Clinical implications of head trauma in frontotemporal dementia and primary progressive aphasia

Abstract

Background: Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications.

Methods: We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education).

Results: Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1).

Conclusions: Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

Keywords: Frontotemporal dementia; Primary progressive aphasia; Repetitive head impacts; Risk factor; Traumatic brain injury.

Fig. 1

Differences in duration contact/collision sport (LEFT) and American football (RIGHT) participation between Healthy Controls (N = 41) and FTD/PPA (N = 40) reporting at least 1 year of play (i.e., not including those who never participated). The dashed line represents the minimum duration of participation (1 year). Duration of contact/collision sport exposure was longer in FTD/PPA than HC (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008). For American football, participants with FTD/PPA played about twice as long as HC (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003)

Fig. 2

Association between age of symptom onset and prior head trauma exposure among participants with FTD/PPA. Differences in age of symptom onset are shown as a function of prior TBI (left), prior participation in contact/collision sport (middle), and prior participation in American football (right). Group-specific age of symptom onset is displayed within each figure (mean ± standard deviation). Alpha levels (p values) provided for 3 group comparisons represent the chi square linear-by-linear association test evaluating statistical significance for a stepwise effect across the 3 groups

Fig. 3

Association of prior American football participation with objective memory test scores among individuals with behavioral variant frontotemporal dementia (bvFTD). Objective memory scores were significantly lower among those who had played American football