Neurite‐based white matter alterations in MAPT mutation carriers: A multi‐shell diffusion MRI study in the ALLFTD consortium

Abstract

AbstractBackgroundWe aimed to assess axonal integrity in MAPT mutation carriers and early white matter (WM) neurodegeneration in asymptomatic carriers using traditional diffusion tensor imaging (DTI) measurements, i.e., fractional anisotropy (FA) and mean diffusivity (MD), and neurite orientation dispersion and density imaging (NODDI).MethodWe included available multi‐shell diffusion MRI data from 21 MAPT mutation carriers (16 asymptomatic; 5 symptomatic) and 31 non‐carrier family members as controls from the ALLFTD consortium. We used linear mixed‐effect models to assess WM abnormalities measured with FA and MD, neurite density index (NDI) and orientation dispersion index (ODI), combined across hemispheres. Separate models were conducted in all MAPT mutation carriers relative to controls while accounting for relatedness and age, then in symptomatic and asymptomatic carriers relative to controls. ComBat was used to harmonize data across sites.ResultIn models contrasting all MAPT carriers versus controls, WM alterations involved the cingulum bundle (FA, ODI), fronto‐temporal, entorhinal (FA, MD, NDI), and the inferior temporal WM (FA) after correcting for multiple comparisons (Fig. 1). In models contrasting symptomatic and asymptomatic MAPT carriers versus controls, symptomatic carriers had widespread involvement of the fronto‐temporal WM including the cingulum (FA, ODI), entorhinal (MD, FA, NDI), amygdala (MD, NDI) and inferior temporal (FA) areas after correcting for multiple comparisons. Asymptomatic carriers showed higher entorhinal MD and lower inferior temporal and cingulum FA relative to controls, and a more widespread pattern of higher ODI involved the medial temporal, superior temporal and occipital WM as well as long association and projection fibers including the internal capsule, cingulate bundle and fronto‐occipital fasciculi, although they were not statistically significant after correction for multiple comparisons.ConclusionTraditional DTI and novel NODDI measurements revealed some extent of overlap as well as divergences in patterns of WM abnormalities, indicating axonal loss is a feature of neurodegeneration in MAPT mutation carriers. Our results suggest that traditional DTI and novel NODDI measurements may have different sensitivities to WM alterations in MAPT mutation carriers, and that axon‐based metrics, particularly ODI measurements, may be more sensitive to the early WM involvement during the asymptomatic stage of the disease.