Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible disease characterized by gait disturbance, a frontal-subcortical pattern of cognitive impairment, and urinary incontinence with disproportionately enlarged ventricles. Its prevalence rises with aging. Patients with iNPH are treated with shunt placement, and predicting the surgical outcome is not always easy. Cerebrospinal fluid (CSF) has inevitably been an attractive matrix for biomarker identification in both the diagnosis and treatment of iNPH and the disease may have individual CSF composition changes. Additionally, in order to detect iNPH earlier, implement treatment faster, and have better therapeutic effects, the incorporation of CSF biomarkers in the diagnostic and treatment process is essential. In this review, CSF biomarkers of Alzheimer’s disease pathology, axonal damage, neuronal damage, astroglial dysfunction, myelin damage, inflammation, and extracellular matrix protein remodeling have been evaluated and tried to emphasize those of which have highly consistent findings in the studies. CSF samples collected only at a single time point may not be sufficient to identify a promising marker in such a dynamic and used to be a common comorbid condition to other neurodegenerative diseases. These confounders demonstrate the limitations of using solely biomarkers to diagnose the disease and to foresee the outcome of the shunt surgery. Therefore, CSF samples collected antemortem at different time points and biopsy-confirmed iNPH patients with and without other neurodegenerative diseases would fill the gaps in identifying a valid biomarker. Longitudinal observations of shunt responders and non-responders in multicenter with well-defined cohorts are also needed to understand iNPH-specific markers. Finally, biomarkers of a bioinformatic approach that includes micro-RNAs, extracellular vesicles, metabolomics, the microbiome, or else are warranted to identify novel and useful diagnostic and prognostic biomarker tools in iNPH.
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