Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720,
Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720.
J Neurosci. 2018 May 9;38(19):4482-4489. doi: 10.1523/JNEUROSCI.0485-18.2018. Epub 2018 Apr 23.
Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of β-amyloid (Aβ). However, the accumulation of Aβ begins slowly, years before biomarkers become abnormal. We used longitudinal [C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans ( = 71; mean age 75 years; 35% male). We used [F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample ( = 37). We found evidence for an inverted-U relationship between baseline Aβ levels and Aβ slope in asymptomatic older adults, suggesting a slowing of Aβ accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aβ predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aβ increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative. The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.
目前，阿尔茨海默病（AD）的早期检测方法依赖于将个体标记为与β-淀粉样蛋白（Aβ）核心病理相关的生物标志物的“阳性”或“阴性”。然而，Aβ的积累是缓慢的，在生物标志物异常之前的几年就开始了。我们使用纵向[C]匹兹堡化合物 B PET 扫描和神经心理学评估来研究 AD 病理学的最早变化以及它如何影响认知正常的老年人的记忆（= 71；平均年龄 75 岁；35%为男性）。我们在观察期结束时使用[F] AV-1451 PET 扫描来测量我们样本中的一部分随后的 tau 沉积（= 37）。我们在无症状的老年人中发现了基线 Aβ水平与无症状 Aβ斜率之间存在倒 U 型关系的证据，这表明即使在认知正常的成年人中，Aβ的积累也在减慢。在名义上淀粉样蛋白阴性的参与者中，淀粉样蛋白的积累速度和 Aβ的基线水平都预测了与 AD 相关的皮质 Braak 区域的早期 tau 沉积。淀粉样蛋白测量仅在 Aβ基线水平增加时才对记忆下降敏感，这表明病理性积累发生在影响记忆之前。这些发现支持即使在淀粉样蛋白阴性的患者中也需要进行早期的淀粉样蛋白降低治疗。如果要减缓疾病进展，就需要尽早发现病理性或认知变化，因此，阿尔茨海默病（AD）的进行性性质需要尽可能早地发现病理或认知变化。我们研究了开始出现 AD 病理的认知正常的老年人，目的是早期发现 AD 病理或认知变化。我们发现淀粉样蛋白测量在预测随后的早期 tau 沉积方面具有早期敏感性。此外，在临床前 AD 中，淀粉样蛋白积累的速度似乎已经开始减慢，这表明它是 AD 进展的相对晚期阶段。因此，在淀粉样蛋白水平饱和之前，早期检查老年人至关重要，以便进行干预以减缓疾病进展。
