Cerebrospinal Fluid Amyloid-β Oligomer Levels in Patients with Idiopathic Normal Pressure Hydrocephalus

Kaito Kawamura, Masakazu Miyajima, Madoka Nakajima, Mitsuyasu Kanai, Yumiko Motoi, Shuko Nojiri, Chihiro Akiba, Ikuko Ogino, Hanbing Xu, Chihiro Kamohara, Shinya Yamada, Kostadin Karagiozov, Takeshi Ikeuchi, Akihide Kondo, Hajime Arai, Kaito Kawamura, Masakazu Miyajima, Madoka Nakajima, Mitsuyasu Kanai, Yumiko Motoi, Shuko Nojiri, Chihiro Akiba, Ikuko Ogino, Hanbing Xu, Chihiro Kamohara, Shinya Yamada, Kostadin Karagiozov, Takeshi Ikeuchi, Akihide Kondo, Hajime Arai

Abstract

Background: The amyloid-β oligomers, consisting of 10-20 monomers (AβO10-20), have strong neurotoxicity and are associated with cognitive impairment in Alzheimer's disease (AD). However, their role in patients with idiopathic normal pressure hydrocephalus (iNPH) is poorly understood.

Objective: We hypothesized that cerebrospinal fluid (CSF) AβO10-20 accumulates in patients with iNPH, and its clearance after CSF shunting contributes to neurological improvement. We measured CSF AβO10-20 levels before and after CSF shunting in iNPH patients evaluating their diagnostic and prognostic role.

Methods: We evaluated two iNPH cohorts: "evaluation" (cohort-1) with 32 patients and "validation" (cohort-2) with 13 patients. Comparison cohorts included: 27 neurologically healthy controls (HCs), and 16 AD, 15 Parkinson's disease (PD), and 14 progressive supranuclear palsy (PSP) patients. We assessed for all cohorts CSF AβO10-20 levels and their comprehensive clinical data. iNPH cohort-1 pre-shunting data were compared with those of comparison cohorts, using cohort-2 for validation. Next, we compared cohort-1's clinical and CSF data: 1) before and after CSF shunting, and 2) increased versus decreased AβO10-20 levels at baseline, 1 and 3 years after shunting.

Results: Cohort-1 had higher CSF AβO10-20 levels than the HCs, PD, and PSP cohorts. This result was validated with data from cohort-2. CSF AβO10-20 levels differentiated cohort-1 from the PD and PSP groups, with an area under receiver operating characteristic curve of 0.94. AβO10-20 levels in cohort-1 decreased after CSF shunting. Patients with AβO10-20 decrease showed better cognitive outcome than those without.

Conclusion: AβO10-20 accumulates in patients with iNPH and is eliminated by CSF shunting. AβO10-20 can be an applicable diagnostic and prognostic biomarker.

Keywords: Amyloid-β peptides; biomarkers; cerebrospinal fluid; neurodegenerative diseases; normal pressure hydrocephalus.

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-0226r3).

Figures

Fig. 1
Fig. 1
Study designs. First, we compared iNPH cohorts with comparison cohorts: AD, PD, PSP, and HCs (Study 1). Second, we compared iNPH cohort-1’s measurement before and after CSF shunting (Study 2). Third, we subdivided iNPH cohort-1 members into AβO10–20 decrease or increase subgroups and compared them in terms of biomarkers and neurological statuses at before and 1 and 3 years after CSF shunting (Study 3). AD, Alzheimer’s disease; AβO10–20, amyloid-β oligomer10–20; CSF, cerebrospinal fluid; iNPH, idiopathic normal pressure hydrocephalus; HCs, healthy controls; PD, Parkinson’s disease; PSP, progressive supranuclear palsy.
Fig. 2
Fig. 2
AβO10–20 levels in each group. AβO10–20 levels for each individual group are represented in a scatter plot. The vertical axis shows the CSF concentrations of AβO10–20. Significance testing was done with the One-way ANOVA followed by the Tukey honestly significant difference test and is indicated as **p < 0.01 or ***p < 0.001 (Versus iNPH cohort-1) and # #p < 0.01 or # # #p < 0.001 (Versus iNPH cohort-2). AD, Alzheimer’s disease; AβO10–20, amyloid-β oligomer10–20; iNPH, idiopathic normal pressure hydrocephalus; HCs, healthy controls; PD, Parkinson’s disease; PSP, progressive supranuclear palsy.
Fig. 3
Fig. 3
AUROC analysis in study 1. AUROC analysis of AβO10–20 levels (blue), Aβ42 levels (green), and pTau levels (purple) as tools for differentiating groups. A) AβO10–20 levels differentiated members of iNPH cohort-1 from members of the AD groups with an AUC value of 0.678. B) AβO10–20 levels differentiated members of the iNPH cohort-1 from members of the PD and PSP groups with an AUC value of 0.944. AD, Alzheimer’s disease; AUC, area under the curve; Aβ42, amyloid beta 42; AβO10–20, amyloid-β oligomer10–20; CI, confidence interval; iNPH, idiopathic normal pressure hydrocephalus; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; pTau, phosphorylated tau.
Fig. 4
Fig. 4
Cognitive outcomes in AβO10–20 decrease and increase subgroups. A distribution of preoperative and postoperative grade of dementia severity according to MMSE scores in AβO10–20 decrease and increase subgroup displayed as the table. Numbers in each box indicate the number of patients. Blue boxes indicate patients in “good outcome” and orange boxes indicate patients in “poor outcome”. AβO10–20, amyloid beta oligomer10–20; CSF, cerebrospinal fluid; G, grade.

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