Hidden Objective Memory Deficits Behind Subjective Memory Complaints in Patients With Temporal Lobe Epilepsy

International audienceBackground and Objectives The aim of this work was to test the hypothesis that patients with temporal lobe epilepsy (TLE) with subjective initial memory complaints (not confirmed by an objective standard assessment) and various phenotypes also show objective very long-term memory deficit with accelerated long-term forgetting. We tested patients with TLE with 2 surprise memory tests after 3 weeks: the standard Free and Cued Selective Reminding Test (FCSRT) and Epireal, a new test specifically designed to capture more ecologic aspects of autobiographical memory. Methods Forty-seven patients with TLE (12 with hippocampal sclerosis, 12 with amygdala enlargement, 11 with extensive lesions, 12 with normal MRI) who complained about their memory, but for whom the standard neuropsychological assessment did not reveal any memory impairment after a standard delay of 20 minutes, underwent 2 surprise memory tests after 3 weeks. They were compared to 35 healthy controls. Results After 3 weeks, FCSRT and Epireal recall scores were significantly lower in patients than in controls ( p < 0.001). There was no significant correlation between FCSRT and Epireal scores ( p = 0.99). Seventy-six percent of patients with TLE had objective impairment on at least 1 of these very long-term memory tests, regardless of the existence and type of lesion or response to antiseizure medication. Easily applicable, Epireal had a higher effect size, detected deficits in 28% more patients, and is a useful addition to the standard workup. Discussion Assessing long-term memory should be broadened to a wide spectrum of patients with TLE with a memory complaint, regardless of the epileptic syndrome, regardless of whether it is associated with a lesion. This could lead to rethinking TLE nosology associated with memory

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes

International audienceAbstract Background Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications