CHIT1 levels at diagnosis may predict future MS progression
Immune cell protein seen to work better than other biomarkers in study
Levels of the immune cell protein CHIT1 at diagnosis, taken from the spinal fluid via a spinal tap, may strongly predict how fast disability progression will occur in people with multiple sclerosis (MS), a new study suggests.
Compared with standard clinical measures used to predict disease progression — such as age, current disability, or disease duration — CHIT1 levels measured at diagnosis emerged as the next most important predictor, before other well-known spinal fluid biomarkers.
“We believe CHIT1 has potential to cater to the unmet need for tools to aid MS clinicians in patient stratification and therapy selection,” the researchers wrote, adding that the measure “might enable a more personalized approach in the treatment of MS patients.”
The study, “CHIT1 at diagnosis predicts faster disability progression and reflects early microglial activation in multiple sclerosis,” was published in Nature Communications.
Researchers tested 5 proteins for ability to predict MS outcomes
MS is an autoimmune condition marked by damage to the myelin sheath, a fatty protective coating surrounding nerve fibers, in the brain and spinal cord. Depending on which parts of the nervous system are most affected, MS symptoms and severity can vary widely from person to person.
As a result, accurately predicting long-term outcomes across the range of MS patients remains a major challenge in disease care.
Emerging evidence suggests that immune cells that reside in the brain, called microglia, as well as immune macrophages, which are very similar to microglia but enter the brain from the bloodstream, both play a role in the altered immune response that drives MS.
These cells “are anticipated to provide novel strategies in the development of biomarkers for MS disease activity,” according to a team led by scientists at KU Leuven, in Belgium.
Thus, the team investigated whether the levels of five microglia/macrophage-related proteins found in the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, at diagnosis can predict MS outcomes.
CSF was collected via a lower spinal tap from 192 newly diagnosed MS patients, of whom more than half were women (60.9%). Most (80.7%) had symptoms of relapsing-remitting MS (RRMS). Their median age at disease onset was 33.9 years.
Among the five potential biomarkers, only CHIT1 levels showed a significant association with disability at a median follow-up of 5.4 years. The higher the levels of this biomarker at diagnosis, the worse the disability at this assessment.
The researchers used three different assessments in this study to measure disability: Age-Related Multiple Sclerosis Severity (ARMSS), Multiple Sclerosis Severity Score (MSSS), and Expanded Disability Status Scale (EDSS).
When multiple EDSS assessments were examined up to 15 years after diagnosis, MS patients with initially higher CHIT1 similarly experienced faster disability progression over time. Men and women had similar results.
CHIT1 levels found to be ‘robust predictor’ for MS progression
A machine learning analysis confirmed several known factors that best predict disability progression in MS, including disease course and EDSS scores, age at diagnosis, and disease duration at diagnosis. After these, CHIT1 levels at diagnosis emerged as the next most important predictor.
“Our machine learning model thus demonstrated the prognostic superiority of CHIT1 over the other CSF biomarkers,” the researchers wrote.
We demonstrated that CHIT1 concentration in CSF [cerebral spinal fluid] at diagnosis is a robust predictor for faster disability progression in MS patients.
To identify the source of CHIT1 in the CSF, researchers examined MS brain tissue. High levels of CHIT1 production were revealed in a subset of microglia cells. Samples taken from the edge of lesions, or areas of myelin damage, and lesions with chronic inflammation, were most enriched in cells with CHIT1.
When MS brain tissue was stained, normal-appearing white matter, composed of fully myelinated nerve fibers, showed no signs of CHIT1. In comparison, CHIT1-producing cells were found in nearly all actively demyelinating lesions (95.2%), but not in inactive lesions.
Gene activity patterns in microglial cells known to be associated with MS showed considerable overlap in the subset of CHIT1-producing microglial cells. These overlap patterns extended cells undergoing foam cell differentiation, when immune cells engulf a lot of fat-lipids, such as those found in myelin, giving them a foamy appearance.
Lastly, increased production of CHIT1 coincided with microglia cells transitioning from an inactive, resting state to a more active MS-like state.
“We demonstrated that CHIT1 concentration in CSF at diagnosis is a robust predictor for faster disability progression in MS patients and reflects early microglial activation,” the researchers wrote.
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