Introduction ORATORIO est le seul essai de phase III ayant montré la supériorité d’un traitement vs PBO pour ralentir la progression du handicap dans la SEP PP. L’effet de l’OCR chez les patients plus âgés et handicapés reste encore à mieux comprendre. Objectifs ORATORIO-HAND est un essai de phase IIIb, multicentrique, randomisé, en double aveugle, contrôlé par PBO, évaluant l’efficacité et la sécurité de l’OCR chez les patients atteints de SEP PP, y compris, pour la première fois, pour des SEP plus avancées. Méthodes Les adultes atteints de SEP-PP âgés de ≤65 ans, avec un score EDSS entre 3 et 8 ont été randomisés 1:1 pour recevoir 600mg d’OCR ou un PBO tous les 6 mois pendant 144 sem ou jusqu’à observation d’au moins 340 événements de progression. Le critère d’évaluation principal est le délai d’apparition d’une progression confirmée du handicap à 12 sem avec un critère composite incluant le 9HPT et l’EDSS chez tous les patients randomisés et chez un sous-groupe de patients ayant une activité IRM à l’inclusion. Résultats Chez les patients sous OCR (n=505) et sous placebo (PBO) (n=508), l’âge médian à l’inclusion était de 48 ans (18–66) vs 47 ans (22–66) et le score EDSS médian était de 6 (3–8) vs 6 (2, 5–8). Le pourcentage de patients OCR et PBO présentant un 12W-CDP sur le critère composite était de 32,7 % vs 40,4 % (réduction du risque [RR] de 30 % ; p=0,0007), de 16,7 % vs 24,9 % sur le 9HPT (RR : 41 % ; p=0,0002) et 23,0 % vs 30,8 % sur l’EDSS (RR : 33 % ; p=0,0013). Dans le sous-groupe de patients actifs à l’IRM, le pourcentage de patients présentant une CDP-12W sur le critère composite était de 26,8 % contre 45,9 % (RR : 55 % p<0,0001). Discussion Cette étude a permis de démontrer le bénéfice d’ocrélizumab dans une large population atteinte de SEP-PP, incluant des patients à un stade plus avancé de la maladie. Conclusion OCR est supérieur au placebo pour retarder la progression du handicap et l’aggravation de la fonction des membres supérieurs. Le profil de tolérance était similaire entre les deux groupes, conformément au profil de sécurité connu d’OCR.

BACKGROUND:The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly regarding hand function preservation. METHODS:ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries. Patients with PPMS aged 18-65 years and Expanded Disability Status Scale (EDSS) score of 3·0-8·0 were randomly assigned 1:1 to intravenous ocrelizumab 600 mg or placebo every 6 months for 144 weeks or until a prespecified number of progression events occurred. Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab. Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments. MRI scans were evaluated by a masked central reader, and laboratory parameters that could reveal treatment allocation were masked to site personnel until the primary analysis. Two coprimary estimands were defined, with the endpoint of time to onset of 12-week composite confirmed disability progression (12W-cCDP) in 9-Hole Peg Test or EDSS evaluated in all randomly assigned patients, and the same endpoint evaluated in a subset of patients with MRI activity at baseline. This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting. FINDINGS:Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]). The proportion of patients with 12W-cCDP was 165 (33%) of 505 with ocrelizumab and 205 (40%) of 508 with placebo (hazard ratio, 95% CI 0·70 0·57-0·86; relative risk reduction=30%; p=0·0007). In the MRI-active subgroup, a significant risk reduction was also observed in 12W-cCDP (risk reduction=55%; p<0·0001). The overall safety profile was similar in both groups. More infections (245 [48%] of 506 vs 226 [45%] of 506) were observed with ocrelizumab, but not after COVID-19 was excluded (38% vs 37%). Rates of serious adverse events and serious infections were similar between groups. INTERPRETATION:Ocrelizumab was superior to placebo in delaying disability progression, with stronger effect on hand function, in a broad PPMS population including older patients and those with more advanced disease, while maintaining a manageable safety profile. FUNDING:F Hoffmann-La Roche.

