CSF Parvalbumin Levels at Multiple Sclerosis Diagnosis Predict Future Worse Cognition, Physical Disability, Fatigue, and Gray Matter Damage.

BACKGROUND AND OBJECTIVES

Cognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the time of diagnosis, may have a prognostic role in patients with MS.

METHODS

In this cohort study, CSF analysis of PVALB and Nf-L levels was performed on all patients at diagnosis (T0) and combined with physical, cognitive, and MRI assessment after an average of 4 years of follow-up (T4) from diagnosis. Cognitive performance was evaluated with a comprehensive neuropsychologic battery: both global (cognitively normal, CN, mildly CI, mCI, and severely CI, sCI) and domain cognitive status (normal/impaired in memory, attention/information processing speed, and executive functions) were considered. Cortical thickness and gray matter volume data were acquired using 3T MRI scanner.

RESULTS

A total of 72 patients with MS were included. At diagnosis, PVALB levels were higher in those patients who showed a worsening physical disability after 4 years of follow-up ( = 0.011). CSF PVALB levels were higher in sCI patients than in CN ( = 0.033). Moreover, higher PVALB levels significantly correlated with worse global cognitive ( = 0.024) and memory functioning ( = 0.044). A preliminary clinical threshold for PVALB levels at diagnosis was proposed (2.57 ng/mL), which maximizes the risk of showing CI (in particular, sCI) at follow-up, with a sensitivity of 91% (specificity 30%). No significant results were found for these associations with Nf-L. In addition, patients with higher levels of PVALB at diagnosis showed higher cognitive ( = 0.024) and global fatigue ( = 0.043) at follow-up. Finally, higher PVALB levels also correlated significantly with more pronounced CTh/volume at T4 in the inferior frontal gyrus ( = 0.044), postcentral gyrus ( = 0.025), frontal pole ( = 0.042), transverse temporal gyrus ( = 0.008), and cerebellar cortex ( = 0.041) and higher atrophy (change T0-T4) in the right thalamus ( = 0.038), pericalcarine cortex ( = 0.009), lingual gyrus ( = 0.045), and medial frontal gyrus ( = 0.028).

DISCUSSION

The significant association found between parvalbumin levels in the CSF at diagnosis and cognitive, clinical, and neuroradiologic worsening after 4 years of follow-up support the idea that parvalbumin, in addition to Nf-L, might represent a new potential prognostic biomarker, reflecting MS neurodegenerative processes occurring since early disease stages.