Frailty is a clinical state reflecting a decrease in physiological reserve capacities, known to affect numerous biological pathways and is associated with health issues, including
neurodegenerative diseases. However, how global
protein expression is affected in the central nervous system in frail subject remains underexplored. In this post hoc cross-sectional
biomarker analysis, we included 90 adults (52-85 years) suspected of
normal pressure hydrocephalus (NPH) and presenting with markers of
neurodegenerative diseases. We investigated the human proteomic profile of cerebrospinal fluid associated with
frailty defined by an established cumulated
frailty index (FI, average = 0.32), not enriched for neurology clinical features. Using a label-free quantitative proteomic approach, we identified and quantified 999
proteins of which 13 were positively associated with
frailty. Pathway analysis with the top positively
frailty-associated
proteins revealed enrichment for
proteins related to
inflammation and immune response. Among the 60
proteins negatively associated with
frailty, functional pathways enriched included neurogenesis, synaptogenesis and neuronal guidance. We constructed a
frailty prediction model using ridge regression with 932 standardized
proteins. Our results showed that the "proteomic model" could become an equivalent predictor of FI in order to study chronological age. This study represents the first comprehensive exploration of the proteomic profile of
frailty within cerebrospinal fluid. It sheds light on the physiopathology of
frailty, particularly highlighting processes of
neuroinflammation and inhibition of neurogenesis. Our findings unveil a range of biological mechanisms that are dysregulated in
frailty, in NPH subjects at risk of neurodegenerative impairment, offering new perspectives on
frailty phenotyping and prediction.