Search

Background: Episodic memory (EM) deficits are a hallmark of Alzheimer's disease (AD). The Free and Cued Selective Reminding Test (FCSRT) is the most specific official diagnostic tool detecting AD‐linked EM alterations in advanced preclinical stages (Grober et al., 2021). However, new tools that anticipate diagnosis to the at‐risk phase are needed, to reach more meaningful therapies. Based on existing research, we aim to investigate the Memory Binding Test (MBT) promising capacity to detect the appearance of subtle AD‐linked EM alterations and anticipate AD‐diagnosis to an at‐risk phase (Bushcke ey al., 2017; Mowrey et al., 2018). Methods: FCSRT and MBT scores were collected yearly during 5 years from the INSIGHT‐preAD cohort. We selected 3 groups controlled for age, education level, gender, beta‐amyloid burden (AB+), and neurodegeneration status based on 15 individuals who converted to prodromal‐AD during follow‐up, as follows: converters/AB+; non‐converters/AB+; controls/AB‐. Evaluation of both list‐learning tests is mainly based on free recall (FR) and total (cued) recall (TR) scores. The FCSRT uses 1‐list of words to remember while the MBT uses 2‐lists, introducing a binding component sensitive to subtle EM alterations. Data was analysed using mixed effect models including age, gender, and education as covariates. Results: When compared with the FCSRT, the MBT anticipated the detection of AD‐linked EM alterations in the converters/AB+ versus the other groups. In the MBT decline started up to 5 years prior to diagnosis, in delayed FR (mainly associated to executive dysfunction), followed by decline in 4 binding‐associated scores 1 year later (linked to storage deficits associated with the amnesic hippocampal syndrome characteristic of AD). Therefore, at an at‐risk phase, MBT outperformed FCSRT, both in the year of diagnosis and in the number of scores confirming AD‐linked EM deficits. Conclusion: We show the MBT capacity to detect the initial subtle EM alterations and to anticipate diagnosis to the at‐risk phase, while participants remain cognitively normal. We argue that the MBT (at‐risk phase detection) and the FCSRT (preclinical phase classification) could be complementary rather than concurrent tools, fostering meaningful innovative treatments to prolong quality of life in AD, a disease that remains without a cure. [ABSTRACT FROM AUTHOR]

Background: The challenge in Alzheimer's disease (AD) research ‐the world most prevalent dementia‐remains on finding preclinical markers that can predict progression to the disease. In this respect electrophysiological (EEG) measures seem promising, based on their sensitivity to the appearance of subtle episodic memory (EM) alterations, which become an AD risk‐factor when in the presence of B‐amyloid burden (AB+; AD‐biomarker) (Paitel et al., 2021; Olichney et al., 2011). We aimed to identify event‐related potential (ERP) signatures of AD‐linked EM alterations in elder cognitively normal subjects at‐risk for AD. Methods: EEG data was collected longitudinally with an EGI 256‐channels cap, over 6 yearly sessions, in 15 controls (AB‐), 15 non‐converters (AB+), and 15 converters to prodromal‐AD (AB+; who converted during follow‐up but were only considered before diagnosis) from the INSIGHTpre‐AD cohort. We analysed the typical ERP response to a classic task of verbal memory recognition of old or new words (i.e. P3 and FN400 [0.25‐0.34 and 0.51‐0.57ms], P600 [0.62‐0.77ms], and monitoring [0.87‐1.04ms]). The new words were related to the old words (previously encoded) either in their number of repetitions (NR) or in their semantic content but presented once (NU). Source‐localization analysis of these data is currently underway. Results: During follow‐up, the converters showed increased reaction time and decreased accuracy in word recognition when compared with the other groups. The converters significantly showed greater mean amplitude in the fronto‐parietal left and parieto‐occipital central regions typically linked to EM recollection, in the 0.25‐0.34 ms time‐window when compared with the controls, and in the 0.51‐0.57ms time‐window when compared with the non‐converters. Through our period of interest, old words activated mostly central‐posterior left regions (semantic networks/familiarity), NR words activated the frontal right region (i.e. novelty detection), and NU words frontal‐temporal right regions (semantic interference detection). Conclusion: Our findings show amplitude differences associated with AD‐linked EM alterations years before individuals are diagnosed, representing potential ERP signatures of progression to AD in at‐risk individuals, while they remain cognitively normal. Anticipation of diagnosis contributes to the development of more effective tailor‐made treatments that potentially ease quality of life of patients and caregivers. [ABSTRACT FROM AUTHOR]

