To evaluate pathologic correlates of white matter hyperintensities (WMH) on post-mortem MRI in frontotemporal degeneration (FTD). 

WMH are not typically considered a prominent imaging feature of FTD. Current diagnostic criteria cite focal lobar atrophy, without explicitly describing white matter lesions; indeed, significant WMH burden may prompt alternative diagnostic considerations. However, prominent WMH on in vivo MRI have been described in individuals with pathogenic progranulin mutations (FTD-TDP43). On post-mortem MRI, we have noted confluent frontal WMH in some patients with FTD. In this study, we aimed to characterize the underlying neuropathologic change via image-guided tissue sampling.

We compared 12 brains with FTD neuropathology (7 FTD-tau, 5 FTD-TDP43) to 26 controls (low/no neuropathology). Image guided samples of three white matter blocks were selected for quantitative immunohistochemistry analysis (HALO): two frontal regions (prefrontal and middle frontal gyrus), and primary visual cortex. HALO analysis (% area positive for staining) was performed for white matter integrity (neurofilament/2F11; myelin basic protein [MBP]) and gliosis (microglia/IBA1; astrocyte/GFAP). Post-mortem MRIs were blindly rated for presence or absence of confluent WMH globally and in each sampled region. Statistical testing was based on two-sample test for difference in proportions.

WMH were seen globally more frequently in FTD-tau brains (6/7) than in FTD-TDP brains (1/5), p=0.018. Low 2F11 was seen more frequently in white matter blocks sampled from FTD brains than control brains (e.g., prefrontal: % average area positive 4.57 FTD, 24.31 controls; p=0.067). There was no observed difference in 2F11 signal in FTD brains comparing those with or without WMH, nor in MBP, IBA1, GFAP comparing FTD with controls.

Low 2F11 in frontal and occipital white matter could indicate widespread axonal disruption in FTD. However, more research is needed to validate these preliminary observations. We are performing additional analyses to investigate pathophysiologic contributions to postmortem WMH in FTD.