INCREASED PREVALENCE OF NON-THYROID AUTOIMMUNE DISEASE IN PATIENTS WITH FAMILIAL FRONTOTEMPORAL DEMENTIA ASSOCIATED WITH PROGRANULIN MUTATIONS

Abstract

Familial frontotemporal dementia (FTD) is most commonly due to mutations in progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Recent research has observed an increased prevalence of non-thyroid autoimmune disease in ‘TDP-43-opathies’ such as GRN- and C9orf72- related FTD and motor neuron disease. To investigate this further, we analysed the prevalence of systemic autoimmune disease across a well-characterised cohort of symptomatic familial FTD patients and healthy controls. We assessed 31 patients with GRN mutations (2 with dual GRN/C9orf72 mutations), 40 with MAPT mutations, 36 with C9orf72 expansions (2 with dual C9orf72/GRN mutations and 1 with a dual C9orf72/SQSTM1 mutation) and 24 healthy controls. Presence/absence of autoimmune disease was recorded through retrospective case notes review. Autoimmune conditions were sub-classified into ‘thyroid’ or ‘non-thyroid’ disease. Presence of autoimmune disease and gender were compared between groups using Chi squared and Fisher's exact tests, with a significance threshold of p<0.05. Gender did not differ significantly between groups. Total autoimmune disease was significantly more prevalent in the total GRN mutation group than the MAPT group (35.5% vs. 7.5%; p=0.003), with a trend towards a greater prevalence when compared with controls (35.5% vs. 12.5%; p=0.052), but not compared with the total C9orf72 mutation carriers (22.2%). This was due to an increased prevalence of non-thyroid, rather than thyroid, disease in the GRN group (19.4%) compared with the MAPT group (2.5%; p=0.038) and controls (0.0%; p=0.030). The greater prevalence in the GRN group compared with the MAPT group was seen even if the dual GRN/C9orf72 mutations were excluded (31.0% vs. 7.5%; p=0.011). Prevalence of total, thyroid and non-thyroid autoimmune disease was not significantly different between other groups. FTD patients with GRN mutations have a particularly high prevalence of non-thyroid systemic autoimmune disease, confirming observations from previous studies. In this study, the prevalence in patients with C9orf72 or MAPT mutations is not different from controls, suggesting that the underlying disease mechanism may not be as closely linked to autoimmune disease. Impairment of the immune functions of GRN could cause systemic and cerebral immune dysregulation from an early age in GRN mutation carriers.