From the Departments of Neurology (M.E.F., K.V.P., R.F.B., A.P.S., M.J.P., P.V., D.R.M., R.A.S.) and Radiology (H.I.L.J., B.J.H., K.A.J.), Massachusetts General Hospital, Harvard Medical School; Center for Alzheimer Research and Treatment (K.V.P., R.F.B., P.V., D.M.R., K.A.J., R.A.S.), Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Florey Institute of Neuroscience and Mental Health (R.F.B.); Melbourne School of Psychological Sciences (R.F.B.), University of Melbourne, Australia; Faculty of Health, Medicine and Life Sciences (H.I.L.J.), School for Mental Health and Neuroscience, Alzheimer Centre Limburg, Maastricht University, the Netherlands; and Cliniques Universitaires Saint-Luc (B.J.H.), Université Catholique de Louvain, Brussels, Belgium.
Neurology. 2022 Apr 12;98(15):e1512-e1524. doi: 10.1212/WNL.0000000000200137. Epub 2022 Mar 25.
Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology.
One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time.
Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40).
Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function.
This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.
阿尔茨海默病（AD）临床试验正根据β-淀粉样蛋白（Aβ）和 tau 病理学的新迹象提前进行。如果早期治疗是干预的正确时机，那么找到正确的测试方法来优化临床试验中的认知结果测量就至关重要。我们旨在确定与早期可检测到的新型 Aβ 和 tau 病理学相关的认知测量方法。
我们纳入了 112 名来自哈佛老化大脑研究（HABS）的具有纵向匹兹堡化合物 B（PiB）-正电子发射断层扫描（PET）、F-氟脱氧酪氨酸（FTP）-PET 和至少 7 年认知数据的临床正常成年人。分析评估了最初被分类为 PiB-（低于 Centiloid [CL] 20）的个体，然后扩展到包括 PiB+个体，直到 CL40，这是皮质 tau 增殖开始的大致阈值。单独的线性混合效应模型评估了在额颞叶（entorhinal and inferior temporal [IT] cortices）中，新出现的全局 Aβ（PiB 斜率）和 tau（基线 FTP 水平和 FTP 斜率）对多种认知任务和临床前阿尔茨海默病认知复合指标（Preclinical Alzheimer's Cognitive Composite [PACC]）的影响。
在 <CL20 的个体中，PiB 斜率越大，与处理速度下降（数字符号替代测试 [Digit Symbol Substitution Test [DSST]、连线测试 A 部分）相关，而在 <CL40 组中，这种相关性扩展到了学习/记忆检索（自由选择连续测试-即时回忆 [Free-Choice Serial Recall Test-FR]、选择性提醒测试总回忆 [Selective Reminding Test Total Recall [SRT-tr]、逻辑记忆即时回忆）。在 <CL20 时，FTP 的影响有限，只有右侧 IT FTP 斜率升高与 FCSRT-FR 和 SRT-tr 学习/记忆检索的下降相关。当我们扩展到包括最初 <CL40 的个体时，FTP 水平或斜率的升高与所有任务的下降有关，而 PiB 斜率对记忆检索的影响但对 DSST 分数的影响降低。处理速度和记忆检索任务的综合指标在 CL40 时提供了最强的下降预测，而 PACC 分数在高水平的 Aβ（>CL40）时仍然是最佳的。
在临床正常的老年人中，我们发现了与新出现的 AD 病理学相关的、与 Aβ 有关的认知处理速度减慢，以及与 Aβ 和 tau 病理学有关的早期记忆检索下降。这些测量方法的综合可能有助于确定在病理出现的早期，给予抗 Aβ 或抗 tau 治疗是否可能保留认知功能。
本研究提供了 I 级证据，表明在临床正常的老年人中，新出现的 PET 检测到的 AD 病理学与处理速度下降和记忆检索下降有关。
