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. 2018 Jan 22:6:5.
doi: 10.1186/s40364-018-0119-x. eCollection 2018.

Comparative analysis of cerebrospinal fluid metabolites in Alzheimer's disease and idiopathic normal pressure hydrocephalus in a Japanese cohort

Yuki Nagata  1 , Akiyoshi Hirayama  2 , Satsuki Ikeda  2 , Aoi Shirahata  2 , Futaba Shoji  2 , Midori Maruyama  2 , Mitsunori Kayano  3 , Masahiko Bundo  4 , Kotaro Hattori  5 , Sumiko Yoshida  5 , Yu-Ichi Goto  5 , Katsuya Urakami  6 , Tomoyoshi Soga  2 , Kouichi Ozaki  1 , Shumpei Niida  1
Affiliations

Comparative analysis of cerebrospinal fluid metabolites in Alzheimer's disease and idiopathic normal pressure hydrocephalus in a Japanese cohort

Yuki Nagata et al. Biomark Res. .

Abstract

Background: Alzheimer's disease (AD) is a most common dementia in elderly people. Since AD symptoms resemble those of other neurodegenerative diseases, including idiopathic normal pressure hydrocephalus (iNPH), it is difficult to distinguish AD from iNPH for a precise and early diagnosis. iNPH is caused by the accumulation of cerebrospinal fluid (CSF) and involves gait disturbance, urinary incontinence, and dementia. iNPH is treatable with shunt operation which removes accumulated CSF from the brain ventricles.

Methods: We performed metabolomic analysis in the CSF of patients with AD and iNPH with capillary electrophoresis-mass spectrometry. We assessed metabolites to discriminate between AD and iNPH with Welch's t-test, receiver operating characteristic (ROC) curve analysis, and multiple logistic regression analysis.

Results: We found significant increased levels of glycerate and N-acetylneuraminate and significant decreased levels of serine and 2-hydroxybutyrate in the CSF of patients with AD compared to the CSF of patients with iNPH. The ROC curve analysis with these four metabolites showed that the area under the ROC curve was 0.90, indicating good discrimination between AD and iNPH.

Conclusions: This study identified four metabolites that could possibly discriminate between AD and iNPH, which previous research has shown are closely related to the risk factors, pathogenesis, and symptoms of AD. Analyzing pathway-specific metabolites in the CSF of patients with AD may further elucidate the mechanism and pathogenesis of AD.

Keywords: 2-hydroxybutyrate; Alzheimer’s disease; Cerebrospinal fluid; Diagnostic marker; Glycerate; Idiopathic normal pressure hydrocephalus; N-acetylneuraminate; Serine.

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Conflict of interest statement

This study was approved by the Institutional Review Board of NCGG, NCNP and Tottori University, with the committee’s reference numbers of 443-6, A-2013-056 and 2188, respectively. Informed consents were obtained from all donors.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Statistically significant metabolites in the cerebrospinal fluid between Alzheimer’s disease and idiopathic normal pressure hydrocephalus. Four metabolites were statistically significant in the multiple logistic regression analysis
Fig. 2
Fig. 2
Receiver operator characteristic (ROC) curve analysis of statistically significant metabolites in the cerebrospinal fluid between Alzheimer’s disease (AD) and idiopathic normal pressure hydrocephalus (iNPH). ROC curve analysis was performed to compare the predictive power of AD and iNPH with the combined metabolites
Fig. 3
Fig. 3
Correlation diagram of p-tau versus the four metabolites. (a) serine, (b) glycerate, (c) Neu5Ac, and (d) 2-HB with regression lines are indicated
Fig. 4
Fig. 4
Correlation diagram of Aβ42 versus the four metabolites. (a) serine, (b) glycerate, (c) Neu5Ac, and (d) 2-HB with regression lines are indicated
Fig. 5
Fig. 5
Receiver operator characteristic (ROC) curve analysis of p-tau and Aβ42 in the cerebrospinal fluid between Alzheimer’s disease and idiopathic normal pressure hydrocephalus. ROC curve analysis was performed to compare the predictive power of p-tau (left) and Aβ42 (right)
Fig. 6
Fig. 6
A model of the relationship of Alzheimer’s disease-specific metabolites indicated in this study. Serine, glycerate, Neu5Ac, and 2-HB are depicted with the AD-related metabolites, phenomenon, structures and metabolic pathways. Metabolites detected in this study are indicated in green oval with bold letters. Other related metabolites are indicated in light green oval. Enzymes are indicated in light blue oval. The phenomena, structure and pathways known to participate with AD pathogenesis are indicated in square. Valid allows indicate the interactions previously reported. Dotted allows indicate predicted interactions. Red bold line indicates the brain and CSF boundary. 2-KB: 2-ketobutyrate; 2-HB: 2-hydroxybutyrate; AD: Alzheimer’s disease; LDH: lactate dehydrogenase; NADPH: nicotinamide adenine dinucleotide phosphate; Neu5Ac: N-acetylneuraminate; PC: phosphatidylcholine; PE: phosphatidylethanolamine; PPP: pentose phosphate pathway; PSS: phosphatidylserine synthase
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