Assessing neuroinflammatory differences in FTLD‐Tau vs FTLD‐TDP using free water diffusion

Abstract Background Frontotemporal lobar degeneration (FTLD) is associated with two pathological substrates: Tau and TAR‐DNA‐binding protein 43 (TDP‐43). In‐vivo detection of the pathological substrate is still not possible in FTLD‐related syndromes but progressive supranuclear palsy (PSP) is consistently associated with FTLD‐Tau while semantic‐variant primary progressive aphasia (svPPA) and FTD‐MND (FTD‐ALS) are associated with FTLD‐TDP. In the absence of disease‐specific markers in FTLD, it is necessary to identify biomarkers that can help distinguish FTLD‐Tau and FTLD‐TDP. Recent research has implicated neuroinflammation as a common feature across FTLD subtypes (Bright et al., 2019), however further research is required to investigate neuroinflammatory differences between FTLD‐Tau and FTLD‐TDP, given that microglial burden and activation may differ in FTLD subtypes (Woollacott et al., 2020). The free water fraction (FW), a metric generated from diffusion MRI (dMRI) (Pasternak et al., 2009), is a non‐specific marker of neuroinflammation (Bergamino, Walsh and Stokes, 2021). We will investigate differences in FW diffusion between patients with presumed FTLD‐Tau versus FTLD‐TDP. We hypothesize that differences in neuroinflammation between FTLD‐Tau and FTLD‐TDP can be identified using the free water measure, which may infer neuroinflammatory differences. Method Free‐water maps were generated from dMRI datasets obtained from 43 subjects: 19 with presumed FTLD‐Tau (PSP, mean age = 70), 6 with presumed FTLD‐TDP (mean age = 67, 4 svPPA, 2 FTD‐ALS), and 19 healthy controls (mean age 63). Grey matter (GM) was segmented from T1‐weighted MRIs using FSL’s ‘fast’, projected onto the diffusion MRI space, where free‐water maps were averaged across the GM. The average free water estimates from FTLD‐Tau, FTLD‐TDP and control datasets were tested for group differences using student’s t‐tests and analysis of covariance (ANCOVA), with age as a covariate. Results ANCOVA revealed significant differences between the groups (F = 6.47, p < 0.01). Post‐hoc tests showed significantly higher free‐water in FTLD‐Tau (p<0.01) and FTLD‐TDP (p<0.01) compared to controls. There was also higher free water in FTLD‐TDP in comparison to FTLD‐Tau, approaching significance (p = 0.0503) Conclusion Our preliminary data shows significant differences between healthy controls and patients with FTLD‐Tau and FTLD‐TDP and a trend for increased free water in FTLD‐TDP patients vs FTLD‐Tau, which may be indicative of neuroinflammatory differences.