Genetic influences on atrophy patterns in familial Alzheimer's disease: a comparison of APP and PSEN1 mutations.
Genetic influences on atrophy patterns in familial Alzheimer's disease: a comparison of APP and PSEN1 mutations.
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DOI：
10.3233/jad-121255
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Fox NC
中科院分区：
文献类型：
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作者：
Scahill RI;Ridgway GR;Bartlett JW;Barnes J;Ryan NS;Mead S;Beck J;Clarkson MJ;Crutch SJ;Schott JM;Ourselin S;Warren JD;Hardy J;Rossor MN;Fox NC
早老素1 （PSEN1）和淀粉样蛋白β前体（APP）基因的突变是大多数常染色体显性遗传性阿尔茨海默病（AD）病例的原因。我们希望评估和比较这两组突变产生的脑损失模式。对携带APP （n = 10）和PSEN1 （n = 18）基因突变的临床AD患者以及健康对照（n = 18）进行体积磁共振成像和神经心理学评估。进行了基于体素的形态测量（VBM）、皮质厚度和感兴趣区域分析。两个疾病组的精神状态测试分数相似，表明疾病严重程度相似。有证据表明APP受试者的海马体积比PSEN1受试者小（p = 0.007），并且有微弱证据表明APP受试者的全脑和灰质体积更大（p = 0.07）。虽然APP和PSEN1在VBM或皮质厚度分析上没有统计学上的显著差异，但效应图提示APP受试者有更多的内侧颞叶萎缩，相反PSEN1受试者有更多的新皮层损失。神经心理学数据与这些区域差异一致，表明APP患者的记忆缺陷更大，PSEN1组的非记忆域损伤更大，尽管这些差异没有统计学意义。我们得出结论，APP和PSEN1突变导致神经元丢失的机制可能不同，这进一步加深了我们对AD神经病理学基础的理解，并可能为未来的治疗策略和试验设计提供信息。
Mutations in the presenilin1 (PSEN1) and amyloid β-protein precursor (APP) genes account for the majority of cases of autosomal dominantly inherited Alzheimer’s disease (AD). We wished to assess and compare the patterns of cerebral loss produced by these two groups of mutations. Volumetric magnetic resonance imaging and neuropsychological assessments were performed in individuals with clinical AD carrying mutations in the APP (n = 10) and PSEN1 (n = 18) genes and in healthy controls (n = 18). Voxel-based morphometry (VBM), cortical thickness, and region of interest analyses were performed. Mini-Mental State Examination scores were similar in the two disease groups suggesting similar levels of disease severity. There was evidence that APP subjects have smaller hippocampal volume compared with PSEN1 subjects (p = 0.007), and weak evidence that they have larger whole-brain and grey matter volumes (both p = 0.07). Although there was no evidence of statistically significant differences between APP and PSEN1 in VBM or cortical thickness analyses, effect-maps were suggestive of APP subjects having more medial temporal lobe atrophy and conversely PSEN1 subjects showing more neocortical loss. Neuropsychological data were consistent with these regional differences and suggested greater memory deficits in the APP patients and greater impairment in non-memory domains in the PSEN1 group, although these differences were not statistically significant. We conclude that the mechanisms by which APP and PSEN1 mutations cause neuronal loss may differ which furthers our understanding of the neuropathology underlying AD and may inform future therapeutic strategies and trial designs.