1、Multiple Types of Dementia Linked to Other Parkinsons Plus,张振馨PUMC Hospital,Dementia with Lewy Bodies,DLB,2nd common dementing disorder in late-life,Concomitant AD (66% of DLB)Only 45% of autopsy-confirmed DLB cases correctly diagnosis during life in one seriesParkinsonism in 50% DLB, Visual hall in
2、 42%,Criteria for Clinical Diagnosis,进行性认知功能下降, 认知损害的主要方面 注意力 and 额叶皮层下技能 and视空间能力很可能: 具备二个核心特征; 可能:具备一个核心特征波动性认知伴不同程度的注意和警觉能力反复发生的视幻觉完整而详细自发的 parkinsonism,Criteria for Clinical Diagnosis,支持性特征反复跌倒晕厥短暂意识丧失Neuroleptic sensitivity系统化的妄想，错认其他形式的幻觉REM睡眠行为障碍抑郁不太可能有的特征StrokeAny physical illness and other
3、brain disorder,DLBD,痴呆发病在先 (较重)，或者在PD发病后一年内发生痴呆早期出现幻觉(视)，谵妄波动性认知障碍, 觉醒和注意力变化对称性parkinsonism, 无震颤，无异动，无肌紧张不全,DLB Features,Onset age 50-90Duration 6-10 yearsMen WomenApo E4 genotype risk factorParkinsonism: Primarily of Bradykinesia and Rigidity50% rest tremor20% myoclonus70% transient beneficial resp
4、onse to L-dopa,DLB Features: Dementia,AttentionSpontaneous periods of impaired alertness and concentration昏昏欲睡 但能或不能意识到 他周围的环境Several minutes to a day检测警觉度和复杂的反应时间,检测EEG,DLB Features: Dementia,Visuospatial视知觉功能：物体大小的辨别力 , overlapping figure identification, visual counting比AD更差： picture arrangement,
5、block design,物体装配任务 Less severely on memory, naming abilities Frontal subcortical skillsMore than AD, on verbal fluency, assesment of response inhibition,DLB Features: Neuropsychiatric,行为视幻：包括动物, 人物和情景，在病人周围活动Misidentification delusions: Capgras syndromeDLB vs AD Frequency : 视幻 72/38%, 妄想 70/68%, 抑郁
6、 48/18%, 听幻 44/12%, 错误认别 40/10%DLB vs PDD: more delu in DLBDLB vs FTD: Less euphoria and disinhibitionDLB：行为 (often present) 与认知(mild)的相关性较弱,DLB Features: Neuropsychiatric,REM睡眠行为四肢或躯干的跳动(jerking)和复杂的运动梦境有暴力行为各种原因的痴呆综合征中，痴呆伴REM睡眠行为最常见于DLB 其他类型睡眠障碍: 白天睡眠过度，夜间出现周期性肢体活动，醒来出现错乱，入睡做恶梦(bad dreams),DLB Fea
7、tures: Neuropsychiatric,NPI最常见的症状：淡漠、 妄想、幻觉、 , AMB (异常的运动行为)不太常见：抑郁、焦虑、激惹、攻击、脱抑制 不存在：欣快,DLB Features: Neuroimaging,MRI中颞和海马萎缩，不如AD严重SPECT, FDG, PET皮层的灌注和代谢降低很少影响原始的躯体运动皮层(somatomotor). 不同于AD,明显的低灌注or低代谢主要位于 occipital皮层Basal gangliaDLB: BG 的多巴胺能活性降低PET(F18), SPECT(DAT),Disorder with LB,Dementia with
8、LBForm with dementia preceding parkinsonism Form with Parkinsons disease preceding dementia Diffuse LB diseaseSporadic (without AD path, presenile or juvenile age with Parkinsonism and progressive D)FamilialParkinsons disease SporadicA-syneclein mutationMPTP-parkinsonism,Disorder with LB,Miscellaneo
9、us condition孤立的咽下困难脑干迷走神经核有LB临床综合症: PSP, dystonia, Motor Neuron DPSP-like disorderDystonia-type disorderMotor neuron disorder-type disorderPure autonomic failure,Pathological Hallmark,Lewy bodies in 脑干&皮层脑干: SN, 蓝斑, Meynert N皮层下: core, round, one or more in cytoplasm of the neuron皮层: small, less wel
