Mitochondrial complex I activity in microglia sustains neuroinflammation

Nature, Journal Year: 2024, Volume and Issue: 628(8006), P. 195 - 203

Published: March 13, 2024

Abstract Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation diverse functional states 2 However, how these act to perpetuate inflammation central nervous system unclear. Here, using multiomics approach, we identify molecular signature that sustains microglia through complex I activity driving reverse electron transport production reactive oxygen species. Mechanistically, blocking in pro-inflammatory protects against neurotoxic damage improves outcomes an animal disease model vivo. Complex potential therapeutic target foster neuroprotection inflammatory disorders 3

Language: Английский

Imaging chronic active lesions in multiple sclerosis: a consensus statement

Brain, Journal Year: 2024, Volume and Issue: 147(9), P. 2913 - 2933

Published: Jan. 16, 2024

Abstract Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery innovative MRI PET-derived biomarkers has made it possible to detect CAL, some extent quantify them, brain persons with sclerosis, vivo. Paramagnetic rim on susceptibility-sensitive sequences, MRI-defined slowly expanding T1-weighted T2-weighted scans, 18-kDa translocator protein-positive PET promising candidate CAL. While partially overlapping, these do not equivalent sensitivity specificity histopathological Standardization use available imaging measures CAL identification, quantification monitoring is lacking. To fast-forward clinical translation North American Imaging Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance radiological definition measurement The proposed manuscript presents this summarizes multistep process leading it, identifies remaining major gaps knowledge.

Language: Английский

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(1), P. 1 - 20

Published: April 3, 2024

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of disease underlies progression disability, which proceeds relentlessly independently clinical radiological relapses (PIRA). The complex system pathological events driving "chronic" worsening likely linked with early accumulation compartmentalized inflammation within central nervous as well insufficient repair phenomena mitochondrial failure. These mechanisms are partially lesion-independent differ those causing formation new focal demyelinating lesions; they lead to neuroaxonal dysfunction death, myelin loss, glia alterations, finally, neuronal network outweighing (CNS) compensatory mechanisms. This review aims provide an overview state art neuropathological, immunological, knowledge about underlying activity, focusing on possible biomarkers their translation into practice. ANN NEUROL 2024;96:1-20.

Language: Английский

Using the Progression Independent of Relapse Activity Framework to Unveil the Pathobiological Foundations of Multiple Sclerosis

Neurology, Journal Year: 2024, Volume and Issue: 103(1)

Published: June 18, 2024

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) relapses, has gained popularity as potential clinical trial outcome. We discuss its shortcomings and appraise the challenges implementing it settings, experimental trials, research. The current definition PIRA assumes that acute inflammation, which can manifest relapse, neurodegeneration, manifesting progressive accrual, be disentangled by introducing specific time windows between onset relapses observed increase disability. term PIRMA (progression MRI activity) was recently introduced indicate absence both new brain spinal cord lesions. Assessing practice is highly challenging because necessitates frequent assessments scans. commonly assessed using Expanded Disability Status Scale, scale heavily weighted toward motor disability, whereas more granular assessment deterioration, including cognitive decline, composite measures or other tools, such digital would possess greater utility. Similarly, an outcome measure randomized trials also requires methodological considerations. underpinning pathobiology accumulation, not associated with may encompass chronic active lesions (slowly expanding paramagnetic rim lesions), cortical lesions, atrophy, particularly gray matter, diffuse focal microglial activation, persistent leptomeningeal enhancement, white matter tract damage. propose use understand main determinant observational, cohort studies, where regular scans are included, introduce "advanced-PIRMA" investigate contributions abovementioned processes, conventional advanced imaging. This supported knowledge reflects MS pathogenic mechanisms better than purely descriptors. Any residual remains unexplained after considering all these imaging, will highlight future research priorities help complete our understanding pathogenesis.

Language: Английский

Smouldering‐Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

Annals of Neurology, Journal Year: 2024, Volume and Issue: 96(5), P. 826 - 845

Published: July 25, 2024

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition "progression independent relapsing activity." We propose concept smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, remain unmet targets. provide a consensus-based framework possible substrates manifestations MS, we discuss clinical, radiological, serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, share considerations optimizing disease surveillance implications clinical trials to promote integration MS into routine practice future research efforts. ANN NEUROL 2024;96:826-845.

