This thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre... Show moreThis thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre-frail elderly and Huntington’s disease patients, we used phosphorous magnetic resonance spectroscopy as the main method to measure mitochondrial function in vivo. Other in vivo methods included Near Infrared Spectroscopy and the novel Protoporphorin-9 Triplet State Lifetime Technique, besides in vitro ELISA methods to measure activity of separate complexes of the mitochondrial electron transport chain. Using these modalities, we showed mitochondrial dysfunction in pre-frail elderly, emphasizing the importance of an active lifestyle in the prevention of sarcopenia and frailty. Using the mitotoxicity of simvastatin, and its reversibility by ubiquinol, we validated the first proof-of-pharmacology model in healthy volunteers to evaluate efficacy of novel mitochondrial function improving compounds. We also described the importance of measuring (mitochondrial) oxygen consumption as a means to measure mitotoxicity of commonly described medications. Lastly, we evaluated the safety and efficacy of the novel compound SBT-020 in a placebo-controlled, double-blinded, randomized controlled trial in mild to moderate Huntington’s disease patients and compared central to peripheral mitochondrial function for the first time, gaining inside into therapeutic possibilities in this complex and devastating disease. Show less
Ronen, I.; O'Reilly, T.; Froeling, M.; Webb, A.G. 2020
We examined approaches for obtaining H-1 NMR spectra of brain metabolites on a low-field (B-0 = 0.05 T) portable MRI scanner, which was developed in our laboratory with the aim of bringing cost... Show moreWe examined approaches for obtaining H-1 NMR spectra of brain metabolites on a low-field (B-0 = 0.05 T) portable MRI scanner, which was developed in our laboratory with the aim of bringing cost-effective radiological services to populations in underserved, remote regions. The low static magnetic field B-0 dictates low signal to noise ratio for metabolites in the mM concentration range, and results in an overall spectral region for the H-1 resonances of these metabolites narrower than the linewidth obtainable in our scanner. The narrow spectral range also precludes the possibility of suppressing the large contribution of the water resonance at the acquisition stage.We used a spectroscopic Carr-Purcell-Meiboom-Gill (CPMG) sequence to acquire multiecho data from solutions of J-coupled brain metabolites, focusing on lactic acid, a metabolite whose concentration is negligible in the healthy brain and increases significantly in several disease conditions. The J spectra we obtained for lactate from the Fourier transformation of the multiecho data are spectrally well-resolved for a range of echo spacing values. We show that the J spectra at different echo spacings fit well with simulations of the evolution of echo train signal of the lactate under the same conditions. Applying a Jrefocused variant of the CPMG sequence, the J modulation of the echo decay is removed, providing a way for subtracting the large contribution of the non-modulated component in the J spectrum in conditions where notching it using post-processing methods is impossible. We also demonstrate by means of experimental data and simulations that in our experimental conditions, J-spectra of other prominent brain metabolites, such as the neurotransmitter glutamate, do not yield discernible peaks and only contribute to a broad peak at zero frequency. (C) 2020 The Author(s). Published by Elsevier Inc. Show less