Noninvasive neuroinflammation measurement remains a major barrier for Alzheimer disease (AD) therapeutics. We present generalized diffusion basis spectrum imaging (g-DBSI), a diffusion MRI framework that decomposes the tissue signal into biologically interpretable microstructural compartments. In postmortem Knight ADRC brains, g-DBSI-derived restricted isotropic fraction (RIF) and restricted anisotropic fraction (RAF) mapped cellularity and neurofilament density, while their ratio (RIF/RAF) tracked inflammatory cell density and peri-plaque amyloid-beta with higher specificity and regional consistency than RIF alone. In 112 living Knight ADRC participants stratified by PET amyloid, g-DBSI metrics showed amyloid-dependent trajectories: in low-amyloid individuals, RIF and RAF rose together with amyloid, consistent with early neuropil expansion and glial elaboration, whereas in high-amyloid individuals, RIF/RAF increased, and RAF declined, indicating established neuroinflammatory remodeling and neurofilament loss. CSF proteomics linked RIF/RAF to glia-enriched immune and vascular pathways, supporting g-DBSI as a clinically compatible MRI biomarker of neuroinflammation and neurodegeneration in AD. Teaser:g-DBSI provides noninvasive MRI biomarkers of neuroinflammation and neurodegeneration in AD, validated by histopathology and CSF proteomics.

Introduction Dans l’étude ORATORIO, une exposition plus élevée à OCR était corrélée à une plus grande déplétion des LB et à un risque réduit de progression confirmée du handicap sans augmentation de la fréquence ou de la gravité des événements indésirables. Objectifs GAVOTTE, une étude de phase IIIb, multicentrique, randomisée, en double aveugle, en groupes parallèles, évalue l’efficacité et la tolérance d’une dose élevée d’OCR chez les patients atteints de SEP PP vs la dose IV approuvée de 600mg d’OCR. Méthodes Les patients atteints de SEP-PP (18–55 ans, score EDSS : 3–6,5) ont été randomisés 2 :1 pour recevoir, soit une dose élevée d’OCR (1200mg pour les patients<75kg ou 1800mg pour les patients ≥75kg), soit la dose approuvée d’OCR de 600mg, administrée toutes les 24 semaines pendant ≥120 semaines. Le critère d’évaluation principal est le délai d’apparition d’une progression du handicap confirmée à 12 semaines, définie comme une augmentation du score EDSS ou du T25FW ou du 9HPT. Résultats Les 753 patients randomisés ont reçu au moins une perfusion d’OCR ; 84,5 % des patients n’avaient reçu aucun traitement modificateur de la maladie. L’âge moyen à l’inclusion était de 41,8 ans ; 53,1 % étaient des femmes et 87,5 % étaient caucasiens. Le score EDSS initial moyen était de 4,7 ans, et le délai moyen depuis l’apparition des symptômes de la SEP et le diagnostic était respectivement de 6,2 ans, et 3,2 ans. Les principaux résultats d’efficacité et de tolérance seront présentés. Discussion Les caractéristiques initiales de l’étude GAVOTTE concordent avec celles de la population de patients de l’étude ORATORIO. Conclusion Les résultats principaux détermineront si une exposition accrue à l’OCR ralentit davantage la progression de la maladie dans la SEP-PP.

Introduction La sclérose en plaques à début pédiatrique (POMS) est une maladie souvent très active. Cependant, les traitements de fond (DMT) de haute efficacité sont limités. Objectifs Évaluer la sécurité et l’efficacité d’ocrélizumab par voie intraveineuse (IV) versus fingolimod chez des patients de 10 à 17 ans atteints de sclérose en plaques récurrente-rémittente (SEP-RR) à début pédiatrique. Méthodes Les 187 patients ont été randomisés pour recevoir ocrélizumab IV 600mg toutes les 24 semaines ou fingolimod oral 0,5mg quotidiennement. L’objectif principal était de démontrer la non-infériorité d’ocrélizumab par rapport au fingolimod sur le taux annualisé de poussées. Les objectifs secondaires comprenaient un nombre de lésions T2 nouvelles/en expansion et de lésions T1 rehaussées par le gadolinium (Gd+). Les objectifs de sécurité comprenaient l’incidence et la gravité des événements indésirables. Résultats Sur les 187 patients randomisés, 69,0 % étaient des femmes. L’âge médian à l’inclusion était de 15,0 ans. Le poids médian était de 63,1kg. À l’inclusion, les patients présentaient un nombre médian de lésions T2 de 43 et T1 Gd+ de 0,5 ; 47,1 % des patients présentaient des lésions T1 Gd+. Le score EDSS médian était de 1,5. Les résultats de l’analyse principale, y compris efficacité et sécurité, seront présentés. Discussion Davantage d’options de DMT sont nécessaires pour la POMS. Conclusion S’il est approuvé, l’ocrélizumab pourrait constituer un traitement hautement efficace et bien toléré pour la POMS, avec un profil de sécurité déjà bien établi chez l’adulte.

