CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis. Issue 3 (23rd January 2021)

• Record Type: Journal Article
• Authors: Magliozzi, Roberta; Pitteri, Marco; Ziccardi, Stefano; Pisani, Anna Isabella; Montibeller, Luigi; Marastoni, Damiano; Rossi, Stefania; Mazziotti, Valentina; Guandalini, Maddalena; Dapor, Caterina; Schiavi, Gianmarco; Tamanti, Agnese; Nicholas, Richard; Reynolds, Richard; Calabrese, Massimiliano
• Is Part Of: Annals of clinical and translational neurology. Volume 8:Issue 3(2021)
• Page Start: 534
• Page End: 547
• Publication Date: 2021-01-23
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.51298
• Languages: English
• ISSNs: 2328-9503

Abstract

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.