Brain Sodium Linked to Cognitive Deficits in MS

Pauline Anderson

December 28, 2016

Total sodium accumulation in the gray matter of patients with relapsing-remitting multiple sclerosis (RRMS) better explains their cognitive impairment than does gray matter atrophy, a new study suggests.

Investigators, led by Adil Maarouf, MD, Aix-Marseille University Medical School, Marseille, France, found that total sodium accumulation in patients with MS and cognitive impairment is mainly located in the neocortex.

Of the three main pathologic events involved in MS, only inflammation and demyelination can be explored by using imaging. There are currently no robust biomarkers to asses the third issue — degeneration.

"With sodium MRI, we try to overcome this deficiency. This is all the more important as degeneration is probably the most destructive of these three phenomena and is crucial to explain disability of MS patients," said Dr Maarouf.

Dr Adil Maarouf

However, use of imaging methods to assess neurodegenerative processes "is on the way," as are neuroprotective drugs, he added.

The findings were published online December 14 in Neurology.

Virtual Hypoxia

The study included 58 patients with MS and a control group of 31 matched healthy controls.

In addition to using the Expanded Disability Status Scale to evaluate patient disability, researchers also used neuropsychological assessments. Patients were classified as cognitively impaired if they had a score below 2 standard deviations for at least two tests compared to the mean score of the matched controls.

Of the 58 patients with MS, 21 were classified as cognitively impaired and 37 as cognitively preserved.

Using MRI, researchers obtained the total sodium concentration (TSC) in different brain compartments (lesions, normal-appearing white matter, and gray matter [GM]) and assessed GM atrophy.

The study found that cognitively impaired patients had a lower GM fraction (percentage of GM compared to the total brain volume) compared to cognitively preserved patients and controls (P = .015).

Although patients with cognitive impairment "were slightly more atrophic" than patients without cognitive impairment, atrophy did not explain cognitive status, said Dr Maarouf.

This is probably related to the relatively short disease duration among study patients (median <3 years) "and consequently to the restricted level of atrophy," he said.

Neuronal Suffering

TSC was increased in GM and normal-appearing white matter in cognitively impaired patients compared with CP patients and controls. TSC increases were found in cognitively impaired patients relative to cognitively preserved patients within the prefrontal cortices, cingulate cortices, cingulum, precuneus, left middle temporal gyrus, and left somatosensory association cortex.

Sodium accumulation, particularly in GM, in cognitively impaired patients "affects regions involved in brain communication and neural integration," said Dr Maarouf.

"These regions are the crossroads of neural information."

The study showed that older age (P = .026) and a higher GM TSC (P = .004) were the best predictors of global cognitive impairment.

At the individual level, TSC values in GM (area under the curve, 0.73) helped differentiate between cognitively impaired and cognitively preserved patients with a sensitivity of 76% and a specificity of 71%.

Dr Maarouf explained that a chronic state of "virtual hypoxia" is induced in chronically inflamed and demyelinated axons in patients with MS, which causes sodium accumulation within the axon and the neuron.

Through complex phenomena of ion exchange and enzymatic cascades, this sodium accumulation leads to calcium accumulation and neuronal apoptosis.

"So sodium accumulation is a reflection of a neuronal suffering just before irreversible loss, and is seen early in MS patients with cognitive impairment but also at more advanced stages of the disease: for example, in patients with a disease duration of more than 15 years and those with a progressive form of the disease," said Dr Maarouf.

Treatment Implications?

Reversing sodium accumulation — and the subsequent calcium-dependent cytotoxicity — might involve "fighting against" chronic inflammation and demyelination, said Dr Maarouf.

However, he pointed out that a previous study that tried to block sodium channels with lamotrigine failed to prevent neurodegeneration.

The researchers believe that sodium MRI can highlight the "neuronal suffering" — before irreversible neuronal loss as depicted by atrophy, said Dr Maarouf.

He hopes that it will eventually be possible to intervene therapeutically at the onset of cognitive impairment, although how such a therapy would work is "not yet clearly defined."

In a "broader perspective," though, sodium MRI "is on the way to becoming a biomarker accessible for clinical trials, especially those assessing neuroprotective drugs," he said.

Although not an expert in sodium metabolism in MS, Barbara Giesser, MD, professor, neurology and medical director, Marilyn Hilton Multiple Sclerosis Achievement Center, University of California at Los Angeles, agreed that the study results could have treatment implications.

"If the results of this small study are replicated, it may suggest novel pharmacologic approaches for treatment," said Dr Giesser when asked to comment on the study.

She noted that cognitive impairment is estimated to occur in at least half of MS patients. "There are currently no effective medications for this."

Dr Maarouf received travel grants from commercial pharmaceutical companies: Biogen Idec, Novartis, Merck Serono, Bayer Schering, MedDay, and Teva Santé. Dr Giesser has disclosed no relevant financial relationships.

Neurology. Published online December 14, 2016. Abstract

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