Objective: To mechanistically stratify Parkinson’s disease (PD), applying a combination of putaminal ³¹Phosphorus magnetic resonance spectroscopy (³¹P-MRS) with detailed assessment of mitochondrial and lysosomal function in peripheral tissue.

Background: PD is an aetiologically heterogeneous disorder. Identification of distinct pathogenic mechanisms, such as mitochondrial or lysosomal function, in individual patients is crucial to develop future “Precision Medicine” approaches. ³¹P-MRS is a non-invasive tool to assess key bioenergetic metabolites such as ATP, phosphocreatine and inorganic phosphate (Pi) in the brain. We previously undertook the largest mechanistic deep phenotyping study in peripheral tissue of sporadic PD and controls.¹

Method: 60 participants (35 PD and 25 healthy controls) underwent ³¹P-MRS targeting the putamen using 2D Chemical Shift Imaging. Spectra were analysed using the jMRUI software package and the AMARES spectral fitting algorithm.^2,3 Skin biopsies were obtained to establish fibroblast cell lines to assess intracellular ATP, mitochondrial membrane potential (MMP) and the number and morphology of mitochondria and lysosomes, using high content live cell imaging. Composite z-scores were calculated comprising ³¹P-MRS imaging parameters and each fibroblast assay parameter. Correlation between ³¹P-MRS and fibroblast data was performed using Pearson’s correlation coefficient.

Results: In PD, lower ³¹P-MRS putaminal ATP correlated with lower MMP and greater numbers of both mitochondria and lysosomes in peripheral tissue. This inverse correlation between ³¹P-MRS putaminal ATP and MMP was strongest for smaller mitochondria. In contrast, in healthy controls higher ³¹P-MRS putaminal ATP correlated positively with higher mitochondrial counts in peripheral tissue as expected. The inverse correlations between ³¹P-MRS putaminal ATP and lysosome count or MMP in peripheral tissue (as observed in PD patients) was absent in healthy controls.

Conclusion: This is the first study to mechanistically stratify PD by combining in vivo measures of bioenergetic dysfunction in the brain with relevant pathogenic mechanisms in peripheral tissue. The observation of lower ³¹P-MRS putaminal ATP correlating with an increased number of small, dysfunctional mitochondria and accumulation of lysosomes in peripheral tissue would be in keeping with increased mitophagy.

References: 1. Carling PJ, Mortiboys H, Green C, et al. Deep phenotyping of peripheral tissue facilitates mechanistic disease stratification in sporadic Parkinson’s disease. Prog Neurobiol. Apr 2020;187:101772. doi:10.1016/j.pneurobio.2020.101772
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. 1997;129(1):35-43. doi:10.1006/jmre.1997.1244
3. Stefan D, Cesare FD, Andrasescu A, et al. Quantitation of magnetic resonance spectroscopy signals: the jMRUI software package. Measurement Science and Technology. 2009;20(10)doi:10.1088/0957-0233/20/10/104035

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multimodal-mechanistic-disease-stratification-in-sporadic-parkinsons-disease/