Daniel Ontaneda

Background and ObjectivesSubspecialty exchange programs in neuroimmunology are scarce and have not been formally evaluated. We assessed participant-reported outcomes of the Neuroimmunology Exchange...

The 2024 McDonald criteria allow diagnosis of multiple sclerosis (MS) in individuals presenting with symptoms not specific for MS or incidental imaging findings suggestive of demyelination when supported by biomarker evidence, reflecting a shift toward diagnostic definitions increasingly grounded in biological mechanisms of disease. The diagnostic yield of these criteria in such populations has not been evaluated in multicenter cohorts. We aimed to determine the proportion of individuals with nonspecific or incidental imaging presentations who meet the 2024 McDonald criteria and describe the contribution of central vein sign and cerebrospinal fluid (CSF) oligoclonal bands (OCBs) to diagnostic classification. This cross-sectional post-hoc analysis used data from the Central Vein Sign in Multiple Sclerosis (CAVS-MS) study, a multicenter observational cohort. Adults aged 18–65 years referred for diagnostic evaluation of possible MS were adjudicated by an expert panel (eFigure1). This analysis focused on participants with symptoms not specific for MS or incidental imaging findings suggestive of demyelination. Dissemination in space (DIS) and time (DIT) were assessed using 2017 MRI criteria. Fulfillment of the 2024 McDonald criteria at baseline—the primary outcome—was determined using the Select-6 central vein sign and CSF OCBs. Select-6 assessment was available for all participants, whereas OCB data were available for a subset based on prior clinical evaluation. Of 420 participants enrolled, 191 (45%) presented with either nonspecific symptoms (n=166) or incidental imaging findings (n=25). Mean age was 42 years, and 78% were female. Thirty-six (19%) met the 2024 McDonald criteria at baseline, including 28 (17%) in the nonspecific symptom cohort and 8 (32%) in the incidental imaging cohort. Among 51 participants meeting 2017 DIS, 22 (43%) were Select-6 positive, 17 (33%) had positive OCBs, and 4 (8%) met 2017 DIT. Nonspecific sensory symptoms, visual disturbances, and subacute cognitive decline were most associated with a diagnosis of MS. Application of the 2024 McDonald criteria identified nearly one-fifth of individuals without typical presentations as meeting diagnostic criteria for MS at baseline. Biomarker incorporation—particularly the central vein sign—accounted for a substantial proportion of diagnostic yield. Interpretation is limited by availability of CSF data and absence of longitudinal follow-up.

Background: There is growing support for high-efficacy disease-modifying therapy (DMT) in multiple sclerosis (MS), but escalation (ESC) approaches remain common. Objective: To describe decision-making in a pragmatic trial of early high-efficacy treatment (EHT) versus ESC. Methods: DELIVER-MS is a multi-center, pragmatic, randomized controlled trial (RCT) with a parallel observational study (OBS), which enrolled treatment-naïve people with RRMS in 31 UK/US sites. Primary outcome was as follows: 36-month brain volume loss according to initial treatment approach (EHT vs. ESC). Stepwise multivariable logistic regression was used to predict participation in RCT versus OBS and choice of EHT versus ESC within the OBS cohort. Results: In total, 816 people with MS were enrolled. Participants declined randomization due to preference for a particular DMT (85%), efficacy concerns (20%), and safety concerns (9%). RCT versus OBS participation was associated with lower relapse rate ( p = 0.043) and greater brain parenchymal fraction ( p = 0.002). Among 374 in the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT. People commencing EHT had higher education attainment ( p < 0.001) and relapse rate ( p = 0.025). Conclusion: Baseline DELIVER-MS data demonstrate that participants with milder disease are more likely to participate in RCT. The choice of EHT versus ESC was associated with demographic factors and disease activity. Clinical trial registration: NCT03535298

Growing evidence suggests that first-line (1L) treatment with high-efficacy disease-modifying therapies (HE-DMTs) may have greater clinical benefit in multiple sclerosis (MS) than delaying HE-DMTs to second- or subsequent-line (2L+) therapy. However, MS treatment is often initiated using an escalation approach, involving initial treatment with low- to moderate-efficacy DMTs followed by escalation to HE-DMTs in the presence of new disease activity or disability worsening. Ocrelizumab is a HE-DMT approved for the treatment of relapsing and primary progressive MS, but real-world outcomes of ocrelizumab as a 1L vs 2L+ therapy are not well characterized. Real-world data from people with MS (pwMS) receiving treatment at four centers in the USA were analyzed. The effectiveness of ocrelizumab when administered as 1L or 2L+ treatment was compared for up to 60 months in follow-up. The primary outcome was time to confirmed disability worsening (based on Patient-Determined Disease Steps [PDDS]). Secondary outcomes were time to requiring a walking aid (PDDS ≥ 4), annualized patient-reported relapse rate, and magnetic resonance imaging measures (e.g., brain volume and number and volume of new T2 lesions). A total of 403 pwMS (1L n = 309, 2L+ n = 94) were identified. Overall, pwMS who received 1L ocrelizumab experienced less confirmed disease worsening (25.8% vs 42.6%; P = 0.03) and requirement for a walking aid (6.5% vs 27.4%; P < 0.01) compared with the 2L+ cohort. The 1L group also had a significantly lower change in T2 lesion volume (mean difference - 0.797 mL; P < 0.05) and a lower risk of developing new T2 lesions than the 2L+ group (incidence rate ratio 0.88 [95% CI 0.78-0.99]; P = 0.04). Relapse rate and brain volume outcomes were not significantly different between groups. This study contributes to the growing pool of evidence that 1L treatment with HE-DMTs such as ocrelizumab can improve clinical outcomes for pwMS compared with delaying HE-DMT to 2L+ .

