title: Longitudinal imaging inC9orf72mutation carriers: Relationship to phenotype.
abstract: Expansion mutations in theC9orf72gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described forC9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelatedC9orf72expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated withC9orf72mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6-month time frame, and appears to be faster in patients with cognitive impairment.
authors.affiliation: Motor Neuron Disorders Unit, OCD, NINDS, NIH 10 Center Drive Room 7-5680 Bethesda, MD 20892-1404, United States.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Floeter
authors.affiliation: Motor Neuron Disorders Unit, OCD, NINDS, NIH 10 Center Drive Room 7-5680 Bethesda, MD 20892-1404, United States.
authors.forename: Devin
authors.initials: D
authors.lastname: Bageac
authors.affiliation: Motor Neuron Disorders Unit, OCD, NINDS, NIH 10 Center Drive Room 7-5680 Bethesda, MD 20892-1404, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Danielian
authors.affiliation: Motor Neuron Disorders Unit, OCD, NINDS, NIH 10 Center Drive Room 7-5680 Bethesda, MD 20892-1404, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Braun
authors.affiliation: Neuromuscular Disease Research Section LNG, NIA, NIH 35 Convent Drive Room 1A213 Bethesda, MD 20892-3707, United States.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: Department of Neurology, University of Maryland, 110 S. Paca Street, Baltimore, MD 21201, United States.
authors.forename: Justin Y
authors.initials: JY
authors.lastname: Kwan
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D001284:Atrophy / Q000473:pathology; D000073885:C9orf72 Protein / Q000235:genetics*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D002552:Cerebral Ventricles / Q000000981:diagnostic imaging / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D057180:Frontotemporal Dementia / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human
keywords: ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS functional rating scale — revised; ANCOVA, analysis of covariance; ANOVA, analysis of variance; Amyotrophic lateral sclerosis; C9orf72; C9 +,  subjects with C9orf72 expansion mutations; CSF, cerebrospinal fluid; Cortical thickness; DRS-2, Mattis dementia rating scale; DTI, diffusion tensor imaging; Diffusion tensor imaging; FBI, frontobehavioral inventory; FDR, false discovery rate correction; FTD, frontotemporal dementia; Frontotemporal dementia; MRI, magnetic resonance imaging; SD, standard deviation; TIV, total intracranial volume; Ventricular volume; bvFTD, behavioral variant frontotemporal dementia; sALS, sporadic ALS