Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington’s Disease

Journal of Huntington s Disease, vol. 9, pp. 335–344

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.

Authors 12

1. Marcus P.J. van Diemen Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, The Netherlands

2. Ellen P. Hart Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, The Netherlands

3. Pieter W. Hameeteman Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, The Netherlands

4. Emma M. Coppen Aachen Department of Neurology, Leiden University Medical Center (LUMC)

   Leiden University Medical Center

   Affiliation as printed

   Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

5. Jessica Y. Winder Aachen Department of Neurology, Leiden University Medical Center (LUMC)

   Leiden University Medical Center

   Affiliation as printed

   Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

6. Jonas M. den Heijer Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, The Netherlands

7. Matthijs Moerland Aachen Centre for Human Drug Research (CHDR)

   Centre for Human Drug Research

   Affiliation as printed

   Centre for Human Drug Research, Leiden, The Netherlands

8. Hermien E. Kan Aachen Gorter Center for High‐Field MRI

   Leiden University Medical Center

   Affiliation as printed

   Gorter Centre for High-field MRI, Leiden University Medical Center, Leiden, The Netherlands

9. Jeroen van der Grond Aachen Radiology Research Center Department of Radiology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Radiology Research Center, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

10. ANDREW G. WEBB Aachen Gorter Center for High‐Field MRI

    Leiden University Medical Center

    Affiliation as printed

    Gorter Centre for High-field MRI, Leiden University Medical Center, Leiden, The Netherlands

11. Raymund A.C. Roos Aachen Department of Neurology, Leiden University Medical Center (LUMC)

    Leiden University Medical Center

    Affiliation as printed

    Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands

12. Geert Jan Groeneveld corresponding Aachen Centre for Human Drug Research (CHDR) Department of Anesthesiology, Leiden University Medical Center

    Leiden University Medical Center · Centre for Human Drug Research

    Affiliation as printed

    Centre for Human Drug Research, Leiden, The Netherlands

    Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands