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The following summarizes some of the highlights from Day 3 of the American Academy of Neurology annual meeting (AAN), San Diego, CA, April 5-9, 2025.

MS risk with head trauma
Efficacy of first-line ofatumumab in patients without highly active disease
Semaglutide may reduce MS progression
Higher MS risk with earlier menarche
Biomarker dynamics after DMT initiation
Clinical tip of the day

CONGRESS HIGHLIGHTS – WEDNESDAY EDITION

MS risk with head trauma
Three decades ago, Charles Poser speculated that head trauma, by disrupting the blood-brain barrier, might be a risk factor for the development or worsening of MS, although he thought that attempts to prove such a link were inappropriate (Poser CM. Clin Neurol Neurosurg 1994;96:103-110). A meta-analysis subsequently reported that premorbid head trauma increased the risk of developing MS by about 40% (Lunny et al. J Neurol Sci 2014;336:13-23). The same result was reported in a new meta-analysis of 15 studies (odds ratio 1.41) (Mohamed et al. AAN 2025;P10.005). Full results were published last year (Abouelmagd et al. Mult Scler Relat Disord 2024:92:106183). The risk was consistent across categories of head trauma, including traumatic brain injury and concussion. The MS risk associated with trauma is reportedly worsened in patients with MS-associated HLA genotypes such as HLA-DRB1*1501 (Johansson et al. J Neurol Neurosurg Psychiatry 2024;95:554-560).

Efficacy of first-line ofatumumab in patients without highly active disease
A post-hoc analysis of the ALITHIOS extension study found that >90% of early MS patients with non-highly active disease activity had no evidence of disease activity (NEDA) at year 6 of treatment (Ziemssen et al. AAN 2025;P11.003). Early MS was defined as symptom onset <5 years; non-highly active disease activity was defined as no more than 1 relapse/year in the previous 1 or 2 years, treatment-naïve or only one prior DMT, and EDSS score <3.0. Mean age was 36 years; mean EDSS score was 1.8. In patients receiving continuous ofatumumab, 92% achieved NEDA at year 2 compared to 35% in the teriflunomide group; sNfL concentrations were substantially lower with ofatumumab vs. teriflunomide at year 2. In both the continuous ofatumumab and teriflunomide/ofatumumab switch groups, the odds of NEDA were >93% at year 6. Earlier treatment with ofatumumab was associated with a 33% reduction in the number of 6-month confirmed disability worsening events. A total of 83.5% of patients receiving early ofatumumab were free of 6M CDW events after six years. Serum IgG levels were stable with continuous ofatumumab over six years.

Semaglutide may reduce MS progression
Glucagon-like protein-1 (GLP-1) is a hormone that stimulates insulin release during hyperglycemic conditions. GLP-1 agonists were developed for diabetes and are now widely used for weight loss. It was speculated a decade ago that GLP-1 agonists may have anti-inflammatory neuroprotective properties (Holscher C. CNS Drugs 2012;26:871-882). More recent reviews have suggested that anti-inflammatory effects may be due to targeting of GLP-1 receptors on macrophages, monocytes and lymphocytes (Kaye et al. Cureus 2024;16:e67232). Animal studies have shown that GLP-1 agonists slow the onset and reduce the severity of EAE and promote myelination and nerve regeneration in nerve-crush injury models.

A retrospective cohort study compared MS patients treated with (N=7101) vs. without (N=249,175) concomitant GLP-1 agonists (Ali et al. AAN 2025;P11.007). Mean age was 53 years; 54% had comorbid Type 2 diabetes; and 46% had obesity. The risk of neurological deficits was significantly higher in all eight functional systems in MS patients not receiving a GLP-1 agonist. Risk ratios were 2.033 for pyramidal, 1.548 for cerebellar, 1.746 for brainstem, 1.359 for sensory, 1.528 for bowel/bladder, 1.745 for visual, 1.764 for cerebral and 2.916 for ambulation. The greatest reductions in the risk of neurological dysfunction were seen for bowel/bladder (14.42% to 9.45%), cerebellar (12.82% to 8.23%), and sensory (14.05% to 10.34%). The authors speculated that GLP-1 agonists may modulate the inflammatory response of immune cells, reduce leukocyte invasion into the CNS, improve antioxidant effects and/or protect oligodendrocytes and promote remyelination.

A separate retrospective propensity-score-matched analysis (n=205,870) of obese adults and controls reported that GLP-1 agonist use was associated with a lower risk of neurodegenerative disorders (Siddeeque et al. AAN 2025;S25.006). Risks were reduced for multiple sclerosis (RR 0.574), Parkinson’s disease (RR 0.784), Alzheimer dementia (RR 0.627), Lewy body dementia (RR 0.590), vascular dementia (RR 0.438), amyotrophic lateral sclerosis (RR 0.833), and Wilson’s disease (RR 0.833). There was also an overall reduction in mortality with GLP-1 agonist use (HR 0.525).

Higher MS risk with earlier menarche
A systematic review of 15 studies examined the association between MS risk and age at menarche (Shahraki et al. AAN 2025;P10.017). The group estimated that MS risk decreased 8% for every year that menarche occurred later. The same group previously reported that risk decreased 12% per year that menarche was delayed (Azimi et al. BMC Neurol 2019;19:286). An analysis of the Danish National Birth Cohort reported that individuals later diagnosed with MS had a significantly earlier onset of puberty (Nielsen et al. Am J Epidemiol 2017;185:712-719). For every additional year in age at menarche, the risk of MS was reduced by 13%.

Biomarker dynamics after DMT initiation
Serial measures (4-6/year) of neurofilament-light chain (NfL) and glial fibrillary acidic protein (GFAP) were evaluated in the first year after diagnosis in 106 MS patients (Uher et al AAN 2025;P6.012). Mean age was 33.6 years; mean baseline EDSS score was 2.0. Mean follow-up was 4.8 years. The largest proportion of patients had low sNfL Z-scores that remained stable (41.5%) or increased slightly (25.4%) after treatment initiation. In the two groups with the highest baseline sNfL Z-scores, sNfL was normalized (23.5%), or was reduced but remained elevated (9.4%). A higher sNfL Z-score at 1 year was predictive of a shorter time to relapse (hazard ratio 1.67). Most patients (63.2%) showed minimal change in serum GFAP Z-scores in the first year of treatment. In the group with increasing sGFAP Z-scores (n=33.9%), there was a trend to a higher risk of EDSS worsening.

Clinical tip of the day
OCB-positivity does not necessarily translate to a more severe initial presentation in MS patients. A retrospective analysis according to OCB status in RRMS patients (N=2324) found no significant difference in the age of onset, distribution of first MS symptoms, mean EDSS scores or cognitive test results in OCB-positive vs. OCB-negative patients (Alizada et al. AAN 2025;P11.015). Over the longer term, however, OCB-positivity is prognostic of worse outcomes (Joseph et al. J Neurol Neurosurg Psychiatry 2009;80:292-296).

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