Rates of Brain Atrophy Across Disease Stages in Familial Frontotemporal Dementia Associated With <i>MAPT</i>, <i>GRN</i>, and <i>C9orf72</i> Pathogenic Variants
Authors: Adam M. Staffaroni, Sheng-Yang M. Goh, Yann Cobigo, Elise Ong, Suzee E. Lee, Kaitlin B. Casaletto, Amy Wolf, Leah K. Forsberg, Nupur Ghoshal, Neill R. Graff-Radford, Murray Grossman, Hilary W. Heuer, Ging-Yuek R. Hsiung, Kejal Kantarci, David S. Knopman, Walter K. Kremers, Ian R. Mackenzie, Bruce L. Miller, Otto Pedraza, Katya Rascovsky, M. Carmela Tartaglia, Zbigniew K. Wszolek, Joel H. Kramer, John Kornak, Bradley F. Boeve, Adam L. Boxer, Howard J. Rosen
Journal: JAMA Network Open (2020)

<h3>Importance</h3> 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. <h3>Objective</h3> To characterize regions and rates of atrophy in the 3 primary f-FTLD genetic groups (<i>MAPT</i>,<i>GRN</i>, and<i>C9orf72</i>) across all disease stages from asymptomatic to dementia. <h3>Design, Setting, and Participants</h3> 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 (<i>MAPT</i>[n = 28],<i>GRN</i>[n = 33], or<i>C9orf72</i>[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). <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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).<i>MAPT</i>and<i>GRN</i>pathogenic variants were associated with increased rates of volume loss compared with controls at all stages of disease. In<i>MAPT</i>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<sup>3</sup>per year during the presymptomatic stage, −381 [208] mm<sup>3</sup>per year during the mild stage, and −1485 [1025] mm<sup>3 </sup>per year during the symptomatic stage (<i>P</i>&lt; .05).<i>GRN</i>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<sup>3</sup>per year in the presymptomatic stage and −182 [90] mm<sup>3 </sup>per year in the mild stage, but −1169 [555] mm<sup>3</sup>per year in the symptomatic stage. Compared with the other groups,<i>C9orf72</i>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<i>C9orf72</i>expansion carriers was −272 (118) mm<sup>3</sup>per year in presymptomatic stages, −310 (189) mm<sup>3</sup>per year in mildly symptomatic stages, and −251 (145) mm<sup>3</sup>per year in symptomatic stages. <h3>Conclusions and Relevance</h3> These findings are relevant to clinical trial planning and suggest that the mechanism by which<i>C9orf72</i>pathogenic variants lead to symptoms may be fundamentally different from the mechanisms associated with other pathogenic variants.