A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1‐weighted MRI of 337 participants were included, divided into amyloid‐β negative (Aβ−) controls, cerebral spinal fluid p‐tau positive (T+) and negative (T−) preclinical AD (Aβ+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2‐year‐follow‐up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T− preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross‐sectional MTL measures, longitudinal cognitive measures (PACC, ADAS‐Cog) and cross‐sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross‐sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.

中文翻译：

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临床前阿尔茨海默病早期 Braak 区域的纵向萎缩。

随着干预研究开始针对这一人群，阿尔茨海默病 (AD) 研究的一个主要焦点是在临床前 AD 中寻找对疾病进展的敏感结果指标。我们假设，与标准认知和血浆 NfL 测量相比，内侧颞叶 (MTL) 子区域（最早皮质缠结病理部位）的纵向变化的定制测量对临床前 AD 中的疾病进展更敏感。包括 337 名参与者的纵向 T1 加权 MRI，分为淀粉样蛋白 β 阴性 (Aβ-) 对照、脑脊髓液 p-tau 阳性 (T+) 和阴性 (T-) 临床前 AD（Aβ+ 对照）和早期前驱期广告。前/后海马、内嗅皮层、布罗德曼区 (BA) 35 和 36 以及海马旁皮层在基线 MRI 中使用新型管道进行分割。在 2 年的随访期内，使用 MRI 扫描估计了子区域的无偏变化率。实验结果表明，T+临床前AD和早期前驱AD的所有MTL亚区的纵向萎缩率均显着高于对照组，但T-临床前AD则不然。后海马体和 BA35 分别在海马体和 MTL 皮质中表现出最大的组差异。横断面 MTL 测量、纵向认知测量（PACC、ADAS-Cog）和横断面或纵向血浆 NfL 在临床前 AD 中均未达到显着性。总之，纵向萎缩测量反映了活动性神经变性，因此比横断面测量与活动性疾病进展更直接相关。而且，临床前 AD 中的加速萎缩似乎仅在伴随 tau 病理学存在时发生。建议的纵向测量可以作为临床试验中有效的结果测量。