Wood Ruth A, Moodley Kuven K, Lever Colin, Minati Ludovico, Chan Dennis
Department of Medicine, Brighton and Sussex Medical School, Falmer, UK; Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, London, UK.
Department of Medicine, Brighton and Sussex Medical School , Falmer , UK.
Front Neurol. 2016 Dec 1;7:215. doi: 10.3389/fneur.2016.00215. eCollection 2016.
The hippocampus is one of the first regions to exhibit neurodegeneration in Alzheimer's disease (AD), and knowledge of its role in allocentric spatial memory may therefore aid early diagnosis of AD. The 4 Mountains Test (4MT) is a short and easily administered test of spatial memory based on the cognitive map theory of hippocampal function as derived from rodent single cell and behavioral studies. The 4MT has been shown in previous cross-sectional studies to be sensitive and specific for mild cognitive impairment (MCI) due to AD. This report describes the initial results of a longitudinal study testing the hypothesis that allocentric spatial memory is predictive of conversion from MCI to dementia. Fifteen patients with MCI underwent baseline testing on the 4MT in addition to CSF amyloid/tau biomarker studies, volumetric MRI and neuropsychological assessment including the Rey Auditory Verbal Learning Test (RAVLT) and Trail Making Test "B" (TMT-B). At 24 months, 9/15 patients had converted to AD dementia. The 4MT predicted conversion to AD with 93% accuracy (Cohen's = 2.52). The predictive accuracies of the comparator measures were as follows: CSF tau/β-amyloid ratio 92% ( = 1.81), RAVLT 64% ( = 0.41), TMT-B 78% ( = 1.56), and hippocampal volume 77% ( = 0.65). CSF tau levels were strongly negatively correlated with 4MT scores ( = -0.71). This proof-of-concept study provides initial support for the hypothesis that allocentric spatial memory testing is a predictive cognitive marker of hippocampal neurodegeneration in pre-dementia AD. The 4MT is a brief, non-invasive, straightforward spatial memory test and is therefore ideally suited for use in routine clinical diagnostic practice. This is of particular importance given the current unmet need for simple accurate diagnostic tests for early AD and the ongoing development of potential disease-modifying therapeutic agents, which may be more efficacious when given earlier in the disease course. By applying a test based on studies of hippocampal function in rodents to patient populations, this work represents the first step in the development of translatable biomarkers of hippocampal involvement in early AD for use in both animal models and human subjects.
海马体是阿尔茨海默病（AD）中最早出现神经退行性变的区域之一，因此了解其在以自我为中心的空间记忆中的作用可能有助于AD的早期诊断。四山测试（4MT）是一种基于海马功能认知地图理论的简短且易于实施的空间记忆测试，该理论源自啮齿动物单细胞和行为研究。在先前的横断面研究中已表明，4MT对AD所致的轻度认知障碍（MCI）具有敏感性和特异性。本报告描述了一项纵向研究的初步结果，该研究检验了以自我为中心的空间记忆可预测MCI向痴呆转化这一假设。15名MCI患者除了接受脑脊液淀粉样蛋白/ tau生物标志物研究、容积性MRI以及包括雷伊听觉词语学习测验（RAVLT）和连线测验“B”（TMT - B）在内的神经心理学评估外，还接受了4MT的基线测试。在24个月时，15名患者中有9名已转化为AD痴呆。4MT对AD转化的预测准确率为93%（科恩系数 = 2.52）。比较指标的预测准确率如下：脑脊液tau/β - 淀粉样蛋白比率为92%（ = 1.81），RAVLT为64%（ = 0.41），TMT - B为78%（ = 1.56），海马体体积为77%（ = 0.65）。脑脊液tau水平与4MT得分呈强烈负相关（ = -0.71）。这项概念验证研究为以下假设提供了初步支持：以自我为中心的空间记忆测试是痴呆前AD中海马体神经退行性变的一种预测性认知标志物。4MT是一种简短、非侵入性、直接的空间记忆测试，因此非常适合用于常规临床诊断实践。鉴于目前对早期AD简单准确诊断测试的需求未得到满足，以及正在开发的潜在疾病修饰治疗药物，在疾病进程早期给药可能更有效，这一点尤为重要。通过将基于啮齿动物海马功能研究的测试应用于患者群体，这项工作代表了开发可转化的海马体参与早期AD生物标志物的第一步，这些生物标志物可用于动物模型和人类受试者。
