Correlative magnetic resonance and near-infrared technologies for the evaluation of mitochondrial disease.

Abstract

Magnetic resonance imaging (MRI), 31 P magnetic resonance spectroscopy ( 31 P-MRS) and nearinfrared spectroscopy (NIRS) are non-invasive methods for characterizing the dynamic aspects of human muscle contraction. MRI is employed for investigating the general morphology of muscles and for longitudinal evaluations of abnormalities such as inflammation or fat infiltration. By contrast, biopsy provides diagnostic information on a small sample of tissue, for example, identification of the cell types found in the inflammatory infiltrate. Biopsy is not suitable for frequent repeat examinations. Clearly, MRI and biopsy are clinically complementary. The various morphological and pathological findings can be correlated with metabolic data obtained with 31 P-MRS [1,2]. 31 P-MRS is a technique for determining the levels of ATP, phosphocreatine (PCr), inorganic phosphate (Pi) and also pH in resting and exercising muscles. Minute-by-minute changes in the metabolities during exercise can be measured with 31 P-MRS and thereby enable bioenergetic studies of contracting muscles. The efficiency of the generation and utilization of the high energy phosphate compounds, ATP and PCr, can be ascertained from the ratio of the concentrations of Pi and PCr, namely, the Pi=PCr ratio. During exercise by normal muscles, the Pi=PCr ratio becomes elevated due to increased Pi and decreased PCr levels. If the Pi=PCr ratio is elevated above normal values, a dysfunctional bioenergetic status exists and exercise performance is impaired. For example, in mitochondrial myopathies the Pi=PCr ratio during exercise is elevated well above normal values, indicating a severely impaired bioenergetic status which may in part account for muscle dysfunction. After exercise the rate of resynthesis of PCr is substantially reduced in the diseases muscles [3]. NIRS evaluates kinetic changes in oxygen levels in muscles during exercise and the subsequent recovery period. Adequate oxygen delivery and utilization are essential for efficient synthesis of the ATP required for repetitive contractions and overall physical endurance. The NIRS measurements of oxygen saturation can be correlated with 31 P-MRS data for ATP and PCr turnover. In the case of mitochondrial myopathy, there is an abnormal “paradoxical oxygenation” of the exercising muscles (poor oxygen utilization) rather than the usual deoxygenation (fast utilization) seen in normal muscles. Impaired oxygen utilization and deficient ATP synthesis correlate with the clinical findings of weakness and fatigue [4]. In summary, MRI, 31 P-MRS and NIRS, provide unique quantitative data for studies of normal muscle function and for more complex investigations of muscle disorders. These non-invasive examinations