10、l-defined rare have coreContain neurofilament subunit, ubiquitin, a- /-synuclein (modulate a-syn aggregation & toxicity)PD: LB 分布于脑干, 皮层很少LBD: more in limbic system or limbic & neocortex,Pathological Hallmark,Typical DLBOnset over 60 Cortical LB with aplaques50% have tangles (less sever in DLB than
11、AD)Amyloid deposits in blood vessels, common in DLBSeverity of Dementia in DLB associated with abundance of cortical LB,Neurochemical,Reduction of dopamine in BG for DLB, similar for PDCholinergic deficits more severe in DLB than ADMarkedly in DLB with vis hallReduced choli, preserved DAnergic, sero
12、tonergic is characteristic of DLB with hallIncreased M1 receptor binding/D3 receptor density correlated with occurrence of psychosis in DLB,Pharmacotherapy,Parkinsonian syndromeDopaminergic (70% partial relief)Potential exacerbation of vis hall, delu must be monitoredCognitive deficitsCholinesterase
13、 inhibitorsBehavioral Cholinesterase inhibitorsPsychotropic medicationCholinesterase inhibitors for BCOpen-label for donepezil, rivastigmineDouble-blind placebo-controlled trial for rivastigmine,Parkinsons Disease with Dementia: PDD,Multiple types of dementias linked to PD,Dementia in PD: cortical L
14、ewy bodiesTwo syndromesSubcortical Dementia: primarily with executive dysfunctionDementia with LBFluctuating cognitionMore severe in language, visuospatial skill, executive,PD诊断性分期1-6,意义：focus on SN, Step by step over a longer period of time, early diagnosis运动前期1：(IX,X运动神经背核) 嗅觉；运动前期2：(延髓和桥脑被盖) 睡眠，头
15、痛，运动减少，情感；运动前期3：(致密部) 色觉，体温调节，认知，抑郁，背疼；期4：四主症；期5：(新皮层) 运动波动，频发疲劳；期6：(新皮层) 错乱，视幻觉，痴呆，精神症状,Two principal pathways to dementia with LB,Initial Dementia,Initial Parkinsons,PathologyCortical LBBrainstem LBDopamine deficit,PathologyBrainstem LB Cortical LBCortical cholinergic deficit,Clinical featuresPark
16、insonismFluctuating cognitionVisual HallucinationsWorsenting dementia,Clinical featuresParkinsonismFluctuating cognitionIncreased neuro-psychiatric symptems,Dementia with LB,PDD,PD with dementia 18-40% another 30-40%: cognition impairment (executive)(underestimated, due Dementia increased PD mortali
17、ty)Risk factor for occurrence of D in PDReduced verbal fluencyMore advanced PDDepressionAny evidence of cognitive impairmentOlder at onset PD, longer period of courserarecaudate in PDDopamine receptors upregulated in early PDPSP in an-/posterior putatum; PD in posteriorPD +Depress: Dorsolateral hypo
18、perfusion DAT reduced in orbito-frontal,Functional MRI,SPECT, FDG, PETPD 伴D: Hypoperfusion, hypometabolism in F, T, P regions; similar to ADPD 不伴D: generalized Presynaptic cholinergic terminal densities(measure using I-iodobenzobesamicol binding)Reduction in P, O cortex in PD-no DSevere reduction in
19、 entitle cerebral cortex and hippocampus in PD+D,Other Parkinsons Plus Linked to Dementia,FTLD: features,痴呆综合症伴失语，神经精神症状中年发病，病程10年，许多家族病人17号染色体，Tau代谢异常分类：1、FTD脱抑制,人与人之间的交往差，自我控制力差（不考虑别人的感受，自我为中心）, 冲动的行为,执行功能差2、PNA:3、语义痴呆，语义失语，失用,三大神经系统体征,运动神经元病帕金森症初级反射,FTD: Diagnostic features,Core Insidious onset a
