Energy failure in multiple sclerosis and its investigation using MR techniques

Abstract

Energy failure is an emerging concept in multiple sclerosis research. Pathological studies have indicated that axonal modifications in response to demyelination may increase neuronal energy demand. At the same time, soluble mediators of inflammation may impair mitochondrial function, and brain perfusion may also be decreased. Insufficient energy production for demand can lead to intracellular sodium accumulation, calcium influx and cell death. Magnetic resonance (MR) is a promising technique to investigate these pathology driven hypotheses in vivo. MR spectroscopy can inform on mitochondrial function with measures of N acetyl aspartate (NAA), and requirement for extra-mitochondrial glycolysis via measurement of lactate. MR measurement of phosphorous ((31)P) and sodium ((23)Na) allows direct assessment of energy availability and axonal sodium handling. MR techniques for imaging perfusion can quantify oxygen delivery and nascent MR techniques that exploit the paramagnetism of deoxyhaemaglobin may be able to quantify oxygen utilization. This report reviews the physical principles underlying these techniques, their implementation for human in vivo imaging, and their application in neurological conditions with an emphasis on multiple sclerosis. Combination of these techniques to obtain a comprehensive picture of oxygen delivery, energy production and utilization may provide new insights into the pathophysiology of multiple sclerosis and may provide outcome measures for trials of novel treatments.

Association between Anemia and Multiple Sclerosis

“…Persistent inflammatory processes characterizing MS may lead to chronic anemia by the mechanisms described earlier; also, preexisting anemia could determine a reduced oxygenation of tissues depleting their energy reserve. This mechanism may be similar to the one that involves the mitochondrial deficits [26], and further supports an emerging concept of energy metabolism failure in MS leading to intracellular sodium accumulation, calcium influx and cell death [27]. …”

Reduced R2′ in multiple sclerosis normal appearing white matter and lesions may reflect decreased myelin and iron content

“…Experimental and animal studies suggest that disturbance in neuronal metabolism may be a common pathway to progressive neuroaxonal loss 9. Suggested mechanisms include mitochondrial dysfunction, hypermetabolism and hypoperfusion 10. Accumulation of iron could also lead to tissue damage by catalysing the production of free radicals, increasing oxidative stress 11.…”

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…In line with these observations, lactate has long been suggested as an imaging marker of neuroinflammation in the clinic. A few studies on MS patients have used 1 H magnetic resonance spectroscopy (MRS)/ MRS imaging (MRSI) approaches and detected increased levels of 1 H lactate in gadolinium-enhancing lesions (19,20) as well as in the cerebrospinal fluid of patients with such active lesions (21-24).Over the last decade, dissolution dynamic nuclear polarization coupled with 13 C MRSI has developed as a metabolic imaging approach of high potential (25,26). Through increase in the MRdetectable signal of 13 C compounds by up to 50,000 [so-called hyperpolarized (HP) probes] this methodology has enabled the noninvasive monitoring of several metabolic reactions in vivo (27)(28)(29)(30)(31)(32).…”

“…In line with these observations, lactate has long been suggested as an imaging marker of neuroinflammation in the clinic. A few studies on MS patients have used 1 H magnetic resonance spectroscopy (MRS)/ MRS imaging (MRSI) approaches and detected increased levels of 1 H lactate in gadolinium-enhancing lesions (19,20) as well as in the cerebrospinal fluid of patients with such active lesions (21)(22)(23)(24).…”