OBJECTIVES:Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. METHODS:This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging. RESULTS:After a 3-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as MRI, amyloid-beta PET, tau-PET, and fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression. CONCLUSIONS:Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes. ADVANCES IN KNOWLEDGE:This systematic review identifies sex-specific patterns in neuroimaging biomarkers of AD, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy.

Background:Wearable digital health technologies offer a unique opportunity to assess gait at the stride level in real-world settings. Walking impairment is a major cause of disability in multiple sclerosis (MS), yet current clinical metrics lack sensitivity to early and progressive changes in mobility. Methods:We conducted two studies (NCT04888689/NCT04882891) using a wearable device to develop and validate digital mobility outcome measures based on individual strides in patients with MS. First, we assessed technical performance in a controlled, single-center environment between September 12 and September 18, 2021. We then conducted a 12-month longitudinal study under daily living conditions across six sites between March 2021 and January 2024. The evaluated metrics included stride velocity 95th centile, walking distance 90th centile, and strides per hour. Findings:The controlled and longitudinal studies included 21 and 78 participants, respectively. The device demonstrated high stride detection accuracy (precision: 0·99) and a mean absolute error in stride velocity of 0·019 m/s. In the longitudinal study, stride velocity 95th percentile showed excellent reliability (ICC (2,1) = 0·97, SEM = 0·06) and strong agreement with Expanded Disability Status Scale (Spearman's rho = 0·65, p < 0·001) and Timed 25-Foot Walk (Spearman's rho = -0·71, p < 0·001), sensitivity to 12-month progression in both relapsing-remitting and progressive MS (p = 0·049 and p = 0·006, respectively), outperforming the Expanded Disability Status Scale. Walking distance 90th percentile and strides per hour were reliable and valid but less sensitive to progression. Interpretation:Stride velocity 95th percentile derived from real-world, stride-level data, provides a valid, reliable, and sensitive digital outcome for detecting MS progression. It may serve as an early indicator of progression and support the accelerated evaluation of treatments targeting progression. Funding:This study was funded by F. Hoffmann-La Roche Ltd.

Introduction Le fénébrutinib est un BTKi oral, hautement sélectif, non covalent et réversible pénétrant le SNC comme l’a démontré l’étude de phase II FENopta. Cependant, il existe un besoin non couvert chez les patients atteints de formes progressives. Objectifs L’objectif de l’étude FENtrepid était d’évaluer l’efficacité et la tolérance du fénébrutinib (FEN) par rapport à l’ocrélizumab (OCR) chez des patients adultes atteints de sclérose en plaques progressive primaire. Méthodes FENtrepid est une étude de phase III, multicentrique, randomisée en double aveugle avec double placebo. Les patients ont été randomisés 1:1 pour recevoir 200mg de FEN par voie orale 2 fois par jour, ou 600mg d’OCR par voie IV toutes les 24 semaines. Le critère d’évaluation principal est le délai d’apparition d’une progression du handicap confirmée, définie comme une augmentation confirmée sur 12 semaines d’au moins un des scores suivants : EDSS, test de marche de 7,62m ou test des 9 trous. Résultats L’étude FENtrepid a inclus 985 patients atteints de SEP progressive primaire ; 84 % d’entre eux n’avaient pas reçu de traitement de fond récent. L’âge moyen (écart-type) à l’inclusion était de 48,9 (10,3) ans. Le score EDSS médian à l’inclusion était de 5,0 ; la durée moyenne (écart-type) depuis l’apparition des symptômes de la SEP et le diagnostic était respectivement de 9,0 (6,7) et 4,7 (5,4) ans. Discussion L’étude FENtrepid fournira les premières données probantes sur l’effet du traitement par fénébrutinib sur la progression du handicap chez les patients atteints de SEP primaire progressive, par rapport à un comparateur actif, l’ocrélizumab. Conclusion L’étude FENtrepid fournira les premières données probantes sur l’effet du traitement par fénébrutinib sur la progression du handicap chez les patients atteints de SEP primaire progressive, par rapport à un comparateur actif, l’ocrélizumab.

