BrainMicrostructureRevealsEarlyAbnormalitiesmorethan TwoYearspriortoClinicalProgressionfromMildCognitive ImpairmenttoAlzheimer'sDisease

Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationshipwithunderlyingneuropathologycanbecomplex.Here,weexaminedbothvolumetricandbrainmicrostructureabnormalitiesin13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimer’s disease (AD) no earlier than 2 years afterbaselinescanning,inordertofocusonearly,andhencemoresensitive,imagingmarkers.Wecomparedthemto22stableamnestic MCIpatientswithsimilarcognitiveperformanceandepisodicmemoryimpairmentbutwhodidnotshowprogressionofsymptomsfor atleast3years.Significantgroupdifferencesweremainlyfoundinthevolumeandmicrostructureofthelefthippocampus,whilewhite matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the correspondinggraymatterregions.Themicrostructuralmeasureobtainedinthelefthippocampususingdiffusionimagingshowedthe mostsubstantialdifferencesbetweenthetwogroupsandwasthebestsinglepredictoroffutureprogressiontoAD.Anoptimalprediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These resultshighlightthebenefitofusingtheinformationofbrainmicrostructuraldamage,inadditiontotraditionalgraymattervolume,to detectearly,subtleabnormalitiesinMCIpriortoclinicalprogressiontoprobableADand,incombinationwithCSFmarkers,toaccurately predictsuchprogression.