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

Background: A mutation in 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 and 15 with 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: 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 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 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 carriers.