American Academy of Neurology annual meeting – 13-18 April 2024
The following summarizes some of the highlights from Day 1 of AAN 2024.
April 18 Edition
April 17 Edition
April 16 Edition
BTK inhibitors in MS: update on fenebrutinib
Prognostic value of NfL in MS
NfL higher after sleep in Parkinson disease
Immune profiling of DMT response
CONGRESS HIGHLIGHTS – MONDAY EDITION
BTK inhibitors in MS: update on fenebrutinib
Evobrutinib, the first Bruton’s tyrosine kinase (BTK) inhibitor, posted negative results for its phase III trial (see Evobrutinib in MS – ACTRIMS Forum update, NeuroSens, March 11, 2024). Phase II and III trials of other BTK inhibitors are ongoing. In the FENopta trial, 106 RMS patients were randomized to fenebrutinib 200 mg BID or placebo for 12 weeks (Bar-Or et al. AAN 2024;S31.004). Fenebrutinib was associated with a 92% reduction in Gd+ lesions and a 90% reduction in new T2 lesions versus placebo at week 12. In a separate safety analysis of phase II studies, adverse events included elevated liver enzymes (5.5%) and urinary tract infection (5.5%) (Oh et al. AAN 2024;P9.012). Grade ≥2 elevations in hepatic transaminases occurred more frequently with fenebrutinib compared to placebo in MS patients (8.2% vs. 2.8%).
Prognostic value of NfL in MS
In the ASCLEPIOS I/II trials of ofatumumab, baseline sNfL concentration was predictive of new/enlarging T2 lesions (Hauser et al. N Engl J Med 2020;383:546-555). Subsequent analyses have examined whether the predictive value of baseline sNfL differs with age, body-mass index (BMI) and ethnicity. A cut-off value of 9.3 pg/mL was used to stratify high vs. low sNfL. A cut-off value of 24.5 kg/m2 was used to stratify higher vs. lower BMI. The cut-off for younger vs. older age was 38 years.
A higher vs. lower baseline sNfL was significantly predictive of new T2 lesions in the lower BMI group (annualized rate 4.04 vs. 2.10, relative risk 1.92) and in the higher BMI group (4.14 vs. 1.66, RR 2.49) (Cross et al. AAN 2024;P6.011). A higher vs. lower baseline sNfL was also significantly predictive of new T2 lesions in younger (annualized rate 5.68 vs. 2.91, RR 1.95) and older patients (2.50 vs. 0.94, RR 2.66). A separate study reported that a higher vs. lower baseline sNfL level was also predictive of new lesion formation in patients who are Black (RR 2.50) and Asian (RR 2.68) (Freeman et al. AAN 2024;P9.006).
In addition, sNfL during treatment is predictive of new disease activity, according to a new analysis of ASCLEPIOS I/II (Leist et al. AAN 2024;S42.003). Patients with a high sNfL level at month 3 of treatment had a significant 2.17-fold higher mean annualized rate of new T2 lesions compared to patients with a lower sNfL level (3.67 vs. 1.69). At month 12 of treatment, a higher sNfL level continued to be predictive of T2 lesion formation (4.90 vs. 1.37, RR 3.57). These findings support ongoing NfL assessment during treatment.
Interestingly, a U.S. pilot study reported that diet can significantly reduce sNfL (Verter et al. AAN 2024;P2.004). Mean sNfL concentration decreased from 18.54 to 15.43 pg/mL over a six-month period in women with MS who switched to a modified Mediterranean diet. NfL levels did not significantly change in the group that continued on their usual diet.
NfL higher after sleep in Parkinson disease
Sleep disturbances may contribute to disease progression and dementia in patients with Parkinson disease. A new study has examined biomarkers of neurodegeneration and neuroinflammation in 31 PD patients with and without cognitive impairment (Dintino et al. AAN 2024;P7.002). NfL levels were 16% higher in the morning vs. evening (6:30 am vs. 8:00 pm) in PD patients with mild cognitive impairment; NfL levels were not significantly different in non-MCI PD patients. Similarly, morning levels of TNF-alpha were higher in PD patients with MCI but not in non-MCI PD patients. No significant differences were seen in levels of alpha-synuclein, IL-6 or the chemokine Monocyte Chemoattractant Protein-1 (MCP-1). Sleep disturbance may impair clearance of proteins and metabolites by the glymphatic system and has been linked to neurodegenerative changes. The authors concluded that mechanisms of CSF clearance may need to be considered if NfL is used as a biomarker in PD.
Immune profiling of DMT response
A Canadian study has examined the impact of disease-modifying therapies on immune markers in CSF and blood samples obtained from MS patients (Arsenault et al. AAN 2024;S42.009). Significant increases were observed in CD8+ T cells and CD19+ B cells in the CSF of treatment-naïve patients compared to controls. The number of T cells, B cells and NK cells was lower in DMT-treated patients. cNfL levels were correlated with B cells and NK cells in CSF. The IgG index was correlated with cNfL, memory T cells and B cells. The authors concluded that immune profiling may be useful as a measure of treatment response.
April 18 Edition
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April 16 Edition