Multiple sclerosis: two decades of progress

Cree, Bruce A.C.; Oksenberg, Jorge R.

doi:10.1016/s1474-4422(22)00040-0

Cited by 21 publications

(10 citation statements)

References 21 publications

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“…Despite a good control of the peripheral immune response in relapsing–remitting MS, patients still experience ongoing atrophy and worsening of symptoms related to different functional systems and anatomical areas [ 9 , 53 ]. Hence, a better understanding of regionally restricted neuronal and glial subtype diversity and how these subtypes differ in their transcriptomic response to inflammatory demyelination, would help decode compartmentalized pathology in MS [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Cross-regional homeostatic and reactive glial signatures in multiple sclerosis

et al. 2022

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Multiple sclerosis (MS) is a multifocal and progressive inflammatory disease of the central nervous system (CNS). However, the compartmentalized pathology of the disease affecting various anatomical regions including gray and white matter and lack of appropriate disease models impede understanding of the disease. Utilizing single-nucleus RNA-sequencing and multiplex spatial RNA mapping, we generated an integrated transcriptomic map comprising leukocortical, cerebellar and spinal cord areas in normal and MS tissues that captures regional subtype diversity of various cell types with an emphasis on astrocytes and oligodendrocytes. While we found strong cross-regional diversity among glial subtypes in control tissue, regional signatures become more obscure in MS. This suggests that patterns of transcriptomic changes in MS are shared across regions and converge on specific pathways, especially those regulating cellular stress and immune activation. In addition, we found evidence that a subtype of white matter oligodendrocytes appearing across all three CNS regions adopt pro-remyelinating gene signatures in MS. In summary, our data suggest that cross-regional transcriptomic glial signatures overlap in MS, with different reactive glial cell types capable of either exacerbating or ameliorating pathology.

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Section: Discussionmentioning

confidence: 99%

Cross-regional homeostatic and reactive glial signatures in multiple sclerosis

et al. 2022

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confidence: 99%

“…Defining a patient as progressive MS rather than relapsing-remitting MS is therefore challenging and may only be correctly classified years after the biological transition has taken place. 9,10 The accurate enrollment of patients with progressive MS in clinical trials is in fact critical to succeed in identifying effective therapies for progressive MS. Treatments that affect the peripheral immune system reduce disease activity in patients with relapsing-remitting MS or patients with active secondary progressive MS but have so far been disappointing in treating nonactive progressive MS. 11,12 In contrast, patients with active progressive MS may respond to highly effective therapies, making the accurate identification of this patient group crucial.…”

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confidence: 99%

Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients With Progressive Multiple Sclerosis

Barro

Healy

Liu

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesNeurodegeneration and astrocytic activation are pathologic hallmarks of progressive multiple sclerosis (MS) and can be quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying patients with progressive MS based on progression and disease activity status.MethodsWe leveraged our Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) natural history study, which includes clinical, MRI data and serum samples collected over more than 20 years. We included patients with MS with a confirmed Expanded Disability Status Scale (EDSS) score ≥3 that corresponds with our classifier for patients at high risk of underlying progressive pathology. We analyzed sNfL and sGFAP within 6 months from the confirmed EDSS score ≥3 corresponding with our baseline visit. Patients who further developed 6-month confirmed disability progression (6mCDP) were classified as progressors. We further stratified our patients into active/nonactive based on new brain/spinal cord lesions or relapses in the 2 years before baseline or during follow-up. Statistical analysis on log-transformed sGFAP/sNfL assessed the baseline association with demographic, clinical, and MRI features and associations with future disability.ResultsWe included 257 patients with MS who had an average EDSS score of 4.0 and a median follow-up after baseline of 7.6 years. sNfL was higher in patients with disease activity in the 2 years before baseline (adjusted β = 1.21; 95% CI 1.04–1.42;p= 0.016), during the first 2 years of follow-up (adjusted β = 1.17; 95% CI = 1.01–1.36;p= 0.042). sGFAP was not increased in the presence of disease activity. Higher sGFAP levels, but not sNfL levels, were associated with higher risk of 6mCDP (adjusted hazard ratio [HR] = 1.71; 95% CI = 1.19–2.45;p= 0.004). The association was stronger in patients with low sNfL (adjusted HR = 2.44; 95% CI 1.32–4.52;p= 0.005) and patients who were nonactive in the 2 years prior or after the sample.DiscussionHigher levels of sGFAP correlated with subsequent progression, particularly in nonactive patients, whereas sNfL reflected acute disease activity in patients with MS at high risk of underlying progressive pathology. Thus, sGFAP and sNfL levels may be used to stratify patients with progressive MS for clinical research studies and clinical trials and may inform clinical care.

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“…imaging of the central veins within MS lesions, meningeal B cell aggregates, quantitation of grey matter and spinal cord pathology) and serum biomarkers (e.g. neurofilament measurement as surrogate markers of neuronal loss) [56].…”

Section: Reliability Of Diagnosismentioning

confidence: 99%

The future of diagnosis in clinical neurosciences: Comparing multiple sclerosis and schizophrenia

Misiak,

Samochowiec,

Kowalski

et al. 2023

Eur. Psychiatr.

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The ongoing developments of psychiatric classification systems have largely improved reliability of diagnosis, including that of schizophrenia. However, with an unknown pathophysiology and lacking biomarkers, its validity still remains low, requiring further advancements. Research has helped establish multiple sclerosis (MS) as the central nervous system (CNS) disorder with an established pathophysiology, defined biomarkers and therefore good validity and significantly improved treatment options. Before proposing next steps in research that aim to improve the diagnostic process of schizophrenia, it is imperative to recognize its clinical heterogeneity. Indeed, individuals with schizophrenia show high interindividual variability in terms of symptomatic manifestation, response to treatment, course of illness and functional outcomes. There is also a multiplicity of risk factors that contribute to the development of schizophrenia. Moreover, accumulating evidence indicates that several dimensions of psychopathology and risk factors cross current diagnostic categorizations. Schizophrenia shares a number of similarities with MS, which is a demyelinating disease of the CNS. These similarities appear in the context of age of onset, geographical distribution, involvement of immune-inflammatory processes, neurocognitive impairment and various trajectories of illness course. This article provides a critical appraisal of diagnostic process in schizophrenia, taking into consideration advancements that have been made in the diagnosis and management of MS. Based on the comparison between the two disorders, key directions for studies that aim to improve diagnostic process in schizophrenia are formulated. All of them converge on the necessity to deconstruct the psychosis spectrum and adopt dimensional approaches with deep phenotyping to refine current diagnostic boundaries.

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Multiple sclerosis: two decades of progress

Cited by 21 publications

References 21 publications

Cross-regional homeostatic and reactive glial signatures in multiple sclerosis

Cross-regional homeostatic and reactive glial signatures in multiple sclerosis

Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients With Progressive Multiple Sclerosis

The future of diagnosis in clinical neurosciences: Comparing multiple sclerosis and schizophrenia

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