Artificial neural network applied to fragile X-associated tremor/ataxia syndrome stage diagnosis based on peripheral mitochondrial bioenergetics and brain imaging outcomes

Abstract

No proven prognosis is available for the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Artificial neural network analyses (ANN) were used to predict FXTAS progression using data from 127 adults (noncarriers and FMR1 premutation carriers with and without FXTAS) with five outcomes from brain MRI imaging and 22 peripheral bioenergetic outcomes from two cell types. Diagnosis accuracy by ANN predictions ranged from 41.7 to 86.3% (depending on the algorithm used), and those misclassified usually presented a higher FXTAS stage. ANN prediction of FXTAS stages was based on a combination of two imaging findings (white matter hyperintensity and whole-brain volumes adjusted for intracranial volume) and four bioenergetic outcomes. Those at Stage 3 vs. 0–2 showed lower mitochondrial mass, higher oxidative stress, and an altered electron transfer consistent with mitochondrial unfolded protein response activation. Those at Stages 4–5 vs. 3 had higher oxidative stress and glycerol-3-phosphate-linked ATP production, suggesting that targeting mGPDH activity may prevent a worse prognosis. This was confirmed by the bioenergetic improvement of inhibiting mGPDH with metformin in affected fibroblasts. ANN supports the prospect of an unbiased molecular definition in diagnosing FXTAS stages while identifying potential targets for personalized medicine.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation

“…The severity of WMHs is associated with multiple FMR1 molecular markers (i.e., CGG repeat length and mRNA level), peripheral measures of mitochondrial bioenergetics, and the activity of a cellular stress marker, the enzyme AMP-activated protein kinase [ 17 , 180 , 392 ]. In a recent study applying artificial neural network analysis [ 393 ], the combination of both the mitochondrial bioenergetics and MRI measures of WMHs and whole brain volumes was useful for classifying the FXTAS stage in 127 male and female PM carriers with and without FXTAS. In addition, a longitudinal study investigated the effect of ventricular expansion on brain deformation using a periventricular white-matter structure, the corpus callosum, and a nonperiventricular nucleus, the putamen [ 394 ].…”

Glycerol 3-phosphate dehydrogenases (1 and 2) in cancer and other diseases

“…Therefore, histological (antibody staining), pharmacological (inhibitors), and biochemical (enzyme activity) experiments have provided somewhat discordant views on the roles of GPS in different brain cell types, and studies incorporating different approaches in the same setting should be performed to obtain better insight. Apart from GPS activity, targeting GPD2 with metformin in brain abnormalities has been studied 98 , 99 , but the effect may not be specifically due to GPD2 inhibition, considering the various effects of metformin.…”

Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X‐associated tremor/ataxia syndrome

“…Studies of FMR1 PM carriers and FXTAS patients have long hinted at abnormal mitochondrial oxidative phosphorylation that may contribute to the disease pathologies. 10,13,24 We measured the activity and quantity of mitochondrial respiratory complexes IV and V in postmortem frozen brain tissues from patients with FXTAS, and also quantified the same measures in NDEVs isolated from the plasma of living FMR1 PM carriers, similar to NDEV studies in other cohorts. 19,20,25,26…”