20、nd gradual progressionEarly decline in social interpersonal conductEarly impairment in regulation of personal conductEarly emotional blunting; Early loss of insightSupportiveBehavior disorderDecline in personal hygiene and groomingMental rigidity inflexibilityDistractibility and impersistenceHyperor
21、ality and dietary changesPerseverative and strereotyped behaviorUtilization behavior,FTD: Diagnostic features,Sleep and languageAltered speech outputAspontanity and economy speech, Press of speech Strereotypy of speechEcholalia模仿言语Perseveration mutism Physical signsPrimitive reflexesIncontinenceAkin
22、esia, rigidity, tremor Low and不稳定的blood pressure,FTD: Diagnostic features,InvestigationNeuropsychology: significant Impairment on F lobe tests, in absence severe amnesia, aphasia, perceptuo-spatial dis.EEG: normal, despite clinical dementia Brain Imaging: F and/or anterior T abnormal Clinical featur
23、esOnset 65, Positive family history of similar dis.Bulbar palsy, muscular weakness, wasting fasciculations(associated MND present in a minority of patient),Distinguish FTD and AD,Distinguish FTD and AD,进行性非流利失语(PNA),语言表达障碍起病，贯穿全病程。其他认知相对保留Core Dx FeaturesInsidious onset, gradual progressionNonfluent
24、 spontaneous speech with at least one of the following: Agrammatism, phonemic paraphasias, anomia,进行性非流利失语(PNA),Supportive Dx FeaturesApeech and languageStuttering or oral apraxiaImpaired repetitionAlexia, agraphiaEarly preservation of word meaningLate mutism,进行性非流利失语(PNA),Supportive Dx Features行为早期
25、保留社会技能晚期行为改变类似FTD体征晚期对侧出现原始反射、少动、僵直和震颤实验室所见神经心理：无严重记忆或无视空障碍时，发生非流利失语EEG正常，或轻微不对称性异常以主侧半球为主,进行性非流利失语(PNA),Supportive Dx Features临床特点C ：SND为主；MSA-P (2/3) MSA-C (c only, 1/3) SND，Shy-drager (SDS)，sOPCAAge at onsetIPD: 60, 5%远；颈部姿势差或无L-DOPA治疗反应早期发生吞咽/构音障碍早期发生认知障碍, 包括至少2项: apathy, abstract thought, verba
26、l fluency, imitation behavior, frontal release signs排除无关L-dopa 治疗的 hall, delu Recent history of Alien limb syn, cortical sensory deficits, focal F or T P atriphyCortical dementia of Alzheimers disease Early 自主神经功能不良, early cerebellar symSevere asymmetric PNeuroradiologic evidence of relevant structu
27、ral abnormalWhipples disease, confirmed by polymerase chain reaction,皮质基底神经节变性(CBD),不对称 (经典)僵直- 运动不能 (akinesia)，L-dopa无效肌紧张不全，jerk粗大震颤，肌阵挛alien limb，失用，皮层感认知 variability affect上视麻痹无植物神经功能不良,皮质基底神经节变性(CBD),认知 Cortical and frontal-subcortical-type disturbancesExecutive, prominent: card sorting tests,
28、verbal fluencyMarked Visuospatial disturbancesMemory: retrieval deficit, without the marked amnesia typical of ADDepression and apathy,CBD诊断标准,Inclusion criteriaRigidity plus one cortical sign(apraxia, cortical sensory loss, or alien limb phenomenon) or;Asymmetric rigidity, dystonia, and focal refle
