Defining active progressive multiple sclerosis

Sellebjerg, Finn; Börnsen, Lars; Ammitzbøll, Cecilie; Nielsen, Jørgen E.; Vinther-Jensen, Tua; Hjermind, Lena E.; Essen, Marina Rode von; Ratzer, Rikke; Sørensen, Per Soelberg; Christensen, Jeppe Romme

doi:10.1177/1352458517726592

Cited by 48 publications

(43 citation statements)

References 38 publications

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“…On the other hand, CSF analysis in patients with 'active progressive MS' (having either a relapse the previous year or presence of lesions with gadolinium enhancement at baseline MRI) has higher levels of MMP-9 and CXCL13 (a B-cell activation marker) than inactive progressive MS patients. This coincides with higher levels of neurofilament light chain as a measure of ongoing axonal damage, and of MBP as indicator of demyelination [194].…”

Section: Matrix Metalloproteinases In Multiple Sclerosissupporting

confidence: 58%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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Metalloproteinases-such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)-are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood-brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which-when correctly applied and dosed-harbor the potential to improve the outcome of different neuroinflammatory diseases.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Matrix Metalloproteinases In Multiple Sclerosissupporting

confidence: 58%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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“…Conversely, serum CHI3L1 levels were not significantly different between groups in the aforementioned studies [185,187] . Elevated levels of CHI3L1 were also detected in both PPMS and SPMS compared with healthy controls [189] . Patients who fulfilled diagnostic criteria for active progressive MS or showed elevated levels of MMP-9 and CXCL13 also had higher concentrations of CHI3L1 [189] .…”

Section: Chitinase-3-like-1mentioning

confidence: 91%

CSF biomarkers in multiple sclerosis: beyond neuroinflammation

Toscano¹,

Patti²

2020

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For many years, quantifiable biomarkers in neurological diseases have represented a hot topic. In multiple sclerosis (MS), cerebrospinal fluid biomarkers have played a diagnostic role since the introduction of Poser's criteria in 1983, with IgG oligoclonal bands playing a supporting role in an epoch prior to magnetic resonance imaging and a complementary one after the introduction of McDonald criteria in 2001. Nowadays, that supporting role has turned into a main one in substituting for dissemination in time and defining the diagnosis of MS in patients with a first clinical event, according to the 2017 revised McDonald criteria. Possibly kappa free light chains, N-CAM, chitinase 3-like protein 1 and IgM oligoclonal bands, not yet implemented in clinical practice, could similarly gain importance in the near future. Furthermore, the increasing knowledge of molecular mechanisms leading to chronic inflammation has enhanced interest in looking for biomarkers of disease activity, better defining the MS phenotype and patients with highly active disease. Accordingly, myelin proteins, intermediate filaments, metalloproteinases and other molecules involved in the inflammatory cascade, are currently under investigation. Finally, it has long been known that axonal loss occurs from the early phases, leading to a progressive neurological deterioration. Since established criteria to assess treatment failure and transition to progressive forms are still lacking, both treatment response and prognostic biomarkers would be useful to predict MS course, and neurofilaments seem to have this potential. The purpose of this review article was to illustrate biomarkers that have been already validated or require further validation after proving to be useful in exploratory studies and potentially could prove useful in clinical practice in the coming years.

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“…Interestingly, NfL levels were significantly increased in patients with RRMS in association with cortical lesions and relapses, whereas they were not different in patients with progressive MS in comparison with healthy controls. Sellebjerg et al [62] measured CSF NfL levels in 26 patients with PPMS, 26 with SPMS, and 24 healthy controls and observed higher values in cases with active progressive MS in comparison with those with inactive progressive MS, thus supporting the role of NfL in distinguishing active vs. inactive cases. These data further confirm the specific association between NfL concentration and active disease at sampling, which has a significant impact on axonal damage [61] .…”

Section: Nfl In Progressive Msmentioning

confidence: 96%

Neurofilament light chain in demyelinating conditions of the central nervous system: a promising biomarker

Bozzetti¹,

Ferrari²,

Gajofatto³

et al. 2020

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Neurofilaments are the major structural proteins of the neuronal cytoskeleton and are classified according to molecular weight into heavy, intermediate, and light chains. They are released into the interstitial fluid and cerebrospinal fluid (CSF) as a consequence of axonal damage. In particular, the light chain (NfL) represents the most abundant and soluble subunit and has been demonstrated to be increased in the CSF of patients with inflammatory, degenerative, vascular, or traumatic injuries in correlation with clinical and radiological activity. Similar results have been obtained measuring serum NfL with high-sensitivity single-molecule array, which enables reliable and repeatable measurement of the low NfL concentrations in serum. In particular, CSF and serum NfL values are strongly correlated in patients with multiple sclerosis (MS) and have been demonstrated to be increased in patients with MS and clinically isolated syndromes (CIS) in accordance with clinical and radiological activity. NfL levels increase in patients with a recent relapse and seem to predict cognitive impairment, longterm outcome, and conversion of CIS to MS. The few available data on patients with other demyelinating diseases suggest that NfL levels are also increased in neuromyelitis optica spectrum disorders and related conditions in correlation with attack severity, suggesting that axonal damage may occur in these disorders. We herein report and discuss published data on the role of NfL as a possible predictor of disease activity, clinical outcome and treatment response in patients with demyelinating conditions of the central nervous system.

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Defining active progressive multiple sclerosis

Cited by 48 publications

References 38 publications

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

CSF biomarkers in multiple sclerosis: beyond neuroinflammation

Neurofilament light chain in demyelinating conditions of the central nervous system: a promising biomarker

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