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1、1,认知功能障碍诊断、治疗新观念,2,3,4,痴呆是一种获得性多认知障碍疾病，通常包含记忆损害以及非谵妄条件下的至少其他一种认知功能损害失语、失用、失认和执行功能受损（归纳、计划、启动、排序、跟踪、终止）。,5,6,Wimo A, et al. Alzheimers Disease International World Alzheimer Report 2010.,7,修改至Cummings JL. Primary Psychiatry. Vol 15, No 2. 2008,8,阿尔茨海默病（Alzheimers disease） AD (AD-P & AD-C) 的新理念、诊断新指南NI
2、A2011 AD研究热点 AD治疗及预防新进展 血管性认知功能障碍（Vascular Cognitive Impairment） FTDP-17病例报道,9,10,11,Alois Alzheimer，1864-1915，德国神经病理学家、精神病学家。1906年11月3日，第一次定义了阿尔茨海默病。 1901年，Alzheimer在Frankfurt Asylum遇见患者Mrs. Auguste Deter，一位有着短期记忆丧失在内的各种奇怪行为症状的患者。随后，Alzheimer对其进行了随访。1906年， Mrs. Deter去世，她的脑组织与病史被送往Munich的Kraepelin实验
3、室。于是，Alzheimer与两位意大利同事通过组织染色发现了淀粉样斑块和神经纤维缠结。最后于1906年11月3日，Alzheimer进行了第一次早老性痴呆临床与病理特征的报道。,12,A, Tau,内侧颞叶萎缩、颞顶叶低代谢,记忆认知行为障碍,13,14,15,AD (AD-P & AD-C) 的新理念、诊断新指南NIA2011,16,Lancet Neurol 2010; 9: 111827,The International Working Group Howard H Feldman Jeff rey L Cummings Philip Scheltens,New research c
4、riteria,17,Diagnosis of AD: High accuracy, at earliest stage,Revising AD definition “dual clinicopathological entity” (1) 临床表型：a progressive dementia episodic memory impairment as a defining feature and involvement of other cognitive domains or skills, (2) 特异的神经病理改变 intraneuronal (neurofibrillary ta
5、ngles), extracellular parenchymal lesions (senile plaques), synaptic loss and vascular amyloid deposits. AD “双重临床生物学实体”: in-vivo biological evidence of Alzheimers pathology,18,病理生理升级模式,P Tau,分子病理变化,地形学变化,临床表型,个体易感性,Co-morbidity,病理损害和生物标记物密切相关,19,AD的病理级联动态生物标志物模型,生物标记物和临床表型密切相关,Extent of biomarkers,2
6、0,AD两个临床阶段: AD-P and AD-C,AD-P: AD-pathophysiological process AD-C: Clinical phases of AD as “AD-Clinical” including not only AD dementia, but also MCI due to AD-P Between AD-P and AD-C Time lag: 10 yrs or more (evidence: genetic at-risk and aging cohorts) Extent of biomarkers as predictor? Modulate
7、 the relationship between AD-P and AD-C “a specific threshold or regional distribution of AD pathology, and/or a specific combination of biomarker abnormalities” remains unknown To be clarified AD could one day be diagnosed preclinically by the presence of biomarker evidence of AD-P, which may event
8、ually guide therapy before the onset of symptoms. The hypothesis that many individuals with laboratory evidence of AD-P are indeed in the preclinical stages of AD, and determine which biomarker and cognitive profiles are most predictive of subsequent clinical decline and emergence of AD-C.,21,New Re