Background: Cognitive reserve (CR) is present in Alzheimer's disease (AD) seniors with high education attainment making them clinically resilient to extended brain neuropathology and neurodegeneration. Here we tested whether subjective memory complaint (SMC) seniors with AD neuropathology and high education attainment may present abnormal eyes‐closed resting state posterior electroencephalographic (rsEEG) rhythms around individual alpha frequency peak (IAFp), typically altered in AD patients with mild cognitive impairment and dementia. Method: We selected all individual baseline data of the prospective INSIGHT‐preAD cohort (Paris) including mini mental state examination score ≥ 28, artifact‐free markers of 18F‐florbetapir positron emission tomography (amyPET), structural magnetic resonance imaging, and rsEEG rhythms (e.g., 172 SMC seniors). Delta, theta, alpha1, alpha2, and alpha3 bands were determined on individual basis based on IAFp, while beta1 (14‐20 Hz), beta2 (20‐30 Hz), and gamma (30‐40 Hz) were standard fixed bands. Result: The SMC participants negative to amyPET AD markers (SMCneg) with high (over low‐moderate) education level showed higher posterior alpha 2 power density (possibly "neuroprotective"). Furthermore, amyPET‐positive SMC (SMCpos) participants with high (over low‐moderate) education level showed higher temporal alpha 3 power density (possibly "neuroprotective") and lower posterior alpha 2 power density (possibly "compensatory"; Figure 1). This effect may reflect CR as no differences in brain gray‐white matter and cognitive functions were observed between these SMCpos/SMCneg sub‐groups. Conclusion: Preclinical Alzheimer's neuropathology may interact with education attainment and neurophysiological mechanisms generating cortical alpha rhythms around IAFp (i.e., alpha 2 and 3) in quiet wakefulness. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) patients are often unaware of their memory deficits even at early stage of disease. Anosognosia has been related to frontal dysfunction although its underlying neural mechanism is still unknown. We hypothesized that it may result from an inability to monitor ongoing behavior due to a failure in the error‐monitoring system. Our main objective was to study this system in individuals at risk for AD. Method: The study involved the 318 cognitively normal individuals of the INSIGHT cohort. All were age 70 and over at entry with a known brain amyloid status assessed by PET. We recorded the error negativity (ERN) and error positivity (Pe) of event‐related potentials (ERPs) in each of these individuals annually over 5 years. The cognitive task was the recognition of words, which had been memorized one hour before. ERPs were obtained by averages that were time‐locked to the erroneous response. All differences were tested through linear mixed‐effects models with group (Prog A+, NotProg A+; i.e., amyloid positive individuals who progressed or not to AD) and time (M0, M60, or Mdiag; i.e., months from study admission or month of AD diagnosis), as well as interaction between both as fixed effects, the subject identifier as a random effect to account for the paired measurements at M0 and M60 or Mdiag, and inclusion of age at M0 for covariate adjustment. Post hoc tests were performed on the interaction. Result: Our study focused on two subgroups identified after 5 years of follow‐up: 1) amyloid positive (A+) individuals who progressed to AD (Prog A+, n=15); and 2) A+ individuals who did not progress to AD (NotProg A+, n=35). When compared to M0 for intragroup analysis or to M60 for intergroup analysis, the Prog A+ group at Mdiag displayed significantly slower reactions and higher error rates, and its Pe amplitude was also significantly lower. Conclusion: Our results indicate the existence of a monitoring system failure in early stages of AD, which may be the substrate of anosognosia. [ABSTRACT FROM AUTHOR]