Longitudinal assessment of neuroinflammation and axonal loss in white matter tracts in Alzheimer’s disease

Background Free‐water fraction (FW), proxy to neuroinflammation, and apparent fiber density (AFD) are two recently developed diffusion MRI (DMRI) white matter (WM) measures. Methods We aimed to longitudinally assess FW (24 months) and AFD (12 months) in specific WM tracts in normal controls (NC) (n = 27), MCI (n = 50) and Alzheimer’s disease (AD) (n = 16) selected from the ADNI2 database. The FW and AFD maps were computed and tractography was used to automatically extract 6 WM tracts: cingulum (CG), uncinate, inferior fronto‐occipital and inferior longitudinal fasciculi (UF, IFOF, ILF), and genu/splenium of the corpus callosum (CC2/CC7). Correlations were also performed to assess association between the changes of the FW and cortical b‐amyloid (18F‐AV45‐PET), as well as between the AFD and plasma neurofilament light chain (NfL). Results The FW significantly increased after 2 years in the CC2, CC7, UF and CG in AD (4‐11%), with no change in MCI and NC. For the AD group, the change of cortical b‐amyloid over 2 years was positively correlated with the change of FW in the ILF, CC2, CC7, UF and CG (r = 0.31 ‐ 0.57; P = 0.02 ‐ 0.05; Fig. 1). The AFD significantly decreased after 1 year in the CG, ILF, and IFOF in AD (7‐8%), and MCI (3‐5%), with no change in NC. Only for the AD group, the change of AFD over 1 year was negatively correlated with the change of plasma NfL in the 6 tracts of interest (r = ‐0.56 ‐ ‐0.67; P = 0.01 ‐ 0.03; Fig. 2) and in the whole white matter (r = ‐0.61; P = 0.009). Conclusions The longitudinal assessment of FW shows increase only in AD, while the decrease of AFD is similar in MCI and AD, hence the loss of axonal density seems to appear in earlier stages. These results may also reinforce the link between: i) cortical b‐amyloid accumulation and neuroinflammation, and ii) plasma Nfl and loss of axonal density, both shown for the first time with in‐vivo imaging biomarkers: FreeWater and Apparent Fiber Density.