Centre for Human Drug Research, Leiden, The Netherlands
| [b] Gorter Centre for High-field MRI, Leiden University Medical Center, Leiden, The Netherlands
| [c] Radiology Research Center, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| [d] Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| [e] Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
Correspondence to: Geert Jan Groeneveld, MD, PhD, Centre for Human Drug Research, Zernikedreef 8, 2333CL Leiden, The Netherlands. Tel.: +31 715246400; E-mail: [email protected].
Abstract: Background:Huntington’s disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. Objective:We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. Methods:We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington’s Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. Results:We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = –0.45 and –0.48), which increased in a subgroup with the largest number of CAG repeats. Discussion:We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.