Age-related functional brain changes in FMR1 premutation carriers

Abstract

The FMR1 premutation confers a 40-60% risk for males of developing a neurodegenerative disease called the Fragile X-associated Tremor Ataxia Syndrome (FXTAS). FXTAS is a late-onset disease that primarily involves progressive symptoms of tremor and ataxia, as well as cognitive decline that can develop into dementia in some patients. At present, it is not clear whether changes to brain function are detectable in motor regions prior to the onset of frank symptomatology. The present study therefore aimed to utilize an fMRI motor task for the first time in an asymptomatic premutation population. Premutation carriers without a diagnosis of FXTAS (n = 17) and a group of healthy male controls (n = 17), with an age range of 24-68 years old, were recruited for this cross-sectional study. This study utilized neuroimaging, molecular and clinical measurements, employing an fMRI finger-tapping task with a block design consisting of sequential finger-tapping, random finger-tapping and rest conditions. The imaging analysis contrasted the sequential and random conditions to investigate activation changes in response to a change in task demand. Additionally, measurements were obtained of participant tremor, co-ordination and balance using the CATSYS-2000 system and measures of FMR1 mRNA were quantified from peripheral blood samples using quantitative real-time PCR methodology. Premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWE_corr < 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 (FWE_corr < 0.001). 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.

Keywords: FXTAS; Fragile X premutation; Neurodegeneration; Neuroimaging; fMRI.

Fig. 1

Finger-tapping task behavioural conditions and block design.

Fig. 2

Between group imaging results a) Premutation group significantly less activated (FWE_corr < 0.001, T = 5.59) at the bilateral lobules VI of the cerebellum, left lobule V and the left hippocampus (subiculum) in the sequential > random condition contrast. Cluster co-ordinate of maximum voxel: − 12,− 36,− 12, k = 2040, normalised voxel size: 2 mm³ b) Mean extracted voxel response by grouping at [− 12,− 36,− 12].

Fig. 3

Age-related between group imaging results a) Significant group × age interaction (FWE_corr < 0.001, T = 5.22) at the left BA17, left hippocampus (CA), left inferior parietal cortex and left temporal in the sequential > random condition contrast. Cluster co-ordinate of maximum voxel: − 26,2,36, k = 2105, normalised voxel size: 2 mm³ b) Fit linear regression lines comparing positive control BOLD response and age relationship compared to negative premutation carrier BOLD response and age relationship at maximum cluster voxel [− 26,2,36].

Fig. 4

FMR1 mRNA quantification. a) FMR1 mRNA amount relative to 18 sRNA control for carrier and control groups b) Carrier FMR1 mRNA amount relative to 18 sRNA normalised to age-matched control levels and control FMR1 mRNA amount relative to 18 sRNA normalised to control average.