In Vivo Detection of Changes Related to Cortical Columnar Organization and Neuroinflammation Across the AD Continuum

Background Alzheimer's disease (AD) neuropathology reveals progressive microstructural alterations of cortical architecture. Recent studies reported intriguing biphasic trajectories of cortical structural changes in the early stages of Alzheimer's disease (AD), comprising decreased mean diffusivity (MD) and increased cortical thickness in cognitively normal amyloid-positive individuals, ahead of increases and decreases, respectively, in subsequent disease stages. Objective To better understand the cytoarchitectural correlates of these observations, we assessed novel cortical diffusion tensor imaging (DTI) metrics that are correlated with disruption of cortical minicolumns and protein deposition. Design Cross-sectional and longitudinal analysis of whole brain and temporal lobe cortical diffusivity measures. Investigation of associations between baseline cortical diffusivity values and 24-month longitudinal structural-MRI changes. Investigations of the relationships between cortical diffusivity measures and biomarkers of neuroinflammation. Setting Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants Twenty-four amyloid-negative controls (CN-), 28 amyloid-positive controls (CN+), 46 amyloid-positive subjects with mild cognitive impairment (MCI+) and 22 amyloid-positive subjects with AD were included. Measurements 3DT1 and DTI scans at baseline and approximately 24-month follow-up were used to calculate cortical MD and three novel cortical diffusivity measures: the angle between the radial minicolumnar axis and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD(+)), and the principal diffusion component parallel with the minicolumns (ParlPD). Cortical macrostructural measurements (cortical volume fraction and cortical thickness), were used to test the hypothesis that baseline cortical diffusivity values can predict change in structural MRI outcomes over approximately 24 months. CSF soluble TREM2 and progranulin (PGRN) concentrations were used to investigate associations with microglial activity and potentially other aspects of neuroinflammation. Results Cortical diffusivity metrics revealed a dependence on disease stage, with AngleR and PerpPD(+) displaying biphasic relationships and ParlPD a monotonic relationship with clinical severity. The novel metrics were able to differentiate between Amyloid+ and Amyloid- controls (AngleR) and to differentiate among disease stages along the AD continuum (PerpPD(+)). Linear regression revealed significant associations between baseline cortical diffusivity values and subsequent 24-month longitudinal structural-MRI changes. AngleR values were significantly associated with CSF sTREM2 and PGRN concentrations. Conclusions Cortical diffusivity parameters reflecting minicolumnar organization and neuroinflammation may provide a sensitive and biologically interpretable measurement of cortex quality and microstructure across the AD continuum.

Automated summary

Recent studies have shown intriguing biphasic trajectories of cortical structural changes in early Alzheimer's disease stages, with decreased mean diffusivity and increased cortical thickness in cognitively normal amyloid-positive individuals. Novel cortical diffusion tensor imaging (DTI) metrics may provide insights into cortical minicolumn disruption and protein deposition, contributing to a better understanding of Alzheimer's disease pathology.