Novel Insight in Idiopathic Normal Pressure Hydrocephalus (iNPH) Biomarker Discovery in CSF

Enrica Torretta,Cecilia Gelfi,Manuela Moriggi,Daniela Mari,Paolo Dionigi Rossi,Pietro Barbacini,Beatrice Arosio,Daniele Capitanio,Matteo Cesari,Mario Clerici

doi:10.3390/ijms22158034

Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disease, causing motor and cognitive dysfunction and dementia. iNPH and Alzheimer’s disease (AD) share similar molecular characteristics, including amyloid deposition, t-tau and p-tau dysregulation; however, the disease is under-diagnosed and under-treated. The aim was to identify a panel of sphingolipids and proteins in CSF to diagnose iNPH at onset compared to aged subjects with cognitive integrity (C) and AD patients by adopting multiple reaction monitoring mass spectrometry (MRM-MS) for sphingolipid quantitative assessment and advanced high-resolution liquid chromatography–tandem mass spectrometry (LC–MS/MS) for proteomic analysis. The results indicated that iNPH are characterized by an increase in very long chains Cer C22:0, Cer C24:0 and Cer C24:1 and of acute-phase proteins, immunoglobulins and complement component fragments. Proteins involved in synaptic signaling, axogenesis, including BACE1, APP, SEZ6L and SEZ6L2; secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and LCAT) were statistically lower in iNPH. In conclusion, at the disease onset, several factors contribute to maintaining cell homeostasis, and the protective role of very long chains sphingolipids counteract overexpression of amyloidogenic and neurotoxic proteins. Monitoring specific very long chain Cers will improve the early diagnosis and can promote patient follow-up.

Highlights

Despite differences in the disease etiology, idiopathic normal pressure hydrocephalus and Alzheimer’s disease (AD) share cognitive dysfunction as common clinical manifestations [1]
Proteins involved in synaptic signaling, axogenesis, including beta-secretase 1 (BACE1), amyloid precursor protein (APP), seizure 6-like protein (SEZ6L) and seizure-related 6 homolog-like 2 (SEZ6L2); secretory proteins (CHGA, SCG3 and VGF); glycosylation proteins (POMGNT1 and DAG1); and proteins involved in lipid metabolism (APOH and Lecithin-cholesterol acyltransferase (LCAT)) were statistically lower in Idiopathic normal pressure hydrocephalus (iNPH)
Gender composition was homogeneous across groups whereas the age range was slightly different, being iNPH patients older compared to aged subjects with cognitive integrity (C) and AD patients (ANOVA on ranks p-value < 0.001; Dunn’s p-value < 0.05 for iNPH vs. C comparison and iNPH vs. AD comparison)

Summary

Introduction

Despite differences in the disease etiology, idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD) share cognitive dysfunction as common clinical manifestations [1]. These two disorders have multiple causes, heterogeneous presentations and a different impact on patients. It is remarkable that AD and iNPH patients present similar molecular characteristics [5], including amyloid deposition [6,7,8] and t-tau and p-tau dysregulation [9]. An enlargement of the panel of molecules targeting different areas such as amyloid β (aβ) production and aggregation, cortical neuronal damage, tau pathology, axonal damage, astrocyte activation and lipid raft would define iNPH patients more precisely

Methods

Results

Conclusion