A novel histological staging of hippocampal sclerosis that is evident in grey matter loss in vivo.

INTRODUCTIONHippocampal sclerosis of aging (HS) is defined by end-stage histological findings, strongly associated with limbic-predominant age-related TDP-43 encephalopathy (LATE). We aimed to characterize features of early HS to refine the understanding of its role within combined pathology. METHODSWe studied 159 brain donations from the multimodal Vallecas Alzheimers Center Study. A staging system (0 to IV) was developed to account for HS progression and analyzed in relation to pre-mortem cognitive and MRI data. RESULTSOur HS staging system displayed a significant correlation with disease duration, cognitive performance and combined neuropathologies, especially with LATE. Two-level assessment along the hippocampal longitudinal axis revealed an anterior-posterior gradient of HS severity. In vivo MRI showed focally reduced hippocampal grey matter density as a function of HS staging. DISCUSSIONThe association of this staging system with clinical progression and structural differences supports its utility in the characterization and potential in vivo monitoring of HS.