Functional MRI in FMR1 premutation carriers: a cross-sectional study of neurodegeneration and neurodevelopment
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Date
01/12/2017Author
Brown, Stephanie Sian Gabriella
Metadata
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.