Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus

Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Chihiro Akiba, Kaito Kawamura, Chihiro Kamohara, Keiko Fusegi, Yoshinao Harada, Takeshi Hara, Hidenori Sugano, Yuichi Tange, Kostadin Karagiozov, Kensaku Kasuga, Takeshi Ikeuchi, Takahiko Tokuda, Hajime Arai, Madoka Nakajima, Masakazu Miyajima, Ikuko Ogino, Chihiro Akiba, Kaito Kawamura, Chihiro Kamohara, Keiko Fusegi, Yoshinao Harada, Takeshi Hara, Hidenori Sugano, Yuichi Tange, Kostadin Karagiozov, Kensaku Kasuga, Takeshi Ikeuchi, Takahiko Tokuda, Hajime Arai

Abstract

Background: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer's disease (AD) pathology is debated.

Objective: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH.

Methods: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n = 24; mean age 75.7 years [SD 5.3]) and high (n = 11; mean age 76.0 years [SD 5.6]) p-Tau groups.

Results: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2 = 0.352, p < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group.

Conclusions: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology.

Keywords: Alzheimer’s disease; cerebrospinal fluid shunt; normal pressure hydrocephalus; phosphorylation; prognosis; tau proteins.

Figures

Fig.1
Fig.1
Study patient flow chart. Forty patients with a diagnosis of iNPH who had three years of follow-up after lumboperitoneal shunting were divided into two groups according to their CSF p-Tau levels: 28 patients with p-Tau levels

Fig.2

Comparison of MMSE performance in the…

Fig.2

Comparison of MMSE performance in the low and high p-Tau groups. MMSE performance progress…

Fig.2
Comparison of MMSE performance in the low and high p-Tau groups. MMSE performance progress in individual patients from before shunting to three years after shunting is shown for the low (n = 24) and high (≥30 pg/mL, n = 11) p-Tau groups. The black line shows the average value in each group. A temporary improvement was observed in the high p-Tau group, while the improvement in the low p-Tau group was maintained throughout follow-up.

Fig.3

Correlation between p-Tau levels and MMSE…

Fig.3

Correlation between p-Tau levels and MMSE scores in iNPH patients. Correlation between the MMSE…

Fig.3
Correlation between p-Tau levels and MMSE scores in iNPH patients. Correlation between the MMSE scores and p-Tau levels before (left) and three years after (right) shunt surgery. While no significant correlation was observed before the treatment, a significant negative correlation was observed three years after surgery (R2 = 0.352, p < 0.001).

Fig.4

Comparison of mRS performance between the…

Fig.4

Comparison of mRS performance between the low and high p-Tau groups. Changes in the…

Fig.4
Comparison of mRS performance between the low and high p-Tau groups. Changes in the individual patients’ mRS scores from before to three years after shunt treatment are shown for the low (n = 24) and high (≥30 pg/mL, n = 11) p-Tau groups. The arrows show individual improvements (blue) or declines (red).

Fig.5

Heat map of iNPHGS impairments in…

Fig.5

Heat map of iNPHGS impairments in the low and high p-Tau groups over three-year…

Fig.5
Heat map of iNPHGS impairments in the low and high p-Tau groups over three-year follow-up. Scores on the three iNPHGS subcategories (gait disturbance, urinary disturbance, and dementia) in the low (n = 24; lower panel) and high (≥30 pg/mL, n = 11; upper panel) p-Tau groups during the follow-up period are colored by the degree of severity.
Fig.2
Fig.2
Comparison of MMSE performance in the low and high p-Tau groups. MMSE performance progress in individual patients from before shunting to three years after shunting is shown for the low (n = 24) and high (≥30 pg/mL, n = 11) p-Tau groups. The black line shows the average value in each group. A temporary improvement was observed in the high p-Tau group, while the improvement in the low p-Tau group was maintained throughout follow-up.
Fig.3
Fig.3
Correlation between p-Tau levels and MMSE scores in iNPH patients. Correlation between the MMSE scores and p-Tau levels before (left) and three years after (right) shunt surgery. While no significant correlation was observed before the treatment, a significant negative correlation was observed three years after surgery (R2 = 0.352, p < 0.001).
Fig.4
Fig.4
Comparison of mRS performance between the low and high p-Tau groups. Changes in the individual patients’ mRS scores from before to three years after shunt treatment are shown for the low (n = 24) and high (≥30 pg/mL, n = 11) p-Tau groups. The arrows show individual improvements (blue) or declines (red).
Fig.5
Fig.5
Heat map of iNPHGS impairments in the low and high p-Tau groups over three-year follow-up. Scores on the three iNPHGS subcategories (gait disturbance, urinary disturbance, and dementia) in the low (n = 24; lower panel) and high (≥30 pg/mL, n = 11; upper panel) p-Tau groups during the follow-up period are colored by the degree of severity.

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