測 MRI(voxel based morphometry)

of Aβ Phase I trial, uneventful Phase II study,

confirmed at autopsy 海馬に萎縮があるのかどうか視診上断定できない 80 代女性認知症

2 髄液バイオマーカー τ Pτ Aβ HVA 5HIAA アルツハイマー病 MRI 糖代謝ペット (FDG)

13 Immunization with Aβ 容量計測 MRI(voxel based morphometry) 70 代女性物忘れ MMSE28 点 Experimental evidence with clearance of Aβ Phase I trial, uneventful Phase II study, suspended due to fatal encephalitis Clearance of Aβ, confirmed at autopsy 海馬に萎縮があるのかどうか視診上断定できない 80 代女性認知症 MMSE18 点 VSRAD 統計解析では海馬傍回萎縮は青で示されるアルツハイマー病初期の可能性を含めてフォローを要する Z score1.9 軽度萎縮は疑えるが判断に困難を感ずるのは間違いない Z score 2.2 髄液バイオマーカー τ Pτ Aβ HVA 5HIAA アルツハイマー病 MRI 糖代謝ペット (FDG) アミロイドベータ蛋白 (PIB) ペット所見パーキンソン病レヴィー小体型痴呆進行性核上性麻痺神経原線維変化優位型痴呆嗜銀顆粒性痴呆皮質基底核変性症クロイツフェルトヤコブ病ブレインバンク生前同意登録者 ( アルツハイマー病疑い ) 13

14 Pick s disease Six Isoforms of τ protein Prototypes of frontotemporal dementia Famous but infrequent (about 1% of Alzheimer s disease) Pure tauopathy Lobar atrophy Pick body FTDP17 66M Pick/ Pick 68 14

Parkinson s disease The most common degenerative

the elderly Treatable disease with L-Dopa

Lewy body and Lewy neurites Active role of

with mutation, or triplication Close association with

15 Parkinson s disease The most common degenerative disease, causing motor and cognitive impairment in the elderly Treatable disease with L-Dopa Accumulation of phosphorylated α-synuclein, forming Lewy body and Lewy neurites Active role of α-synuclein, confirmed by familial Parkinson disease with mutation, or triplication Close association with ubiquitin Systemic disease involving both central and peripheral nervous system 15

Ser129 phosphorylated α-synuclein Specific

A53T LB509 124 129 134 AYEMPSEEGYQ PO 3 H

16 Ser129 phosphorylated α-synuclein Specific monoclonal antibody (#64) P 140 A30P A53T LB AYEMPSEEGYQ PO 3 H 2 Multiple system atrophy 1. Sporadic neuroglial synucleinopathy 2. Most common cause of spinocerebellar degeneration 3. Three systems, involved Olivo-ponto-cerebellar system Striato-nigral system Autonomic system 16

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Diagnosis of Dementia: Update

Diagnosis of Dementia: Update 10 C A 1 2 Normal SMI MCI Early Dementia B Moderate Dementia 3 Severe Dementia 4 5 D AD, VD, FTD, DLB, PDD Depression Dementia d/t GMC Modifiable risk factors and preventive factors for dementia 6-5 -