Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients

Abstract

Background: The cerebrospinal fluid (CSF) molecular milieu is a marker of diffuse intrathecal inflammation in the meninges that, in turn, targets the grey matter (GM) in multiple sclerosis (MS). Cognitive impairment (CI) is associated with brain damage in MS and is often present early in people with MS (pwMS). Objective: To investigate whether a specific CSF inflammatory profile is associated with different degrees of CI in newly diagnosed pwMS. Methods: Sixty-nine pwMS and 43 healthy controls (HCs) underwent neuropsychological testing. The presence and levels of 57 inflammatory mediators in the CSF were assessed. Results: Apparently cognitively normal (ACN) pwMS had impaired executive functioning compared to HCs but performed better than pwMS with mild and severe CI (mCI and sCI) in all tests. CSF mediators involving innate immunity and immune activation and recruitment, differentiate ACN from pwMS with mCI, while CSF mediators related to B- and T-cell immunity and chemotaxis differentiate both ACN and mCI from those with sCI. CXCL13 was the only molecule that differentiated sCI from mCI pwMS. Conclusion: Specific CSF molecular patterns, reflecting the involvement of both innate and adaptive immune responses, are associated with the severity of CI in newly diagnosed pwMS.

Cerebrospinal fluid CXCL13 identifies a subgroup of people living with HIV with prominent intrathecal synthesis, immune activation, and neurocognitive impairment regardless of effective antiretroviral therapy

“…One subject with detectable CSF CXCL13 versus none among those with undetectable chemokine had also persistence of HIV-associated dementia and spastic tetraparesis with a brain MRI imaging compatible with advanced HIV encephalopathy despite being on effective treatment since more than two years. In multiple sclerosis, which shows several overlaps with HIV-related CNS inflammatory processes (Bonnan et al 2015), CSF CXCL13 has been usually reported as moderately higher (20 pg/mL up to more tha 500 pg/mL) compared to what we measured in our study population (Khademi et al 2011;Alvarez et al 2013;DiSano et al 2020;Pitteri et al 2022). Increased CSF CXCL13 levels have been linked with disease activity, relapse rate, number of brain lesions and unfavourable overall prognosis (Khademi et al 2011;Alvarez et al 2013;DiSano et al 2020).…”

“…Increased CSF CXCL13 levels have been linked with disease activity, relapse rate, number of brain lesions and unfavourable overall prognosis (Khademi et al 2011;Alvarez et al 2013;DiSano et al 2020). Interestingly, CSF CXCL13 levels were used to discriminate mild from severe cognitive impairment in patients suffering from multiple sclerosis (Pitteri et al 2022). In PLWH, increased intrathecal synthesis has been previously associated with a worse neurocognitive outcome (Bonnan et al 2015;De Almeida et al 2021); herein, we have introduced in this relationship a further piece represented by CSF CXCL13 that could be is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint…”

Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications

“…These follicles might contain the oligoclonal B cell expansions and follicular T H cells that have been identified by singlecell transcriptome analysis in the CSF of patients with MS 134,135 . Levels of C-X-C chemokine ligand 13 (CXCL13), a chemokine that is involved in C-X-C chemokine receptor type 5 (CXCR5)-dependent migration of both B cells and follicular T H cells, correlate with disease severity at the first clinical manifestation of MS 136,137 . In addition, CXCR3 + TBX21 + B cells are abundant in the CNS of patients with MS and might be equipped with superior brain-homing capacity compared with other B cell subsets 138 .…”

Cognitive Decline in Older People with Multiple Sclerosis—A Narrative Review of the Literature

“…Even though the meta-analysis did not assess the association of these markers with cognitive performance, some studies have shown that CSF total tau is associated with disability and cognitive impairment [ 53 , 54 ]. In addition to markers of neurodegeneration, inflammatory markers have been also examined, and found to correlate with cognitive impairment in MS [ 92 , 93 ]. How aging and other age-related neurodegenerative processes may play a role in shifting neurodegenerative or inflammatory profiles in the CSF is less clear, and has only been examined by a few [ 94 ].…”