Objective To assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)‐specific neurodegeneration using longitudinal multimodal neuroimaging measures. Methods Change in verbal fluency was analyzed among 2261 non‐demented individuals with a follow‐up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non‐amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow‐up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18 F‐fluorodeoxyglucose brain positron emission tomography ( 18 F‐FDG‐PET) imaging (n = 756) using linear regression models across 2 years of follow‐up. Results Semantic fluency declined—fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)—while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18 F‐FDG‐PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus–posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole‐brain neurodegeneration over time was associated with faster decline in both fluencies, while AD‐specific regions were associated with a faster rate of decline in semantic but not letter fluency. Interpretation This study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD‐specific neurodegeneration.

Introduction Subjective cognitive complaints may be a signature of preclinical stage Alzheimer's disease. However, the link between subjective cognitive and non‐cognitive complaints and brain alterations remains unclear. Methods The relationship between cognitive and non‐cognitive complaints and brain biomarkers, measured by structural magnetic resonance imaging, was investigated in 2056 participants of the MEMENTO cohort of outpatients, who were dementia‐free at baseline. We assessed whether the cognitive status at inclusion or the presence of the apolipoprotein E gene variant (APOE) ε4 could modulate the association between the intensity of complaints and brain lesions. Results Smaller hippocampal volume was associated with higher memory complaints and discomfort in daily life. In APOE ε4 carriers, smaller whole‐brain white matter and gray matter volumes and gyrification indices in several regions of interest of the parietal and temporal lobes, in the entorhinal and the para‐hippocampal gyrus, were associated with higher memory complaint score. Conclusions The intensity of subjective complaints in not only memory but discomfort in daily life was associated with brain degeneration markers. The presence of APOE ε4 modulated the relationships between subjective memory complaints and brain alterations.

Purpose Digital PET cameras markedly improve sensitivity and spatial resolution of brain 18F-FDG PET images compared to conventional cameras. Our study aimed to assess whether specific control databases are required to improve the diagnostic performance of these recent advances. Methods We retrospectively selected two groups of subjects, twenty-seven Alzheimer's Disease (AD) patients and twenty-two healthy control (HC) subjects. All subjects underwent a brain 18F-FDG PET on a digital camera (Vereos, Philips®). These two group (AD and HC) are compared, using a Semi-Quantitative Analysis (SQA), to two age and sex matched controls acquired with a digital PET/CT (Vereos, Philips®) or a conventional PET/CT (Biograph 6, Siemens®) camera, at group and individual levels. Moreover, individual visual interpretation of SPM T-maps was provided for the positive diagnosis of AD by 3 experienced raters. Results At group level, SQA using digital controls detected more marked hypometabolic areas in AD (+ 116 cm3 at p < 0.001 uncorrected for the voxel, corrected for the cluster) than SQA using conventional controls. At the individual level, the accuracy of SQA for discriminating AD using digital controls was higher than SQA using conventional controls (86% vs. 80%, p < 0.01, at p < 0.005 uncorrected for the voxel, corrected for the cluster), with higher sensitivity (89% vs. 78%) and similar specificity (82% vs. 82%). These results were confirmed by visual analysis (accuracies of 84% and 82% for digital and conventional controls respectively, p = 0.01). Conclusion There is an urgent need to establish specific digital PET control databases for SQA of brain 18F-FDG PET images as such databases improve the accuracy of AD diagnosis.

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