9、search Criteria framework for the Diagnosis of AD,新：病理生理标记物适用于各阶段的AD 新：AD传统的单一的临床实体转化为双重的临床和病理 实体的结合 新：AD的诊断是临床伴活体病理肯定的诊断，不再是可能 或很可能的单一的临床诊断，尸检只用于验证诊断,the International Working Group,Clinically symptomatic Typical AD Atypical AD AD dementia Mixed AD Prodromal AD,Clinically asymptomatic Preclinical s
10、tates of AD “asymptomatic at-risk state for AD” “presymptomatic AD” Mild cognitive impairment,22,A new lexicon for Alzheimers disease,AD涉及两个临床阶段: 前驱期AD and AD dementia 前驱期AD = memo+, bio+，无痴呆，一定进展为ADD 临床前期AD： 无症状AD的危险状态:不诊断AD，(memo-, bio+)，无AD症状，条件转化为AD 症状前期不诊断AD，(memo-, bio-)，无AD症状，有AD单基因突变 MCI 不诊断
11、AD，(memo-, bio-)，无AD症状，不一定转化为AD,23,New Research Criteria framework for the Diagnosis of AD,AD dementia phase: Typical AD early & progressive episodic memory, remains dominant in later stages, followed by other CI and NPI supported by 1 in-vivo biomarkers of Alzheimers pathology Mixed AD fully fulfil
12、 the diagnostic criteria for typical AD present with clinical and brain imaging/biological evidence of other comorbid disorders Atypical AD confirmed neuropathologically as being AD with atypical features include non-amnestic focal cortical syndromes, such as progressive non-fluent aphasia, logopeni
13、c aphasia, and posterior cortical atrophy,the International Working Group,24,Recommendations for diagnosis,Clinical history 应有知情者补充 (Level A). A neurological and physical examination, ADL assessed (Level A). Cognitive assessment (Level A). For questionable or very early AD (Level B) Assessment of BP
14、SD (Level A). Assessment of co-morbidity should always be considered as a possible cause of BPSD (Level C). Blood levels of folate, vitamin B12, thyroid stimulating hormone, calcium, glucose, complete blood cell count, renal and liver function tests should be evaluated at the time of diagnosis serol
15、ogical tests for syphilis, borelia and HIV might also be needed in cases with atypical presentation or clinical features suggestive of these disorders (good practice point).,25,26,Probable AD dementia with increased level of certainty,All patients who met criteria for “probable AD” by the 1984 NINCD
16、SADRDA criteria Probable AD dementia with documented decline Progressive cognitive decline Not for increase AD pathophysiology. Probable AD dementia in a carrier of a causative AD genetic mutation Evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2) Not for carriage of the 34 allele In
