Ringman John M, O'Neill Joseph, Geschwind Daniel, Medina Luis, Apostolova Liana G, Rodriguez Yaneth, Schaffer Barbara, Varpetian Arousiak, Tseng Benjamin, Ortiz Freddy, Fitten Jaime, Cummings Jeffrey L, Bartzokis George
UCLA Department of Neurology, Alzheimer's Disease Research Center, 10911 Weyburn Ave, Suite 200, Los Angeles, CA 90095-7226, USA.
Brain. 2007 Jul;130(Pt 7):1767-76. doi: 10.1093/brain/awm102. Epub 2007 May 23.
Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.
需要采取措施来识别那些将会患上阿尔茨海默病的人，以便针对他们进行预防性干预。动物、病理学和影像学研究的证据表明，白质破坏在阿尔茨海默病病程中出现，且可能是早期事件。先前的研究表明，髓鞘形成较晚的区域或连接边缘结构的白质特别容易退化。因完全显性遗传改变（家族性阿尔茨海默病或FAD）而注定会患该病的人提供了一个模型，在这个模型中可以识别出疾病的早期甚至症状前变化。在本研究中，我们对2名痴呆患者和21名有遗传FAD突变风险的受试者进行了扩散张量成像（DTI）。我们比较了FAD突变携带者和非携带者在疾病临床前期（临床痴呆评定量表<1，n = 20）和症状前阶段（临床痴呆评定量表= 0，n = 15）白质中的整体和局部各向异性分数（FA）测量值。在绝对年龄、相对于其家族中疾病典型诊断年龄的年龄、性别或简易精神状态检查评分方面，突变携带者和非携带者之间没有显著差异。在临床前期FAD突变携带者（n = 12）中，相对于非携带者（n = 8），平均全脑白质FA（P = 0.045）、穹窿柱的FA（P = 0.012）、双侧穿通通路的面积（右侧：P = 0.028，左侧：P = 0.027）和左侧眶额叶（P = 0.024）均降低。我们还发现，与7名非携带者相比，8名症状前突变携带者穹窿柱的FA（P = 0.008）和左侧眶额叶白质的FA（P = 0.045）降低。逻辑回归表明，穹窿柱的FA比穹窿的横截面积、整体平均白质FA和左侧额叶白质FA更能预测突变状态。在线性回归分析中，白质体积（P = 0.002）、海马体积（P = 0.023）和突变状态（P = 0.032）显著预测穹窿FA。我们得出结论，在临床前期甚至症状前FAD突变携带者的白质中FA降低，特别是在连接边缘结构的髓鞘形成较晚的 tracts中。穹窿柱FA的降低在早期FAD中尤为明显，可能为散发性阿尔茨海默病的早期疾病提供一个生物标志物。
