Arenn F Carlos, Shunsuke Koga, Neill R Graff-Radford, Matthew C Baker, Rosa Rademakers, Owen A Ross, Dennis W Dickson, Keith A Josephs
{"title":"阿尔茨海默病中与老年斑相关的转录反应 DNA 结合蛋白 43:跨越 16 年记忆丧失的病例报告。","authors":"Arenn F Carlos, Shunsuke Koga, Neill R Graff-Radford, Matthew C Baker, Rosa Rademakers, Owen A Ross, Dennis W Dickson, Keith A Josephs","doi":"10.1111/neup.12938","DOIUrl":null,"url":null,"abstract":"<p><p>Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming \"apple-bite\" or \"flame-shaped\" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. The clinical correlate of this plaque-associated TDP-43 appears to be a slowly progressive amnestic syndrome.</p>","PeriodicalId":19204,"journal":{"name":"Neuropathology","volume":null,"pages":null},"PeriodicalIF":1.3000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10828111/pdf/","citationCount":"0","resultStr":"{\"title\":\"Senile plaque-associated transactive response DNA-binding protein 43 in Alzheimer's disease: A case report spanning 16 years of memory loss.\",\"authors\":\"Arenn F Carlos, Shunsuke Koga, Neill R Graff-Radford, Matthew C Baker, Rosa Rademakers, Owen A Ross, Dennis W Dickson, Keith A Josephs\",\"doi\":\"10.1111/neup.12938\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming \\\"apple-bite\\\" or \\\"flame-shaped\\\" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. 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引用次数: 0
摘要
在额颞叶变性(FTLD-TDP)和阿尔茨海默病(AD-TDP)中发现了转录反应DNA结合蛋白43(TDP-43)病理包涵体。虽然临床表现不同,但 FTLD-TDP 和 AD 中的 TDP-43 包涵体可能具有相似的形态特征。然而,TDP-43与tau共聚焦并形成 "苹果咬合 "或 "火焰形 "神经元胞浆包涵体(NCI)仅见于AD-TDP。在此,我们描述了一例 AD 和神经斑块相关 TDP-43 的病例。患者是一名 96 岁的右撇子高加索女性,80 岁时出现了与典型 AD 相似的缓慢进展性失忆综合征。基因检测显示她患有 APOE ε3/ε4、GRN r5848 CT 和 MAPT H1/H2 基因型。与发病年龄大、病程长相一致的是,尸检时发现了以边缘为主的AD,海马计数高而皮质神经纤维缠结(NFT)计数低。存在海马和杏仁核硬化。磷酸化-TDP-43免疫组化显示出NCIs、萎缩性神经元、与FTLD-TDP A型一致的罕见神经元核内包涵体以及与tau NFT相关的TDP-43包涵体。在杏仁核、内视网膜皮层、海马、枕颞回和颞下回等部位经常出现这些包涵体,但在额叶中层皮层则很少见。此外,在海马齿状筋膜的分子层中存在 TDP-43 免疫反应性包涵体,形成斑块样结构。使用硫黄素-S荧光显微镜和磷酸化-tau免疫组化法证实了同一区域存在神经斑块。双标记免疫荧光显示,TDP-43和tau在神经斑块内共定位。其他病变包括主要影响杏仁核和嗅球的轻度路易体病变、与衰老相关的tau星形胶质细胞病变以及伴有数个皮质微梗塞的混合性小血管疾病(动脉硬化和淀粉样血管病)。总之,我们在 AD 的神经斑块中发现了 TDP-43 与 tau 的共聚焦,这将 TDP-43 与 tau 在 AD 中的关联扩展到了 NFTs 之外。这种斑块相关的TDP-43的临床相关性似乎是一种缓慢进展的失忆综合征。
Senile plaque-associated transactive response DNA-binding protein 43 in Alzheimer's disease: A case report spanning 16 years of memory loss.
Transactive response DNA-binding protein 43 (TDP-43) pathological inclusions are found in frontotemporal lobar degeneration (FTLD-TDP) and Alzheimer's disease (AD-TDP). While clinically different, TDP-43 inclusions in FTLD-TDP and AD can have similar morphological characteristics. However, TDP-43 colocalizing with tau and forming "apple-bite" or "flame-shaped" neuronal cytoplasmic inclusions (NCI) are only found in AD-TDP. Here, we describe a case with AD and neuritic plaque-associated TDP-43. The patient was a 96-year-old right-handed Caucasian woman who had developed a slowly progressive amnestic syndrome compatible with typical AD at age 80. Genetic testing revealed APOE ε3/ε4, GRN r5848 CT, and MAPT H1/H2 genotype. Consistent with the old age at onset and long disease duration, limbic-predominant AD was found at autopsy, with high hippocampal yet low cortical neurofibrillary tangle (NFT) counts. Hippocampal and amygdala sclerosis were present. Immunohistochemistry for phospho-TDP-43 showed NCIs, dystrophic neurites, and rare neuronal intranuclear inclusions consistent with FTLD-TDP type A, as well as tau NFT-associated TDP-43 inclusions. These were frequent in the amygdala, entorhinal cortex, hippocampus, occipitotemporal gyrus, and inferior temporal gyrus but sparse in the mid-frontal cortex. Additionally, there were TDP-43-immunoreactive inclusions forming plaque-like structures in the molecular layer of the dentate fascia of the hippocampus. The presence of neuritic plaques in the same region was confirmed using thioflavin-S fluorescent microscopy and immunohistochemistry for phospho-tau. Double labeling immunofluorescence showed colocalization of TDP-43 and tau within neuritic plaques. Other pathologies included mild Lewy body pathology predominantly affecting the amygdala and olfactory bulb, aging-related tau astrogliopathy, and mixed small vessel disease (arteriolosclerosis and amyloid angiopathy) with several cortical microinfarcts. In conclusion, we have identified TDP-43 colocalizing with tau in neuritic plaques in AD, which expands the association of TDP-43 and tau in AD beyond NFTs. The clinical correlate of this plaque-associated TDP-43 appears to be a slowly progressive amnestic syndrome.
期刊介绍:
Neuropathology is an international journal sponsored by the Japanese Society of Neuropathology and publishes peer-reviewed original papers dealing with all aspects of human and experimental neuropathology and related fields of research. The Journal aims to promote the international exchange of results and encourages authors from all countries to submit papers in the following categories: Original Articles, Case Reports, Short Communications, Occasional Reviews, Editorials and Letters to the Editor. All articles are peer-reviewed by at least two researchers expert in the field of the submitted paper.