Deficits in verbal fluency in presymptomatic C9orf72 mutation gene carriers-a developmental disorder

Abstract

Background: A mutation in C9orf72 constitute a cross-link between amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). At clinical manifestation, both patient groups may present with either cognitive impairment of predominantly behaviour or language (in FTD) or motor dysfunctions (in ALS).

Methods: In total, 36 non-symptomatic mutation carriers from ALS or FTD families were examined, including 21 subjects with C9orf72 and 15 with SOD1 mutations. Data were compared with 91 age-matched, education-matched and gender-matched healthy subjects (56 were first-degree relatives from ALS or FTD families, 35 with no known family history of ALS/FTD). MRI scanning for diffusion tensor imaging was performed to map fractional anisotropy (FA). Subjects performed an extensive neuropsychological assessment to address verbal fluency, language, executive, memory and visuospatial function. Measurements were repeated after 12 months.

Results: C9orf72 expansion carriers performed significantly worse in verbal fluency and non-verbal memory and presented with distinct alterations in structural white matter integrity indicated by lower FA values in inferior and orbitofrontal cortical areas compared with carriers of SOD1 mutations or healthy subjects. Loss of structural integrity was associated with decreased verbal fluency performance. White matter alterations and cognitive performance showed no changes over 12 months in all subjects.

Discussion: Reduced verbal fluency performance seems to be a distinct clinical feature of C9orf72 carriers before symptomatic disease onset without evidence for change over time in our cohort. The results support the emerging hypothesis of a general disorder in development in addition to neurodegeneration in C9orf72 carriers.

Figure 1

Verbal fluency performance in C9orf72 carriers (C9orf72), SOD1 mutation carriers (SOD1) compared with subjects with (FM controls) and subjects without a family history of ALS/motor neuron disease (non-FM controls). *Statistical significance with p<0.05. ALS, amyotrophic lateral sclerosis; FM, family member.

Figure 2

White matter integrity analysis of n=22 asymptomatic C9orf72 carriers versus n=21 controls (non-FM controls). (A) Whole brain-based spatial statistics (WBSS) in slice wise view (MNI±19/31/3; near local bihemispherical maxima) (left) and in sagittal projectional view (right). (B) regions of interest (ROI)-based analysis. Left panel: ROI definition for group comparison and correlation analysis (r=30 mm at MNI±19/31/3). ROIs were displayed on a coloured FA-map background. Right panel: FA comparison for frontal ROIs at the group level for C9orf72 subjects versus controls. **p<0.001. FA, fractional anisotropy; FDR, false-discovery-rate; FM, family member; MNI, Montreal Neurological Institute.

Figure 3

Association of cognitive performance in verbal fluency and FA values in bilateral association fibres to the inferior frontal cortex (ROI ±19/3/13) in C9orf72 carriers; Pearson correlation indicated significant association (r=0.32, p=0.02). FA, fractional anisotropy.