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.

Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients

“…Overall, these results suggest that a detailed analysis of a complex and specific CSF inflammatory pattern, and not of a single biomarker, may help in the early recognition of the degree and severity of CI and, therefore, to define specific MS endophenotypes earlier. In line with this assumption, we did not find a significant difference among the three groups (ACN, mCI, sCI) in the level of CSF Nf-L 33 despite CSF Nf-L levels being proposed as potential prognostic biomarker of CI in MS. 21 Beyond visible structural damage, systemic inflammation might be able to influence synaptic properties, leading to altered circuit dynamics and synaptic plasticity failure in key brain structures related to cognitive functioning. 34 Together with neurodegeneration, inflammation-mediated loss of synapses’ ability to participate in the correct functioning of neuronal circuits involved in cognitive functioning could contribute to the pathogenesis of MS-related CI.…”

Microstructural MRI Correlates of Cognitive Impairment in Multiple Sclerosis: The Role of Deep Gray Matter

“…This is in line with a previous study in which all cognitive scores were significantly lower in pwMS with CI compared with non-CI patients [ 38 ]. Although the definitions and the diagnostic criteria of CI differ between studies [ 39 ], the present results confirm the clinical usefulness of this conservative approach to effectively classify patients with CI [ 27 , 28 ].…”

“…Among the whole MS cohort, neuropsychological assessment classified 11 (30%) pwMS as being apparently cognitive normal (ACN; 0 tests below the cut-off) and 25 (70%) pwMS as having CI (1 or more test below the cut-off; see also [ 27 , 28 ]). Demographic and clinical characteristics of the MS cohort and each group of pwMS are listed in Table 1 .…”

The potential of serum neurofilament as biomarker for multiple sclerosis

“…Parvalbumin is a protein expressed in GABAergic interneurons and has been proposed as a marker of cortical grey matter neurodegeneration in patients with multiple sclerosis. 77 , 78 A reduction in CSF parvalbumin correlated with meningeal inflammation, cortical lesion load, cortical thickness and cognitive impairment; all of which possibly showed a better correlation of gradual degenerative pathology than NfL levels. Extending these findings in larger, multicentre longitudinal studies is warranted to assess a possible combination of both biomarkers.…”