PDF(Pubmed)
Abstract：
Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer\'s disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages.
Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.
Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.
We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.
Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.
Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition.
Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures.
We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials.
Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.
摘要：
背景：淀粉样变，包括脑淀粉样血管病,和小血管疾病（SVD）的标志物在显性遗传性阿尔茨海默病（DIAD）早老素-1（PSEN1）突变携带者中有所不同。我们研究了相对于密码子200（前/后密码子200）的突变位置如何影响这些病理特征和不同阶段的痴呆。
方法：来自已知PSEN1突变家族（n=393）的个体接受了神经影像学和临床评估。我们对匹兹堡区域化合物B-正电子发射断层扫描的吸收进行了横断面评估，磁共振成像标志物SVD（基于扩散张量成像的白质损伤，白质高强度体积，和微出血)，和认知。
结果：与前密码子200携带者相比，后密码子200携带者在所有区域的淀粉样蛋白负荷较低，但SVD标志物更差，临床痴呆评分®评分更差，这是症状发作的估计年份的函数。SVD的标志物部分介导了突变位置对临床措施的影响。
结论：我们证明了时空淀粉样变性背后的基因型变异性，SVD,和DIAD的临床表现，这可以告知患者预后和临床试验。
结论：突变位置影响Aβ负荷，SVD,和痴呆症。PSEN1pre-200组Aβ负荷与疾病分期之间有更强的关联。PSEN1post-200组SVD标志物和疾病分期之间有更强的关联。在疾病晚期阶段，PSEN1200后的痴呆评分比200前的痴呆评分差。基于扩散张量成像的SVD标志物介导的突变位置对晚期痴呆的影响.
方法：来自已知PSEN1突变家族（n=393）的个体接受了神经影像学和临床评估。我们对匹兹堡区域化合物B-正电子发射断层扫描的吸收进行了横断面评估，磁共振成像标志物SVD（基于扩散张量成像的白质损伤，白质高强度体积，和微出血)，和认知。
结果：与前密码子200携带者相比，后密码子200携带者在所有区域的淀粉样蛋白负荷较低，但SVD标志物更差，临床痴呆评分®评分更差，这是症状发作的估计年份的函数。SVD的标志物部分介导了突变位置对临床措施的影响。
结论：我们证明了时空淀粉样变性背后的基因型变异性，SVD,和DIAD的临床表现，这可以告知患者预后和临床试验。
结论：突变位置影响Aβ负荷，SVD,和痴呆症。PSEN1pre-200组Aβ负荷与疾病分期之间有更强的关联。PSEN1post-200组SVD标志物和疾病分期之间有更强的关联。在疾病晚期阶段，PSEN1200后的痴呆评分比200前的痴呆评分差。基于扩散张量成像的SVD标志物介导的突变位置对晚期痴呆的影响.
