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

摘要

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.