1、Degenerative Diseases of the CNS劉秀枝Hsiu-Chih Liu, MD National Yang-Ming University School of MedicineDepartment of Neurology Taipei Veterans General Hospital,References:1.Victor M, Ropper AH. Degenerative diseases of the nervous system. In Adams and Victors Principles of Neurology, 7th ed. McGraw-Hi
2、ll, 2001, pp 1106-1174.2.Scarpini E, et al. Treatment of Alzheimers disease: current status and new perspective. Lancet Neurology 2003;2:39-547.,Clinical Characteristics of Neurodegnerative Diseases,Insidious onset Gradually progressive course Familial occurrence Bilateral symmetry,General pathologi
3、c Features ofNeurodegenerative diseases,Selective involvement (Selective vulnerability)CSF and neuroimaging usually normal,Degenerative Diseases of the CNS,Cerebral cortex Alzheimer disease Frontotemporal dementia Lewy body disease Basal ganglia Huntington disease Basal ganglia / brainstem Progressi
4、ve suparnuclear palsy Striatonigral degeneration,Degenerative Diseases of the CNS,Midbrain Parkinson diseaseBrainstem, cerebellum, spinal cord Friedreichs ataxia Olivopontocerebellar atrophy Spinocerebellar atrophySpinal Cord Amyotrophic lateral sclerosis Spinobulbar muscular atrophy Spinal muscular
5、 atrophy,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 ophthal
6、moplegia 8. Neurosensory deafness,Neurodegenerative Diseases,Dementia Alzheimers disease (AD) Frontotemporal dementia (FTD) Diffuse Lewy body disease (DLB) Movement disorders Parkinsons disease (PD) Huntington disease (HD) Progressive Ataxia Olivopontocerebellar atrophy (OPCA) Spinocerebellar ataxia
7、 (SCA) Motor Neuron Disease (ALS),PARKINSONSDISEASE,FRONTALDEMENTIA,ALZHEIMERSDISEASE,SEMANTICDEMENTIA,LEWY BODYDISEASE,HD,PICKSDISEASE,Dementias Can be Classified by Initial Symptoms,PSP CBD,DEMENTIAIN DOWNS,CJD,PCA,PPA,ALS,OTHER,LINGUISTICDISORDER,MEMORYDISORDER,MOVEMENTDISORDER,BEHAVIORALDISORDER
8、,VasD,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,Delirium （譫妄） Amnesia （失憶） Dementia（失智、痴呆）,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%
9、 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,阿茲海默症Alzheimers disease 50-60%,血管性失智Vascular dementia 10-20%,混合性 Mixed dementia 10%,其他 Other dementia 10-20%,失智症的診斷,病史身體及神經檢查心智評估: MMSE,CASI,ADAS-Cog,Clock,CDR4. 實驗室檢查 AD DSM-IV, NINCDS-ADRDA,Clinical Dementia Rating Scale (CDR, 臨床失智評分表) 將認知功能分
10、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,失智症之實驗室檢查,必要常規檢查,特殊病情需要,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,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）,阿茲海默症 (AD),最常
11、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,DSM-IV阿茲海默症的診斷標準（1994）,A、多種認知障
12、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,The Molecular Pathogenesis of Alzheimers Disease,Senile plaques: beta/A4 peptide (beta-amyloid,amyloid beta-protein) beta-amyloid precursor protein (APP)Neuro
13、fibrillary tangles: paired helical filaments(PHF) microtubule-associated protein (MAP) tau proteins,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 Pharmacoth
14、erapy for behavioral problems知能改善 Pharmacotherapy for cognitive symptoms,阿茲海默氏症之異常行為(Behavioral Problems),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),阿茲海默氏症的症狀治療（Symptomatic treatment）,增加乙醯膽鹼的藥物 （1
15、）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,Cholinergic Synaptic Transmission,ChE inhibitors reduce acetylcholine hydrolysis in remaining neurons and help to normalize cholinergic function,乙醯膽鹼酶抑制劑 (Ach-I)The standard t
16、herapy 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,乙醯膽鹼酶抑制劑(AchE-I),療效:相當, modest, 25 - 50% responders 阿症量表 (ADAS-
17、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,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,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 (An
18、ti-inflammatory agents, NSAID)抗氧化物 (Antioxidants)：維他命E, Selegiline,Elio Scarpini, LANCET Neurol 2003; 2:539-47,Risk factors,Nerve cell loss,Neurochemical deficits,Dementia syndrome,Mutations,Amyloid production and aggregation,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
19、年高血壓 （4）老年憂鬱症,Cognitive Continuum,Criteria for Mild Cognitive Impairment（MCI）,Memory complaint corroborated by an informantNormal general cognitive functionNormal activities of daily living Memory impairment for age and educationNot demented,Current Prevention Trials,Cognitive Function,Time,AAMI,MCI
20、,AD,Celecoxib vs. Placebo,1.Donepezil vs. Vitamin E vs. Placebo2.Rivastigmine vs. Placebo,Syndrome of Progressive Dementia,Diffuse cerebral atrophy Alzheimers disease Diffuse Lewy-body dementiaCircumscribed cerebral atrophy Picks disease (Frontotemporal dementia),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,DLB,Examples of Differential Clinical Features*,VA Guidelines p.23,
