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Degenerative Diseases of the CNS 劉秀枝 Hsiu-Chih Liu, MD National Yang-Ming University School of Medicine

Degenerative Diseases of the CNS 劉秀枝 Hsiu-Chih Liu, MD National Yang-Ming University School of Medicine Department of Neurology Taipei Veterans General Hospital . References:

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Degenerative Diseases of the CNS 劉秀枝 Hsiu-Chih Liu, MD National Yang-Ming University School of Medicine

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  1. Degenerative Diseases of the CNS 劉秀枝 Hsiu-Chih Liu, MD National Yang-Ming University School of Medicine Department of Neurology Taipei Veterans General Hospital

  2. References: 1.Victor M, Ropper AH. Degenerative diseases of the nervous system. In Adams and Victor’s Principles of Neurology, 7th ed. McGraw-Hill, 2001, pp 1106-1174. 2.Scarpini E, et al. Treatment of Alzheimer’s disease: current status and new perspective. Lancet Neurology 2003;2:39-547. .

  3. Clinical Characteristics of Neurodegnerative Diseases • Insidious onset • Gradually progressive course • Familial occurrence • Bilateral symmetry

  4. General pathologic Features ofNeurodegenerative diseases • Selective involvement (Selective vulnerability) • CSF and neuroimaging usually normal

  5. Degenerative Diseases of the CNS • Cerebral cortex • Alzheimer disease • Frontotemporal dementia • Lewy body disease • Basal ganglia • Huntington disease • Basal ganglia / brainstem • Progressive suparnuclear palsy • Striatonigral degeneration

  6. Degenerative Diseases of the CNS • Midbrain Parkinson disease • Brainstem, cerebellum, spinal cord Friedreich’s ataxia Olivopontocerebellar atrophy Spinocerebellar atrophy • Spinal Cord Amyotrophic lateral sclerosis Spinobulbar muscular atrophy Spinal muscular atrophy

  7. Classification of Neurodegnerative Disorders By Syndromes 1.Progressive dementia 2.Progressive dementia with other neurological abnormalities 3.Disordered posture and movement 4.Progressive ataxia 5.Muscular weakness and atrophy 6.Spastic paraplegia 7.Progressive blindness or ophthalmoplegia 8. Neurosensory deafness

  8. Dementias Can be Classified by Initial Symptoms BEHAVIORAL DISORDER MOVEMENT DISORDER ALS HD FRONTAL DEMENTIA PARKINSON’S DISEASE PSP CBD PICK’S DISEASE LEWY BODY DISEASE PCA VasD SEMANTIC DEMENTIA ALZHEIMER’SDISEASE DEMENTIA IN DOWN’S PPA LINGUISTIC DISORDER MEMORY DISORDER CJD OTHER

  9. Dementia • Acquired syndrome of decline in memory and at least one other cognitive function (e.g., apraxia, aphasia, agnosia) sufficient to affect daily life in an alert person. -Small et al. JAMA 1997;278:1363-1371

  10. Delirium（譫妄） • Amnesia（失憶） • Dementia（失智、痴呆）

  11. 失智症:醫療資源、公共衛生的重大議題 • 失智症的盛行率(65歲): 2.5% ~ 5.0% • 台灣65歲以上人口 (2002年8月): 200萬 • 估計台灣有五萬(2.5%)~十萬(5%) 失智症人口

  12. 其他Other dementia 10-20% 混合性Mixed dementia 10% 阿茲海默症Alzheimer’s disease 50-60% 血管性失智Vascular dementia 10-20%

  13. 失智症的診斷 • 病史 • 身體及神經檢查 • 心智評估: MMSE,CASI,ADAS-Cog,Clock,CDR 4. 實驗室檢查 AD DSM-IV, NINCDS-ADRDA

  14. Clinical Dementia Rating Scale (CDR, 臨床失智評分表)將認知功能分成: • 記憶 • 定向力 •判斷及解決問題 • 社區事務 •家居及嗜好 •個人照料 依五個不同嚴重的缺損程度評分 (由輕到重): 0 (健康) 0.5 (疑似或輕微) 1 (輕度) 2 (中度) 3 (重度) ”個人照料” 無 0.5 的缺損程度評分. 只評估因認知功能失常所造成的缺損程度 若在兩個程度當中, 請圈選嚴重程度

  15. 失智症之實驗室檢查 必要常規檢查 特殊病情需要 紅血球沈澱速率 愛滋病檢查 胸部X光、尿液檢查 神經心理測驗 腦脊髓液檢查 腦電波 單光子電腦斷層檢查 （PET/SPECT） 血液常規（CBC） 生化檢查（肝腎功能） 維他命B12濃度 甲狀腺功能 梅毒血清檢查 腦部電腦斷層或磁振照影

  16. 阿茲海默症 (AD) • 最常見的失智症The most common disease causing dementia • 大腦退化(neurodegeneration): 類澱粉斑(amyloid plaques)及神經纖維叢(neurofibrillary tangles) • 神經傳導素以乙醯膽鹼之減少為主Deficiency of acetylcholine • 臨床診斷A clinical diagnosis with no specific biological markers • 平均存活8-12年 Average survival: 8-12 years

