中英097 | JAMA | 尸检 | Pick病 语义性痴呆SD --由成金
A man in his late 40s presented with cognitive decline characterized by gradually increasing difficulty expressing his thoughts and ideas. His family noted word-finding difficulty, especially with the names of people, but no problems with his memory for recent events. Initial workup findings were unremarkable, but during the course of the next decade left anterior temporal atrophy was noted on magnetic resonance imaging and the patient developed increasing reasoning difficulty, apathy, and disinhibition. Several degenerative causes were considered. The patient died 22 years after symptom onset, and the final diagnosis was confirmed at autopsy.
男性患者，40多岁后出现认知衰退，临床特征表现为渐进性的语言表达困难，家属观察出患者出现找词困难，尤其叫不出人名，但近记忆力正常。最初体检未发现明显异常，但接下来的十年里MRI上观察到左侧颞前叶萎缩。随着病情的加重，患者出现渐进性逻辑推理能力下降情感淡漠和脱抑制。曾考虑了几种退行性病变。该患者发病22年后死亡，尸检确定了最后诊断。
A right-handed man in his late 40s with 12 years of education presented with a 1.5-year history of cognitive decline, characterized by gradually increasing difficulty expressing his thoughts and ideas. His family noted word-finding difficulty but no problems with his memory for recent events. Two of his relatives developed dementia in their 70s.
男性，右利手，12年教育，40多岁，表现认知功能下降一年半，特点是逐渐地越来越难以表达自己的想法和意见。家属发现患者找词困难，但对近期事件记忆力正常。他的两位亲属在70多岁时患有痴呆。
His initial mental status examination findings were notable for problems with calculation, abstraction, and recall, while his language examination revealed difficulty following complex commands and anomia on confrontational naming with intact repetition. His neurologic examination findings were otherwise normal.
他的最初的精神状态检测显示明显的计算、抽象能力和回忆障碍，而语言检测显示不能执行复杂命令、命名不能，但复述良好。神经系统查体正常。
Findings of an extensive workup, including laboratory studies and neuroimaging, were unremarkable. He returned a few months later, at which point neuropsychometric testing revealed markedly impaired category and letter fluency, impaired registration on logical and audio-verbal memory, poor comprehension of complex instructions, and severe anomia.
广泛的检查结果，包括实验室检查和神经影像，无明显异常。几个月后他又回来了，此时进行神经心理测试显示明显的分类能力障碍和字母流利性下降，逻辑和音频语言记忆项目受损，对复杂指令理解能力差，严重的命名性失语。
At follow-up 2 years after his initial presentation, he had developed more comprehension difficulties and had resorted to pointing at objects because of his profound word-finding difficulty. At 4-year follow-up, his memory for recent events as well as his reasoning abilities had declined, although he still was independent in most of his activities of daily living including managing medications, driving, and dressing. He could read some words in the newspaper but could not understand what they meant. The following year, he was noted to have more difficulty with concepts and planning and was unable to name or demonstrate the use of a knife or a saw. His vocabulary became more restricted, and he often used the word “job” instead of specific nouns. At his last follow-up 10 years after symptom onset, he had very few vocalizations and minimal comprehension. He also had developed apathy, a preference for sweets, and disinhibition. He had no eye movement abnormalities, no pyramidal or extrapyramidal signs, and no hallucinations. He became mute, moved into a skilled nursing facility shortly afterward, and was dependent in all activities of daily living until he died more than a decade later, 22 years after symptom onset.
初次发病后2年随访，患者理解能力更差，因为明显的找词困难，他不得不指点物体。4年后随访，虽然他大部分日常活动包括服药、驾车、穿衣都可以自理，但推理能力下降，连近期事件记忆力也下降。他能够读报纸上的一些词，但却不能理解其含义。第二年对概念和计划更困难，不能说出刀或锯的名称或示范怎么使用它们。他的词汇更有限，经常用单词“工作”替代具体名词。在他发病后10年时的最后一次随访，他几乎不说话，理解力极差。患者变得情感淡漠、喜爱甜食、脱抑制。无眼球运动异常，无锥体束和锥体外系体征，无幻觉。患者变得缄默，不久被送去高级保健所，所有日常生活都不能自理有10余年，直到发病22年后去世。
Laboratory and Neuroradiologic Data
实验室和神经影像学资料
Imaging 影像
While magnetic resonance imaging findings of his brain during initial workup were unremarkable, at 6 years into the illness there was marked left anterior and inferior temporal lobe atrophy (Figure 1). Left insular atrophy with widening of the perisylvian fissure also was evident. Four years later, repeated imaging showed interval worsening of the left anterior and inferior temporal atrophy, with a knife-edge appearance of the gyri at the temporal pole.
