White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease.
White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer's disease.
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DOI：
10.1093/brain/awy229
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Ewers M
中科院分区：
文献类型：
--
作者：
Araque Caballero MÁ;Suárez-Calvet M;Duering M;Franzmeier N;Benzinger T;Fagan AM;Bateman RJ;Jack CR;Levin J;Dichgans M;Jucker M;Karch C;Masters CL;Morris JC;Weiner M;Rossor M;Fox NC;Lee JH;Salloway S;Danek A;Goate A;Yakushev I;Hassenstab J;Schofield PR;Haass C;Ewers M
有关本文的科学评论，请参阅雅各布斯和巴克利(DOI：)。尽管阿尔茨海默病的白质改变很普遍，但它们在症状前阶段的发生情况却鲜为人知。阿拉克-卡巴列罗等人。据报道，在常染色体显性遗传性阿尔茨海默病的痴呆症状出现前大约10年，弥漫性改变首先发生在胼胝体前部和后部纤维内。大多数阿尔茨海默病型痴呆症患者都有白质改变。然而，阿尔茨海默病痴呆症状之前脑白质变化的时空模式仍不清楚，这主要是由于临床前阶段固有的诊断不确定性，以及晚发性阿尔茨海默病混淆年龄相关性血管疾病和中风的风险增加。在以常染色体为主的早发性遗传性阿尔茨海默病中，参与者注定会患上痴呆症，这提供了在症状出现前几年评估大脑变化的机会，并且在没有与衰老相关的血管疾病的情况下。在这里，我们评估了突变携带者和45名非携带者家系非携带者脑白质平均弥散率的变化。使用基于区域的空间统计方法，我们绘制了突变状态与平均扩散系数之间的相互作用关系，即从症状开始到平均扩散的估计年限。对于主要的atlas来源的纤维束，我们确定了在突变携带者中可以检测到异常平均扩散率变化的最早时间点。最后，我们评估了平均弥散系数与脑脊液生物标志物淀粉样蛋白、tau蛋白、磷酸化tau蛋白和可溶性TREM2之间的关系，后者是小胶质细胞活性的标志。结果显示，突变携带者与非携带者相比，突变状态之间存在显著的交互作用，即突变携带者与非携带者相比，顶后白质和额叶内侧白质平均弥散率的增加更明显。在估计症状出现之前的5到10年间，最早观察到平均扩散率增加的是大钳、小钳和长投射纤维-许多连接默认模式网络区域-。纤维束的平均弥散率较高与纤维束投影区的灰质体积较低有关。全球平均弥散率与较低的脑脊液淀粉样蛋白-β1-42水平以及较高的tau、磷酸化tau和可溶性TREM2水平相关。总而言之，这些结果表明，地区性选择性白质变性发生在估计的症状出现之前数年。这种白质改变与阿尔茨海默病的原发病理和大脑中的小胶质细胞活动有关。
See Jacobs and Buckley (doi:) for a scientific commentary on this article. Despite the prevalence of white matter alterations in Alzheimer's disease, their occurrence in the presymptomatic phase is poorly understood. Araque-Caballero et al. report that diffusivity alterations occur first within the anterior and posterior callosal fibres approximately 10 years before the onset of dementia symptoms in autosomal dominant Alzheimer's disease. White matter alterations are present in the majority of patients with Alzheimer’s disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer’s disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer’s disease. In early-onset autosomal-dominantly inherited Alzheimer’s disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres—many connecting default mode network regions—between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts’ projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer’s disease pathology and microglia activity in the brain.
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影响因子：
5.7
作者：
de Groot M;Vernooij MW;Klein S;Ikram MA;Vos FM;Smith SM;Niessen WJ;Andersson JL
通讯作者：
Andersson JL
DOI：
10.1186/s13195-017-0328-9
发表时间：
2017-12-29
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Bos I;Verhey FR;Ramakers IHGB;Jacobs HIL;Soininen H;Freund-Levi Y;Hampel H;Tsolaki M;Wallin ÅK;van Buchem MA;Oleksik A;Verbeek MM;Olde Rikkert M;van der Flier WM;Scheltens P;Aalten P;Visser PJ;Vos SJB
通讯作者：
Vos SJB
影响因子：
2.4
作者：
Englund, E
通讯作者：
Englund, E
影响因子：
5.7
作者：
Bach, Michael;Laun, Frederik B.;Maier-Hein, Klaus H.
通讯作者：
Maier-Hein, Klaus H.
影响因子：
9.9
作者：
Chhatwal, Jasmeer P.;Schultz, Aaron P.;Sperling, Reisa A.
通讯作者：
Sperling, Reisa A.