17、crease AD pathophysiology,27,Probable AD dementia with evidence of the AD pathophysiological process,Increase the certainty: clinical dementia syndrome is AD pathophysiological process. Biomarkers of brain amyloid-beta (Ab) protein deposition Biomarkers of downstream neuronal degeneration or injury
18、Not advocate: use of AD biomarker tests for routine diagnostic purposes at the present time Biomarkers: appropriately designed, standardization of biomarkers from one locale to another, varying degrees in community settings useful in three circumstances: investigational studies, clinical trials, and
19、 as optional clinical tools for use where available and when deemed appropriate by the clinician,28,29,30,Medial temporal lobe atrophy,31,Multidetector CT in dementia,64 slices, 0.6 mm slice collimation, 5 sec acquisition time,Wattjes M, et al Radiology, 2009,32,Hippocampus,Gyrus parahippocampalis,E
20、ntorhinal cortex,Volumetry of MTA,33,34,35,Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. Journal of the American Medical Association 2001;286:2120-2127.,FDG PET,-sensitivity of 93% (191/206) and speci
21、ficity of 76% (59/78) -in pathologically verified cases sensitivity was 94% and specificities of 73% (AD) and 78% (other dementias); -a negative PET scan indicates no progression in a 3 year follow-up,36,37,CSF biomarkers: Over 50 studies covering more than 3000 cases,Eelevation of CSF tau： a relati
22、vely accurate marker to identify AD 53. Reduced CSFAb42： indicative of AD dementia with a se of 85% and a sp of 87%, but Ab42 may not be able to discriminate between AD and other forms of dementia, such as vascular dementia and frontotemporal dementia on an individual basis 52,54. Eelevation of CSF
23、phosphorylated tau also demonstrate diagnostic potential, but some overlap between AD dementia and other dementias reduces the diagnostic value. Simultaneously measure: Importantly for early diagnosis a combination of high CSF tau & low CSF Ab42 can identify about 95% of individuals with MCI who wil
24、l eventually develop AD 52.,38,D1182 王效茹 女 61岁（1949年） 初中 工人 北京市,脑脊液：2010-9-30,39,Neurochemical Dementia Diagnostics in Alzheimers Disease,Where Are We Now and Where Are We Going?,Posted: 09/30/2011; Expert Rev Proteomics. 2011;8(4):447-458.,Our recently published preliminary study demonstrated that
25、NDD characterizes with higher sensitivity and shows alterations earlier than single-photon emission computed tomography neuroimaging, whereas the latter characterizes with better specificity and correlation with the disease severity.,40,Where are we now?,The sensitivity and specificity of A142 alone
