CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics

Anna Jeppsson, Carsten Wikkelsö, Kaj Blennow, Henrik Zetterberg, Radu Constantinescu, Anne M Remes, Sanna-Kaisa Herukka, Tuomas Rauramaa, Katarina Nagga, Ville Leinonen, Mats Tullberg, Anna Jeppsson, Carsten Wikkelsö, Kaj Blennow, Henrik Zetterberg, Radu Constantinescu, Anne M Remes, Sanna-Kaisa Herukka, Tuomas Rauramaa, Katarina Nagga, Ville Leinonen, Mats Tullberg

Abstract

Objective: To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer's disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders.

Methods: The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson's disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer's disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1).

Results: Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers.

Conclusions: The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH.

Keywords: Alzheimer’s disease; CSF; Multiple systems atrophy; Parkinson’s disease; Progressive supranuclear palsy; biomarkers; corticobasal degeneration; frontotemporal dementia; idiopathic normal pressure hydrocephalus; vascular dementia.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Biomarker concentrations in CSF as individual values in each diagnostic group. Biomarker concentrations in CSF plotted as individual values for each group. In each graph, values are given for HIs, iNPH, AD, FTLD, VAD, PD, MSA, PSP and CBD. (A) Concentration of T-tau, (B) P-tau, (C) NFL, (D) Aβ38, (E) Aβ40, (F) Aβ42, (G) sAPPα, (H) sAPPβ and (I) MCP-1. Bar indicates mean value. Y-axes are broken to enhance visibility. Aβ, AD-related amyloid β; AD, Alzheimer’s disease; CBD, corticobasal degeneration; CSF, cerebrospinal fluid; FTLD, frontotemporal lobar degeneration; HIs, healthy individuals; iNPH, idiopathic normal pressure hydrocephalus; MCP-1, monocyte chemoattractant protein 1; MSA, multiple system atrophy; NFL, neurofilament light; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; P-tau, phosphorylated tau; sAPP, soluble amyloid precursor protein; T-tau, total tau; VAD, vascular dementia.
Figure 2
Figure 2
ROC curves to separate iNPH with the multivariable model 10*MCP-1 *- Aβ40–5*T-tau. ROC curves for the simplified model 10*MCP-1-Aβ40-5*T-tau. ROC curves are given for (A) iNPH versus HI (AUC = 0.8715), (B) iNPH versus non-iNPH (AUC = 0.8581), (C) iNPH versus cognitive disorders (AUC = 0.9161) and (D) iNPH versus movement disorders (AUC = 0.8035). Aβ, AD-related amyloid β; iNPH, iNPH=idiopathic normal pressure hydrocephalus; HI, healthy control; MCP-1, monocyte chemoattractant protein 1; T-tau; total tau.
Figure 3
Figure 3
Prediction plot of iNPH versus non-iNPH disorders. Prediction plot showing probability of iNPH. T-tau is given in four concentrations, Aβ40 is given in eight different intervals, whereas MCP-1 is shown as a continuous variable on the X-axes. Estimated probability of iNPH is given on the Y-axes. Aβ, AD-related amyloid β; iNPH, iNPH=idiopathic normal pressure hydrocephalus; MCP-1, monocyte chemoattractant protein 1; T-tau, total tau.

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