CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis.
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
Neurofilament Proteins
/ cerebrospinal fluid
Parvalbumins
/ cerebrospinal fluid
Young Adult
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
17
06
2020
revised:
15
10
2020
accepted:
11
11
2020
pubmed:
24
1
2021
medline:
3
11
2021
entrez:
23
1
2021
Statut:
ppublish
Résumé
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. 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. 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.
Identifiants
pubmed: 33484486
doi: 10.1002/acn3.51298
pmc: PMC7951111
doi:
Substances chimiques
Biomarkers
0
Neurofilament Proteins
0
PVALB protein, human
0
Parvalbumins
0
neurofilament protein L
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
534-547Informations de copyright
© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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