26、 to distinguish AD from elderly controls were 78 and 81%, respectively, in the study by Hulstaert et al . The meta-analysis of Sunderland et al. was based on data from 17 reports on A42 and 34 reports on CSF Tau in AD, and all of these studies reported increased CSF total Tau in AD. recently shown t
27、hat the phosphorylated Tau (pTau)396/404 to total Tau ratio in CSF could discriminate AD from other dementias and neurological disorders with a sensitivity of 96% and specificity of 94% . Tau protein phosphorylated at both threonine 231 and serine 235 was increased in patients with mild cognitive im
28、pairment (MCI) who developed AD during follow-up.,41,Where are we now?,42,Where are we going?,Finding of novel biomarkers (characterizing with better diagnostic-related performance, such as improved sensitivity and/or specificity, better robustness or price); Searching for biomarkers in other, more
29、easily accessible body fluids (e.g., in blood); Improving the analytical performance of the CSF biomarkers already available (better precision and correctness of measurements and improvement of inter-laboratory comparison of results); Minimizing the volume of CSF required to enable improved manageme
30、nt of the samples (for example by the application of multiplexing technologies).,43,Where are we going?,44,no gold standard of AD diagnosis exists,45,46,AD研究热点（1） TOMM40：A newly identified risk gene for AD,TOMM40基因poly-T长度多态性与大脑灰质萎缩相关： 研究一： 70例 APOE 3纯合子健康成年人（平均年龄57岁），其中TOMM40 poly-T 长度VL/VL型 33例，s/
31、s型 37例 容量成分形态计量法测定脑灰质体积，发现 VL/VL TOMM40组脑灰质（腹侧扣带回后部和楔前叶）体积明显低于s/s组,Sterling C. Johnson, Ph.D. University of Wisconsin,47,AD研究热点（1） TOMM40：A newly identified risk gene for AD,TOMM40基因poly-T长度多态性与记忆衰退相关： 研究二： 726例有AD家族史，并已接受TOMM40 和APOE基因分型的中年人纳入研究，平均年龄54岁，其中高危版TOMM40 229例，低危版TOMM40 129例 RAVLT（Rey Aud
32、itory Verbal Learning Test)显示高危版TOMM40组学习记忆能力明显低于低危版TOMM40组，并且该结果与APOE基因型无关,Mark Sager, MD. University of Wisconsin,48,AD研究热点（2） LCPs，New Imaging Tool For Study Of Protein Deposites in AD Patients,运用新型生物标记物 LCPs (luminescent conjugated polymers)发光共轭多聚体，研究AD患者脑内蛋白沉积的不同形态 APOE 4 / 4基因型AD患者斑块核心区和脑血管壁淀粉
33、样物质形态不同，而APOE 3 / 3 基因型无此区别 APOE 4 / 4基因型AD患者脑内神经原缠结密度明显高于APOE 3 / 3 基因型,Hannah Brautigam, BS. Mount Sina School of Medicine,49,AD研究热点（3） Intranasal Insulin shows some benefits in AD and MCI,经鼻腔胰岛素治疗有助于改善早期AD和MCI患者的认知和日常生活功能： 109例AD或MCI患者分别接受20/40U胰岛素或安慰剂治疗，经鼻给药4个月，于基线、治疗第2个月、第4个月、治疗接受后2个月随访 15例胰岛素治
