Ante mortem imaging of cortical microstructure relates to post mortem locus coeruleus hypopigmentation in autopsy‐confirmed Alzheimer’s disease

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AbstractBackgroundSeveral lines of evidence indicate that Locus Coeruleus (LC) abnormalities occur early in Alzheimer’s disease and are linked to tau pathology. However, the mechanisms underlying alterations in LC structure and function, and their contributions to pathogenesis and disease progression remain unclear. We investigate ante mortem cortical microstructural changes in patients with autopsy‐confirmed Alzheimer’s disease neuropathological changes (ADNC), stratified by Locus Coeruleus hypopigmentation (LCh).MethodParticipants with intermediate or severe ADNC and ante mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=29) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=6). Participants were grouped by LCh severity (15 with none/mild and 20 moderate/severe).Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures, at whole‐brain and regional levels: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, interval between scan and date of death, site‐ID, number of dMRI images, and diffusion b‐value, with false discovery rate correction (pFDR<0.05).ResultThe more severe LCh group was significantly younger; no significant differences were detected for cortical or hippocampal volumes, cortical thickness, CDR or MMSE. At whole‐brain level, more severe LCh exhibited significantly higher PerpPD and ParlPD. The regional investigation revealed a widespread pattern of higher PerpPD, while ParlPD showed significantly higher values mainly in parieto‐occipital regions (Figure1).ConclusionTogether, these findings suggest that LCh severity might contribute to different patterns of cortical microstructural changes in individuals with the same ADNC severity. The more severe LCh group was significantly younger, consistent with the idea that noradrenergic hyperactivity in a more impaired LC might accelerate the spreading of AD neuropathology due to an influence of noradrenergic projections (Weinshenker, 2018). Cortical microstructural measures from dMRI could help stratify patients in clinical trials based on patterns linked to noradrenergic dysfunction, supporting pharmacological treatment focused on hyperactivities of the noradrenergic system.