# ATP and NAD+
## 4 Discussion
While some of these associations may be due to chance, the consistent association between higher ATPmax and fewer motor symptoms, as measured by both the UPDRS part 3 and the motor subset of the PRO-PD, is notable. This study has several limitations that should be considered when evaluating these results. In this study, it was not possible to specify whether the metabolic dysfunction we observed was a primary effect of PD or a secondary effect due to behavioral and mobility changes caused by PD. All of the PD subjects in this pilot study were mid-stage with [PERSON] and Yahr scores of 2-3, indicating that all the subjects were experiencing PD symptoms and motor deficits. As an initial attempt to address this, we performed a sub-group analysis to compare results for ATPmax and muscle fatigue between subjects with either left- or right-side onset of symptoms. All of the measurements were made on the right side. Neither ATPmax nor muscle fatigue showed any effect of the side of onset in this analysis. This study enrolled individuals with mid-stage PD; future studies should determine whether these findings are seen in the prodomal phase of PD and immediately following diagnosis or whether individuals in late-stage disease have even greater reductions in mitochondrial function. Skeletal muscle metabolism and performance are closely tied to activity level and nutritional status, which this pilot study was not powered to evaluate. Future studies should attempt to evaluate whether exercise frequency and intensity or nutritional status are related to mitochondrial function. Subsequent studies should also aim to determine whether these findings are unique to idiopathic PD or observed in other forms of parkinsonism as well. Finally, this pilot study compared newly recruited PD subjects with the historical control dataset that we had collected at the UW; future studies should enroll healthy controls as a quality control measure, as reference ranges have not been established. Following the demonstration of dopamine deficiency in PD, dopamine augmentation strategies have become an essential part of PD management. Similarly, the recent identification of metabolic deficiencies of NAD and ATP in the PD brain [47] and now skeletal muscle in vivo makes a compelling case for mitochondrial augmentation as a therapeutic strategy. MRS may have utility as a theragnostic biomarker in drug development, where it may be able to detect and monitor an intervention's ability to improve mitochondrial function, as was recently demonstrated in the NADPARK study [30]. These are the first data to demonstrate an association between mitochondrial impairment of function and muscle function and worse PD symptoms, specifically motor symptoms. The following supporting information can be downloaded at: [[https://www.mdpi.com/article/10.3390/nu15040943/s1](https://www.mdpi.com/article/10.3390/nu15040943/s1)]([https://www.mdpi.com/article/10.3390/nu15040943/s1](https://www.mdpi.com/article/10.3390/nu15040943/s1)), Figure S1: Comparing effect of side of onset of PD symptoms; Table S1: List of inclusion and exclusion criteria for PD subjects; Table S2: PD symptom severity correlations with Leg [NAD], Leg [ATP] and Hand [ATP] by simple linear regressions. Non-normally distributed variables were square root transformed. Conceptualization, D.J.M., E.S. and L.K.M. ; methodology, D.J.M., E.S., L.K.M., S.Z.L. and D.J.F. ; software, E.S. and S.Z.L. ; validation, E.S. and D.J.M. ; formal analysis, S.B., S.Z.L., E.S. and D.J.F. ; investigation, L.K.M., E.S., S.Z.L. and S.B. ; resources, L.K.M. and D.J.M. ; data curation, L.K.M., S.B. and S.Z.L. ; writing--original draft preparation, D.J.M., D.J.F. and E.S. ; writing--review and editing, D.J.M., D.J.F. and E.S. ; visualization, D.J.M., E.S., L.K.M. and D.J.F. ; supervision, L.K.M. and D.J.M. ; project administration, L.K.M. and D.J.M. ; funding acquisition, D.J.M. All authors have read and agreed to the published version of the manuscript. This research was funded by Michael J Fox Foundation (#16838).