Objective: To determine if ³¹P-MRS can identify mitochondrial dysfunction in-vivo and if this correlates with in-vitro measures of mitochondrial function obtained from patient derived fibroblasts

Background: Sporadic Parkinson’s is increasingly recognized as an aetiologically heterogeneous disorder. Identification of the distinct mechanism contributing to neuronal cell loss in an individual will be crucial to develop future “Precision Medicine” approaches. ³¹P-MRS is a non-invasive tool that measures relative quantities of key compounds involved in energy metabolism, such as adenosine triphosphate (ATP) and phosphocreatine.

Method: ³¹P-MRS scans were undertaken in 35 people with Parkinson’s and 25 healthy age and sex matched controls. Spectra were analysed using the jMRUI software package and the AMARES spectral fitting algorithm [1,2]. Amplitudes of spectral resonances of interest were normalised to total phosphorus signal within each participant. All research participants also had a 3mm punch skin biopsy obtained to establish fibroblast cell lines for various mitochondrial assays including total cellular ATP, mitochondrial membrane potential and mitochondrial count per cell. Clinical assessment included widely utilised clinical rating inlcuding MDS-UPDRS Part 3, genetic analysis and the calculation of predicted risk of disease progression [3].

Results: Interim analysis of baseline ³¹P-MRS data revealed there is a significant difference in variance in total normalised ATP levels in the midbrain between Parkinson’s and controls by F test (p <0.01), with around a third of patients more than 2 standard deviations from the control mean. Total normalised phosphocreatine in the midbrain showed a significant linear relationship with predicted disease progression in Parkinson’s (linear regression p<0.01, r²=0.519).

Conclusion: ³¹P-MRS may help to identify a subgroup of Parkinson’s with significant mitochondrial dysfunction or at high risk of more rapid progression. ³¹P-MRS may therefore be useful to stratify patients for future neuroprotection trials. Assessment of mitochondrial function in fibroblast cell lines is on-going and will allow us to determine a possible correlation between central and peripheral measures of mitochondrial dysfunction.

References: 1. Stefan, D., Di Cesare, F., Andrasescu, A., Popa, E., Lazariev, A., Vescovo, E., Strbak, O., Williams, S., Starcuk, Z., Cabanas, M., van Ormondt, D., Graveron-Demilly. D. Quantitation of magnetic resonance spectroscopy signals: the jMRUI software package. Measurement Science and Technology 20:104035 (9 pp), 2009. doi: 10.1088/0957-0233/20/10/104035 2. Vanhamme, L., van den Boogaart, A., Van Huffel, S. Improved method for accurate and efficient quantification of MRS data with use of prior knowledge. Journal of Magnetic Resonance 129: 35-43, 1997. 3. Velseboer, D. C., R. M. de Bie, L. Wieske, J. R. Evans, S. L. Mason, T. Foltynie, B. Schmand, R. J. de Haan, B. Post, R. A. Barker and C. H. Williams-Gray (2016). “Development and external validation of a prognostic model in newly diagnosed Parkinson disease.” Neurology 86(11): 986-993.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/developing-31-phosphorus-magnetic-resonance-spectroscopy-31p-mrs-as-an-imaging-biomarker-to-identify-mitochondrial-dysfunction-in-parkinsons-disease/