Cerebrospinal fluid and plasma biomarkers in idiopathic normal pressure hydrocephalus: comparison with Alzheimer's and Parkinson's diseases

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Background Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder whose diagnosis is complicated by clinical overlap with neurodegenerative diseases. Fluid biomarkers may provide insight into disease mechanisms and support differential diagnosis. Methods We performed a small exploratory study at the Neurology and Neurosurgery Sections of the University Hospital of Perugia, between 2024 and 2025, comparing cerebrospinal fluid (CSF) and plasma biomarkers among patients with iNPH, Alzheimer's disease (AD), Parkinson's disease (PD), and non-neurodegenerative controls (CTRL). CSF concentrations of amyloid-β peptides (Aβ42, Aβ40, Aβ42/Aβ40 ratio), tau proteins (p-tau 181 and t-tau) and neurofilament light chain (NfL) were measured. In plasma, amyloid-β peptides (Aβ42, Aβ40, Aβ42/Aβ40 ratio), tau proteins (p-tau 217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed. Both CSF and plasma biomarkers were measured using standardized immunoassays. Group differences and correlations between CSF and plasma biomarkers were analyzed. Results CSF Aβ40 levels were significantly lower in iNPH compared with all other groups (all p < 0.005), and showed preliminary apparent discrimination for iNPH, requiring external validation, with an AUC of 0.95, sensitivity of 95%, and specificity of 86% at a cut-off of 9,327.5 pg/mL. AD patients were clearly distinguished from iNPH and the other groups by AD-specific changes in fluid biomarkers. CSF Aβ42 levels were lower in iNPH than in CTRL ( p = 0.001) and PD ( p = 0.009), while CSF p-tau181 and t-tau were decreased compared with AD ( p < 0.001) and CTRL ( p ≤ 0.024). The CSF Aβ42/Aβ40 ratio remained preserved in iNPH, distinguishing it from AD ( p < 0.001). Plasma NfL correlated strongly with CSF levels in each diagnostic group, including iNPH ( r = 0.77, p = 0.0012), whereas plasma amyloid biomarkers poorly reflected CSF concentrations. Conclusions iNPH is associated with low CSF Aβ40 levels, possibly reflecting altered CSF dynamics rather than a primary pathophysiological mechanism. In iNPH, plasma NfL showed a preliminary correlation with CSF NfL; however, larger age-adjusted studies are required before peripheral markers can be considered clinically informative in this setting.

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