For nearly a century after French neurologist Jean-Martin Charcot first identified multiple sclerosis (MS) in 1868, the only way clinicians could measure the progress of the disease was to observe a patient's relapses, along with the gradual physical and cognitive degeneration.

During MS, the body's immune system damages the myelin sheaths that wrap around the axons, or nerve fibres, in the brain and spinal cord. This results in demyelination of the axons, along with scars, called lesions, in the brain and spinal cord. Much of the scarring results from inflammation. In the 1980s, magnetic resonance imaging (MRI) allowed scientists to view the lesions, which range from a few millimetres to several centimetres in diameter, and see how MS was devastating the nervous system. In 1993, the first treatment to tackle the cause of the disease was approved, a drug called interferon β. Doctors could finally both slow the progression of neurological deterioration and monitor MS in the nervous system.

Today, researchers have a greater understanding of the disease and realize that the lesions made visible by MRI offer only a partial view of the neural deterioration caused by MS. “What we now image with MRI is associated with inflammation,” says Peter Calabresi, director of the Johns Hopkins Multiple Sclerosis Center in Baltimore, Maryland. “What we'd like to know is the integrity of the nerve wires, the axons.”

MRI of a person with MS brain shows regions that have begun to lose their myelin sheath (yellow) near the centre of the brain. Credit: SCOTT CAMAZINE/SCIENCE PHOTO LIBRARY

Since 1993, five injectable drugs and, more recently, one oral drug have been approved (see Graham-Rowe article). They all combat the early, inflammatory stage of the disease. However, 10–15 years after diagnosis, most patients experience neurological impairment, such as fatigue, difficulty walking and some form of cognitive decline, signifying neural degeneration. “Neurons and axons die because of demyelination that is somewhat related to inflammation, but not directly,” says Moses Rodriguez, professor of immunology and neurology at the Mayo Clinic in Rochester, Minnesota. The drugs that target inflammation might not be having a significant long-term effect on demyelination. And MRI scans do not offer a detailed image of the myelin sheath or a way of assessing the success of any treatment that attempts to rebuild the myelin and improve the health of the nervous system. In response, several technologies are being developed to peer more closely into a patient's neural networks.

Beyond MRI

A conventional MRI scan sends out pulses of radio waves that excite the nuclei of the atoms in water, especially the hydrogen protons. The scan then measures the signal from the nuclei and contrasts it with the time it takes the nuclei to return to their original state. The difference in signals from various types of matter, such as grey and white, or fluid in the brain, creates a map. But the water molecules that are bound to the fatty myelin sheaths — unlike freely moving unbound ones — relax too quickly to be detected, so conventional MRI does not provide much detail about the health of the myelin.

As a result, researchers have turned to a type of MRI developed in the early 1990s, called magnetization transfer ratio (MTR), which sends out a slightly different signal that is tailored to excite those bound molecules. This measurement is then compared with the original signals from freely moving water molecules. The ratio of the two signals reveals the amount of water bound to the myelin sheaths. In animals, MTR levels have been shown to correspond to the amount of myelin. This correlation has also been observed in post-mortem human brains, and was verified in a study of six living MS patients at McGill University's Montreal Neurological Institute and Hospital in Canada.

However, MTR has its drawbacks. For example, the view of the health of the myelin sheaths can be complicated by other factors in the brain, such as inflammation. What is more, the technology is too time-consuming for routine patient monitoring. But it could be a valuable analytical tool in clinical trials, and Rodriguez plans to use a version of MTR to quantify the reconstruction of myelin in a trial to be held at the Mayo Clinic this year.

To capture more detail of the movement and location of water along nerve cells, researchers use a technique called diffusion tensor imaging (DTI), which offers complementary details to fill out the picture from an MTR scan. In normal neurons, water moves freely along the length of an axon but is blocked by the myelin from moving in and out of it. Changes in the nervous-system tissue, such as those caused by inflammation or demyelination, affect the permeability of cell structures and alter the movement of water. Using DTI allows researchers to detect this greater permeability and spot areas of myelin loss. The technique now has a variety of medical uses, such as evaluating the white matter around a brain tumour in the area to be excised, and is a diagnostic tool to determine the extent of traumatic brain injury and the progression of neurodegenerative disorders such as Alzheimer's disease.

“MTR will give you a very good picture of the whole white matter, all the interconnected bundles of axons that connect left to right and front and back [in the brain] and down into the spinal cord, but it doesn't differentiate among the bundles of white matter,” says physicist Andrew Blamire at Newcastle University's Magnetic Resonance Centre in the United Kingdom, who published a paper in the British Journal of Radiology on the development and future of MRI technology. Using DTI allows researchers to differentiate among those axon bundles, and perhaps pinpoint areas of degeneration.

