Protein tyrosine phosphatase receptor type Q in cerebrospinal fluid reflects ependymal cell dysfunction and is a potential biomarker for adult chronic hydrocephalus

M Nakajima, T Rauramaa, P M Mäkinen, M Hiltunen, S-K Herukka, M Kokki, T Musialowicz, H-K Jyrkkänen, N Danner, A Junkkari, A M Koivisto, J E Jääskeläinen, M Miyajima, I Ogino, A Furuta, C Akiba, K Kawamura, C Kamohara, H Sugano, Y Tange, K Karagiozov, V Leinonen, H Arai, M Nakajima, T Rauramaa, P M Mäkinen, M Hiltunen, S-K Herukka, M Kokki, T Musialowicz, H-K Jyrkkänen, N Danner, A Junkkari, A M Koivisto, J E Jääskeläinen, M Miyajima, I Ogino, A Furuta, C Akiba, K Kawamura, C Kamohara, H Sugano, Y Tange, K Karagiozov, V Leinonen, H Arai

Abstract

Background and purpose: Protein tyrosine phosphatase receptor type Q (PTPRQ) was extracted from the cerebrospinal fluid (CSF) of patients with probable idiopathic normal-pressure hydrocephalus (iNPH) by proteome analysis. We aimed to assess the feasibility of using CSF PTPRQ concentrations for the additional diagnostic criterion of iNPH in Japanese and Finnish populations.

Methods: We compared PTPRQ concentrations among patients with probable iNPH and neurologically healthy individuals (normal control [NC] group), patients with normal-pressure hydrocephalus (NPH) of acquired and congenital/developmental aetiologies, patients with Alzheimer's disease and patients with Parkinson's disease in a Japanese analysis cohort. A corresponding iNPH group and NC group in a Finnish cohort was used for validation. Patients in the Finnish cohort who underwent biopsy were classified into two groups based on amyloid and/or tau deposition. We measured PTPRQ expression levels in autopsied brain specimens of iNPH patients and the NC group.

Results: Cerebrospinal fluid PTPRQ concentrations in the patients with NPH of idiopathic, acquired and congenital/developmental aetiologies were significantly higher than those in the NC group and those with Parkinson's disease, but iNPH showed no significant differences when compared with those in the Alzheimer's disease group. For the patients with iNPH, the area under the receiver-operating characteristic curve was 0.860 in the Japanese iNPH and 0.849 in the Finnish iNPH cohorts. Immunostaining and in situ hybridization revealed PTPRQ expression in the ependymal cells and choroid plexus. It is highly possible that the elevated PTPRQ levels in the CSF are related to ependymal dysfunction from ventricular expansion.

Conclusions: Cerebrospinal fluid PTPRQ levels indicated the validity of this assay for auxiliary diagnosis of adult chronic hydrocephalus.

Keywords: RNA in situ hybridization; biomarker; cerebrospinal fluid; idiopathic normal-pressure hydrocephalus; protein tyrosine phosphatase receptor type Q.

Conflict of interest statement

The authors declare that they have no financial or other conflicts of interest.

© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

Figures

Figure 1
Figure 1
Study design. Aβ42, amyloid β 1‐42; CSF, cerebrospinal fluid; NC, healthy controls (individuals with normal cognition); iNPH, idiopathic normal‐pressure hydrocephalus; MMSE, Mini‐Mental State Examination; PTPRQ, protein tyrosine phosphatase receptor type Q; PD, Parkinson's disease; p‐tau, tau phosphorylated at threonine 181; t‐tau, total tau. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 2
Figure 2
Group comparison of protein tyrosine phosphatase receptor type Q (PTPRQ) concentrations in the cerebrospinal fluid (CSF) determined by enzyme‑linked immunosorbent assay. PTPRQ concentrations in the CSF determined by ELISA. Comparisons of CSF biomarkers between neurologically healthy individuals (normal control [NC] group), Alzheimer’s disease (AD), Parkinson’s disease (PD), Japanese patients with probable idiopathic normal‐pressure hydrocephalus (Japanese iNPH), and Finnish patients with iNPH (Finnish iNPH) groups are shown. The middle line represents the mean, while the upper and lower edges represent the SD. *P < 0.05, **P < 0.01, ***P < 0.001. [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 3
Figure 3
Group comparison of protein tyrosine phosphatase receptor type Q (PTPRQ) concentrations in the cerebrospinal fluid (CSF) between idiopathic normal‐pressure hydrocephalus (iNPH) and non‐idiopathic NPH. Comparisons of PTPRQ concentrations in the CSF between Japanese patients with probable iNPH and non‐idiopathic NPH (acquired aetiologies + congenital/developmental aetiologies). CSF PTPRQ concentrations were significantly higher in non‐idiopathic NPH (mean [SD] 1704 [861] pg/ml) compared to the iNPH group (**P = 0.002). [Colour figure can be viewed at wileyonlinelibrary.com]
Figure 4
Figure 4
Protein tyrosine phosphatase receptor type Q (PTPRQ) immunohistochemistry and mRNA in situ hybridization. Immunohistochemistry of the post‐mortem brain tissue using anti‑PTPRQ antibodies. (a) and (b) are serial sections of the choroid plexus (CP), and (c), (d) and (e) are serial sections of the ependymal lining (EL) of the third ventricle in patients with idiopathic normal‐pressure hydrocephalus (iNPH). PTPRQ immunostaining (a, c) is completely abolished following addition of the antigen peptide to the primary antibody solution (b, d). (a), (b), (c) and (d) are serial sections in case 10 (Tables [Link], [Link], [Link]). (e) The ependymal cells were immunofluorescently stained with anti‑PTPRQ antibody in case 8. The nuclei in the ependymal cells were immunostained with anti‑PTPRQ antibody and Hoechst, and the sections were examined under a confocal scanning microscope. Scale bar = 20 μm. The results from mRNA in situ hybridization were analysed by counting existing dots of mRNA in patients with iNPH (Tables [Link], [Link], [Link]: case 8, male, 72 years). PTPRQ mRNA was expressed in the cytoplasm of ependymal cells (f) and the CP (g) in iNPH patients (black and white arrows). Each red dot (black/white arrow) indicates one mRNA copy. Scale bar = 20 μm.

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