最初体检他的头MRI无明显异常，发病6年时左侧颞前和颞下叶明显萎缩（图1）。左侧岛叶也明显萎缩，大脑外侧裂增宽。4年后复查影像显示左侧颞前和颞下叶萎缩加重，颞极脑回呈“刀缘”样。
Laboratory Studies 实验室检查
As part of his initial evaluation, he had complete blood cell count, basic metabolic profile, vitamin B12, folate, thyroid function cascade, and syphilis testing performed, all of which had results that were negative or within normal limits. A lumbar puncture revealed 2 nucleated cells, 52% lymphocytes (to convert to proportion of 1.0, multiply by 0.01), a glucose level of 55 mg/dL (to convert to millimoles per liter, multiply by 0.0555), a protein level of 52 mg/dL (reference range <35 mg/dL), and negative results with Gram staining, bacterial and fungal cultures, and cytologic analysis.
最初检测包括全血细胞计数、基本生化指标、维生素B12、叶酸、甲状腺功能系列和梅毒等，所有这些结果都正常或阴性。腰穿脑脊液发现2个有核细胞，52%淋巴细胞（转换为1.0比例，乘以0.01），葡萄糖55mg/dL（转换为毫摩尔/升，乘以0.0555），蛋白52mg/dL（参考值<35mg/dL)，革兰氏染色、细菌和真菌培养、细胞学分析结果均阴性。
图1 磁共振图像
MRI A和B，T2加权Flair像（A）和T1加权非增强序列（B），显示发病后6年明显的左侧颞前叶萎缩。C和D，T2加权Flair像（C）和T1加权非增强序列（D），显示发病后10年左侧颞叶萎缩加重，呈“刀缘”样脑回萎缩。
Clinical Discussion (Dr Botha)
临床讨论（博塔医生）
The presentation is that of an early-onset, progressively dementing illness. Early-onset dementia usually is defined as acquired cognitive impairment interfering with activities of daily living, with onset before age 65 years. The distinction is important because nondegenerative and potentially treatable causes are far more common in this age group. Autoimmune, inflammatory, and infectious causes are especially important to identify, but in the current case a degenerative etiology is almost certain given the long duration and steady decline as well as the slowly worsening atrophy on imaging.
临床表现是早发性、进展性痴呆。早发性痴呆被定义为65岁前发病的获得性认知功能障碍，影响日常活动。鉴别诊断很重要，因为在这个年龄组非变性疾病和潜在的可治性疾病更常见。识别自身免疫、炎症和感染性病因尤为重要。然而鉴于此病例病程长、持续衰退，影像示萎缩缓慢加重等特点，几乎可以确定是变性性疾病。
This patient presented with language dysfunction, and aphasia seems to have dominated the early phase of his disease. Furthermore, there is nothing to suggest significant impairments in his activities of daily living, beyond difficulties related to his aphasia, early in the disease course. As the illness progressed, the patient developed more general cognitive impairment as well as a prominent behavioral syndrome. The patient would meet core criteria for a diagnosis of primary progressive aphasia (PPA).1 His bedside cognitive examination and formal neuropsychometric testing did show impaired performance on nonlanguage tasks, but it is clear that these tests may also be negatively affected by an underlying aphasia and should not preclude a diagnosis of PPA.2
该患者表现语言障碍，失语似乎是疾病早期的主要症状。此外，疾病早期除了与失语相关的困难外，日常活动能力无明显受损。随着疾病进展，患者出现了突出的行为异常和更广泛的认知损害。患者符合原发性进行性失语（PPA）诊断的核心标准【1】。虽然床旁认知能力检查和正式的神经心理学测试确实发现执行非语言任务的能力受损，但很明显的是这些测试也可以受潜在的失语负面影响，不应该除外PPA的诊断【2】。
