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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架

发表日期:2018-10-24 | 文章来源 :互联网
TDP-43是阿尔茨海默病的潜在生物标志物
TDP-43 could be potential new biomarker for Alzheimer’s disease
梅奥医院的研究者发现,已被证明与痴呆、肌萎缩侧索硬化症等神经退行性疾病相关的TDP-43蛋白,可能也参与阿尔茨海默病的脑萎缩,从而有望成为该病的新生物标志物和治疗靶点。
明尼苏达州罗切斯特梅奥医院的Jennifer L. Whitwell医生在年度阿尔茨海默病协会国际会议上报告,这项脑扫描研究纳入了133例尸检时诊断为阿尔茨海默氏病的患者,发现43 kDa的TAR DNA结合蛋白(即TDP-43)与海马和皮质萎缩速度加快有关。这种蛋白也涉及疾病相关的记忆丧失和临床特征。
上述结果提示,TDP-43可能是一个治疗靶点,应当在未来的研究和临床试验中加以考虑。“如果我们能够清除这种蛋白或阻止其累积,或许可以减缓海马丢失。”
北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
Jennifer L. Whitwell医生
Whitwell医生是梅奥医院Keith Josephs研究组的成员。该研究组近期发现,在342例阿尔茨海默病患者中,近60%的大脑中存在这种蛋白(ActaNeuropathol. 2014;127:811-24)。TDP-43阳性患者死亡时存在认知障碍的几率是TDP-43阴性患者的10倍(部分患者在死亡时认知正常)。TDP-43阳性患者几乎不存在弹性认知(resilient cognition)。而且,该蛋白在BraakⅣ期、Ⅴ期中的影响比在Ⅵ期中更大。
研究组从这342例患者中选择了133例死亡前曾接受2次MRI检查(平均间隔时间为3.4年)的患者。从再次MRI检查至死亡的平均间隔时间为3.7年,平均死亡年龄为82岁,男女比例基本相等。研究者在海马和外侧颞叶皮层(在阿尔茨海默病中受累的区域)寻找TDP-43和tau神经纤维缠结,然后测定海马和皮层萎缩率,以确定其缩小是否是由TDP-43和/或tau驱动的。
该研究结果表明,TDP-43的存在于海马体积缩小显著相关,而tau蛋白没有这样的关联。
在皮层中,TDP-43和tau蛋白均与体积变化率有关,tau蛋白表现出更强的关联(tau的P<0.0001,TDP-43的P=0.01)。皮层萎缩率还与死亡年龄密切相关,而海马萎缩率则不然。研究者在模型中校正了在阿尔茨海默病患者大脑中发现的其他特征,如β-淀粉样斑块和路易体。
阿尔茨海默病协会顾问委员会主席Ralph Nixon博士在该协会网站上发表评论称,该研究结果提示“TDP-43可能是一个新靶点和充满希望的新生物标志物,它可能正是我们一直在寻找的缺失因素之一”。
本项研究由国立老化研究所资助。Whitwell医生和Nixon博士均无利益冲突披露。
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COPENHAGEN – TDP-43, a protein that has been associated with neurodegenerative diseases such as dementia and amyotrophic lateral sclerosis, could also be contributing to brain shrinkage in Alzheimer’s disease, adding another potential biomarker and treatment target for the disease, according to researchers at the Mayo Clinic.
The study of brain scans for 133 patients with Alzheimer’s disease diagnosed at autopsy revealed that TAR DNA binding protein of 43 kDa, or TDP-43, was associated with faster rates of hippocampal and cortical atrophy. The protein was also associated with memory loss and clinical features associated with the disease, said Jennifer L. Whitwell, Ph.D., of the Mayo Clinic, Rochester, Minn., who presented the study at the annual Alzheimer’s Association International Conference.
The results suggest that TDP-43 could be a target for treatment and should be considered in future studies and clinical trials, Dr. Whitwell said. "Can we target TDP-43 and try to slow down the disease processes?" she asked. "If we can remove it or prevent it from accumulating, perhaps we could slow down the rate of hippocampal loss."
Dr. Whitwell is part of Dr. Keith Josephs’s team at the Mayo Clinic. The group recently showed that the protein was present in almost 60% of 342 Alzheimer’s disease brains they studied using the Mayo Clinic neuropathological database (ActaNeuropathol. 2014;127:811-24).
They found that TDP-43–positive subjects were 10 times more likely to be cognitively impaired at death, compared with TDP-43–negative individuals. (Some patients had normal cognition at death.) Resilient cognition seemed to be almost nonexistent in the presence of TDP-43, Dr. Whitwell said. Also, the protein seemed to have a greater effect in Braak stage IV and V than with stage VI.
In a longitudinal analysis of the same 342 subjects, the team analyzed the data for 133 individuals who had two MRIs before death, separated by a mean interval of 3.4 years. There was a mean of 3.7 years between the repeat scan at the time of death. They looked for presence of TDP-43 and tau neurofibrillary tangle burden in the hippocampus and the lateral temporal cortex, an area affected in Alzheimer’s disease. They then measured the rates of hippocampal and cortical atrophy and tried to decide if the shrinkage was driven by TDP-43, tau, or both.
The average age of death was 82 years, and the population was split almost evenly by sex.
The results showed that the presence of TDP-43 was significantly associated with volume loss at the hippocampus, while tau showed no such association.
In the cortex, both TDP-43 and tau were associated with the rate of volume change, although tau showed a stronger association (P less than .0001 for tau vs. P = .01 for TDP-43). Also, the rate of cortical atrophy was strongly associated with age of death, while the rate of hippocampus shrinkage wasn’t. The investigators adjusted their models for other features found in the brains patients with Alzheimer’s disease, such as the presence of amyloid-beta plaques and Lewy bodies, Dr. Whitwell said.
The findings "would suggest that [TDP-43] might be a new target," said Ralph Nixon, Ph.D., chair of the Alzheimer’s Association Medical and Scientific Advisory Council, in a comment on the association’swebsite. "This might be one of the missing factors that we’ve been looking for, for quite some time, any it maybe a hopeful prospect for a new biomarker."
The study was funded by the National Institute on Aging. Dr. Whitwell and Dr. Nixon had no financial disclosures.
北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
北京国仁医院特邀会诊专家徐俊教授:新的AD分子病理标志物:TDP-43分级诊断框架
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