Bassett Susan Spear, Yousem David M, Cristinzio Catherine, Kusevic Ivana, Yassa Michael A, Caffo Brian S, Zeger Scott L
Department of Psychiatry, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Brain. 2006 May;129(Pt 5):1229-39. doi: 10.1093/brain/awl089.
Alzheimer's disease poses a looming crisis for the health care system as well as society in general. The low efficacy of current treatments for those already affected with this disease has prompted the suggestion that interventions might be more successful if they were applied before the development of significant pathology, that is, when individuals are clinically asymptomatic. Currently, the field requires a sensitive and specific diagnostic tool for identifying those individuals destined to develop this disease. As a first step, we present here an analysis of cross-sectional data for 95 asymptomatic offspring (50-75 years of age) of autopsy-confirmed late-onset familial Alzheimer's disease cases and 90 age-matched controls, studied with functional magnetic resonance imaging (fMRI) to investigate brain activation patterns. Analysis of activation in response to a paired-associates memory paradigm found significantly different patterns in these groups. At-risk individuals showed more intense and extensive activation in the frontal and temporal lobes including the hippocampus during memory encoding, an increase unrelated to the APOE epsilon4 allele. They also showed decreased activation particularly in the cingulum and thalamus during both the encoding and recall phases of the task. These results demonstrate that asymptomatic individuals, at genetic risk for development of late-onset Alzheimer's disease by virtue of familial clustering, show functional activation patterns distinct from those without such risk more than a decade before their parent's onset age. While longitudinal study is needed to determine whether these patterns, or a subset of them, are predictive of disease onset, these findings suggest that functional neuroimaging holds promise as a method of identifying pre-clinical Alzheimer's disease.
阿尔茨海默病对医疗保健系统乃至整个社会都构成了迫在眉睫的危机。目前针对已患此病患者的治疗效果不佳，这促使人们提出，如果在显著病理变化出现之前，即个体临床无症状时进行干预，可能会更成功。目前，该领域需要一种灵敏且特异的诊断工具来识别那些注定会患此病的个体。作为第一步，我们在此呈现对95名经尸检确诊为晚发性家族性阿尔茨海默病病例的无症状后代（50 - 75岁）和90名年龄匹配的对照者的横断面数据的分析，采用功能磁共振成像（fMRI）来研究大脑激活模式。对配对联想记忆范式的激活分析发现，这些组之间存在显著不同的模式。有患病风险的个体在记忆编码期间，额叶、颞叶包括海马体表现出更强烈和广泛的激活，这种增加与APOE ε4等位基因无关。在任务的编码和回忆阶段，他们在扣带和丘脑的激活也有所减少。这些结果表明，由于家族聚集而有患晚发性阿尔茨海默病遗传风险的无症状个体，在其父母发病年龄前十多年就表现出与无此类风险个体不同的功能激活模式。虽然需要纵向研究来确定这些模式或其中一部分是否能预测疾病发作，但这些发现表明功能神经成像有望成为识别临床前阿尔茨海默病的一种方法。