More specifically, within the PPA framework, the patient’s presentation is most consistent with semantic dementia (SD), or the semantic variant of PPA.1,3 As one of the language variants of frontotemporal dementia, it is well known to result in a secondary behavioral syndrome in a subset of patients. The prominent and early comprehension difficulties as well as calculation difficulty are somewhat atypical, but in light of the prominent anterior temporal atrophy as well as the apparent loss of object knowledge and word meaning, SD remains the most appropriate classification. Patients with SD may present with memory concerns and tend to perform poorly on verbal tests of episodic memory, often leading to an incorrect diagnosis of Alzheimer disease (AD).4
更具体地，在PPA范畴里，患者的临床表现最符合语义性痴呆（SD）或是PPA的语义变异型【1.3】。作为额颞叶痴呆的语言变异型之一，众所周知其在患者的亚型中会引起继发性行为异常综合征。虽然突出症状和早期理解困难和计算障碍有点不典型，但是鉴于明显的颞前叶萎缩，对象知识和语义明显丢失，SD一直是最合适的分类。SD患者表现记忆障碍，倾向于在情景记忆中语言测试表现不佳，经常误诊为阿尔茨海默病（AD）【4】。
Approximately three-quarters of SD cases have underlying TAR DNA-binding protein 43 (TDP-43) pathology, usually type C, with tau and AD neuropathologic change (AD pathology) accounting for the rest (for a recent review, see the article by Harris and Jones5). Pick disease, characterized by 3-repeat tau deposition, accounts for the overwhelming majority of cases with tau pathologic features. Although the proportion of cases due to AD pathology varies significantly from center to center, recent amyloid positron emission tomographic imaging suggests that it might account for more cases than suggested by pathologically confirmed series, which would make it the second most common cause of SD.3
大约3/4的SD病例病理学上有潜在的TAR DNA结合蛋白43（TDP-43），通常是C型，其它是tau和AD神经病理学改变（AD病理）（最近的一篇综述，见Harris和Jones写的文章【5】）。Pick病，以3R tau蛋白沉积为特点，在具有tau蛋白病理特点的病例中占了大多数。尽管因AD病理致病的病例比例在各中心不同，最近淀粉样蛋白正电子发射体层断层摄影提示，与病理上证实的病例所占的比例相比较，它可能占了更多病例，这使它成为SD的第二大常见病因。
The main diagnostic challenge in this case involves predicting which of these 3 pathologies underlies the patient’s presentation. No definitive pathologic signatures exist, but there are clues we can use to adjust our base probability, which would place TDP-43 as the most likely.
该病例诊断的主要挑战是预测这3种病理中的哪一个引起患者的症状。不存在明确的病理特征，但是这里有我们能用来调整诊断可能性的线索，认为TDP-43最有可能。
A secondary behavioral syndrome is common in both TDP-43– and Pick disease–related SD but is virtually unreported in cases with AD pathology.6 Early executive dysfunction and dyscalculia were found to be more common in Pick disease cases than among TDP-43 cases, although the small number of Pick disease cases in the study is an obvious limitation.6 Mutism, regardless of initial presentation, is often seen later in Pick disease cases.6 Age at onset within SD does not seem to differ depending on underlying pathology.4 Both TDP-43 type C and Pick disease pathology can result in remarkably long disease durations in SD.6
继发性的行为异常综合征在TDP-43相关和Pick病相关的语义性痴呆中都常见，但在有AD病理表现的疾病中实际上未报道【6】。Pick病患者中发现早期执行功能障碍、计算困难的要比TDP-43病例中发现的更常见，尽管研究中Pick病人数量少是一个明显的局限性【6】。无论最初症状是什么，在Pick病晚期缄默是常见症状【6】。语义性痴呆的发病年龄并不因潜在的病理表现不同而不一样【4】。C型TDP-43和Pick病的病理都能明显延长语义性痴呆的病程【6】。
