Can CSF biomarkers predict future MS disease activity and severity?

Magliozzi, Roberta; Cross, Anne H.

doi:10.1177/1352458519871818

Cited by 34 publications

(28 citation statements)

References 47 publications

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“…Similar to other CSF biomarkers thought to reflect activity or damage associated with MS pathology and released into the CSF, 38 PVALB is most likely released into the CSF as a consequence of interneuronal loss. Compared to Nf‐L, our results show that CSF PVALB levels correlate better with cortical thinning and cognitive impairment than Nf‐L and also earlier, at the time of diagnosis.…”

Section: Discussionmentioning

confidence: 91%

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

Magliozzi

Pitteri

Ziccardi

et al. 2021

Ann Clin Transl Neurol

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Introduction and methods In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS‐specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post‐mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf‐L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis. Results PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post‐mortem CSF‐PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = −0.64, P < 0.001) and increased MHC‐II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = −0.69, P < 0.05), shorter time to wheelchair (r = −0.49, P < 0.05) and early age of death (r = −0.65, P < 0.01). Increased CSF‐PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF‐PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = −0.46, P < 0.001), better than Nf‐L levels. CSF‐PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients. Conclusions CSF‐PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS‐specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline.

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Section: Discussionmentioning

confidence: 91%

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

Magliozzi

Pitteri

Ziccardi

et al. 2021

Ann Clin Transl Neurol

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“…However, the study also observed that higher accuracy in the diagnosis between AD patients and MCI patients was seen when combining the latter biomarkers with NfL 33 . Similarly, higher levels of biomarkers such as GFAP and YKL-40 are correlated with increased MS disease progression while NfL determined changes in brain volume and neuronal injury 34 . NfL was also found to have accurate diagnostic value in neurodegenerative dementias when used in conjunction with tau 35 .…”

Section: Neurofilament Light With Other Biomarkersmentioning

confidence: 98%

Neurofilament light: a narrative review on biomarker utility

Narayanan¹,

Shanker²,

Khera³

et al. 2021

Fac Rev

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Neurofilament light (NfL) is a scaffolding protein that is located primarily within myelinated axons and that provides increased conduction speed and structural support. In recent years, NfL has been used as a disease biomarker on the basis of the observation that axonal injury results in elevated levels of NfL in cerebrospinal fluid or blood. This review focuses on how cerebrospinal fluid and plasma NfL have been studied in various disorders such as Alzheimer’s disease (AD) and multiple sclerosis (MS) in relation to neuroinflammation and cognitive dysfunction. Focusing on the role of NfL as a biomarker for AD and MS, this review aims to further explore the potential of NfL as a promising biomarker with regard to surgery- and anesthesia-based incidents for postoperative cognitive decline and delirium. A search of the PubMed database yielded 36 articles, 31 of which are from within the last 3 years, that show how NfL has been observed and studied under various types of trials and disease cohorts and potential future directions. Higher levels of NfL have frequently been correlated with disease progression and prognosis of AD and MS, and delirium has been found to share a neuroinflammatory pathophysiology that NfL could help to measure. Focusing on NfL as a biomarker for neurodegenerative decline, these studies indicate that the protein could be further tested and related to postoperative aspects that result in cognitive dysfunction, and it has the potential to be an established delirium biomarker, particularly in the realm of the perioperative course.

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“…In the control group (tumor-free), only one out of eight patients (13%) with idiopathic intracranial hypertension exhibited BBB dysfunction. For the MS patient group, we did not calculate CSF/serum quotients of albumin, IgG, IgA and IgM concentration as the CSF contains inherently more IgG [18]. This high degree of BBB dysfunction in the analyzed clinical entries underlined the necessity to consider leakage of plasma proteins into the CSF to avoid the selection of false-positive candidate biomarkers for further validation.…”

Section: Analysis Of Bbb Dysfunction In the Discovery Cohortmentioning

confidence: 99%

A Multiplex Assay for the Stratification of Patients with Primary Central Nervous System Lymphoma Using Targeted Mass Spectrometry

Waldera-Lupa

Poschmann

Kirchgaessler

et al. 2020

Cancers

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Primary central nervous system lymphomas (PCNSL) account for approximately 2% to 3% of all primary brain tumors. Until now, neuropathological tumor tissue analysis, most frequently gained by stereotactic biopsy, is still the diagnostic gold standard. Here, we rigorously analyzed two independent patient cohorts comprising the clinical entities PCNSL (n = 47), secondary central nervous system lymphomas (SCNSL; n = 13), multiple sclerosis (MS, n = 23), glioma (n = 10), other tumors (n = 17) and tumor-free controls (n = 21) by proteomic approaches. In total, we identified more than 1220 proteins in the cerebrospinal fluid (CSF) and validated eight candidate biomarkers by a peptide-centric approach in an independent patient cohort (n = 63). Thus, we obtained excellent diagnostic accuracy for the stratification between PCNSL, MS and glioma patients as well as tumor-free controls for three peptides originating from the three proteins VSIG4, GPNMB4 and APOC2. The combination of all three biomarker candidates resulted in diagnostic accuracy with an area under the curve (AUC) of 0.901 (PCNSL vs. MS), AUC of 0.953 (PCNSL vs. glioma) and AUC 0.850 (PCNSL vs. tumor-free control). In summary, the determination of VSIG4, GPNMB4 and APOC2 in CSF as novel biomarkers for supporting the diagnosis of PCNSL is suggested.

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Can CSF biomarkers predict future MS disease activity and severity?

Cited by 34 publications

References 47 publications

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

Neurofilament light: a narrative review on biomarker utility

A Multiplex Assay for the Stratification of Patients with Primary Central Nervous System Lymphoma Using Targeted Mass Spectrometry

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