https://repositorio.fleni.org.ar/xmlui/handle/123456789/27 Sat, 10 Oct 2026 17:49:43 GMT 2026-10-10T17:49:43Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1621 Microbiome-derived metabolites from vitamin B2 and B9 pathways modulate MAIT cells from multiple sclerosis patients Correale, Jorge; Marrodán, Mariano; Piedrabuena, María Agustina; Soman, Karthik; Farez, Mauricio Franco; Baranzini, Sergio E. Background: Mucosal-associated invariant T (MAIT) cells recognize microbial vitamin B2 and B9 metabolites via MR1 and have been implicated in multiple sclerosis (MS). How patient-specific gut microbiota shape human MAIT-cell pathogenicity at the clonal level remains unknown.Material and methods: We generated 62 MAIT-cell clones from relapsing-remitting multiple sclerosis (RRMS) patients and 50 from healthy controls (HCs). Clones were stimulated with riboflavin- or folate-pathway metabolites, paraformaldehyde-fixed patient-matched gut bacterial isolates, or interleukin (IL)-12/IL-18. Activation markers, cytokine secretion, cytotoxicity, and competitive MR1-ligand inhibition were assessed. Intestinal permeability was evaluated using I-FABP, LBP, GLP-2, and fecal α-1-antitrypsin. Results: MS-derived MAIT clones showed markedly enhanced activation, increased interferon-gamma (IFN-γ), IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion, and greater cytotoxicity compared with HCs when stimulated with riboflavin-producing taxa isolated from the same patients. Importantly, several responses diverged from predictions based on murine models and genomic inference, including mixed cytokine profiles and graded competitive inhibition by folate-derived ligands. These findings highlight species-specific differences in MR1 ligand handling and MAIT-cell activation. Activation required uptake of intact bacteria and acid-dependent MR1 loading. MS patients exhibited significant intestinal barrier dysfunction, linking dysbiosis to systemic MAIT-cell hyperactivation. Conclusion: At clonal resolution, this study demonstrates that patient-specific microbial metabolism, MR1-ligand competition, and epithelial barrier disruption cooperate to amplify MAIT-cell pathogenicity in MS, revealing human-specific mechanisms not predicted by animal models. Mon, 01 Jun 2026 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1621 2026-06-01T00:00:00Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1604 Early use of high-efficacy disease-modifying therapies reduces the risk of progression independent of relapse and MRI activity in patients with relapsing-remitting multiple sclerosis Guarnaschelli, María Flor; Marrodán, Mariano; Sosa, Brian Ezequiel; Perez Arana, Carolina I.; Farez, Mauricio Franco; Fiol, Marcela Paula; Ysrraelit, María Célica; Correale, Jorge Background: Progression independent of relapse and MRI activity (PIRMA) is a major contributor to long-term disability in relapsing-remitting multiple sclerosis (RRMS). In Latin America, limited access to high-efficacy disease-modifying therapies (DMTs) may influence PIRMA risk, but real-world evidence is scarce. We aimed to estimate the causal effect of DMT efficacy on PIRMA in an Argentine cohort. Methods: We conducted a retrospective observational study including 264 adults with RRMS meeting predefined disability follow-up criteria. Treatment exposure was modeled as a time-varying variable (low-efficacy vs moderate-/high-efficacy), applying a 60-day pharmacological lag after treatment switches. To address time-dependent confounding, we used a marginal structural model with overlap weighting and a weighted Cox proportional hazards model. Results: Median age at treatment initiation was 31.5 years, 62.1% were female, and median baseline EDSS was 1.0. Over a median follow-up of 7 years, 26 PIRMA events occurred. Exposure to low- or moderate-efficacy DMTs was associated with a significantly higher risk of PIRMA compared with high-efficacy therapies (HR 7.05; 95% CI 1.15-43.35). Conclusion: Exposure to low-/moderate-efficacy disease-modifying therapies was associated with a substantially higher risk of PIRMA compared with high-efficacy treatments, supporting the potential benefit of early access to high-efficacy therapies in RRMS. Wed, 29 Apr 2026 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1604 2026-04-29T00:00:00Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1577 Plasma levels of an N-terminal tau fragment predict Alzheimer's and neurodegenerative disease biomarkers in autosomal dominant Alzheimer's disease Schultz, Stephanie A.; Rao, Rao; Liu, Lei; Ostaszewski, Beth; Anderson, Amirah K.; Yau, Wai-Ying Wendy; Shirzadi, Zahra; Gordon, Brian A.; Hassenstab, Jason; Morris, John C.; Perrin, Richard J.; Allegri, Ricardo Francisco; Barthélemy, Nicolas R.; Fox, Nick C.; Day, Gregory S.; Jucker, Mathias; Levey, Allan I.; Levin, Johannes; Mori, Hiroshi; Salloway, Stephen Introduction: Tau