Rates Of Brain Atrophy Across Disease Stages In Familial Frontotemporal Dementia Associated With Mapt, Grn, And C9orf72 Pathogenic Variants

This observation study characterizes regions and rates of atrophy in the 3 primary familial frontotemporal lobar degeneration genes (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia.Importance Several clinical trials are planned for familial forms of frontotemporal lobar degeneration (f-FTLD). Precise modeling of brain atrophy in f-FTLD could improve the power to detect a treatment effect. Objective To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (MAPT, GRN, and C9orf72) across all disease stages from asymptomatic to dementia. Design, Setting, and Participants This investigation was a case-control study of participants enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration or Longitudinal Evaluation of Familial Frontotemporal Dementia studies. The study took place at 18 North American academic medical centers between January 2009 and September 2018. Participants with f-FTLD (n = 100) with a known pathogenic variant (MAPT [n = 28], GRN [n = 33], or C9orf72 [n = 39]) were grouped according to disease stage (ie, Clinical Dementia Rating [CDR] plus National Alzheimer's Coordinating Center [NACC] FTLD module). Included were participants with at least 2 structural magnetic resonance images at presymptomatic (CDR + NACC FTLD = 0 [n = 57]), mild or questionable (CDR + NACC FTLD = 0.5 [n = 15]), or symptomatic (CDR + NACC FTLD = >= 1 [n = 28]) disease stages. The control group included family members of known pathogenic variant carriers who did not carry the pathogenic variant (n = 60). Main Outcomes and Measures This study fitted bayesian linear mixed-effects models in each voxel of the brain to quantify the rate of atrophy in each of the 3 genes, at each of the 3 disease stages, compared with controls. The study also analyzed rates of clinical decline in each of these groups, as measured by the CDR + NACC FTLD box score. Results The sample included 100 participants with f-FTLD with a known pathogenic variant (mean [SD] age, 50.48 [13.78] years; 53 [53%] female) and 60 family members of known pathogenic variant carriers who did not carry the pathogenic variant (mean [SD] age, 47.51 [12.43] years; 36 [60%] female). MAPT and GRN pathogenic variants were associated with increased rates of volume loss compared with controls at all stages of disease. In MAPT pathogenic variant carriers, statistically significant regions of accelerated volume loss compared with controls were identified in temporal regions bilaterally in the presymptomatic stage, with global spread in the symptomatic stage. For example, mean [SD] rates of atrophy in the left temporal were -231 [47] mm(3) per year during the presymptomatic stage, -381 [208] mm(3) per year during the mild stage, and -1485 [1025] mm(3) per year during the symptomatic stage (P < .05). GRN pathogenic variant carriers generally had minimal increases in atrophy rates between the presymptomatic and mild stages, with rapid increases in atrophy rates in the symptomatic stages. For example, in the right frontal lobes, annualized volume loss was -267 [81] mm(3) per year in the presymptomatic stage and -182 [90] mm(3) per year in the mild stage, but -1169 [555] mm(3) per year in the symptomatic stage. Compared with the other groups, C9orf72 expansion carriers showed minimal increases in rate of volume loss with disease progression.For example, the mean (SD) annualized rates of atrophy in the right frontal lobe in C9orf72 expansion carriers was -272 (118) mm(3) per year in presymptomatic stages, -310 (189) mm(3) per year in mildly symptomatic stages, and -251 (145) mm(3) per year in symptomatic stages. Conclusions and Relevance These findings are relevant to clinical trial planning and suggest that the mechanism by which C9orf72 pathogenic variants lead to symptoms may be fundamentally different from the mechanisms associated with other pathogenic variants.Question How does the trajectory of atrophy differ between the 3 primary genetic groups (MAPT, GRN, and C9orf72) associated with familial frontotemporal lobar degeneration? Findings Among 160 members of families affected by familial frontotemporal lobar degeneration in this case-control study, MAPT and GRN pathogenic variants were associated with increases in the rate of volume loss as a function of disease stage, whereas C9orf72 expansion carriers showed minimal increases in the rate of volume loss with disease progression. Meaning This study advances the knowledge of between-gene differences in atrophy rates as a function of disease severity; treatment studies enrolling familial frontotemporal dementia cases should consider the heterogeneity conferred by both the altered gene and the disease stage.