The Genetic Key to Recovery: How BDNF Shapes Rehabilitation Outcomes in Progressive MS

Rehabilitation in progressive multiple sclerosis (MS) is vital, but identifying predictive biomarkers to determine patient responsiveness to therapy remains a challenge. A recent study published in Frontiers in Neurology sheds light on the influence of the BDNF Val66Met polymorphism in predicting motor recovery outcomes post-rehabilitation in progressive MS patients.

The Importance of Brain-Derived Neurotrophic Factor (BDNF)
BDNF is a neurotrophin crucial for synaptic plasticity, brain repair, and neuronal survival. The gene's Val66Met polymorphism (rs6265) involves a valine-to-methionine substitution, which can alter BDNF's intracellular trafficking and activity-dependent secretion. While typically associated with diminished cognitive and motor learning in neurodegenerative conditions, this polymorphism's role in MS rehabilitation outcomes had not been thoroughly explored.

Study Objectives and Design
The study aimed to assess whether BDNF Val66Met or other genetic variants in its receptor gene, NTRK2, are associated with motor recovery after intensive neurorehabilitation. The cohort included 100 progressive MS patients (79 secondary progressive and 21 primary progressive) who underwent an intensive inpatient program comprising strength training, balance exercises, and gait training.

Patients' motor functions were evaluated using:
Six-Minute Walking Test (6MWT): Measures endurance and walking capacity.
Ten-Meter Test (10MT): Evaluates short-distance gait performance.
Nine-Hole Peg Test (9HPT): Assesses manual dexterity.

Genetic data were analyzed using dominant models to correlate SNPs with changes in motor test scores.

Key Findings
BDNF Val66Met Enhances Gait Recovery:
Met-carriers demonstrated significantly greater improvement in 6MWT scores compared to Val homozygotes (p = 0.024).
No significant associations were observed for 10MT and 9HPT.

No Impact from NTRK2 Variants:
Polymorphisms in NTRK2 (rs2289656 and rs1212171) showed no influence on rehabilitation outcomes.

Clinical Predictors:
Higher baseline Expanded Disability Status Scale (EDSS) scores and longer disease duration were linked to poorer rehabilitation outcomes.

Biological Implications
The findings align with previous evidence suggesting that the Val66Met polymorphism may mitigate brain atrophy in MS, particularly in gray matter and hippocampal volumes. Enhanced plasticity and reduced maladaptive cortical changes in Met-carriers could underpin their superior rehabilitation outcomes. However, the effects of this polymorphism appear context-dependent, potentially differing between healthy individuals and those with MS.

Study Limitations
The authors acknowledged limitations, including:
Small Sample Size: Statistical power was constrained.
Retrospective Design: A prospective approach would minimize bias.
Narrow Focus: Additional variables, such as medication effects, fatigue, or neuroimaging, were not explored.

Conclusions and Future Directions
This pioneering study links BDNF Val66Met to improved rehabilitation outcomes in progressive MS, emphasizing its potential as a biomarker for personalized therapy. Larger, prospective studies incorporating neuroimaging and functional assessments are warranted to validate these findings and unravel the molecular pathways involved.

References:
Giordano, A., Clarelli, F., Cannizzaro, M., Mascia, E., Santoro, S., Sorosina, M., ... & Esposito, F. (2022). BDNF Val66Met polymorphism is associated with motor recovery after rehabilitation in progressive multiple sclerosis patients. Frontiers in neurology, 13, 790360.