ABSTRACT NUMBER: ESOC2026A1778 NEUROPSYCHIATRIC AND MRI FINDINGS IN TREX1 MUTATION CARRIERS: LESSONS FROM A SMALL VESSEL DISEASE

Abstract Background and aims Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is an monogenic small vessel disease caused by mutations in TREX1. It neurological phenotype is characterized by focal neurological complaints and vascular dementia. We aimed to investigate the neuropsychological status of presymptomatic and symptomatic patients and whether MRI characteristics (white matter hyperintensities (WMH) and cerebrovascular reactivity (CVR)) were related to cognitive impairment, psychiatric morbidity and functional disability. Methods TREX1 mutation carriers (MC) (n=29) and matched healthy controls (n=29) underwent a comprehensive set of neuropsychological tests. Additionally, the relationship between MRI abnormalities and cognitive, psychiatric and functional measures was examined. Results Overall, TREX1 MC demonstrated greater cognitive and functional impairment, as well as higher psychiatric morbidity, compared to the control group. MC aged <50 demonstrated no cognitive differences compared to controls, but had more depressive symptoms (p=0.047). In MC over 50 years CVR in both white matter en gray matter correlated with overall cognitive functioning p=0.003 and p=0.008. Decreased CVR in gray matter was associated with impaired memory (p<0.001) and praxis (p=0.046). A higher WMH load was associated with worse executive functioning (p=0.024) in patients older than 50 years. Furthermore, in young MC (aged <50) overall psychiatric morbidity correlated with reduced CVR in gray matter (p=0.030). Conclusions RVCL-S patients demonstrate cognitive impairment as well as psychiatric morbidity and functional impairment. Depression occurs early in the disease course and might therefore be a useful early marker. Increased WMH volume and decreased cerebrovascular reactivity correlate with cognitive impairment in RVCL-S. Conflict of interest I. de Boer reports independent support of IRRF, Dutch Heart Foundation and Dioraphte. N. Pelzer: nothing to disclose. E.S. Hoogeveen: nothing to disclose. A.E. Wilms: nothing to disclose. E. van Eijk: nothing to disclose. R. Bunnik: nothing to disclose. M.J.P. van Osch: nothing to disclose. M.C. Kruit: nothing to disclose. H.A.M. Middelkoop: nothing to disclose. G.M. Terwindt reports grants or consultancy support from Abbvie, Lilly, Lundbeck Novartis, Organon, Pfizer, Teva, and independent support from the IRRF, Stichting Dioraphte, Dutch Research Council, Dutch Heart Foundation, Dutch Brain Foundation, European Community.