TDP-43 is a key player in the clinical features associated with Alzheimer's disease.
TDP-43 is a key player in the clinical features associated with Alzheimer's disease.
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DOI：
10.1007/s00401-014-1269-z
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发表时间：
2014
影响因子：
12.7
通讯作者：
Dickson DW
中科院分区：
文献类型：
--
作者：
Josephs KA;Whitwell JL;Weigand SD;Murray ME;Tosakulwong N;Liesinger AM;Petrucelli L;Senjem ML;Knopman DS;Boeve BF;Ivnik RJ;Smith GE;Jack CR Jr;Parisi JE;Petersen RC;Dickson DW
本研究的目的是确定43kDa的TAR dna结合蛋白（TDP-43）是否独立影响阿尔茨海默病（AD）病理典型的临床和神经影像学特征，以及TDP-43病理是否有助于阐明AD的弹性认知现象。对342例病理诊断为AD的受试者进行TDP-43的存在、负担和分布筛查。在死亡之前，所有人都被归类为认知受损或正常。基于图谱的分割和基于体素的形态测量法用于MRI评估区域萎缩。采用控制死亡年龄、载脂蛋白ε4和其他ad相关病理的回归模型，按Braak分期分层，探讨TDP-43与认知或脑萎缩的关系。此外，我们确定TDP-43的作用是否由海马硬化介导。tdp阳性195例（57%）。在考虑了年龄、载脂蛋白ε4和其他病理因素后，TDP-43对AD患者的认知、记忆丧失和内侧颞叶萎缩有很强的影响。这些影响不是由海马硬化介导的。tdp阳性受试者死亡时认知功能受损的可能性是tdp阴性受试者的10倍。更严重的认知障碍和内侧颞叶萎缩与TDP-43负担加重和TDP-43分布更广泛相关。TDP-43是AD临床影像学表现的重要因素。TDP-43似乎还能够抑制所谓的“弹性大脑衰老”。因此，TDP-43应被视为治疗AD的潜在治疗靶点。
The aim of this study was to determine whether the TAR DNA-binding protein of 43kDa (TDP-43) independently has any effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. Additionally, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4, and other pathologies, TDP-43 had a strong effect on cognition, memory loss, and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.
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影响因子：
12.7
作者：
Janocko NJ;Brodersen KA;Soto-Ortolaza AI;Ross OA;Liesinger AM;Duara R;Graff-Radford NR;Dickson DW;Murray ME
通讯作者：
Murray ME
影响因子：
12.7
作者：
Bigio EH;Mishra M;Hatanpaa KJ;White CL 3rd;Johnson N;Rademaker A;Weitner BB;Deng HX;Dubner SD;Weintraub S;Mesulam M
通讯作者：
Mesulam M
影响因子：
4.2
作者：
Ball, M;Braak, H;Khachaturian, Z
通讯作者：
Khachaturian, Z
影响因子：
1.8
作者：
Agresti, A;Coull, BA
通讯作者：
Coull, BA
影响因子：
9.9
作者：
Gosche, KM;Mortimer, JA;Snowdon, DA
通讯作者：
Snowdon, DA