In 2011, scientists from Johns Hopkins and the US National Institutes of Health published a paper suggesting that the combined use of DTI and MTR could help to determine the efficacy of drugs that protect the neurons in MS patients. DTI can identify specific areas to be studied and tell researchers whether the axons are intact, explains Daniel Harrison, a Johns Hopkins neurologist and lead author on the paper. Using MTR gives an overall picture of how much myelin remains in those areas.

The eye might be an ideal location for measuring the health of the axons, says Calabresi. “The eye is a window into the brain,” he explains. “Retinal nerves are not myelinated until they're out of the eye and become the optic nerves — but it's the same nerves.” These nerves pass through the outer boundary of the eye and become myelinated after they leave a mesh of collagen fibres called the lamina cribrosa.

In the brain, various pathologies, including inflammation, can disrupt attempts to create a clear image of demyelination. Optic nerves offer a clearer view. Calabresi is working with researchers at the University of Texas Southwestern Medical Center in Dallas and the University of Pennsylvania in Philadelphia to test the value of optical coherence tomography (OCT) in tracking the course of MS. In OCT, a microscopic picture of the nerves on the retina is taken, and the interference patterns created by the light waves are analysed to provide a detailed view of the thinning of the myelin. “The resolution is spectacular,” Calabresi says — just 3–4 μm, rather than the 50 μm provided by a high-field MRI.

The team has demonstrated that atrophy along the optical nerves correlates with atrophy in the brain. As a result, OCT scans are at least as effective as MRI for lesions. Johns Hopkins, the University of Texas and the University of Pennsylvania all now use OCT machines in their patient-treatment centres to monitor axonal health, and others, including the Cleveland Clinic in Ohio, are following suit. Calabresi says the technology could also be used in clinical trials to demonstrate whether a drug protects axons from degeneration.

Comparing outcomes

The task of imaging MS progression is complicated by the fact that long-term deterioration of the myelin sheath and axons typically takes about 10–15 years. “The big question is this,” says Mayo Clinic neurologist Brian Weinshenker. “Is what we do early in the disease to reduce inflammation effective in preventing the later phases of neurodegeneration?” There's a chance, he says, that the anti-inflammatory drugs are also shielding the nervous system, and that without these drugs a patient's disability would be far worse. Little information is available, however, because there are no long-term studies that have a control group of patients who are not taking any disease-modifying drugs.

“It's been a bit muddy,” says Weinshenker. He points out that some studies claim that patients who stayed on a particular drug seem to do better than those who did not. But there is no clear cause and effect: “Did they do well because they stayed on the drug, or did they stay on the drug because they were doing well?” Having unambiguous data on the underlying pathological changes will help researchers assess whether the current approach of treating everyone with anti-inflammatory drugs as soon as they are diagnosed with MS is justified. Some patients seem to be almost symptom-free with no treatment at all and might not need anti-inflammatories.

Then there is the challenge of managing the effects of MS, rather than the disease process itself. Drugs approved in the past few years treat symptoms such as muscle spasticity, difficulty walking, and uncontrollable laughter and crying. In general, assessing the treatment of such symptoms is straightforward: if the drugs work, the symptoms subside. But the improvement of cognitive function is harder to quantify over the relatively short timeline in which researchers traditionally test new drugs, says Aaron Miller, medical director of the Corinne Goldsmith Dickson Center for Multiple Sclerosis at the Mount Sinai School of Medicine in New York. In addition, Miller points out, performance on cognitive tests might be affected by other factors, such as depression and medications.

Nicholas LaRocca, vice-president of healthcare delivery and policy research at the National Multiple Sclerosis Society in New York, believes that appropriate study design can account for such complications. The society is funding research at the University of California, Los Angeles, to evaluate the impact of exercise on cognitive function. The study uses the paced auditory serial addition test — a standard tool to assess brain injury in which patients add a series of numbers spoken to them — as well as tests of verbal and visual memory, language, attention and executive function. Depression and fatigue are being tracked as well.

The advances in monitoring MS, in terms of both the disease and its symptoms, are a long way from the crude observational metrics developed in the nineteenth century. For individual patients, these tools might provide greater detail about where they are on their MS journey. For researchers and clinicians, the diagnostic information will help to develop treatments to stem the disease's progression — and perhaps, eventually, to find a cure.