BACKGROUND:Ocrelizumab is a humanised anti-CD20 monoclonal antibody approved for people with relapsing (RMS) or primary progressive multiple sclerosis (PPMS). In a post-hoc analysis of phase 3 trials in RMS and PPMS using a 600 mg dose, higher exposure to ocrelizumab was associated with greater B-cell depletion and lower risk of confirmed disability progression. Here, we prospectively assessed the efficacy and safety of a high dose of ocrelizumab in patients with RMS or PPMS. METHODS:Two multicentre, double-blind, phase 3 controlled trials were conducted to compare high-dose ocrelizumab with the approved 600 mg dose of the drug in patients with RMS (MUSETTE) and PPMS (GAVOTTE) aged 18-56 years. MUSETTE involved 122 centres in 21 countries and GAVOTTE involved 149 centres in 22 countries. Participants were randomly assigned 2:1, with a permuted-block randomisation method, to high-dose ocrelizumab (1200 mg or 1800 mg for baseline body weight <75 kg or ≥75 kg, respectively) or 600 mg ocrelizumab. Patients, investigators, and the sponsor were blinded to treatment allocation. Patients received ocrelizumab infusions every 24 weeks for a minimum 120 weeks and until a prespecified minimum number of confirmed disability events (MUSETTE, 205; GAVOTTE, 357) had occurred. In both trials, the primary endpoint was time to onset of 12-week composite confirmed disability progression (cCDP), assessed by prespecified increases in Expanded Disability Status Scale, Timed 25-Foot Walk Test, or 9-Hole Peg Test scores. Efficacy endpoints were evaluated in all randomised participants and safety endpoints were evaluated in participants who received at least one ocrelizumab infusion. These studies are registered with ClinicalTrials.gov: MUSETTE, NCT04544436; GAVOTTE, NCT04548999. FINDINGS:Participants in MUSETTE were enrolled between Nov 26, 2020, and Aug 30, 2022; participants in GAVOTTE were enrolled between Dec 3, 2020, and May 15, 2023. In MUSETTE, 860 patients were randomly assigned (high-dose ocrelizumab, n=577; 600 mg ocrelizumab, n=283) and had median overall treatment duration of 184·4 weeks. In GAVOTTE, 753 patients were randomly assigned (high-dose ocrelizumab, n=500; 600 mg ocrelizumab, n=253) and had median overall treatment duration of 174·1 weeks. In MUSETTE, the percentage of patients with 12-week cCDP was 34% (198 of 577) with high-dose ocrelizumab versus 37% (104 of 283) with 600 mg ocrelizumab (hazard ratio [HR] 0·93 [95% CI 0·73-1·18]; p=0·53). In GAVOTTE, the percentage of patients with 12-week cCDP was 47% (235 of 500) with high-dose ocrelizumab versus 49% (124 of 253) with 600 mg ocrelizumab (HR 0·95 [95% CI 0·76-1·18]; p=0·64). Safety profiles were similar for the high-dose ocrelizumab and 600 mg ocrelizumab; in MUSETTE, rates of adverse events (552 [96%] of 577 and 267 [94%] of 283), serious adverse events (77 [13%] of 577 and 34 [12%] of 283), and fatalities (four [1%] of 577 and one [<1%] of 283) were comparable, as were rates of adverse events (447 [90%] of 499 and 230 [91%] of 254), serious adverse events (61 [12%] of 499 and 29 [11%] of 254), and fatalities (two [<1%] of 499 and three [1%] of 254) in GAVOTTE. INTERPRETATION:In both studies, high-dose ocrelizumab did not further improve control of disability progression in either RMS or PPMS, and no new safety concerns were identified. FUNDING:F Hoffmann-La Roche.

BACKGROUND:Reproducibility and comparability of disability outcomes remain major challenges in multiple sclerosis (MS) research. Definitions of disability progression vary widely across studies, and calculation criteria are often insufficiently documented to enable replication. FRAMEWORK:To address these issues, a consensus process endorsed by the International Advisory Committee on Clinical Trials in MS was conducted to develop practical guidelines for outcome calculation across a range of study designs and research questions. Instead of proposing a single universal endpoint definition, we establish specific recommendations for each use case, within a fixed parameter space derived from extraction and systematisation of common practices for baseline selection, event confirmation, relapse handling, and event categorisation. These criteria are implemented in a shared computational framework, "msprog," available as open-source R and Python software and as a web application. The tool supports different disability scales, facilitates full reporting of parameters, and adapts to both clinical trial and real-world settings. CONCLUSION:The integration of consensus-based guidelines with a standardised, extensible implementation provides a practical basis for consistent and reproducible specification of disability outcomes in MS.

