Parkinson’s disease (PD) is an age-related neurodegenerative disease affecting up to one million individuals in the US. Dopaminergic neuron degeneration in the substantia nigra plays a major role in loss of motor coordination, and more widespread neuronal involvement can lead to symptom heterogeneity. In direct patient care and in clinical trials, diagnosis, disease subtype definition, and assessment of disease severity all rely on clinical judgement. It is therefore imperative that biomarkers are developed to allow accurate and earlier diagnosis, and to aid objective evaluation of therapeutic interventions in clinical trials.
The case for aberrant mitochondrial function and oxidative stress in PD dopaminergic cell demise is supported by multiple lines of evidence from tissue culture, cybrid models, studies of neuronal cell degeneration in animal models of PD, and molecular characterization of genes leading to PD. We therefore propose a pilot case-control study to evaluate the powerful and non-invasive techniques of 31phosphorus and proton magnetic resonance spectroscopic imaging (31P MRSI/1H MRSI) as measures of cerebral mitochondrial dysfunction in early PD. Of note, this study will leverage existing infrastructure for the NINDS-funded multi-center double blind, randomized, placebo-controlled phase III trial of high dose CoQ10 in early PD (nicknamed QE3, PI: Beal).
In the first part of the study, we will determine whether 31P/1H MRSI in specific regions of interest in the brain can distinguish PD from controls, and define PD subtypes based upon metabolic status. We will examine markers (including lactate, free phosphate, and ATP levels) of cerebral mitochondrial metabolism of unmedicated subjects with early PD entering the QE3 trial. We will compare with healthy age-, gender- and ethnicity-matched control subjects without PD to determine whether 31P/1H MRSI can distinguish between the two groups, and will also test within the PD group whether we can define subgroups depending upon degree of mitochondrial dysfunction. This could aid in the future to recruit an “enriched” population of PD patients with a higher degree of mitochondrial impairment, who might benefit preferentially from so-called “mitochondrial therapies” such as coenzyme Q10.
In the second part of the study, we will determine whether 31P/1H MRSI demonstrates predicted changes in spectra, reflecting improved mitochondrial metabolism, as high doses of Coenzyme Q10 (CoQ10) are administered to people with early PD in the QE3 trial. To this end, we will compare repeat 31P/1H MRSI scans at 6 months after their initial baseline scan.