Table_1_Awareness of episodic memory and meta-cognitive profiles: associations with cerebrospinal fluid biomarkers at the preclinical stage of the Alzheimer’s continuum.docx

IntroductionThe lack of cognitive awareness, anosognosia, is a clinical deficit in Alzheimer’s disease (AD) dementia. However, an increased awareness of cognitive function, hypernosognosia, may serve as a marker in the preclinical stage. Subjective cognitive decline (SCD) might correspond to the initial symptom in the dynamic trajectory of awareness, but SCD might be absent along with low awareness of actual cognitive performance in the preclinical stage. We hypothesized that distinct meta-cognitive profiles, both hypernosognosia and anosognosia, might be identified in preclinical-AD. This research evaluated the association between cerebrospinal fluid (CSF) AD biomarkers and the awareness of episodic memory, further exploring dyadic (participant-partner) SCD reports, in the preclinical Alzheimer’s continuum.
MethodsWe analyzed 314 cognitively unimpaired (CU) middle-aged individuals (mean age: 60, SD: 4) from the ALFA+ cohort study. Episodic memory was evaluated with the delayed recall from the Memory Binding Test (MBT). Awareness of episodic memory, meta-memory, was defined as the normalized discrepancy between objective and subjective performance. SCD was defined using self-report, and dyadic SCD profiles incorporated the study partner’s report using parallel SCD-Questionnaires. The relationship between CSF Aβ42/40 and CSF p-tau181 with meta-memory was evaluated with multivariable regression models. The role of SCD and the dyadic contingency was explored with the corresponding stratified analysis.
ResultsCSF Aβ42/40 was non-linearly associated with meta-memory, showing an increased awareness up to Aβ-positivity and a decreased awareness beyond this threshold. In the non-SCD subset, the non-linear association between CSF Aβ42/40 and meta-memory persisted. In the SCD subset, higher Aβ-pathology was linearly associated with increased awareness. Individuals presenting only study partner’s SCD, defined as unaware decliners, exhibited higher levels of CSF p-tau181 correlated with lower meta-memory performance.
DiscussionThese results suggested that distinct meta-cognitive profiles can be identified in preclinical-AD. While most individuals might experience an increased awareness associated with the entrance in the AD continuum, hypernosognosia, some might be already losing insight and stepping into the anosognosic trajectory. This research reinforced that an early anosognosic profile, although at increased risk of AD-related decline, might be currently overlooked considering actual diagnostic criteria, and therefore its medical attention delayed.

引言：认知自知力缺失（疾病失认症，anosognosia）是阿尔茨海默病（AD）痴呆的临床缺损表现。然而，认知功能自知力亢进（hypernosognosia）或可作为AD临床前阶段的生物标志物。主观认知下降（Subjective cognitive decline, SCD）或对应认知自知力动态变化轨迹中的初始症状，但在AD临床前阶段，部分个体可能既无SCD表现，也对自身实际认知功能水平的自知力低下。本研究假设，在AD临床前阶段可识别出两类截然不同的元认知特征：认知功能自知力亢进与疾病失认症。本研究针对阿尔茨海默病临床前连续谱系人群，评估了脑脊液（cerebrospinal fluid, CSF）AD生物标志物与情景记忆自知力的关联，并进一步探索了参与者-伴侣二元主观认知下降报告模式。

研究方法：本研究从ALFA+队列研究中纳入314名认知正常（cognitively unimpaired, CU）的中年个体，其平均年龄为60岁，标准差为4。采用记忆绑定测试（Memory Binding Test, MBT）的延迟回忆任务评估情景记忆能力。情景记忆自知力（元记忆，meta-memory）被定义为客观认知表现与主观认知评价之间的标准化差值。主观认知下降（SCD）通过个体自我报告进行定义，而二元SCD特征则结合了研究对象伴侣采用平行版SCD问卷完成的报告结果。本研究采用多变量回归模型分析脑脊液Aβ42/40、脑脊液磷酸化tau181（p-tau181）与元记忆之间的关联，并通过分层分析进一步探讨SCD状态与二元报告模式的关联作用。

研究结果：脑脊液Aβ42/40水平与元记忆呈非线性关联：在Aβ阳性阈值之前，元记忆（认知自知力）随Aβ42/40水平升高而增强；超过该阈值后，元记忆则出现下降。在无SCD的亚组中，脑脊液Aβ42/40与元记忆之间的非线性关联依然存在。在存在SCD的亚组中，Aβ病理负荷越高与认知自知力增强呈线性相关。仅伴侣报告存在SCD的个体（即无自知力的认知下降者），其脑脊液p-tau181水平更高，且元记忆表现更差。

讨论：上述结果表明，AD临床前阶段可区分出不同的元认知特征亚型。尽管多数个体在进入AD病理连续谱系后会出现认知自知力亢进的表现，但部分个体已开始丧失认知自知力，逐渐走向疾病失认的病程轨迹。本研究进一步证实，早期疾病失认亚型个体虽AD相关认知下降风险更高，但按照当前诊断标准可能被忽视，进而导致医疗干预延迟。