Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS

• Published in: International journal of molecular sciences Vol. 22; no. 17; p. 9171
• Main Authors: Wang, Jun, Napoli, Eleonora, Kim, Kyoungmi, McLennan, Yingratana, Hagerman, Randi, Giulivi, Cecilia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25.08.2021; MDPI
• Subjects: Adenosine Triphosphate - metabolism; Adult; Age; Aged; Aging; Aging - metabolism; Alzheimer's disease; Ataxia - diagnostic imaging; Ataxia - metabolism; Bioenergetics; Biosynthesis; Brain - diagnostic imaging; Brain - growth & development; Cells, Cultured; Energy; Energy Metabolism; Epstein-Barr virus; Female; Fibroblasts; Flavin-Adenine Dinucleotide - analogs & derivatives; Flavin-Adenine Dinucleotide - metabolism; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X Syndrome - diagnostic imaging; Fragile X Syndrome - metabolism; Glucose; Humans; Kinases; Male; Metabolism; Middle Aged; Mitochondria - metabolism; Monocytes - metabolism; Neurodegeneration; Regression analysis; Tremor - diagnostic imaging; Tremor - metabolism; White Matter - diagnostic imaging; White Matter - growth & development; volume; bioenergetics; cognition; MRI; FMR1; mitochondria; white matter hyperintensities; peripheral blood monocytic cells; aging; brain
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22179171

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.