34、疗并接受CSF检测的患者中，记忆和功能状态的改善与CSF tau/A42比值改善相关,Suzanne Craft, PhD. University of Washington/VA puget Sound,50,AD治疗及预防 Once Daily Donepezil 23 mg Extended Release Is Well Tolerated,高剂量多奈哌齐23mg缓释片在中重度AD患者的治疗中具有安全性 为期24周，全球多中心双盲对照研究，纳入病例1434,平均年龄73.8岁，女性62.8%,M.Moline, Eisai Inc. Woodcliff Lake, NJ, USA,51
35、,AD治疗及预防 Beta Amyloid Immunotherapy with Bapineuzumab in AD May Also Reduce Tau,靶向Beta amyloid 的免疫治疗可能有助于改善神经退行性改变进程 多中心、随机、双盲、安慰剂平行对照的Bapineuzumab 剂量爬坡研究,Kaj Blennow, MD, PhD. University of Gothenburg, Sweden,52,AD治疗及预防 Physical activity, Tea, Vitamin D, Walnuts Possibly Maintain Cognitive Ability,
36、3个长期、大规模临床观察显示： 体力活动结合一定的膳食成分（茶，维生素D）可能与维持老年人认知功能和降低AD风险相关 转基因小鼠AD模型研究显示： 膳食补充核桃可能有利于脑功能改善,53,BPSD的识别与干预,54,定义,BPSD是痴呆病人中常见的知觉、思维内容、心境与行为方面紊乱的症状群 它包括通过对病人的观察识别的症状；和通过精神检查与病史采取了解的症状,55,精神病性症状 幻觉1 妄想1 身份识别障碍2,情感症状 抑郁1 情感淡漠1 情感高涨1 焦虑1 脱抑制1,行为症状 异常运动行为1 易激惹1 激越/攻击行为1 睡眠紊乱1 刻板行为3 食欲亢进4 进食紊乱1 性功能亢进4,AD相关的
37、行为与精神症状（BPSD）,1Cummings. Neurology. 1997;48(suppl 6):S10-S16; 2Mendez MF et al. J Nerv Ment Dis. 1992;180:94-6; 3Nyatsanza S, et al. J Neurol Neurosurg Psychiatry. 2003;74:1398-402; 4Burns A et al. Br J Psychiatry. 1990;157:86-94.,56,国内痴呆患者BPSD症状的患病率,解恒革,王鲁宁等.北京部分城乡社区老年人和痴呆患者神经精神症状的调查.中华流行病学杂志2004,1
38、0:829-32,最常见的BPSD症状为抑郁、淡漠、焦虑、睡眠障碍和易激惹,57,n=170 n=595 n=571,频率 %,痴呆进展中精神行为症状越来越明显,58,淡漠 缺乏兴趣 3,PHRC-PRE-AL 245 MCI 个体的发展 平均年龄 = 72 5.5 MMSE = 27.5 1.3 3年后MCI-AD转变情况 n = 59 (27.2%),MCI 精神行为症状,1010名MCI被试中 59% 存在精神行为症状 最常见的行为症状: 淡漠 抑郁 焦虑 易激惹 夜间行为,Feldman et al, Neurology 2004; Robert et al, Clin Neurol
39、Robert et al, Am JGP, 2008,59,观察 交谈 询问 观察交谈询问 测查,60,61,62,BPSD评定,SCAG(老年临床评定量表) Behave-AD(阿尔茨海默病行为异常量表) DBD(痴呆行为障碍量表) CMAI(CM激越问卷) NPI(神经精神科问卷),63,与抑郁的鉴别,按照抑郁治疗疗效不佳的老年人，应考虑存在AD的可能,64,与谵妄的鉴别,65,BPSD相关的神经递质改变,66,干预策略,67,痴呆的诊断,告知诊断（采取恰当的方式）,用朴实的语言解释诊断或病理学特点,积极乐观地探讨照料与保健方案,保健方案,痴呆的治疗与照料,药物治疗,心理社会干预,为照料者
40、提供支持,定期访视，修改保健方案,晚期关怀照料及为照料者提供居丧咨询,(QoLDEM, 2006),68,BPSD的治疗目标,延缓症状的出现 缓解症状的强度和频率 减少抗精神病药物的使用,69,非药物干预,一线选择 中重度症状是药物治疗的指征，但也应与非药物处理相结合 对非药物处理反应良好的症状：轻度抑郁和淡漠；漫游与踏步；重复提问与作态,70,非药物干预,1Cohen-Mansfield J. Am J Geriatr Psychiatry. 2001;9:361-81; 2Caltagirone et al. Drugs Aging 2005;22(Suppl 1):1-26.,人员培训
41、特设的活动 社会接触: 宠物、一对一、家庭录像 照料者支持 过渡性 医疗/护理干预 (助听器, 行为治疗, 疼痛处理) 感官改善: 音乐, 按摩, 光照治疗,71,会导致BPSD恶化的照护者行为,突然且非预期性地改变患者的生活习惯与环境 挑动与患者进行“权利之争” 给患者提出超过他或她能力的要求 过分地苛求患者 忽视患者的要求 过分刻板或循规蹈矩 反复提问或询问以“使”患者记住什么事情 在患者面前表现愤怒与攻击 恶感与愤怒加重,72,BPSD 药物治疗,抗痴呆药物 胆碱酯酶抑制剂 (多奈哌齐, 卡巴拉汀, 加兰他敏) NMDA受体拮抗剂 (美金刚) 其它精神药物 抗精神病药 (SDA) 心境稳
