遗传性阿尔茨海默病患者脑微出血的纵向累积。
Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.
机构信息
From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK; Departments of Neurology (J.P.C., K.A.J.) and Radiology (K.A.J.), Massachusetts General Hospital, Boston; Department of Neurology (H.C.C., J.M.R.), Keck School of Medicine of USC, Los Angeles, CA; Department of Psychiatry and Human Behavior (S.C., A.K.W.L., S.S.), Memory and Aging Program, Butler Hospital, Brown University Alpert Medical School, Providence, RI; Center for Neuroimaging, Department of Radiology and Imaging Science (M.R.F., A.J.S.), Department of Pathology and Laboratory Medicine (B.G.), and Indiana Alzheimers Disease Research Center (A.J.S.), Indiana University School of Medicine, Indianapolis; Departments of Molecular Imaging and Neurology (M.F.), Royal Prince Alfred Hospital, University of Sydney, Australia; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; German Center for Neurodegenerative Diseases (DZNE) (C.L., J.L., I.Y.); Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy (C.L.), University of Tübingen; Department of Neurology (J.L., I.Y.), Ludwig-Maximilians-Universität München; Munich Cluster for Systems Neurology (SyNergy) (J.L., I.Y.), Germany; Florey Institute and The University of Melbourne (C.L.M.), Australia; Department of Neurology (J.M.N.), Columbia University Irving Medical Center, New York, NY; Department of Radiology (K.K., C.R.J., G.M.P.), Mayo Clinic, Rochester, MN; Department of Molecular Imaging and Therapy (C.C.R., V.L.V.), Austin Health, University of Melbourne, Heidelberg, Australia; Clinical Research Center for Dementia (H.S.), Osaka City University; Department of Neurology (M.S.), Hirosaki University Graduate School of Medicine; and Department of Neurology (K.S.), The University of Tokyo, Japan.
出版信息
Neurology. 2021 Mar 23;96(12):e1632-e1645. doi: 10.1212/WNL.0000000000011542. Epub 2021 Jan 25.
OBJECTIVE
To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).
METHODS
Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.
RESULTS
Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).
CONCLUSION
Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.
目的
为了探究与脑微出血（CMHs）或脑微出血相关的固有临床风险，并确定发生出血性淀粉样相关影像异常（ARIA-H）的高危个体，我们对具有常染色体显性遗传阿尔茨海默病（DIAD）的家族进行了纵向评估。
方法
突变携带者（n=310）和非携带者（n=201）接受了神经影像学检查，包括梯度回波 MRI 序列以检测 CMHs，以及神经心理学和临床评估。横断面和纵向分析评估了 CMHs 与神经影像学和疾病的神经影像学和临床标志物之间的关系。
结果
3%的非携带者和 8%的携带者主要在脑叶区域出现 CMHs。有 CMHs 的携带者年龄更大，舒张压和哈钦斯缺血评分更高，且临床、认知和运动障碍更严重，与无 CMHs 的携带者相比。ε4 状态与 CMHs 的患病率或发病率无关。CMHs 的存在预测了临床痴呆评定量表的更快变化，尽管对复合认知测量、皮质厚度、海马体积或白质病变没有影响。重要的是，2 个或更多 CMHs 的存在与随着时间的推移发生更多 CMHs 的显著风险相关（每年 8.95±10.04 个）。
结论
我们的研究强调了与 DIAD 个体 CMHs 发展相关的因素。CMHs 是 DIAD 潜在疾病过程的一部分，与痴呆显著相关。这突显了在接受可能导致 ARIA-H 并发症的药物治疗的试验参与者中，可能难以将 CMHs 的自然发生率与药物相关的 CMHs 区分开来。
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