A family history of dementia in SD is rare4 but is estimated to be around 2% to 7%. However, truly familial SD is extremely rare. Progranulin gene (GRN) mutations can present with strikingly asymmetric atrophy of the left temporal lobe, often presenting with a hybrid between PPA subtypes or atypical logopenic progressive aphasia, but pure SD cases due to GRN mutations are exceedingly rare.7
SD患者家族史罕见【4】，但估计大约2%到7%。然而，真正的家族性SD是极罕见的。前颗粒体蛋白基因（GRN）突变可表现左侧颞叶明显的不对称性萎缩，经常表现为PPA亚型和不典型logopenic进行性失语的混合，但是GRN突变的纯SD病例是非常罕见的【7】。
A central problem with imaging predictors of pathology is the fact that regional atrophy is associated with clinical features to a greater extent than with pathologic findings.8 This is certainly true of TDP-43– and Pick disease–related SD, where the regional atrophy pattern is indistinguishable.6,8 The degree of asymmetry may be helpful: it tends to be greater in Pick disease cases than in TDP-43 cases, and greater in either of these than in cases with AD pathology.6,8 Marked, focal atrophy such that only a sliver of brain remains, so-called knife-edge atrophy, as well as relative sparing of the posterior two-thirds of the superior temporal gyrus are widely reported as suggestive of underlying Pick disease.9 However, these findings were originally described at gross pathology and have not been well studied in the antemortem stage. Knife-edge atrophy has been reported on magnetic resonance imaging in cases due to TDP-43 proteinopathy, corticobasal degeneration, and progranulin mutations, to name a few non–Pick disease etiologies.10 Even at autopsy, superior temporal gyrus sparing does not appear to be specific for Pick disease in the case of SD.11 Some imaging differences do, however, exist between SD due to AD pathology and tau or TDP-43 pathology. Extrahippocampal atrophy is less marked in AD pathology cases but when present tends to involve the superior temporal gyrus, and knife-edge atrophy has not been reported.8 Furthermore, severe atrophy involving the fusiform gyrus suggests non-AD pathology.8 The main distinguishing features are summarized in the Table. Although there are several features in this case that hint at Pick disease as the underlying pathology, it is difficult to choose it over TDP-43 given the high prior probability of the latter.
影像预测病理的主要问题是，区域性萎缩与临床特征的关系比与病理结果的关系更大【8】。这在TDP-43和Pick病相关的SD是明确的，它们的区域性萎缩模式不能区分【6,8】。不对称的程度可能是有帮助的：与TDP-43相比，Pick病不对称性脑萎缩倾向更明显；与AD病理学的病例相比，TDP-43和Pick病不对称性脑萎缩倾向更明显【6,8】。像这样只保留一条脑组织的明显的局部萎缩（所谓的“刀缘”样萎缩），颞上回后2/3相对豁免的特征被广泛报道为潜在的Pick病提示线索【9】。然而这些结果来源于大体病理，没有在临终前阶段好好研究。MRI上报告的“刀缘”样萎缩病例见于TDP-43蛋白病、皮层基底节变性和前颗粒体蛋白基因突变，命名一些非Pick病的病因【10】。即使尸检，在SD病例中颞上回豁免似乎对Pick病也不是特异的【11】。然而，一些影像学在AD病理学所致SD和tau蛋白或TDP-43病理学所致SD间确实存在差异。AD病理学所致海马结构以外萎缩不明显，但有萎缩时倾向于累及颞上回，“刀缘”样萎缩未见报道【8】。此外，菱形脑回严重萎缩提示非AD病理【8】。主要鉴别点总结于下表。尽管该病例有几个特点提示Pick病是潜在的病理，但是鉴于TDP-43的高先验概率，很难选择Pick病不选择它。
表：预测SD病例潜在病理的选择性特征 | 缩写：AD，阿尔茨海默病；TDP-43，TAR DNA结合蛋白43；++，高度支持；+，支持；+/-，不明确；-，不支持。 a许多病理证实的病例不能区分3R-tau和4R-tau或TDP-43亚型；然而，大多数TDP-43病例是C型，大多数tau病例的变化符合现在Pick病定义。 | ||
