Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5′UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings—and the lack of correlations with FXTAS diagnosis/stages—may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.
Highlights
Introduction iationsThe onset of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), fragile X-associated tremor/ataxia syndrome (FXTAS), among others, is believed to be multifactorial; older age is the greatest risk factor [1,2,3]
Our study indicates the feasibility of correlating magnetic resonance imaging (MRI) imaging with some peripheral bioenergetic markers, thereby providing the potential to identify those cases with early signs of premature aging and a potentially worse prognosis
Premutation carriers were grouped by Fragile X-associated tremor/ataxia syndrome (FXTAS) stage, which was scored by a trained physician (RJH) based on the severity of movement and gait impairments
Summary
The onset of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), fragile X-associated tremor/ataxia syndrome (FXTAS), among others, is believed to be multifactorial; older age is the greatest risk factor [1,2,3]. It is likely that cellular and molecular changes associated with aging and/or premature senescence would promote neuronal abnormalities and degeneration. Perturbation of cellular energy metabolism and mitochondrial biogenesis are commonly associated with aging. These changes in energy metabolism have been partly explained by decreased sensitivity to glucose signaling, uptake, and utilization [4] resulting in major metabolic disorders, which are well-known contributors to neurodegeneration.
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