Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions.

Colin J Mahoney,Nick C Fox,Tom Yeatman,Simon Mead,Jon Beck,Melanie Blair,Hannah Golden,Gerard R Ridgway,Laura E Downey,Jason D Warren,Sarah Finnegan,Kelvin K Leung,Jonathan D Rohrer,Shona Clegg

doi:10.1186/alzrt144

Abstract

IntroductionFrontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Understanding the neurobiology and clinical phenomenology of this novel mutation is currently a major research focus. However, few data are available concerning the longitudinal evolution of this genetic disease. Here we present longitudinal neuropsychological and neuroimaging data on a cohort of patients with pathological repeat expansions in C9ORF72.MethodsFollowing a review of the University College London FTD DNA database, 20 cases were retrospectively identified with a C9ORF72 expansion. Twelve cases had longitudinal neuropsychology data available and six of these cases also had longitudinal volumetric brain magnetic resonance imaging. Cortical and subcortical volumes were extracted using FreeSurfer. Rates of whole brain, hemispheric, cerebellar and ventricular change were calculated for each subject. Nonlinear fluid registration of follow-up to baseline scan was performed to visualise longitudinal intra-subject patterns of brain atrophy and ventricular expansion.ResultsPatients had low average verbal and performance IQ at baseline that became impaired (< 5th percentile) at follow-up. In particular, visual memory, naming and dominant parietal skills all showed deterioration. Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group. The thalamus and cerebellum showed significant atrophy whereas no cortical areas were preferentially affected. Longitudinal fluid imaging in individual patients demonstrated heterogeneous patterns of progressive volume loss; however, ventricular expansion and cerebellar volume loss were consistent findings.ConclusionDisease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype.

Highlights

Frontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene chromosome 9 open reading frame 72 (C9ORF72) as a major cause of FTD and motor neuron disease
Mean rates of whole brain atrophy (1.4%/year) and ventricular expansion (3.2 ml/year) were substantially greater in patients with the C9ORF72 mutation than in healthy controls; atrophy was symmetrical between the cerebral hemispheres within the C9ORF72 mutation group
Disease evolution in C9ORF72-associated FTD is linked neuropsychologically with increasing involvement of parietal and amnestic functions, and neuroanatomically with rather diffuse and variable cortical and central atrophy but more consistent involvement of the cerebellum and thalamus. These longitudinal profiles are consistent with disease spread within a distributed subcortical network and demonstrate the feasibility of longitudinal biomarkers for tracking the evolution of the C9ORF72 mutation phenotype

Summary

Introduction

Frontotemporal dementia (FTD) is a common cause of early-onset dementia with a significant genetic component, as underlined by the recent identification of repeat expansions in the gene C9ORF72 as a major cause of FTD and motor neuron disease. Individual crosssectional magnetic resonance imaging (MRI) has revealed a highly variable imaging phenotype with involvement of frontal, temporal and parietal cortices, and limited previous longitudinal data have suggested similar rates of whole brain atrophy in C9ORF72 and MAPT mutation cases [6]. Group-level cross-sectional imaging studies have confirmed this distributed pattern of atrophy as well as emphasising additional cerebellar and subcortical involvement [6,8,9] Both imaging and clinical studies suggest that the neurodegenerative process associated with the C9ORF72 expansion is rather diffuse [10]. Whilst early symptoms are most in keeping with frontal lobe dysfunction, parietal dysfunction becomes more apparent as the disease progresses [6] These clinical features suggest that the disease may propagate along a rostrocaudal gradient, perhaps spreading via a distributed brain network. The concept of network-led degeneration is gaining currency as an important general theme in neurodegeneration [11] and C9ORF72-associated FTD, as a novel genetic proteinopathy, may offer fresh insights into the mechanisms of neurodegenerative disease propagation

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