作者@article {Saracinoe396 ={达里奥Saracinond Leila Sellami and Hugo Boniface and Marion Houot and M{\'e}lanie P{\'e}l{\'e}grini-Issac and Aur{\'e}lie Funkiewiez and Daisy Rinaldi and Maxime Locatelli and Carole Azuar and Val{\'e}rie Causse-Lemercier and Alice Jaillard and Florence Pasquier and Mathieu Chastan and David Wallon and Anne Hitzel and J{\'e}r{\'e}mie Pariente and Amandine Pallardy and Claire Boutoleau-Bretonni{\`e}re and Eric Guedj and Mira Didic and Raffaella Migliaccio and Aur{\'e}lie Kas and Marie-Odile Habert and Isabelle Le Ber and on behalf of Predict-PGRN}, title = {Brain Metabolic Profile in Presymptomatic GRN Carriers Throughout a 5-Year Follow-up}, volume = {100}, number = {4}, pages = {e396--e407}, year = {2023}, doi = {10.1212/WNL.0000000000201439}, publisher = {Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology}, abstract = {Background and Objectives GRN variants are a frequent cause of familial frontotemporal dementia (FTD). Monitoring disease progression in asymptomatic carriers of genetic variants is a major challenge in delivering preventative therapies before clinical onset. This study aimed to assess the usefulness of fluorodeoxyglucose (FDG){\textendash}PET in identifying metabolic changes in presymptomatic GRN carriers (PS-GRN+) and to trace their longitudinal progression.Methods Participants were longitudinally evaluated over 5 years in a prospective cohort study focused on GRN disease (Predict-PGRN). They underwent cognitive/behavioral assessment, plasma neurofilament measurement, brain MRI, and FDG-PET. Voxel-wise comparisons of structural and metabolic imaging data between 2 groups were performed for each time point. Longitudinal PET changes were evaluated with voxel-wise comparisons and the metabolic percent annual changes method. The association of regional brain metabolism with plasma neurofilament and cognitive changes was analyzed.Results Among the 80 individuals enrolled in the study, 58 (27 PS-GRN+ and 31 noncarriers) were included in the analyses. Cross-sectional comparisons between PS-GRN+ and controls found a significant hypometabolism in the left superior temporal sulcus (STS) region (encompassing the middle and superior temporal gyri), approximately 15 years before the expected disease onset, without significant cortical atrophy. The longitudinal metabolic decline over the following 5 years peaked around the right STS in carriers (p \< 0.001), without significantly greater volume loss compared with that in controls. Their estimated annualized metabolic decrease (-1.37\%) was higher than that in controls (-0.21\%, p = 0.004). Lower glucose uptake was associated with higher neurofilament increase (p = 0.003) and lower frontal cognitive scores (p = 0.014) in PS-GRN+.Discussion This study detected brain metabolic changes in the STS region, preceding structural and cognitive alterations, thus contributing to the characterization of the pathochronology of preclinical GRN disease. Owing to the STS involvement in the perception of facially communicated cues, it is likely that its dysfunction contributes to social cognition deficits characterizing FTD. Overall, our study highlights brain metabolic changes as an early disease-tracking biomarker and proposes annualized percent decrease as a metric to monitor therapeutic response in forthcoming trials.AD=Alzheimer disease; ASL=arterial spin labeling; bvFTD=behavioral variant of FTD; CATI=Centre d{\textquoteright}Acquisition et de Traitement d{\textquoteright}Images; CDR+NACC FTLD=Clinical Dementia Rating scale plus National Alzheimer{\textquoteright}s Coordinating Center Frontotemporal Lobar Degeneration; EYO=expected years to onset; FDG=fluorodeoxyglucose; FDR=false discovery rate; FTD=frontotemporal dementia; FWHM=full width at half maximum; GMA=gray matter atrophy; HC=healthy control; LMM=linear mixed model; MDRS=Mattis dementia rating scale; MNI=Montreal Neurological Institute; NfL=neurofilament light chain; PAC=percent annual change; PPA=primary progressive aphasia; PS-GRN+=presymptomatic GRN carrier; ROI=region of interest; SPM=statistical parametric mapping; STS=superior temporal sulcus; VBM=voxel-based morphometry}, issn = {0028-3878}, URL = {//www.ebmtp.com/content/100/4/e396}, eprint = {//www.ebmtp.com/content/100/4/e396.full.pdf}, journal = {Neurology} }