Bruce Anthony Campbell Cree

Schizophrenia spectrum disorders have substantial genetic liability, but their stable incidence and clinical heterogeneity leave open contributions from non-genetic mechanisms. Though autoimmune encephalitis demonstrates that anti-neural antibodies can cause psychosis, encephalitis antibodies are uncommon in schizophrenia. Here we show that multi-platform autoantigen profiling of cerebrospinal fluid and plasma detects rare, anti-neural autoantibodies in schizophrenia spectrum disorders. By antibody profiling the cerebrospinal fluid of 32 schizophrenia spectrum participants and 32 neuropsychiatrically unaffected controls by brain tissue immunostaining, immunoprecipitation–mass spectrometry, phage display immunoprecipitation sequencing, and plasma by complementary protein microarrays, we identify three autoantibodies, including to alpha-crystallin B. The anti-alpha-crystallin B antibody preferentially recognizes phosphorylated serine-45 and is absent from the cerebrospinal fluid of individuals with untreated multiple sclerosis, a disease with frequent antibodies to unphosphorylated alpha-crystallin B. These findings do not define autoimmune psychosis as a new disease but support broader autoantibody searches in psychotic disorders.

Background: Racial and ethnic disparities are evident in multiple sclerosis. Objectives: To assess whether disease progression and treatment response differ between non-Hispanic Black or Hispanic/Latino and non-Hispanic White people with relapsing multiple sclerosis. Methods: This post hoc analysis included people with relapsing multiple sclerosis from ocrelizumab trials (NCT01247324/NCT01412333) self-reporting as non-Hispanic Black ( n = 65), Hispanic/Latino ( n = 213), or non-Hispanic White ( n = 1350). Genetic ancestry was analyzed for consenting participants ( n = 1138). In addition, 24-week composite confirmed disability progression risk and CD19 ⁺ B cells were compared between subgroups. Results: In the interferon beta-1a treatment arm, non-Hispanic Black and Hispanic/Latino people with relapsing multiple sclerosis had increased 24-week cCDP risk compared with non-Hispanic White people with relapsing multiple sclerosis (hazard ratio (95% confidence interval) non-Hispanic Black: 3.0 (1.4–6.5); p = 0.005; Hispanic/Latino: 2.3 (1.6–3.4); p < 0.001). Composite confirmed disability progression risk was greater in people with relapsing multiple sclerosis with higher African (hazard ratio: 4.4 (1.7–11.2); p = 0.002) or Americas ancestry (hazard ratio: 5.8 [2.7–12.4]; p < 0.001) than European ancestry. Non-Hispanic Black and Hispanic/Latino people with relapsing multiple sclerosis had increased baseline CD19 ⁺ B cells. Compared with interferon beta-1a, ocrelizumab reduced B cells in all groups ( p < 0.001) and decreased composite confirmed disability progression risk in all people with relapsing multiple sclerosis, including non-Hispanic Black (hazard ratio: 0.41 (0.13–1.29); p = 0.13) and Hispanic/Latino (hazard ratio: 0.38 (0.20–0.72); p = 0.003). Conclusion: Compared with non-Hispanic White people, non-Hispanic Black and Hispanic/Latino people with relapsing multiple sclerosis showed higher disease progression risk. Ocrelizumab reduced composite confirmed disability progression risk in people with relapsing multiple sclerosis regardless of race, ethnicity, or genetic ancestry.

Treatment targeting progressive multiple sclerosis (MS) have limited efficacy, as central nervous system (CNS) resident B cells are resistant to peripheral B cell depletion by antiCD20 monoclonal antibodies. CD19 targeted chimeric antigen receptor (CAR)T cells offer the promise to deplete B cells more extensively in both the peripheral and CNS compartments. Two adult participants with treatment-refractory progressive MS were treated with 0.33e8 autologous anti CD19 CAR T cells (mivocabtagene autoleucel, miv-cel) intravenously after a preconditioning regimen. Participant 1 (50's year old female, EDSS 6) had no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Participant 2 (60's year old female, EDSS 4.5) had grade 1 CRS and no ICANS. Expansion of CAR T cells in the cerebrospinal fluid (CSF) at Day 14 was noted in both participants, remarkably with sustained disappearance of disease-associated oligoclonal band (OCB) or normalization of IgG index despite peripheral naive B cell reconstitution. MRI and clinical outcomes showed sustained stability at Week 48. Serologic studies showed a decline in anti-Epstein Barr Virus seropositivity. Single cell myeloid and proteomic signatures showed a decline in proinflammatory profiles. In the 2 subjects with progressive MS reported here, low dose anti CD19 CAR T cell therapy (miv-cel) was safe, penetrated the CSF effectively, reduced intrathecal humoral activity, modulated peripheral immune tone, and appeared to stabilize EDSS scores. Overall, these results support the continued investigation of CAR T cell therapy in MS.