  17. DSM-IV阿茲海默症的診斷標準（1994） A、多種認知障礙 （1）記憶障礙（無法學習新知或回想） （2）以下其中至少一項 （a）失語症（aphasia） （b）失用症（apraxia） （c）認識不能（agnosia） （d）執行功能障礙 (executive function) B、A1及A2的障礙足以影響到社交或工作，而且比以前為差

  18. The Molecular Pathogenesis of Alzheimer’s Disease • Senile plaques: beta/A4 peptide (beta-amyloid,amyloid beta-protein) beta-amyloid precursor protein (APP) • Neurofibrillary tangles: paired helical filaments(PHF) microtubule-associated protein (MAP) tau proteins

  19. 阿茲海默症的治療 Treatment of AD • 照顧者輔導諮詢, 減少負擔, 避免意外及感染 Educational interventions of caregivers • 其他非藥物治療 Other nonpharmacologic interventions, such as behavioral modification, music therapy • 精神及行為異常之處理 Pharmacotherapy for behavioral problems • 知能改善 Pharmacotherapy for cognitive symptoms

  20. 阿茲海默氏症之異常行為(Behavioral Problems)

  21. 阿茲海默症之知能改善治療 Pharmacotherapy for cognitive symptoms • 改善知能障礙(Symptomatic therapies) • 停止疾病的進行 (Disease-modifying drugs) • 根治或預防阿茲海默症(Cure or prevention)

  22. 阿茲海默氏症的症狀治療（Symptomatic treatment） • 增加乙醯膽鹼的藥物 （1）乙醯膽鹼酵素抑制劑 （Acetylcholinesterase inhibitors） （2）Muscarinic agonists （3）Nicotinic agonists （4）Acetylcholine precursors • 非乙醯膽鹼藥物

  23. Presynaptic Acetyl CoA ChAT Choline ACh release ACh ACh ChE inhibitor ACh Choline + acetate ACh AChE ACh ACh ACh receptors Postsynaptic Cholinergic Synaptic Transmission ChE inhibitors reduce acetylcholine hydrolysis in remaining neurons and help to normalize cholinergic function

  24. 乙醯膽鹼酶抑制劑(Ach-I)The standard therapy for ADDouble-blind, placebo-control trials, class I evidence • Cognex (Tacrine) (1993, 2000) • Aricept (Donepezil) 愛憶欣 (1996,1998) • Exelon (Rivastigmine) 憶思能 (2000, 2000) • Reminyl (Galantamine)利憶靈 (2001, 2002) No predictors of response

  25. 乙醯膽鹼酶抑制劑(AchE-I) • 療效: 相當, modest, 25 - 50% responders 阿症量表(ADAS-cog) 2 – 5 分 Aricept (2.9-3.1), Exelon (1.6-3.8),Reminyl (0.1-3.4) No predictors of responders • 副作用: 噁心, 嘔吐, 頭暈, 腹瀉 • 藥物的選擇主要考慮其副作用 及使用的方便性

  26. 阿茲海默症之非乙醯膽鹼的藥物治療 • Hydergine • Piracetam (Nootropil) • Gingko biloba (銀杏) • Memantine: glutamate NMDA antagonist

  27. 減緩阿茲海默症知能減退之藥物(Disease Modify drugs) • 女性賀爾蒙(Estrogen) • 抗發炎藥物(Anti-inflammatory agents, NSAID) • 抗氧化物(Antioxidants)：維他命E, Selegiline

  28. Elio Scarpini, LANCET Neurol 2003; 2:539-47

  29. Mutations Risk factors Amyloid production and aggregation Nerve cell loss Neurochemical deficits Dementia syndrome

  30. 老年失智之危險因子 • 遺傳性： 年齡、女性、家族史 唐氏症候群、Apolipoprotein E4 • 非遺傳性： （1）低教育 （2）嚴重腦外傷 （3）中年高血壓 （4）老年憂鬱症

  31. Cognitive Continuum

  32. Criteria for Mild Cognitive Impairment（MCI） • Memory complaint corroborated by an informant • Normal general cognitive function • Normal activities of daily living • Memory impairment for age and education • Not demented

  33. Current Prevention Trials Celecoxib vs. Placebo 1.Donepezil vs. Vitamin E vs. Placebo 2.Rivastigmine vs. Placebo Cognitive Function AAMI MCI AD Time

  34. Syndrome of Progressive Dementia • Diffuse cerebral atrophy Alzheimer’s disease Diffuse Lewy-body dementia • Circumscribed cerebral atrophy Pick’s disease (Frontotemporal dementia)

  35. DLB Dementia with Lewy Bodies • AD與DLB界線模糊 • 相似的病理特徵 : 神經炎斑neuritic plaques (較少神經纖維纏結) • 大腦之膽鹼性cholinergic神經傳導出現缺陷 • LB出現在大腦皮質，故臨床上很早(初期)出現失智症狀 • 進行性的失智病程 • 三大臨床症狀 (至少有兩種) (1) 波動性認知損傷、特別是缺乏注意力 (2) 視幻覺、其它精神紊亂特徵 (3) 帕金森氏徵候群 • 治療的挑戰 • 對抗精神藥物、AChE-I 特別敏感, 會出現 椎體外症候群 • 會引起嚴重、致死的過敏反應，死亡率高出2-3倍

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