Fatigue Severity in MS Predicted by Shrinkage of Certain Brain Regions

Lower-than-normal volumes of certain brain regions at disease onset — indicating shrinkage, or atrophy, in those regions — are significantly associated with current and future fatigue severity in people with multiple sclerosis (MS), a study in Germany shows.

Some of these regions also were found to be central brain network hubs in MS patients with progressive fatigue, suggesting a potential early role in fatigue evolution in this patient population.

These findings point to early, specific brain atrophy as a predictive biomarker of fatigue worsening and support the implementation of fatigue-targeting strategies from disease onset in patients at higher risk, the researchers noted.

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The study, “Subcortical Volumes as Early Predictors of Fatigue in Multiple Sclerosis,” was published in the journal Annals of Neurology.

MS is characterized by the loss of myelin, the protective sheath that covers nerve fibers, or axons, which leads to axonal degeneration in the central nervous system (brain and spinal cord) and neurological damage.

Fatigue, affecting up to 80% of MS patients, is associated with clinical disability and is one of the main causes of reduced quality of life for people with this neurodegenerative disorder.

This symptom is commonly reported in the first year after an MS diagnosis, and among patients with clinically isolated syndrome (CIS), which typically precedes MS. It also has been proposed as early sign of MS, occurring before clinical manifestations of the disease.

However, the underlying mechanisms behind MS-related fatigue remain largely unclear, and there is an unmet need for predictive biomarkers of fatigue worsening that could help implement appropriate approaches to lessen such progression.

Notably, previous studies suggested that fatigue is associated with atrophy of certain brain regions, as assessed with MRI scans.

Since the progressive loss of brain volume, which is mostly driven by atrophy of the brain’s gray matter, is a hallmark of MS, a team of researchers in Germany now sought to assess whether gray matter volume in any brain region was associated with fatigue severity. Of note, gray matter is mainly made of nerve cells bodies, while white matter is made of nerve fibers.

Their study examined fatigue severity at disease onset and after four years in 601 adults — 424 women and 177 men — newly diagnosed with CIS or relapsing-remitting MS (RRMS). A potential link between gray matter loss and fatigue severity also was evaluated in 89 people without a neurological disease, who served as controls.

The patients, recruited at 15 neurological tertiary referral centers in Germany, were participating in a multicenter, prospective, observational study, called the German National MS cohort. None of them had received prior treatment for their condition.

Their mean age was 33.2 years at disease onset, and they had been living with CIS (256 patients) or RRMS (344 patients) for a mean of 7.3 months. Patients’ fatigue was assessed with two validated measures — the Multiple Sclerosis Inventory of Cognition (MUSIC) and the Fatigue Scale for Motor and Cognitive Functions (FSMC) — while disability was measured with the Expanded Disability Status Scale.

The predictive potential of brain volume loss in fatigue severity was assessed in a subgroup of 230 patients who had available follow-up data after four years. Among these patients, 100 had CIS and 130 RRMS.

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At four years, 77% of those who were initially diagnosed with CIS had converted to RRMS, and 44% of patients had started a disease-modifying therapy.

Results showed that, at disease onset, more severe fatigue — as assessed with both measures — was significantly associated with reduced gray matter volume in the caudate and putamen on both sides of the brain. These deep brain regions are known to be involved in cognitive function, reward, and motivation.

Significant links also were observed for the thalamus, on the right side of the brain, which relays sensory impulses, and the hippocampus, on the left side, involved in short-term memory.

No associations between gray matter volume reduction and fatigue were detected among healthy individuals.

For the patients followed for the entire study period, gray matter loss in bilateral caudate, left putamen, bilateral pallidum, and pons at disease onset significantly predicted greater fatigue after four years. The pallidum also is involved in reward and motivation, while the pons is part of the brainstem, a highway-like structure that relays signals between the brain and the body.

Notably, the gray matter volume of some of these deep brain regions was also found to be significantly associated with patients’ current and future MS-related disability.

These findings highlight that “early fatigue is related to [deep gray matter] integrity loss at disease onset,” and that gray matter reductions, “mainly within the caudate, pallidum, and pons, are important scaffolds in predicting emerging fatigue,” the researchers wrote.

Additional analysis revealed that the putamen, the pons, and the brainstem were brain network hubs in patients with fatigue worsening after four years, but not in those with stable fatigue.

This could reflect the brain network’s “response to early tissue damage through structural reorganization,” the team wrote.

Also, the co-localization of these deep brain regions with structural network hubs in patients who experienced fatigue progression “suggests a prominent role of these brain regions in terms of fatigue evolution in the initial stages of the disease and probably even [before clinical manifestations],” they added.

“These observations should urge close follow-up of high-risk patients for fatigue worsening, encourage clinical decisions already from the disease onset and thereby reduce the burden of progressing fatigue,” the researchers concluded.