Objective: Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS), yet associations with functional outcomes remain unclear. Longitudinal associations between serum NfL (sNfL) and daily step count (STEPS) from wearable devices were assessed in a large international progressive MS cohort. Methods: A post hoc analysis of the Phase III randomized controlled trial SPI2 (high‐dose biotin vs. placebo RCT) pooled treatment arms due to no observed therapeutic benefit. Participants with sNfL and step count data were included. STEPS were calculated within ±15‐days of baseline, 6, 12, 15, and 27‐month visits. Mixed‐effects models with 1000 bootstrap iterations assessed contemporaneous associations with each measure alternately specified as the outcome, adjusting for age and sex. Lagged models evaluated whether 0–6‐month sNFL changes predicted subsequent 6–12‐month STEPS changes. Results: Among 506 participants (53.8% female; mean age 52.7 [SD: 7.7] years; median EDSS 6.0 [4.5–6.0]), mean sNfL z ‐score was 1.00 (SD: 0.95), and median STEPS were 3029 [1708–5210]. Higher sNfL was associated with lower STEPS (IRR = 0.97, p = 0.014), consistent across sex, treatment, disability, and disease‐modifying treatment status. Conversely, higher STEPS were associated with lower sNfL z ‐scores; a 10% increase in STEPS corresponded to a 0.015 decrease in sNfL z ‐score (95% CI −0.022 to −0.008; p < 0.001). Greater prior 6‐month increases in sNfL were associated with a lower subsequent STEPS ( β = −141; 95% CI −302 to 21; p = 0.088; trend), corresponding to 141 fewer steps per 1‐SD sNfL increase. Interpretation: Higher sNfL was associated with reduced daily ambulatory activity in progressive MS, and vice versa. Rising sNfL may precede mobility decline, highlighting sNfL as a potential indicator of functional worsening. Trial Registration: ClinicalTrials.gov NCT02936037; EudraCT database 2016‐000700‐29

Background: Progressive multiple sclerosis (MS) leads to increasing disability, commonly assessed using the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk (T25FW). However, these episodically assessed, in-clinic measures miss diurnal fluctuations in mobility. Objective: To evaluate whether diurnal step count patterns reflect MS-related disability and whether these associations persist after accounting for temporal context and Kurtzke Functional Systems Scores (KFS). Methods: Minute-level step count data were collected from 529 progressive MS patients over 27 months in the placebo-controlled, SPI2 trial of MD1003. Function-on-scalar regression (FOSR) was applied to model average daily step-count curves (30-minute bins) against EDSS, T25FW, and demographics. Analyses included overall averages, temporally aligned scores (±3 months), and KFS components. Results: Higher EDSS and slower T25FW were linked to lower step count patterns, particularly during mid-day hours. EDSS demonstrated stronger associations than T25FW, although both provided complementary predictive value. Temporally aligned (±3 months) scores confirmed robust associations. Among KFS domains, ambulation, pyramidal, and cerebellar functions explained the most variation. Conclusions: Diurnal step count patterns provide objective markers of disability in progressive MS, reflecting specific neurologic deficits. These findings highlight their potential to complement clinical scales and to inform the timing of mobility-focused interventions.

This post hoc analysis examined the impact of prior immunosuppressants on the long‐term efficacy and safety of inebilizumab, a cluster of differentiation 19 ⁺ B‐cell–depleting monoclonal antibody, in participants with aquaporin‐4–seropositive neuromyelitis optica spectrum disorder from the N‐MOmentum trial (NTC02200770). Inebilizumab treatment resulted in a sustained low annualized attack rate relative to the pretrial annualized attack rate and a high probability of remaining attack‐free for up to 4 years among participants with and without prior immunosuppressant use. Based on modeling data, inebilizumab had greater long‐term efficacy than historical immunosuppressants. Inebilizumab was well tolerated regardless of prior immunosuppressant use.

Multiple sclerosis (MS) is a chronic progressive, demyelinating autoimmune CNS disease. Autoantibodies to the motif P-(SA)-x-(SGA)-R-(SN)-(LRKH) are a class of predictive markers specific to MS that could add to emerging diagnostic criteria for MS. In this study, we describe the discovery of an MS patient-derived monoclonal antibody (mAb) specific to this motif from memory B cells, and we develop a proof-of-principle autoantibody test to report the prevalence of seropositivity, predict MS early in disease, and identify underlying tolerance-breaking antigens in Epstein-Barr virus (EBV) and the CNS. Peptide tetramers containing the motif were used to screen activated memory B cells, collected from a patient with MS, on the Beacon Optofluidic system. A mAb to the motif and serum samples from clinically diagnosed patients with MS and healthy controls were used to qualify a Luminex xMAP autoantibody serologic test. Antigen discovery methods included phage-immunoprecipitation sequencing (PhIP-Seq), biolayer interferometry, human protein microarrays, isoelectric focusing gels and blots, and immunofluorescence staining of mouse brain cell cultures. A mAb cloned from an MS patient's memory B cells binds diverse peptides containing the MS signature motif with affinities ranging from 2 to 25 nM. Consensus peptides defined by alanine scanning PhIP-Seq were used to develop an autoimmune IgG test with a sensitivity equivalent to 0.5 ng/mL mAb, a precision of <11%, and a positivity rate of 11% among a cohort of 179 patients with MS (n = 91 healthy and n = 49 unrelated neurologic disease serum samples were negative). Utility of the assay for prodromal MS was demonstrated using retrospective, longitudinal samples from cases in the Department of Defense Serum Repository. The mAb identified EBV tegument protein BRRF2 as a tolerance-breaking antigen with nanomolar affinity, containing the motif with reactivity to oligoclonal bands in CSF from MS signature-positive patients. Immunocytochemical staining of mixed mouse neuronal cells showed the dominant cross-reactive human antigen to be vimentin. We describe a test for MS signature autoantibodies that could be used to support MS diagnosis, prodromal research, and early interventions. The integration of this assay with other emerging biomarkers will advance progress toward a combined predictive risk score for MS.

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.