42、定剂 抗抑郁剂,73,Holmes C et al. Neurology. 2004;63:214-9; Cummings et al. Am J Psychiatry. 2004;161:532-8; Finkel et al. Int J Geriatr Psychiatr. 2004;19:9-18; Feldman H et al. Neurology. 2001;57:613-21; Gauthier S et al. Int J Psychogeriatr. 2002;14:389-404; Lee et al. BMJ. 2004;329:75; Pratt et al. Int
43、 J Clin Prac. 2002;56:710-7. Rockwood K, et al. Inter J Geria Psy 2004;19:954-960.,胆碱酯酶抑制剂,已有研究报道, 胆碱酯酶抑制剂(ChEIs)对AD患者的行为问题具有改善作用。 与大多数精神药物不同,胆碱酯酶抑制剂似乎能治疗多种行为症状 (如, 情感的和精神病性的)。 胆碱酯酶抑制剂通常耐受性好。 临床医生调查显示，多奈哌齐改善痴呆患者精神行为症状最主要是淡漠、情感症状和激越。,74,Romn et al Neurology 1993,血管性痴呆: VaD,VaD 是指由各种脑血管病（ cerebrovascu
44、lardisease, CVD），包括梗死、出血和缺血相关性改变所导致的痴呆综合征 VaD诊断标准均强调必须有痴呆和CVD的证据（病史、临床表现和神经影像学证据）以及两者之间存在相关性（即卒中后一定时间内发生痴呆） VaD 的诊断分为2 步：首先要确定为痴呆，然后再与AD相区别（根据血管危险因素、缺血评分和影像学变化等）。,75,SUBTYPES OF VCI/VaD : VASCULAR MECHANISMS AND CHANGES IN THE BRAIN,WML = white matter lesion,Cortical Strategic Subcortical VaD infarc
45、t ischemicVaD Vascular mechanisms VaD SIVD Large-vessel disease Cardiac embolic events Hypoperfusion Small-vessel disease Changes in the brain Arterial territorial infarct Distal field (watershed) infarct Lacunar infarct Focal, diffuse WMLs Incomplete ischaemic injury Heterogeneity + + +,76,大血管疾病,关
46、键 部 位 的 皮 层 梗 塞,额叶,海马, 前脑底部,角回,顶叶,失语、失用、 脱抑制、淡漠,记忆减退,结构能力减退,失读、失写,皮层型痴呆,大面积皮层灶性病变,77,小血管疾病,关键部位的皮层下梗塞,破坏特异性的额叶皮层下通路或者丘脑与皮层间的非特异性联系,丘脑, 尾状核, 内囊,人格改变,注意力减退,淡漠,执行功能障碍,皮层下痴呆,小血管疾病 皮层-皮层下回路VaD,78,并不是有卒中病史，就能诊断血管性痴呆 NINDS-AIREN很可能VaD的诊断,很可能VaD的临床诊断标准包括 痴呆定义为认知功能从以前的高功能水平的下降，表现为记忆力的受损和两个或两个以上领域的认知缺陷（定向力，注意
47、力，语言，视觉空间能力，执行能力，运动控制或实践），最好经过明确的临床检查和有神经精神学检查的记录；这种缺陷已经严重到影响日常生活能力，并且除外日常生活能力的下降是因为脑血管疾病本身的身体障碍引起； 排除标准：有意识障碍，谵妄状态，精神病，严重的失语症或显著的感觉缺陷无法进行神经精神学检查。同时需除外：其他系统疾病或脑部疾病（如AD）引起的认知和记忆力受损； 脑血管疾病的定义为在进行神经学检查时有与脑卒中（有或无脑卒中病史）相一致的局灶性体征，如偏瘫，面部无力，Baninski征阳性，感觉障碍，偏盲，构音障碍等，并且有与脑血管疾病相关的脑部影像学证据（CT或MRI），包括： 多枝大血管卒中 或
48、单枝的有重要意义的血管的梗塞（角回枝，丘脑枝，前脑基底枝，PCA或ACA区域） 轻度的皮质受累及多个基底神经节和白质的腔隙灶（1） 或广泛的脑室周围的白质病变 或是上述的组合,美国国立神经疾病卒中研究所和瑞士神经科学研究国际协会,79,并不是有卒中病史，就能诊断血管性痴呆 NINDS-AIREN很可能VaD的诊断,痴呆与脑血管疾病间有相关性，表现为下述一项或一个以上： 在确定的脑卒中发生后的3个月内开始出现痴呆 认知功能的突然恶化；或波动，认知功能的逐步进行性减退。 与可能VaD相一致的临床表现，包括： 早期出现的步态障碍（小步步态，运动失用或帕金森步态）。 既往有不稳定或经常出现无原因的摔到
49、病史。 不能用泌尿系疾病解释的早期尿频、尿急和泌尿系症状。 性格和情绪的改变，意志力丧失，抑郁，情感不能控制，其他皮层下的功能障碍，包括精神运动延迟和执行功能的异常。 一些不符合Vad的临床特征： 早期出现的记忆力受损和进行性恶化的记忆力和其他认知功能障碍，如语言（经皮质的感觉性失语症），运动技巧（运动性失用）和感觉（失认），但在脑部影像学上无相应的局限性病灶； 除了认知功能障碍，缺乏局灶性的神经学体征； CT或MRI上缺乏脑血管疾病的表现； 用于研究目的时可将血管性痴呆按临床，影像学和神经精神学特点进行分类，分为下述亚类或情况： 皮质血管性痴呆； 皮层下血管性痴呆； 宾斯万格痴呆（Binswangers）； 丘脑性痴呆；,80,VaD的影像学检查结果不同于AD