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Cognitive decline is a common symptom in multiple sclerosis patients, with profound effects on the quality of life. A nonhuman primate model of multiple sclerosis would be best suited to test the effects of demyelination on complex cognitive functions such as learning and reasoning. Cuprizone has been shown to reliably induce brain demyelination in mice. To establish a nonhuman primate model of multiple sclerosis, young adult cynomolgus monkeys were administered cuprizone per os as a dietary supplement. The subjects received increasing cuprizone doses (0.3–3% of diet) for up to 18 weeks. Magnetic resonance imaging and immunohistological analyses did not reveal demyelination in these monkeys.

Objective To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). Methods Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune-cell subsets were determined by flow cytometry, whereas thymic function was assessed using T-cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous system–autoreactive antigen-specific T-cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T-cell responses. Results Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses. Interpretation Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT. ANN NEUROL 2013;73:341–354

Objective To assess demyelination and remyelination in vivo in acute gadolinium (Gd)-enhancing lesions of multiple sclerosis (MS). Methods We measured significant changes in magnetization transfer ratio (MTR) consistent with demyelination and remyelination of individual lesion voxels, as well as the mean normalized MTR over all lesion voxels during and after contrast enhancement, in MS patients participating in a 3-year Canadian trial assessing immunoablation and autologous stem cell transplantation for treatment of MS. Results The average mean normalized lesion MTR over all lesions exhibited partial recovery over 2 to 4 months after Gd enhancement. Voxel-based analysis demonstrated that approximately 70% of the initially enhancing lesion volume (GdLV) was left with stably low MTR over 39 months of evaluation. The percentage of the GdLV undergoing significant increases in MTR consistent with remyelination increased for approximately 7 months after enhancement and then stabilized at 21 %GdLV. Significant decreases in MTR consistent with demyelination were ongoing for approximately 33 months after enhancement, stabilizing at 9 %GdLV. The estimated error of these measurements, based on scan/rescan analysis, was less than 0.4 %GdLV. Interpretation We found significant changes in MTR consistent with demyelination and remyelination that followed different temporal evolutions and were ongoing in different lesion regions for at least 3 years after lesion formation. Ann Neurol 2008

Post-exercise recovery of intracellular pH (pH(i)) assessed using phosphorus magnetic resonance spectroscopy has not been previously evaluated in its entirety due to its complex time-course and missing data points resulting from a transient loss of inorganic phosphate signal. By considering the transition from exercise to recovery as a step function input, pH(i) recovery was modeled based on the creatine-kinase equilibrium, and the entire pH(i) recovery was characterized by calculating the time required for pH(i) recovery (t(pHrec)). Applying this methodology, normal subjects showed a strong linear correlation between phosphocreatine (PCr) half-time and t(pHrec) (r = 0.90, P < 0.001). In mitochondrial myopathy (MM) patients with weakness in the limb examined, 9/10 had faster pH(i) recovery relative to PCr recovery; wide normal ranges from a control group which included deconditioned subjects resulted in 7 of those 10 patients having otherwise normal recovery indices. Therefore, modeling pH(i) recovery allows characterization of the entire pH(i) recovery and detects altered proton handling in MM patients, including those with otherwise normal recovery indices.

Aerobic training has been shown to increase work and oxidative capacity in patients with mitochondrial myopathies, but the mechanisms underlying improvement are not known. We evaluated physiological (cycle exercise, 31P-MRS), biochemical (enzyme levels), and genetic (proportion of mutant/wild-type genomes) responses to 14 weeks of bicycle exercise training in 10 patients with heteroplasmic mitochondrial DNA (mtDNA) mutations. Training increased peak work and oxidative capacities (20-30%), systemic arteriovenous O2 difference (20%), and 31P-MRS indices of metabolic recovery (35%), consistent with enhanced muscle oxidative phosphorylation. Mitochondrial volume in vastus lateralis biopsies increased significantly (50%) and increases in deficient respiratory chain enzymes were found in patients with Complex I (36%) and Complex IV (25%) defects, whereas decreases occurred in 2 patients with Complex III defects (approximately 20%). These results suggest that the cellular basis of improved oxygen utilization is related to training-induced mitochondrial proliferation likely resulting in increased levels of functional, wild-type mtDNA. However, genetic analysis indicated the proportion of wild-type mtDNA was unchanged (3/9) or fell (6/9), suggesting a trend toward preferential proliferation of mutant genomes. The long-term implications of training-induced increases in mutant relative to wild-type mtDNA, despite positive physiological and biochemical findings, need to be assessed before aerobic training can be proposed as a general treatment option.

The purpose of this study was to assess the effect of physical deconditioning on skeletal muscle's oxidative metabolism as evaluated by phosphorus-31 magnetic resonance spectroscopy ((31)P MRS). Twenty-seven subjects without muscle disease, representing a wide range of fitness levels, were evaluated with (31)P MRS. Spectra were obtained at rest and during recovery from in-magnet exercise. The data show a significant correlation between maximum resting metabolic equivalent (MET) score and the following (31)P MRS recovery indices: adenosine diphosphate and phosphocreatine recovery half-time; initial phosphocreatine resynthesis rate; calculated estimation of mitochondrial capacity; pH at end of exercise; and phosphocreatine depletion. In addition, significant differences between the deconditioned and conditioned group were found for all of the aforementioned recovery indices. At rest, only the inorganic phosphate concentration was significantly different between the two groups. These data indicate that physical activity level should be taken into account when assessing patients' oxidative metabolism with (31)P MRS.

We have previously demonstrated that patients with mitochondrial myopathies can benefit from short-term aerobic exercise training. In this study, we compared the responses to short-term aerobic training of patients with mitochondrial myopathies, patients with nonmetabolic myopathies, and sedentary normal subjects. Training consisted of 8 weeks of treadmill exercise at 70% to 85% of estimated maximum heart rate reserve. All groups showed significant improvements in estimated aerobic capacity as well as heart rate and blood lactate at submaximal exercise intensities. The increase in estimated aerobic capacity was greater in the mitochondrial myopathy patients than in the other two groups. Phosphorus magnetic resonance spectroscopy demonstrated increased oxidative capacity of muscle in patients with mitochondrial myopathies in response to this training but not in patients with other, nonmetabolic myopathies or sedentary control subjects. A self-assessed measurement of functional status (SF-36) suggested improved quality of life associated with the training. This study demonstrates that short-term aerobic training at low intensity can benefit patients with nonmetabolic myopathies but to a lesser extent than patients with mitochondrial myopathies.

Phosphorus magnetic resonance (MR) spectroscopy was used to measure the recovery kinetics of calculated cytoplasmic metabolically active adenosine diphosphate (ADP) after exercise in normal subjects and patients with mitochondrial myopathies. These kinetics have previously been fitted with a single exponential function, despite a complex time-dependent undershoot in many subjects. By considering the transition from ischemic-exercise to perfused-recovery as a step function input, a second-order linear system was developed yielding a step response function to fit the ADP recovery. Using this method, an average improvement in fit of 23% resulted in a significant improvement in the characterization of ADP recovery for all normal subjects with substantial undershoot. The patient group had a comparable improvement in fit of 11%. Fitting the ADP recovery with a second-order step response function can provide significantly better characterization of muscle oxidative metabolism in vivo. Magn Reson Med 41:926–932, 1999. © 1999 Wiley-Liss, Inc.