特征 | 病理a | ||
TDP-43 | Tau | AD | |
大约流行率5，% | 74 | 14 | 12 |
临床特征 | |||
继发性行为异常综合征2,12 | ++ | ++ | - |
继发性皮层基底节或明显的失语综合征12 | - | +/- | + |
早期计算困难6 | - | + | - |
早期语音错误12 | - | + | +/- |
疾病过程任何时间缄默6 | - | - | + |
病程中任何时间运动神经元病体征13 | ++ | - | - |
影像表现 | |||
“刀缘”样萎缩6,10 | + | ++ | +/- |
极不对称萎缩6 | + | ++ | +/- |
颞叶前部萎缩重于后部13 | + | + | - |
Pathological Discussion (Dr Parisi)
病理讨论（Parisi医生）
The profoundly atrophic formalin-fixed left hemibrain weighed 340 g (left hemisphere weight, 270 g; left cerebellum and brainstem weight, 70 g). There was severe and sharply circumscribed lobar atrophy with a knife-edge/walnut appearance of gyri in the frontal and temporal lobes, with relative sparing of the precentral and postcentral gyri and the posterior two-thirds of the superior temporal gyrus, less severe involvement of the parietal lobe, and relative pres- ervation of the occipital lobe (Figure 2A).
福尔马林固定的极度萎缩的左半脑重340g（左侧大脑半球重270g；左侧小脑和脑干重70g）。额颞叶脑回严重的边缘锐利的脑叶萎缩呈刀刃样或胡桃样，中央前回、中央后回和颞上回后2/3部分相对豁免，顶叶受累不严重，枕叶相对保存（图2A）。
Coronal sections through the cerebral hemispheres demonstrated marked frontal and temporal atrophy, prominent flattening of the head of the caudate nucleus (Figure 2B, left image), with relative sparing of the remainder of the basal ganglia and the thalamus, thinning of the corpus callosum, enlargement of the lateral ventricles, and reduction of the centrum semiovale. The amygdala and entorhinal cortex were severely atrophic (Figure 2B, middle image), while the hippocampus was relatively spared (Figure 2B, right image). Transverse sections through the brainstem revealed slight pallor of the pars compacta of the substantia nigra.
通过大脑半球的冠状切面证实明显的额颞叶萎缩，尾状核头明显扁平（图2B，左侧图像），基底节其他部分和丘脑相对豁免，胼胝体变薄，侧脑室扩张，半卵圆中心减小。杏仁核和嗅皮质严重萎缩（图2B，中间图像），而海马相对保留（图2B，右侧图像）。通过脑干的横切面显示黑质致密部略显苍白。
Frontal and temporal neocortex showed severe pancortical neuronal loss and gliosis (status spongiosis) (Figure 2C), while less involved regions showed neuronal loss and gliosis mainly in the third and fifth cortical layers. The subcortical white matter showed atrophy and gliosis corresponding to the degree of cortical atrophy.
额颞叶新皮质显示出严重的泛皮质神经元丢失和胶质增生（海绵状）（图2C），受累不严重的区域神经元丢失和胶质增生主要在第三和第五皮质层。皮层下白质萎缩和胶质增生与皮层萎缩的程度相当。
Well-demarcated, amorphous, and slightly basophilic spherical neuronal cytoplasmic inclusions (Pick bodies) were present throughout affected cerebral cortex (mostly in layers II and III) and subcortical gray matter, and they were particularly abundant in the hippocampus (dentate fascia and cornu ammonis 1) and in affected regions of neocortex (Figure 2D). Pick bodies stain intensely with silver stains (Figure 2E) and show striking immunoreactivity to tau (Figure 2F) and 3-repeat tau (Figure 2G) but not to 4-repeat tau (Figure 2H). The findings in this patient were characteristic of Pick disease. No significant coexisting AD neuropathologic changes, α-synuclein–immunoreactive lesions, or TDP-43–immunoreactive lesions were noted.
