White matter pathology in sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Aims: To characterize white matter pathology in frontotemporal lobar degeneration (FTLD) with TDP-43 proteinopathy (FTLD-TDP) and its relationship to gray matter pathology. Material: Fiber tracts from frontal and temporal lobes of 10 sporadic cases of FTLD and 8 controls. Method: Density and spatial patterns of vacuolation, glial cell nuclei, and glial inclusions (GI) were studied in 4 fiber tracts from each case. Results: Densities of vacuoles but not glial cells were greater in FTLD-TDP than controls. No GI were observed in controls, while in FTLD-TDP, greatest densities of GI were observed in the cortex of early-onset cases. Vacuoles, glial cell nuclei, and GI were distributed in clusters which were regularly distributed across the tract. Densities of vacuoles in white matter were positively correlated with those in adjacent gray matter, and correlations were also present between GI in white matter and TDP-43-immunoreactive pathology in gray matter. Conclusions: (1) Degeneration of white matter in sporadic FTLD-TDP was characterized by increased vacuolation and GI, (2) pathological changes were topographically distributed, which suggests propagation of pathological TDP-43 in specific groups of fibers, and (3) both white matter pathology and gray matter pathology need to be considered to quantify the pathological "load" in FTLD-TDP.