Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in <i>C9orf72</i> and granulin (<i>GRN</i>) genes. Clinically asymptomatic subjects from families with <i>C9orf72</i> mutation (15 mutation carriers, <i>C9orf72</i>+; and 23 non-carriers, <i>C9orf72</i>-) and <i>GRN</i> mutations (9 mutation carriers, <i>GRN</i>+; and 15 non-carriers, <i>GRN</i>-) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of <i>C9orf72</i>+ and <i>C9orf72</i>- were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while <i>GRN</i>+ and <i>GRN</i>- groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The <i>C9orf72</i>+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: <i>C9orf72</i>- and <i>GRN</i>- combined). In contrast, the <i>GRN</i>+ group did not show any significant differences compared to NC. <i>C9orf72</i> mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to <i>GRN</i> mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.