边界清楚、不定形、略嗜碱性球形神经元细胞质包涵体(Pick小体）存在于整个受累及的皮层（多在Ⅱ层和Ⅲ层）和皮层下灰质，海马（齿状带和阿蒙角1）和受累的新皮质区尤其丰富（图2D）。Pick小体银染明显，对tau蛋白（图2F）和3R tau蛋白（图2G）显示明显的免疫反应，但是对4R tau蛋白无反应（图2H）。该患者的病理结果是Pick病的特征性表现。未观察到明显的共病AD神经病理变化、α-突触核蛋白免疫反应病变或TDP-43免疫反应病变。
图2 病理发现
A：脑左侧面观示额叶和颞前叶明显的局限性萎缩，顶叶受累不严重（箭头）。B：冠状切面示额叶和颞前叶新皮质变薄，尾状核头扁平（左图，箭头）。杏仁核和嗅皮层严重萎缩（中图，箭头）。而海马相对保存（右图）。C：颞上回前部皮质显示严重的泛皮层神经元丢失和胶质增生或海绵状（苏木精-伊红染色，原始倍数×100）。D：残存的颞上叶神经元内包含特征性的边界清楚的、略嗜碱性的圆型包涵体。这是Pick小体的特征（苏木精-伊红染色，原始倍数×600）。E-H：Pick小体始终出现在海马的齿状带，显示银浓染（箭头）（比尔朔夫斯基银染色）（E），对tau蛋白明显的免疫反应（箭头）（AT8抗体）（F），和对3R tau蛋白选择性tau染色免疫反应（G)，但对4R tau蛋白无免疫反应（H)（原始倍数×600）。
First described clinically by Arnold Pick in 1892, Pick disease is a rare cause of dementia. Disease onset mostly occurs before age 65 years, and there does not appear to be a sex predilection.14 Its clinical course can be variable, with some studies suggesting a rapid decline, but when the presentation is that of SD, disease duration ranges from 8 to 18 years and may be far longer as this case illustrates.6,14 Whereas Pick disease initially referred to a clinical syndrome distinct from AD, as well as a spectrum of pathologic changes, it is now reserved for the specific pattern of 3-repeat tau–related changes described earlier.9 It typically results in focal cortical atrophy, with the clinical syndrome depending on the area involved. The most common presentation is behavioral variant frontotemporal dementia, and the second most common is progressive agrammatic or nonfluent aphasia with or without apraxia of speech. Semantic dementia is estimated to make up fewer than 15% of Pick disease cases.6,14 By virtue of it being a rare cause of dementia, most of the literature is composed of case reports or small series; hence, antemortem clinical signatures of Pick disease have not been well studied, especially when SD is the presenting syndrome. Coupled with the aforementioned problems with imaging predictors of pathology, the result is that, to our knowledge, no evidence-based predictors of Pick disease exist. The hope is that the rise of tau positron emission tomography will address this, where a clinical presentation of SD with a tau-positive and amyloid-negative scan would be suggestive of Pick disease
Pick病是罕见的痴呆病因，1892年Arnold Pick临床上首次描述。疾病发病多在65岁以前，似乎无性别差异【14】。临床进程是不一样的，一些研究显示快速衰退，但是当表现为SD时，病程从8到18年，或如该病例一样病程可能更长【6,14】。而Pick病最初指一个不同于AD的临床综合征和病理改变谱，现在指前面描述的3R tau蛋白相关变化的特殊模式【9】。其通常导致局部的皮层萎缩，临床症状取决于受累部位。最常见的表现是行为变异型额颞叶痴呆，其次是进行性语法错误或非流利型失语，伴有或不伴有言语运用不能。估计语义性痴呆占Pick病的比例不到15%【6,14】。因为它是痴呆的罕见病因，大多数文献是单个病例报道或少数病例组。因此，Pick病病人临终前的临床特征没有被很好地研究，尤其是表现为语义性痴呆症状时。再加上上述提到的影像预测病理的问题，就我们所知，还没有Pick病循证医学预测因素。希望tau蛋白正电子发射断层摄影术的出现将会解决这一问题，临床表现为SD而tau蛋白阳性、淀粉样蛋白阴性的影像将提示是Pick病。
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