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

Abstract

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.

• Authors: Roberta Magliozzi, Marco Pitteri, Stefano Ziccardi, Anna Isabella Pisani, Luigi Montibeller, Damiano Marastoni, Stefania Rossi, Valentina Mazziotti, Maddalena Guandalini, Caterina Dapor, Gianmarco Schiavi, Agnese Tamanti, Richard Nicholas, Richard Reynolds, Massimiliano Calabrese
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 8 Issue 3 Pg. 534-547 (03 2021) ISSN: 2328-9503 [Electronic] United States
• PMID: 33484486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Chemical References

• Biomarkers
• Neurofilament Proteins
• PVALB protein, human
• Parvalbumins
• neurofilament protein L

Topics

• Adult
• Autopsy
• Biomarkers (cerebrospinal fluid)
• Cerebral Cortex (pathology)
• Down-Regulation
• Female
• Gene Expression (genetics)
• Humans
• Interneurons (pathology)
• Magnetic Resonance Imaging
• Male
• Motor Cortex (pathology)
• Multiple Sclerosis, Chronic Progressive (cerebrospinal fluid, pathology)
• Neurofilament Proteins (cerebrospinal fluid)
• Parvalbumins (cerebrospinal fluid, genetics, metabolism)
• Young Adult