Association of Initial Side of Brain Atrophy With Clinical Features and Disease Progression in Patients With <i>GRN</i> Frontotemporal Dementia.

Abstract

Pathogenic variants in the <i>GRN</i> gene cause frontotemporal dementia (FTD-<i>GRN</i>) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD-<i>GRN</i> depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease. Retrospective examination of data from the prospective Genetic Frontotemporal Initiative (GENFI) cohort study that recruits individuals who carry or were at risk of carrying a pathogenic variant causing FTD. GENFI participants underwent a standardized clinical and neuropsychological assessment, MRI, and a blood sample test yearly. We generated an asymmetry index for brain MRI to characterize brain asymmetry in participants with or at risk of FTD-<i>GRN</i>. Depending on the side of the asymmetry, we classified symptomatic <i>GRN</i> patients as right-<i>GRN</i> or left-<i>GRN</i> and compared their clinical features and disease progression. We generated generalized additive models to study how the asymmetry index evolves in carriers and noncarriers and compare its models with others created with volumetric values and plasma neurofilament light chain. A total of 399 participants (mean age 49.7 years, 59% female) were included (63 symptomatic carriers, 177 presymptomatic carriers, and 159 noncarriers). Symptomatic carriers showed higher brain asymmetry (11.6) than noncarriers (1.0, <i>p</i> < 0.001) and presymptomatic carriers (1.0, <i>p</i> < 0.001), making it possible to classify most of them as right-<i>GRN</i> (n = 21) or left-<i>GRN</i> (n = 36). Patients with right-<i>GRN</i> showed more disease severity at baseline (<i>β</i> = 6.9, 95% CI 2.4-11.0, <i>p</i> = 0.003) but a lower deterioration by year (<i>β</i> = -1.5, 95% CI -2.7 to -0.31, <i>p</i> = 0.015) than patients with left-<i>GRN</i>. Brain asymmetry could be found in <i>GRN</i> carriers 10.4 years before the onset of the symptoms (standard difference 0.85, CI 0.01-1.68). FTD-<i>GRN</i> affects the brain hemispheres asymmetrically and causes 2 anatomical asymmetry patterns depending on the side of the disease onset. We demonstrated that these 2 anatomical asymmetry patterns present different symptoms, severity at the time of the first visit, and different disease courses. Our results also suggest brain asymmetry as a possible biomarker of conversion in <i>GRN</i> carriers.