Functional MRI in FMR1 premutation carriers: a cross-sectional study of neurodegeneration and neurodevelopment

Abstract

Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between
 55 and 200 repeats is known as the FMR1 premutation. Carriers of the FMR1 premutation
 may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome
 (FXTAS), which involves progressive symptoms of tremor, ataxia and cognitive decline.
 Evidence also suggests that premutation carriers experience other psychiatric difficulties
 throughout their lifespan.
 The present study aimed to investigate and delineate neurodegenerative and
 neurodevelopmental aspects of the premutation utilising primarily fMRI, clinical
 assessments and molecular measurements in 17 premutation carrier participants and 17 age-matched
 control participants, aged between 20 and 70 years. The functional imaging
 protocol included a motor task and an emotional processing task. A battery of clinical and
 neuropsychological tests outside of the scanner and blood-based measurements of FMR1
 CGG repeat length, FMRP levels and FMR1 mRNA levels were also carried out.
 In the motor task, premutation carriers demonstrated significantly less cerebellar activation
 than controls during sequential versus random finger tapping (FWEcorr<0.001). In addition,
 there was a significant age by group interaction in the hippocampus, inferior parietal cortex
 and temporal cortex originating from a more negative relationship between brain activation
 and age in the carrier group compared to the controls (FWEcorr<0.001). Quantative real-time
 PCR analysis revealed that mean age-matched FMR1 mRNA levels display a trend towards
 being higher in carriers and clinical testing of motor skills additionally showed significantly
 worse tremor and co-ordination scores in non-FXTAS carriers. No significant associations
 were seen between these measurements and neuroimaging data.
 During the emotional processing task, carriers exhibited significantly lower activation
 compared to controls (FWEcorr<0.001) at the bilateral superior parietal lobe, bilateral
 Brodmann Area (BA) 17 (V1), right intraparietal area and right BA18 (V2) when comparing
 high arousal and low arousal conditions. Group by age interaction analyses indicated no
 significant between group differences at a whole brain level. Clinical assessment revealed
 that carriers displayed significantly worse symptoms of obsessive-compulsiveness, anxiety,
 global severity of psychiatric symptoms, facial emotion recognition and autistic traits
 compared to controls and FMRP levels were comparable between groups. No significant
 associations were seen between these measurements and neuroimaging data.
 Here, we present for the first time functional imaging-based evidence for early movement-related
 neurodegeneration in Fragile X premutation carriers. These changes pre-exist the
 diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative
 of FXTAS vulnerability. Additionally, we show significantly altered emotional processing at
 neuropsychological, clinical and functional neuroimaging levels in carriers compared to
 controls, which appear to display stability over age. Overall, we present new evidence in
 keeping with possible neurodegenerative and neurodevelopmental traits in FMR1
 premutation carriers.