Regional pattern of cortical microstructural alterations along the AD continuum and association with plasma neurofilament light

Abstract Background Microstructural changes associated with the progression of Alzheimer's disease (AD) precede macrostructural atrophy. We investigate cortical microstructural changes along the AD continuum in patients with cerebrospinal fluid (CSF) AD biomarkers and plasma neurofilament light chain (NfL). Method Three hundred fifty‐one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with CSF amyloid‐beta 42 (Aβ42) and Phosphorylated Tau 181 (pTau 181 ) were included. The CSF pTau 181 ‐Aβ42 ratio was used to assess the presence (+/‐) of the pathophysiological hallmarks of AD and classify the participants into four groups: 149 cognitively normal biomarker negative (CN‐), 61 cognitively normal positive (CN+), 73 patients diagnosed with Mild Cognitive Impairment positive (MCI+) and 68 AD positive (AD+). Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures: 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, sex and site‐ID, with false discovery rate correction (pFDR<0.05). The association between cortical diffusivity and NfL was investigated in a subset of 111 participants. Result At whole‐brain level, the AD+ group exhibited significantly higher AngleR, PerpPD + , ParlPD and MD values compared to the other groups. PerpPD + was the only measure able to differentiate between all subsequent disease stages (CN‐ and CN+ vs MCI+, and MCI+ vs AD+); regional results are presented in the Figure. Along the AD continuum, the results revealed a widespread progressive pattern of higher PerpPD + , involving mainly fronto‐temporal and occipital regions. Correlation analysis showed significant association between cortical diffusivity measures (PerpPD + and ParlPD) and NfL values. Conclusion Cortical diffusivity measures can detect progressive microstructural changes along the AD continuum and are significantly associated with NfL. Cortical diffusion MRI offers a microstructural marker of neurodegeneration within the ATN framework (Jack et al. 2018); as an imaging measure, regional patterns can provide disease specificity that is lacking for fluid measures like NfL.