Change of Amyloid-β 1-42 Toxic Conformer Ratio After Cerebrospinal Fluid Diversion Predicts Long-Term Cognitive Outcome in Patients with Idiopathic Normal Pressure Hydrocephalus

Chihiro Akiba, Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Yumiko Motoi, Kaito Kawamura, Satoshi Adachi, Akihide Kondo, Hidenori Sugano, Takahiko Tokuda, Kazuhiro Irie, Hajime Arai, Chihiro Akiba, Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Yumiko Motoi, Kaito Kawamura, Satoshi Adachi, Akihide Kondo, Hidenori Sugano, Takahiko Tokuda, Kazuhiro Irie, Hajime Arai

Abstract

Background: Alzheimer's disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-β 1- 42 (Aβ42) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity.

Objective: This observational study points to Aβ42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH.

Methods: The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Aβ42 toxic conformer ratio (%) [Aβ42 toxic conformer/Aβ42×100] (decreased- and increased-conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Aβ42, and Aβ42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively.

Results: In the first cohort, Aβ42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement.

Conclusions: Change in Aβ42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group.

Keywords: Alzheimer’s disease; amyloid clearance; amyloid-β 1-42; cerebrospinal-fluid shunting; cognitive function; idiopathic normal pressure hydrocephalus; oligomer; phosphorylated tau; toxic conformer.

Figures

Fig.1
Fig.1
The flow chart of patient division. 51 consecutive patients with a diagnosis of possible iNPH who had undergone CSF shunting were divided into two groups according to CSF pTau levels; 40 patients with pTau levels 30 pg/ml. After adjustment for age (range 70–84 years old), 27 patients were categorized as the low-pTau group and 11 patients were categorized as the high-pTau group. Consequently, 40 patients in the low-pTau group were divided into two subgroups according to the postoperative change in Aβ42 toxic conformer ratio 1 year after CSF shunting; 26 patients with postoperatively decreased or unchanged Aβ42 toxic conformer ratio were classified into the decreased-conformer subgroup and 14 patients with postoperatively increased Aβ42 toxic conformer ratio were classified into the increased-conformer subgroup.
Fig.2
Fig.2
The analyses of cerebrospinal fluid markers in the three patient groups. A) pTau was significantly higher in the AD group compared to the iNPH group (p < 0.001), or the CN group (p < 0.001). No significant difference was seen between the iNPH and CN groups. B) Aβ42 was significantly low in the AD group (p = 0.008) and the iNPH group (p = 0.029) compared to the CN group. No significant difference was seen between the AD and iNPH groups. C) Aβ42 toxic conformer was high in the AD group compared to the iNPH group (p = 0.006), compared to the CN group (p < 0.001). No significant difference was seen between the iNPH and CN groups. D) Aβ42 toxic conformer ratio, indicating the percentage of Aβ42 toxic conformer to total Aβ42, was highest in the AD group, followed by the iNPH group, and lowest in the CN group (AD versus iNPH: p = 0.002; iNPH versus CN: p = 0.001; AD versus CN: p < 0.001).
Fig.3
Fig.3
Postoperative transitions in MMSE score in the low- and high-pTau groups. A) A scatter plot showing a significant correlation between pTau and age (Pearson’s coefficient 0.289, p = 0.04). B) Postoperative transitions in MMSE scores in the low-pTau group showing significant improvement at 1 year after CSF shunting compared to baseline (p = 0.001). The consequent transitions until 2 years after CSF shunting varied widely, which resulted in no significant change from 1 year after CSF shunting. C) Postoperative transitions in the MMSE scores in the high-pTau group. No significant change in MMSE score was revealed between the baseline and 1 year after CSF shunting; however, the MMSE score 2 years after CSF shunting was significantly lower (p = 0.005) than that of 1 year postoperatively. D) A distribution of 2 years postoperative changes in the MMSE score showing that 9/11 patients (81.8%) of the high-pTau group declined 2 years after CSF shunting, while 9/27 patients (33.3%) of the low-pTau group declined. The right side of a dotted line indicates the improvement in MMSE score.
Fig.4
Fig.4
Postoperative transitions of MMSE scores in the decreased- and increased-conformer group. A) A scatter plot showing no correlation between Aβ42 toxic conformer ratio and age (Pearson’s coefficient 0.026, p = 0.873). B) Postoperative transitions of MMSE scores in the decreased-conformer group showing significant improvement from the baseline at both 1- and 2 years after CSF shunting (both: p < 0.001). C) Postoperative transitions of MMSE scores in the increased-conformer group showing no significant change between the baseline and 1 year after CSF shunting; however, a significant decline was revealed between 1- and 2 years after CSF shunting (p = 0.036). D) A distribution of 2 tears postoperative changes in MMSE scores showing that scores of 11/14 patients (78.6%) of the increased-conformer group declined 2 years after CSF shunting, while scores of only 2/26 patients (7.7%) of the decreased-conformer group declined. The right side of the dotted line indicates an improvement in MMSE score.

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