Background: The central vein sign (CVS) and the paramagnetic rim lesion (PRL) are neuroimaging biomarkers of multiple sclerosis (MS). Objectives: To determine the diagnostic performance of CVS and PRL integration in people presenting for initial diagnostic evaluation of MS. Methods: Adults with clinical/radiological suspicion of MS, aged 18–65, with CVS and PRL assessment from the CentrAl Vein Sign in MS (CAVS-MS) pilot were included. Diagnostic performance of CVS and PRL combinations was evaluated, with 2017 McDonald criteria as the reference standard. Results: Seventy-eight participants were included (71% female, 86% white, 37 with MS). The combination of ⩾1 CVS and ⩾1 PRL demonstrated sensitivity/specificity of 0.76 (95% CI, 0.59, 0.88) and 0.93 (95% CI, 0.80, 0.98). The combination of ⩾6 CVS and ⩾1 PRL demonstrated sensitivity/specificity of 0.57 (95% CI, 0.39, 0.73) and 1.00 (95% CI, 0.91, 1.00). In those with cerebrospinal fluid testing ( n = 46, 24 with MS), ⩾6 CVS and ⩾1 PRL diagnostic specificity was 1.00 (95% CI, 0.85, 1.00), similar to that of oligoclonal bands and dissemination in space by magnetic resonance imaging (0.82 [95% CI, 0.60, 0.95]). Discussion: Integrating CVS and PRL represents potentially advantageous MS diagnostic biomarkers, with increased specificity and without substantial reduction in sensitivity.

Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood–brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer’s disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast–enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention. Graphical Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer’s disease.:

Background: Many factors are associated with aging on multiple sclerosis progression. We assess associations of neighborhood resources and race with outcomes in aging people with multiple sclerosis (PwMS). Purpose: We evaluated if worsening outcomes differed by neighborhood resources and race for PwMS age >55. Methods: A longitudinal cohort study of 1456 PwMS (mean age 61.7 (standard deviation (SD): 5.5), 73% female, 87% White race) was conducted at tertiary MS centers between 2015 and 2021 with 3–5 years of follow-up. Predictors included area deprivation index (ADI) and race. Outcomes included 10 Neuro-QoL domains and three performance measures: manual dexterity test (MDT dominant hand), walking speed test (WST), and processing speed test (PST), with worsening defined using clinically meaningful changes. Results: In adjusted models, greater ADI (i.e. fewer resources) was associated with worsening MDT and WST (odds ratio (95% confidence interval (CI)) = 1.12 (1.05–1.19), 1.09 (1.02–1.16), respectively), and with worsening on Neuro-QoL domains of social roles, stigma, and fatigue. Patients of Black race had less worsening on social roles and depression, compared to patients of White race. Conclusion: Our study demonstrated an association between fewer neighborhood resources and worsening performance measures and self-reported outcomes. This study demonstrates that neighborhood deprivation, but less likely race, may play a role in worsening for PwMS >55 years.

Paramagnetic rim lesions (PRL) are a highly specific imaging biomarker for multiple sclerosis (MS) that are now integrated into the 2024 McDonald criteria. PRL can be detected on standard SWI, which combines data from the homodyne-filtered phase (phase) and enhanced magnitude (SWI) images, as well as on the phase images alone. However, the relative visibility of PRL on SWI versus phase images is unknown and it remains unclear which of these contrasts should be used for PRL evaluation in the clinical setting. The study sample (n=40) consisted of two cross-sectional cohorts-a primary cohort including both MS and non-MS cases (n=20) and a distinct secondary cohort consisting of MS participants only (n=20)-both selected from a prospective, multicenter observational study (CAVS-MS) of participants presenting for initial diagnostic evaluation of suspected MS. Standardized brain MRI sequences (3D T1WI with and without contrast, T2-FLAIR, and vendor-provided SWI) were acquired at 3T. T2-hyperintense lesions were evaluated on SWI and phase images for classification as PRL or non-PRL in separate trials by trained, blinded raters (two raters in the primary cohort, one rater in the secondary cohort). Differences in PRL frequency between SWI and phase images were analyzed with McNemar test in the primary, secondary, and pooled cohorts. 155 PRL were identified in the pooled cohort, of which 66 (42.6%) were detected only on phase images. The number of lesions classified as PRL was 2.7- and 1.4-fold greater when evaluated on phase images compared to SWI in the primary (43 vs. 16, p<0.001) and secondary (109 vs. 73, p<0.001) cohorts, respectively, and 1.7-fold greater in the pooled cohort (152 vs. 89, p<0.001). The main reasons for non-PRL classification on SWI were nodular appearance (37.9%) and discontinuity of the rim (28.8%). Filtered phase images derived from standard SWI outperform enhanced magnitude images for PRL identification and should be primarily used for PRL evaluation in clinical practice.

Background: Compared to the potent efficacy of autologous hematopoietic cell transplantation (AutoHCT) on multiple sclerosis (MS) lesion activity, benefit on disability progression is less clear. Paramagnetic rim lesions (PRLs) are imaging biomarkers associated with progression. Objectives: Evaluate effect of AutoHCT on PRLs using 7T magnetic resonance imaging (MRI). Methods: A single rater evaluated PRLs before/after AutoHCT on 7T MRI at an MS referral center. Results: Seven participants were included with mean age 38.9 years and median disease duration 9 years. Median PRL count pre-transplantation was 2. Post-AutoHCT (median 15 months in 5 participants) none of the PRLs resolved. Conclusion: These results provide low-level evidence that PRLs do not resolve following AutoHCT.