Language: Английский

Fluid biomarkers in multiple sclerosis: from current to future applications

The Lancet Regional Health - Europe, Journal Year: 2024, Volume and Issue: 44, P. 101009 - 101009

Published: Aug. 23, 2024

Multiple sclerosis (MS) is an immune-mediated inflammatory and degenerative disorder of the central nervous system (CNS) with heterogeneous clinical manifestations. In last decade, landscape cerebrospinal fluid (CSF) blood biomarkers as potential key tools for MS diagnosis, prognosis treatment monitoring has evolved considerably, alongside magnetic resonance imaging (MRI). CSF analysis not only to provide information on underlying immunopathology disease exclude differential diagnoses, but also predict risk future relapses disability accrual, guide therapeutic decisions thus improve patient outcomes. This Series article overviews biological framework current applicability MS, exploring their role in molecular characterisation disease. We discuss recent advances field neurochemistry that enabled detection brain-derived proteins blood, opening door much more efficient longitudinal monitoring. Furthermore, we identify challenges application a real-world setting, while offering recommendations harnessing full paraclinical management personalise treatment.

Language: Английский

Serum biomarkers at disease onset for personalized therapy in multiple sclerosis

Brain, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Abstract The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis remains underexplored. We aimed investigate whether sNfL sGFAP values identify distinct subgroups of patients according the risk their response disease-modifying treatments (DMTs). This multicentre study, conducted across 13 European hospitals, spanned from 15 July 1994 18 August 2022, with follow-up until 26 September 2023. enrolled who had samples collected within 12 months disease onset before initiating DMTs. Multivariable regression models were used estimate relapse-associated (RAW), progression independent relapse activity (PIRA) Expanded Disability Status Scale (EDSS) score 3. Of 725 included, median age was 34.2 (interquartile range, 27.6–42.4) years, 509 (70.2%) female. duration 6.43 4.65–9.81) years. Higher associated an elevated RAW [hazard ratio (HR) 1.45; 95% confidence interval (CI) 1.19–1.76; P < 0.001], PIRA (HR 1.43; CI 1.13–1.81; = 0.003) reaching EDSS 3 1.55; 1.29–1.85; 0.001). Moreover, higher linked a achieving 1.36; 1.06–1.74; 0.02) and, low values, 1.86; 1.01–3.45; 0.04). also examined combined effect levels. Patients exhibited all outcomes served as reference. Untreated high showed RAW, Injectable or oral DMTs reduced these but failed mitigate Conversely, high-efficacy counteracted heightened outcomes, except increased 3, which remained unchanged either other In conclusion, evaluating at might phenotypes diverse immunological pathways acquisition therapeutic response.

Language: Английский

Towards a biological view of multiple sclerosis from early subtle to clinical progression: an expert opinion

Journal of Neurology, Journal Year: 2025, Volume and Issue: 272(2)

Published: Feb. 1, 2025

Language: Английский

Assessing disease progression and treatment response in progressive multiple sclerosis

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(10), P. 573 - 586

Published: Sept. 9, 2024

Language: Английский

Longitudinal enlargement of choroid plexus is associated with chronic lesion expansion and neurodegeneration in RRMS patients

Multiple Sclerosis Journal, Journal Year: 2024, Volume and Issue: 30(4-5), P. 496 - 504

Published: Feb. 6, 2024

Background and Objective: We explored dynamic changes in the choroid plexus (CP) patients with relapsing-remitting multiple sclerosis (RRMS) assessed its relationship chronic lesion expansion atrophy various brain compartments. Methods: Fifty-seven RRMS were annually for a minimum of 48 months 3D FLAIR, pre- post-contrast T1 diffusion-weighted magnetic resonance imaging (MRI). The CP was manually segmented at baseline last follow-up. Results: volume significantly increased by 1.4% annually. However, extent enlargement varied considerably among individuals (ranging from −3.6 to 150.8 mm 3 or −0.2% 6.3%). magnitude correlated central ( r = 0.70, p < 0.001) total −0.57, 0.001), white −0.61, deep grey matter −0.60, 0.001). Progressive associated 0.60, but not number new lesions. Conclusion: This study provides evidence progressive RRMS. Our findings also demonstrate that is linked lesions neurodegeneration periventricular patients.

Language: Английский