species lacking truncation of the N-terminal region, including plasma N-terminal tau fragment 1 (NT1), have been previously associated with cognitive decline, neurodegeneration, and tau pathology in late-onset sporadic Alzheimer's disease (AD). Methods: Here, we examined cross-sectional and longitudinal plasma NT1 as a possible predictor of cognitive, clinical, and core AD biomarker trajectories in autosomal dominant AD (ADAD). Results: NT1 levels in ADAD mutation carriers (MC; n = 132) increased across the disease continuum, compared to non-carriers (NC; n = 75), becoming elevated about a decade prior to estimated symptom onset. Cross-sectional and longitudinal NT1 levels in MC were associated with clinical, cognitive, and biomarker changes. NT1 increases continued in symptomatic phases of disease, a distinct trajectory from that seen with CSF p-tau217 and other phospho-tau species. Discussion: Together, our results suggest that plasma NT1-alone or combined with other tau measures-may be useful in studying AD-related clinical, cognitive, and biomarker outcomes. Highlights: Leveraging a deeply phenotyped cohort of individuals carrying a pathogenic variant for autosomal dominant Alzheimer's disease (ADAD) and their non-carrier family members, our results suggest that plasma N-terminal tau fragment 1 (NT1) levels mirrored changes in clinical, cognitive, and neurodegenerative measures in ADAD, particularly in late asymptomatic and early symptomatic phases of disease. NT1 levels correlated with cerebrospinal fluid (CSF) measures of tau pathology but less so with CSF or imaging measures of β-amyloid pathology. Together with previous supportive findings in preclinical and symptomatic sporadic AD, these results suggest that plasma NT1-alone or combined with other tau measures-may be useful in studying AD-related tau pathology and neurodegeneration across a wide spectrum of disease. Mon, 01 Jun 2026 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1577 2026-06-01T00:00:00Z https://repositorio.fleni.org.ar/xmlui/handle/123456789/1573 Recognition memory in individuals with mild cognitive impairment and Alzheimer's dementia: a systematic review Russo, María Julieta; Bueri, José; Ferrara, Lucía Alba; Labos, Edith; Sevlever, Gustavo Emilio; Allegri, Ricardo Francisco Background: Episodic memory impairment is a hallmark of Alzheimer's disease (AD) and is already present in its prodromal stage. While recall deficits are well established as predictors of memory performance, the role of recognition memory-particularly the dissociation between familiarity and recollection-remains less explored. Objective: This systematic review aims to synthesize current evidence on recognition memory performance in healthy controls (HC), individuals with mild cognitive impairment (MCI), and those with AD, with a focus on the distinct contributions of familiarity and recollection processes. Methods: We searched PubMed (MEDLINE), Science Direct, PubPsych, and TRIP Medical databases for studies published until November 2025, which investigated recognition memory performance in individuals with MCI and AD including validated memory tools (such as scales, indices, scores, tests, and assessments). Forty-six studies (n = 3996) met the criteria and were included. Methodological quality was evaluated using the Newcastle-Ottawa scale. This study is registered with PROSPERO, CRD42022343750. Results: Most studies were cross-sectional and conducted in memory clinics or research centers, with considerable heterogeneity in sample size and assessment tools. The majority utilized experimental paradigms to differentiate familiarity and recollection, though traditional memory tests remain prevalent. Across studies, recollection was consistently impaired in MCI and AD, while familiarity showed a more variable pattern-often preserved in early MCI but impaired in advanced stages and AD. Structural and functional neuroimaging studies revealed that hippocampal atrophy is closely linked to recollection deficits, while alterations in entorhinal and parahippocampal cortices are associated with familiarity impairment. Combined deficits in recall and recognition, especially when recognition impairment reflects encoding failure, robustly predict conversion to dementia. Conclusions: Recognition memory assessment, particularly the dissociation between familiarity and recollection, provides valuable information for early detection and prognosis in the AD continuum. Incorporating nuanced recognition memory measures into clinical practice may improve diagnostic specificity and facilitate timely interventions. Further longitudinal research is needed to validate recognition memory as a predictor of dementia progression and to standardize its assessment in diverse populations. Tue, 06 Jan 2026 00:00:00 GMT https://repositorio.fleni.org.ar/xmlui/handle/123456789/1573 2026-01-06T00:00:00Z