Systemic mitochondrial function tests as a biomarker for susceptibility to glaucoma and neurodegeneration in an unselected ageing twin population

Abstract

Purpose : Mitochondrial dysfunction may be a biomarker of biological ageing in neurodegenerative diseases such as glaucoma and Alzheimer’s. We aimed to assess mitochondrial function on optic nerve health and cognitive function for the first time in an aging longitudinal population study.

Methods : Systemic mitochondrial function was measured in 115 volunteers from the TwinsUK cohort using MitoPlates™ S-1 assays on fresh peripheral blood mononuclear cell (PBMC) for 31 different substrate reactions in triplicate. Cross-sectional glaucoma-related endophenotypes (intraocular pressure (IOP), retinal nerve fibre layer (RNFL) thickness and vertical cup to disc ratio (VDCR)) and cognitive measures (Cantab-PAL and the Useful Field of View (UFOV)) were assessed. Linear mixed models adjusted for age, sex and family structure investigated associations between phenotypes and mitochondrial substrates. A backwards stepwise regression model was completed for each phenotype, including all associated substrate maximum reaction rates (RR).

Results : Within the study cohort, mean (SD) age was 66.9(±14.6) years. Mean endophenotype values measured were IOP: 12.8 mmHg (±3.02), VCDR: 0.4 (±0.11) and RNFL: 96.5µm(±10.38). Monozygotic twin correlations were generally higher than dizygotic, suggesting a degree of heritability. Using multivariable regression models, RNFL thickness was associated with increased RR of a-Keto-Isocaproic Acid (β=0.96, p<0.001). Lower IOP was associated with increased RR of a-Keto-Butyric Acid (β=-0.09, p=0.022) , a-Keto-Isocaproic Acid(β=-0.19, p<0.001) and Glycogen(β=-0.08, p=0.002). Larger VCDR was associated with increased RR of D-Gluconate-6-PO4 (β=0.005, p<0.001). For cognition measures, a-Keto-Isocaproic Acid (β=0.08, p=0.003) and Glycogen (β=-0.08, p=0.002) were associated with Cantab-PAL, a-Keto-Butyric Acid (β=-0.04, p=0.042) and Palmitoyl-DL-Carnitine Chloride(β=0.03, p=0.03) with UFOV.

Conclusions : We have identified novel mitochondria-related biomarkers for glaucoma and cognition, particularly in key compounds involved in the biosynthesis of amino acids, secondary metabolites and the tricarboxylic acid cycle. Additional larger and longitudinal studies are required to establish the importance of these pathways and to determine if future mitochondria-related treatments (such as nicotinamide) influence these enzyme reactions.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.