Besides exchanging nutrients, gases, and wastes, placenta is an intermediary between maternal and fetal immune systems. However, no method exists to safely image and monitor placental inflammation during pregnancy. We customized a Magnetic Resonance Imaging (MRI) method, diffusion basis spectrum imaging (DBSI), to measure immune cells in placenta. We validated placental DBSI in simulations and ex-vivo specimens, then applied it to 202 MRI scans from 82 patients whose placentas were classified as non-inflammation (n = 70) or inflammation (n = 12). Our method imaged the 3D distribution of immune cells, revealing significantly greater infiltration in the inflammation placentas from early (2.8% ± 0.7% vs. 4.8% ± 0.65%, p < 0.01) to late pregnancy (4.75% ± 0.9% vs. 7.25% ± 2.13%, p < 0.01). DBSI detects elevated immune cell infiltration associated with placental inflammation and enables non-invasive imaging of placental inflammation, offering early detection and monitoring throughout pregnancy, facilitating personalized care and potentially improving pregnancy outcomes without ionizing radiation.

Neurogenesis has been implicated in the pathogenesis of Alzheimer's disease (AD). However, the relationship between CSF neurogenin-1 levels and cognitive decline, as well as neurodegeneration in older adults, both with and without cognitive impairment, remains unclear. The current study included 666 individuals, comprising 161 cognitively unimpaired (CU) older adults and 505 cognitively impaired (CI) older adults. To examine the association of CSF neurogenin-1 levels with changes in cognitive performance and neurodegeneration over time, we performed a series of linear mixed-effects models. In these models, baseline CSF neurogenin-1 levels served as the predictor of interest, while cognitive measures, such as Mini-Mental State Examination (MMSE) scores, and hippocampal and ventricular volumes, served as the dependent variables. Higher CSF neurogenin-1 levels were associated with a slower rate of cognitive decline over time in the CI individuals but not in the CU individuals. Regarding structural MRI features, we found that higher baseline CSF neurogenin-1 levels were associated with a slower rate of ventricular enlargement in the CI individuals but not in the CU individuals. No association was observed between CSF neurogenin-1 levels and hippocampal atrophy in either group. Our findings suggest that neurogenin-1 may play a neuroprotective role in CI individuals, potentially slowing cognitive decline and structural brain changes associated with the disease.

Amyloid related imaging abnormality edema (ARIA-E) occurs in about 19% of individuals with autosomal dominant Alzheimer disease (ADAD) treated with an anti-amyloid-b monoclonal antibody (Salloway et al., 2021). In a previously reported case, ARIA-E appeared to colocalize with decreases in PiB-PET uptake (Joseph-Mathurin, Llibre-Guerra, et al, 2022), suggesting an association between amyloid-b (Aβ) removal and ARIA-E. Here, we compare longitudinal neuroimaging and corresponding neuropathology in an ADAD individual treated with gantenerumab, who experienced multiple ARIA-E episodes as sulcal effusions that resolved by the end of the four-year trial. PiB-PET and MRI were collected pre- and post-randomization (2 and 4 years). The participant consented to brain donation, which was received a year after trial completion. Four tissue samples were taken from the location of the ARIA-E in the parieto-occipital left hemibrain as identified by MRI (one block contained the sulcus affected by ARIA-E; the rest of the coronal section was captured in the remaining three blocks). Area fractions (AFs) of Aβ (10D5 immunohistochemistry (IHC)), tauopathy (PHF1), microglia (Iba1), and astrocytes (GFAP) in one sulcal region of interest (ROI) from each block and PiB-PET SUVRs of corresponding ROIs were extracted ( n  = 4, Figure 1). Additionally, we included PiB-PET SUVRs corresponding to ARIA-E findings observed in the right hemisphere at baseline, two-year, and four-year visits ( n  = 6). Overall PiB-PET uptake increased during the first two years (before ARIA-E) and decreased during the last two years (including ARIA-E episodes) (0.03±0.05 vs. -0.04±0.04 SUVR/year, p -value=0.01, Figure 2). The decrease seemed more pronounced in ARIA-E ROIs versus normal-appearing sulcus ROIs (-0.05±0.04 vs. -0.02±0.03 SUVR/year). Lower PiB uptake at last visit appeared associated with lower Aβ AF (estimates=0.03±0.01, p -value=0.07). The ARIA-E ROI had an Aβ AF of 0.009 while normal-appearing sulcus ROIs had a mean of 0.02+0.003 (Figure 3). AFs for tauopathy, microglia, and astrocytes were within the range of those of normal-appearing sulcus ROIs, suggesting an Aβ-specific effect, although unexamined markers may play a role. Our preliminary findings indicated that ARIA-E is associated with longitudinal PiB-PET decrease and Aβ AF, supporting the link between ARIA-E, changes in PiB-PET, and local Aβ removal observed at autopsy. Funding : K01AG080123; U01AG042791; R01AG046179; R01AG053267