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:

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.

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Clinical Characteristics of Neurodegnerative Diseases

Insidious onset Gradually progressive course Familial occurrence Bilateral symmetry

General pathologic 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 Progressive suparnuclear palsy Striatonigral degeneration

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

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 ophthalmo

plegia 8. Neurosensory deafness

PARKINSON’SDISEASE

FRONTALDEMENTIA

ALZHEIMER’SDISEASE

SEMANTICDEMENTIA

LEWY BODYDISEASE

HD

PICK’SDISEASE

Dementias Can be Classified by Initial Symptoms

PSP CBD

DEMENTIAIN DOWN’S

CJD

PCA

PPA

ALS

OTHER

LINGUISTIC

DISORDER

MEMORYDISORDER

MOVEMENTDISORDER

BEHAVIORALDISORDER

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 ( 癡呆症 )

Dementia

老年失智症 ( 老年癡呆症 )

Senile dementia

阿茲海默症 Alzheimer’s Disease

Senile dementia of the Alzheimer’s type (SDAT)

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

阿茲海默症Alzheimer’s disease 50-

60%血管性失智Vascular dementia 10-20

%

混合性 Mixed dementia 1

0%

其他 Other dementia

10-20%

失智症的診斷1.病史2.身體及神經檢查3.心智評估 : MMSE,CASI,ADAS-Cog,Clock,CDR

4. 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 fun

ction) 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 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

ALZHEIMER’S DISEASE

Signs Dementia

Familial ~5 %

Onset FAD, mid life: sporadic AD, late life

Duration 8-12 years

Chromosomal loci 21,14,1,early FAD. 19,late FAD

Gene (chromosome) APP (21), presenilin-1(14), presenilin-2(1) in FAD families; ApoE4(19) in late neurons

Selective vulnerability Cortical, hippocampal,and basal forbrain cholinergic neurons

Cytoskeletal pathology Neurofibrillary tangles, neurites.

Neuropil threads

Death of neurons Severe

Amyloid A β deposits

Animal models Aged nonhuman primates: APP transgenic mice

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

阿茲海默氏症之異常行為(Behavioral Problems)

症 狀 發 生 率冷 漠（ apathy ）激 動（ agitation ）焦 慮（ anxiety ）易 怒（ irritability ）憂 鬱（ depression ）過度活動（ motor behavior ）失去控制（ disinhibition ）食慾改變（ appetite change ）夜晚行為（ night behavior ）妄 想（ delusions ）幻 想（ hallucinations ）

70%60%45%42%38%38%36%31%24%22%10%

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 ）乙醯膽鹼酵素抑制劑 （ Acetylcholinesterase inhibit

ors ） （ 2 ） Muscarinic agonists （ 3 ） Nicotinic agonists

（ 4 ） Acetylcholine precursors

非乙醯膽鹼藥物

Cholinergic Synaptic Transmission

Acetyl CoA

Choline

ACh

ACh

ChATChATChATChAT

ACh releaseACh releaseACh releaseACh release

ACh

PresynapticPresynaptic

PostsynapticPostsynaptic

Choline +Choline + acetateacetate

Choline +Choline + acetateacetate

ACh

AChE

ACh

ACh receptorsACh receptors

ChE inhibitorChE inhibitorChE inhibitorChE inhibitor

ACh

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 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

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

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 (Anti-inflammatory agents, NSAID)

抗氧化物 (Antioxidants)：維他命 E, Selegilin

e

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）中年高血壓 （ 4）老年憂鬱症

Cognitive Continuum

Normal

正常Mild Cognitive

impairment (MCI)

輕度知能減退Dementia

失智症

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

Current Prevention TrialsC

ogni

tive

Fun

ctio

n

Time

AAMIMCI

AD

Celecoxib vs. Placebo

1.Donepezil vs. Vitamin E vs. Placebo

2.Rivastigmine vs. Placebo

Syndrome of Progressive Dementia

Diffuse cerebral atrophy Alzheimer’s disease Diffuse Lewy-body dementiaCircumscribed cerebral atrophy Pick’s 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

DLBDLB

Examples of Differential Clinical Features* Diagnosis Clinical Features

Alzheimer’s disease

Memory, language and visuospatial disturbances, indifference, delusions, agitation

Frontotemporal dementia

Marked personality changes, relative preservation of visuospatial skills, executive dysfunction

Lewy body dementia

Marked visual hallucinations, delusions, fluctuating mental status, neuroleptic Sensitivity

VA Guidelines p.23