Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions

Abstract

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. 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.

Methods: Following 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.

Results: Patients 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.

Conclusion: 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.

Figure 1

Group-level longitudinal performance on neuropsychological measures. Verbal IQ (VIQ) and performance IQ (PIQ) reported as raw scores. For the purpose of standardising across tests and to visualise changes in performance, raw scores were converted to percentiles. Where a score of 50th to 75th percentile was reported this was converted to the median value (that is, 62.5) for visualisation.

Figure 2

Change in brain volume and ventricular volume. Change in brain volume (upper panel) and ventricular volume (lower panel) for each subject expressed as a proportion of the total intracranial volume (TIV) and modelled as a function of disease duration.

Figure 3

Coronal, sagittal and axial magnetic resonance imaging images showing areas of contraction and expansion. Coronal (left), sagittal (middle) and axial (right) magnetic resonance imaging brain slices showing longitudinal voxel-compression maps in individual patients, representing areas of contraction (green-blue) and expansion (yellow-red) over time. Sagittal sections are through the right hemisphere. R, right.