Early Cognitive, Structural, and Microstructural Changes in Presymptomatic C9orf72 Carriers Younger Than 40 Years

Abstract

; for the Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (PREV-DEMALS) Study Group IMPORTANCE Presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population. OBJECTIVES To assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers. DESIGN, SETTING, AND PARTICIPANTS The PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9−) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017. MAIN OUTCOMES AND MEASURES Differences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9− individuals. RESULTS Of the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9− individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9− individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; P = .004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9− individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts. CONCLUSIONS AND RELEVANCE Cognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers. TRIAL REGIS...

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study

“…More importantly, the presymptomatic phase of the disease provides an invaluable opportunity to widen the therapeutic window and introduce neuroprotective therapy at the time when GM and WM integrity is still relatively preserved. 19 The frontotemporal, insular, hippocampal, and thalamic changes identified in asymptomatic cohorts are consistent with the genotype-associated signature of symptomatic cohorts. 13 To date, the majority of presymptomatic c9orf72 studies focused on cerebral imaging and captured GM and WM alterations years before expected symptom onset.…”

“…19 Age at imaging, gender, and mutation status were used as fixed effects, whereas family membership was considered as random effect. 19 Age at imaging, gender, and mutation status were used as fixed effects, whereas family membership was considered as random effect.…”

“…19 The clinical evaluation was performed by an investigator (I.L.B.) They were all first-degree relatives of C9orf72 mutation carriers affected by either ALS or FTD.…”

Neurite density is reduced in the presymptomatic phase ofC9orf72disease

“…So these low b-values data are not representative of standard DTI data. Systematic quality checks of MRI results were performed by the Centre d’Acquisition et de Traitement d’Images as in previous work 6. All images were of satisfactory quality except for one T1 acquisition and one single-shell DWI acquisition from different individuals.…”

“…The single-shell DWI data were processed with the same approach as in previous work 6. To summarise, head motion was corrected by rigidly registering the raw DWI volumes to the average b0 image, and an affine registration was used to correct for eddy current-induced distortions.…”