American Academy of Neurology annual meeting – 13-18 April 2024
The following summarizes some of the highlights from Day 4 of AAN 2024.
April 17 Edition
April 16 Edition
April 15 Edition
Early treatment with higher-efficacy DMT more effective regardless of NfL level
PIRA in SPMS
Anti-CD3 MAb in development for SPMS
Higher infection risk with oral DMTs vs. NTZ in MS
Vascular events in people with epilepsy: Canadian data
Inflammatory biomarkers in Alzheimer disease
CONGRESS HIGHLIGHTS – THURSDAY EDITION
Early treatment with higher-efficacy DMT more effective regardless of NfL level
Starting treatment with a higher-efficacy disease-modifying therapy is more effective in controlling disease activity than a modest-efficacy drug regardless of baseline sNfL level, according to an analysis of the ASCLEPIOS I/II trials (Pardo et al. AAN 2024;P9.008). The analysis stratified 576 recently diagnosed and treatment-naïve RMS patients according to lower or higher baseline sNfL level; the cut-off value was 9.3 pg/mL. The annualized rate of new/enlarging T2 lesions was reduced 85.5% with ofatumumab vs. teriflunomide in the higher sNfL group, and to a similar degree (85.8%) in the lower sNfL group. The annualized relapse rate was reduced 63.4% and 37.2% with ofatumumab vs. teriflunomide in the higher and lower sNfL groups, respectively.
PIRA in SPMS
A retrospective study of 178 patients with SPMS identified progression independent of relapse activity (PIRA) in 86 patients over a median follow-up of 11.8 years (Marrodan et al. AAN 2024;P8.010). Overall, 50% of PIRA cases were early PIRA, defined as <5 years after MS onset. Early PIRA was more likely to be identified in older patients and those presenting with myelitis. The median time to PIRA was 7.58 years. Patients with early PIRA progressed to SPMS significantly more rapidly than those with later PIRA (74 vs 162 months).
Anti-CD3 MAb in development for SPMS
Anti-CD3 monoclonal antibodies have been in development for over three decades for transplantation and autoimmune disorders. An early Canadian study of muromonab (OKT3) in progressive MS reported promising efficacy results but treatment was limited due to intolerable side effects (Weinshenker et al. Neurology 1991;41:1047-1052). Interestingly, the term ‘cytokine storm’ was first coined in this study to describe the transient increase in pro-inflammatory cytokines seen in a subset of patients. Next-generation agents such as foralumab, a fully human anti-CD3 MAb, appear to be better tolerated. A small study administered nasal foralumab to 6 non-active SPMS patients (Singhal et al. AAN 2024;S17.002). TSPO-PET imaging was performed at baseline and at three and six months. Foralumab appeared to reduce microglial activation in 5 of 6 patients. White-matter z-scores were reduced 26-36% at three and six months. EDSS scores were stable. A phase II dose-ranging study is now underway (NCT06292923).
Higher infection risk with oral DMTs vs. NTZ in MS
A retrospective chart review over a 10-year period reported that the incidence of serious infections was significantly higher in patients receiving a fumarate (19.0 per 100 patient-years) or an S1PR modulator (15.3/100 PY) compared to natalizumab (4.8/100 PY) (Lambert et al. AAN 2024;P3.006). The incidence of COVID-19 infection was similar for natalizumab and fumarates (13.6 and 13.2/100 PY, respectively); the rate was higher with SIPR modulators (22.5/100 PY). Overall, the most common infections were urinary tract infections (48.2%) and COVID-19 (38.5%).
Vascular events in people with epilepsy: Canadian data
A Quebec study analysed data from the Canadian Longitudinal Study on Aging (CLSA; N=27,230) to determine the risk of new-onset vascular events in people with and without epilepsy (Li et al. AAN 2024;S19.010). Vascular events comprised stroke, myocardial infarction and transient ischemic attacks. Over a six-year period, vascular events occurred in 9.6% of people with epilepsy vs. 4.4% of people without epilepsy (odds ratio 2.44 for any event; OR 2.3 for TIA, 2.13 for MI; 1.91 for stroke). The higher risk of vascular events among people with epilepsy was attributable more to the use of enzyme-inducing antiseizure medications (e,g. carbamazepine, phenytoin, phenobarbital) than to Framingham cardiovascular risk score (26.9% vs. 3.3% of association). A systematic review previously reported an increased risk of hemorrhagic stroke in patients with epilepsy, notably in those receiving oxcarbazepine (Brigo et al. Epilepsy Behav 2020;104(Pt B):106307). A Canadian database analysis found a higher risk of cardiovascular disease in patients taking enzyme-inducing antiseizure drugs (hazard ratio 1.21) (Josephson et al. JAMA Neurol 2021;78:1367-1374).
Inflammatory biomarkers in Alzheimer disease
The McGill Centre for Studies in Aging, in collaboration with U.S. and European centres, conducted a systematic review (N=114 papers) of the role of neuroinflammation in Alzheimer disease (Heneka et al. AAN 2024;P7.013). The three key inflammatory biomarkers in patients with AD-related dementia were YKL-40, sTREM2 and GFAP. YKL-40 (also known as chitinase 3-like protein 1), expressed by reactive astrocytes and microglia, has also been shown to be upregulated in MS, ALS, traumatic brain injury (TBI) and stroke (Llorens 2017; see below to access the full review). TREM (triggering receptor expressed on myeloid cells 2) is expressed by microglia and is reportedly elevated in PD, ALS, stroke and TBI (Gratuze 2018; see below to access the full review). GFAP (glial fibrillary acidic protein) is a marker of astrocytosis and is being studied as a neurodegenerative marker in MS.
In the McGill study, CSF sTREM2 changes were evident during the preclinical stages of AD and were prognostic of the rate of cognitive decline. YKL-40 concentration was elevated during the dementia stage of AD and increased over time in patients with dementia (mild cognitive impairment and AD). A higher baseline YKL-40 level was prognostic of progression to dementia in MCI patients. Similarly, a higher baseline sGFAP was prognostic of a more rapid clinical decline and progression to AD dementia. The authors concluded that fluid biomarkers are useful for prognosis in clinical practice, as outlined in recent draft National Institute on Aging and the Alzheimer’s Association (NIA-AA) guidelines.
Click here to access the draft guidelines, NIA-AA Revised Criteria for Diagnosis and Staging of Alzheimer’s Disease 2023; click here to access figures and tables.
Click to view Llorens et al.
Click to view Gratuze et al.
April 17 Edition
April 16 Edition
April 15 Edition