Magnetic Resonance Spectroscopy to Investigate Mitochondrial Function in Parkinson’s Disease
Claire Henchcliffe, M.D., Ph.D.
Cornell University Medical College, New York, NY
David Mahoney Neuroimaging Program
December 2007, for 2 years
Imaging May Reveal Defects in Energy Metabolism in Brain Cells of Parkinson’s Disease Patients
This study will determine if a conventional brain imaging technique can identify abnormally low energy metabolism in brain cells in the substantia nigra in patients with early Parkinson’s disease (PD) and accurately assess the effects of a therapy designed to raise cell energy generation levels.
PD is produced by progressive degeneration in brain cells that use the neurotransmitter dopamine to communicate, resulting in a range of motor and, sometimes, cognitive disabilities and depression. Prior studies in an animal PD model, and in molecular characterization of genes considered to play a role in PD, indicate that the affected brain cells’ energy-producing components, called mitochondria, are dysfunctional in the early stage of this progressive disease. The researchers hypothesize that dysfunctional energy metabolism in the substantia nigra’s dopamine cells (and perhaps in cells involved in memory and depression in some patients) leads to nerve cell death in PD. Further, they hypothesize, magnetic resonance spectroscopic imaging (MRSI) can identify degrees of energy generation in cells, which can be used as an early marker of PD, and also can be used to differentiate subgroups of PD patients according to the degree of mitochondrial dysfunction.
Using MRSI, the investigators plan to identify patterns of specific chemical compounds that provide a measure of the level of energy generation in cells. They will undertake MRSI imaging in conjunction with an NIH-funded large-scale clinical trial of an experimental therapy called coenzyme Q10 to see if it slows PD progression by improving mitochondrial function. The Dana-supported researchers will enroll healthy adult “controls” and early stage PD patients who are planning to participate in this clinical trial, which is funded by the National Institute of Neurological Disorders and Stroke. The Dana study investigators will use MRSI to compare brain energy metabolism in the controls and PD patients, to see if cell energy generation levels are lower in the PD patients. They also will determine whether the early stage PD patients can be categorized into subgroups that differ in degree of mitochondrial energy dysfunction. They then will image PD patients following coenzyme Q10 treatment to see if the imaging demonstrates predicted changes in mitochondrial metabolism as a result of the therapy.
Significance: MRSI imaging may become a tool for diagnosing PD, determining its likely progressive course, and for assessing the effectiveness of therapies designed to improve energy generation in brain dopamine cells.
Magnetic Resonance Spectroscopy to Investigate Mitochondrial Function in Parkinson's Disease
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.
Claire Henchcliffe, M.D., Ph.D.
Dr. Claire Henchcliffe is Director of the Weill Cornell & Movement Disorders Institute and Assistant Professor of Neurology and Neuroscience at the Weill Medical College of Cornell University. She trained in biochemistry and cell biology at the University of Oxford, UK, where she completed thesis work for her D.Phil. She then gained her MD degree at the College of Physicians and Surgeons of Columbia University, New York, and stayed on to complete Neurology residency and a two-year period of additional fellowship training in Movement Disorders. She now divides her time between clinical research, direct patient care, and teaching. Her research interests focus on biomarker development in Parkinson’s disease, with a long term aim of developing tests that will improve understanding of the molecular disease process and its treatments, allow earlier and more accurate diagnosis, and aid in individualizing therapy for patients. She has a strong interest in developing neuroprotective approaches to Parkinson’s disease and is involved in the lead site team for a multi-center phase III clinical trial of high dose Coenzyme Q10, funded by the NIH.