BDNF Risk Variant Linked to Brain Inflammation in New RRMS Patients

A risk variant in the BDNF gene is tied to increased brain inflammation and reduced cortical thickness on MRI scans in people newly diagnosed with relapsing-remitting multiple sclerosis (RRMS), a recent study found.

“We report for the first time an association between the BDNF [genetic variant] and central inflammation in MS patients at the time of diagnosis,” the researchers wrote.

The study, “The BDNF Val66Met Polymorphism (rs6265) Modulates Inflammation and Neurodegeneration in the Early Phases of Multiple Sclerosis,” was published in Genes.

Multiple sclerosis (MS) is thought to arise from a combination of genetic and environmental risk factors. A genetic variant in BDNF, the gene responsible for making the brain-derived neurotrophic factor (BDNF) protein — a growth factor involved in neuroprotection — previously was identified as a potential MS risk factor.

BDNF also seems to dampen brain inflammation and to promote the formation of myelin, the protective substance surrounding nerve cells that is wrongly targeted in MS.

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To date, the role of this genetic variant — called Val66Met — in MS remains controversial. A team of researchers in Italy set out to determine if the presence of this variant influenced disease features in people with RRMS. The team particularly focused on inflammatory molecules and MRI changes at the time of diagnosis.

Their study involved 218 newly diagnosed patients, 71.1% of whom were female, with a median age of 34 years. These patients had been diagnosed a median of three months earlier.

Every person has two copies of the BDNF gene: one inherited from each parent. Thus, the Val66Met variant can be inherited from one, both, or neither parent. Among these patients, 12 had two copies of Val66Met (5.5%) and 70 had one copy (32.1%). The remaining 136 people had no copies of this variant (62.4%).

Using a machine-learning algorithm that examined the levels of 27 inflammatory molecules, the team found that a combination of several molecules — including TNF, IL-8, and MCP-1 — were significantly higher in people with either one or two copies of the variant (called Met carriers).

Specifically, median TNF levels in Met carriers was 2.8 picograms per milliliter (pg/mL) compared with 1.95 pg/mL for non-carriers. IL-8 levels were a median of 23.8 pg/mL for Met carriers and 19.4 pg/mL for non-carriers, while MCP-1 levels rose from a median of 120.8 pg/mL in non-carriers to 139.4 in carriers.

All three markers have been previously associated with either MS development or disease progression.

“Our results suggest that MS patients [who are Met carriers] may present with higher levels of [brain] inflammation at diagnosis,” the researchers wrote.

This is in line with previous findings that BDNF is anti-inflammatory in mouse models of brain inflammation, including an MS model, suggesting that reduced or altered BDNF function resulting from the Val66Met alteration could increase inflammation.

Consistent with the increased inflammation in Met carriers, these patients also had reduced cortical thickness on MRI scans compared with non-carriers. This thinning is thought to represent neurodegeneration and is often accelerated in neurodegenerative conditions.

In contrast, previous studies suggested that Val66Met could protect against neurodegeneration in MS patients. This could be due to the variant’s ability to counteract BDNF buildup in the brain during the later stages of disease, which also can be toxic.

Since the results of this study were collected shortly after diagnosis, the role for BDNF may be different in these patients, the researchers noted.

“Our findings suggest a role for this [variant] in both inflammatory and neurodegenerative processes and may contribute to explaining its complex influence on the MS course,” the researchers concluded.