29、x myoclonusQualification of inclusion factorsRigidityApraxiaCortical sensory lossAlien limb phenomenonDystoniaMyoclonus,CBD诊断标准,Exclusion criteriaEarly dementia (exc. CBD)Early vertical gaze palsyRest tremorSevere autonomic disturbancesSustained responsiveness to LdopaLesions on imaging studies indi
30、cating another responsible pathologic process,哪些PD临床特征有助于鉴别诊断,鉴别PD/PDS： 跌倒诊断第1年内反复跌倒：PSP较晚跌倒：CBDDLBMSAPD鉴别PD/PDSPDS高HY分级，高UPDRS得分的运动慢少、姿势不稳、步态困难低UPDRS震颤分,哪些PD临床特征有助于鉴别诊断,鉴别PD/MSA对L-dopa反应差/2分；自主神经功能不良/2分包括姿势低血压、尿便失禁、尿潴留须导尿和勃起不良言语和球功能不良/2分；跌倒/4分无L-dopa引起的Confuse/4 =11分 MSA，Se 90.3%；Sp 92.6%在发病头5年内L-d
31、opa 反应不佳/2；早期出现运动波动/2;自主神经功能不良/2；僵直/2=4分 MSA，Se 87.1%；Sp 70.5%,哪些PD临床特征有助于鉴别诊断,对L-dopa 或 apomorphine反应好 急性L-dopa负荷 (250/50 mg)，24月后重复好转30%+：支持PD诊断 (se70.9%，sp81.4%)UPDRS=21 (SE 36.4%, SP 87%)L-dopa负荷 (250 mg, a single oral dose)，Se 77.1%, Sp 71.1%试验前2-3天用DOMPERIDONE防多巴胺能周围副反应Stimulation of growth ho
32、rmone with clonidineNot differ between two groups,诊断Test,Acute L-dopa and apomorphine challenge testsShould not be used in the differential diagnosis of PD Grade BThe use of acute apomorphine challenge to assess where a person with later PD will still respond to dopaminergic medicationStandard pract
33、ice of treating people with L-dopa as an out-patient,哪些PD临床特征有助于鉴别诊断,鉴别PD/PSP或MSA PD：对L-dopa反应好PSP or MSA：无震颤、对称、迅速恶化,哪些诊断Testing有助于鉴别诊断,Olfaction: UPSIT (3 Class II studies)PSP similar to normal / sig. different to PD“Sniffin sticks”PD / Hyposmia or anosmia (mod to severe)MSA, PSP, ET / normal, mil
34、 to modUPSITPSP, CBD / normalMSA / worse than control, better than PDCutoff 25, 鉴别PD 和PDS, se 77%, sp 85%,Smelling Testing,Objective small testingShould not be used in the differential diagnosis of Parkinsonian syndromes,Olfactory dysfunction (hyposmia) in neurodegenerative disease,Olfactory dysfunc
35、tion in a-synucleinopathiesPD: in 80-100% of non-demented patients impaired (olfactory threshold discrimination/ identification) 50% anosmic, 35% severe hyposmia, 15% moderate hyposmia independent of the severity and duration of PD, early in the course of the clinical disease,哪些诊断 testing 有助于鉴别诊断,Di
36、agnostic neurophysiology testing (1 Class III)Electro-oculography (square wave jerk)Impaired gaze holding: PSP/87.5%, MSA/64%, PD/15.3%Latency of horizontal saccades slower in CBDPD% errors on anti-saccade greater in PSPPD&MSASWjerk: PD18%, MSA7%, CBD20%, PSP60%,哪些诊断 testing有助于鉴别诊断,Diagnostic neurop
37、hysiology testing (1 Class III)Anal sphincter EMGMotor unit prolongation Cutoff20 for probable MSA: se62%, sp92%Cutoff=30%; false + 20-30%,推荐于鉴别诊断,鉴别诊断可能无用 (Level C)GH stimulation, electro-oculography, SPECT证据不足Urodynamics, autonomic test, urethral or anal EMG, MRI, brain parenchyma sonography, and FDG PET (Level U),
