Brain derived neurotrophic factor Val66Met polymorphism modifies progression independent of relapse activity and structural damage trajectories in multiple sclerosis

Abstract

Brain-derived neurotrophic factor (BDNF) supports neuroprotection and neuroplasticity, and its functional Val66Met polymorphism has been linked to heterogeneous clinical and MRI phenotypes in multiple sclerosis (MS). We investigated the medium-term effect of Val66Met compared with Val66Val status (wild-type) to disability accrual mechanisms and multimodal MRI markers of tissue damage and smouldering inflammation.

In this longitudinal cohort study, 97 relapsing-onset MS patients underwent BDNF genotyping and serial 3T MRI with contemporaneous neurological assessment. Confirmed disability worsening (CDW) events were classified as relapse-associated worsening (RAW), progression independent of relapse activity (PIRA) or progression independent of relapse and MRI activity (PIRMA). Associations between Val66Met carriage, compared with Val66Val status, and CDW were tested using Andersen–Gill recurrent-event Cox models with time-varying disease-modifying therapy exposure. Longitudinal MRI outcomes (lesion and brain volumes, cervical cord cross-sectional area, and myelin-sensitive standardized (s)T1/T2 indices in normal-appearing white matter and T2-hyperintense brain lesions) were analysed using linear mixed-effects models, to compare trajectories between Val66Met and Val66Val carriers. Slowly expanding lesions (SELs) were identified using a Jacobian-based framework and compared between genotype groups.

Twenty-eight participants (28.9%) were Val66Met carriers, with similar mean follow-up compared with Val66Val participants (8.2 ± 2.8 vs 8.3 ± 3.7 years; p = 0.801). Sixty-eight CDW events were observed. Val66Met carriage was associated with a lower hazard of CDW [hazard ratio (HR) 0.51, 95% CI [0.26, 0.98]; p = 0.042], driven by reduced PIRA (HR 0.44, 95% CI [0.20, 0.94]; p = 0.033) and PIRMA risk (HR 0.38, 95% CI [0.17, 0.86]; p = 0.020), with no association with RAW (HR 0.64, 95% CI [0.22, 1.91]; p = 0.426). Annualised relapse rate did not differ, whereas Val66Met carriers showed higher rates of new T2 lesions (incidence rate ratio 1.18, 95% CI [1.08, 1.28]; p = 0.026) and greater T2 lesion volume accrual (β 0.23, 95% CI [0.12, 0.35]; p < 0.001), alongside faster whole-brain volume loss (β -1.57, 95% CI [-2.86, -0.28]; p = 0.017) and cervical spinal cord atrophy (β -0.23, 95% CI [-0.41, -0.04]; p = 0.017). No genotype-related differences were detected in longitudinal sT1/T2 indices within lesions or normal-appearing white matter, and SEL burden was similar between groups.

Over follow-up, Val66Met carriage was associated with a lower risk of PIRA and PIRMA despite greater inflammatory lesion accrual and accelerated brain and spinal cord volume loss. This dissociation suggests that factors beyond structural injury may contribute to disability trajectories in MS.