%0 Journal Article %J J Alzheimers Dis %D 2019 %T Influx of Tau and Amyloid-β Proteins into the Blood During Hemodialysis as a Therapeutic Extracorporeal Blood Amyloid-β Removal System for Alzheimer's Disease. %A Kitaguchi, Nobuya %A Tatebe, Harutsugu %A Sakai, Kazuyoshi %A Kawaguchi, Kazunori %A Matsunaga, Shinji %A Kitajima, Tomoko %A Tomizawa, Hiroshi %A Kato, Masao %A Sugiyama, Satoshi %A Suzuki, Nobuo %A Mizuno, Masao %A Takechi, Hajime %A Nakai, Shigeru %A Hiki, Yoshiyuki %A Kushimoto, Hiroko %A Hasegawa, Midori %A Yuzawa, Yukio %A Tokuda, Takahiko %X

The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer's disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aβ but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aβ. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aβ migration into the blood. However, as a therapeutic strategy for Alzheimer's disease, it may only be effective for removing Aβ from the brain.

%B J Alzheimers Dis %V 69 %P 687-707 %8 2019 Jun 4 %G eng %N 3 %R 10.3233/JAD-190087 %0 Journal Article %J J Alzheimers Dis %D 2018 %T 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. %A Akiba, Chihiro %A Nakajima, Madoka %A Miyajima, Masakazu %A Ogino, Ikuko %A Motoi, Yumiko %A Kawamura, Kaito %A Adachi, Satoshi %A Kondo, Akihide %A Sugano, Hidenori %A Tokuda, Takahiko %A Irie, Kazuhiro %A Arai, Hajime %X

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.

%B J Alzheimers Dis %V 63 %P 989-1002 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29710721?dopt=Abstract %R 10.3233/JAD-180059 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Preoperative Phosphorylated Tau Concentration in the Cerebrospinal Fluid Can Predict Cognitive Function Three Years after Shunt Surgery in Patients with Idiopathic Normal Pressure Hydrocephalus. %A Nakajima, Madoka %A Miyajima, Masakazu %A Ogino, Ikuko %A Akiba, Chihiro %A Kawamura, Kaito %A Kamohara, Chihiro %A Fusegi, Keiko %A Harada, Yoshinao %A Hara, Takeshi %A Sugano, Hidenori %A Tange, Yuichi %A Karagiozov, Kostadin %A Kasuga, Kensaku %A Ikeuchi, Takeshi %A Tokuda, Takahiko %A Arai, Hajime %X

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.

%B J Alzheimers Dis %V 66 %P 319-331 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30248058?dopt=Abstract %R 10.3233/JAD-180557 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Association between Mid-Regional Proadrenomedullin Levels and Progression of Deep White Matter Lesions in the Brain Accompanying Cognitive Decline. %A Kuriyama, Nagato %A Ihara, Masafumi %A Mizuno, Toshiki %A Ozaki, Etsuko %A Matsui, Daisuke %A Watanabe, Isao %A Koyama, Teruhide %A Kondo, Masaki %A Tokuda, Takahiko %A Tamura, Aiko %A Yamada, Kei %A Akazawa, Kentaro %A Takeda, Kazuo %A Takada, Akihiro %A Mizuno, Shigeto %A Nakagawa, Masanori %A Watanabe, Yoshiyuki %X

BACKGROUND: Adrenomedullin (ADM) is a vasoreactive physiological peptide with anti-inflammatory effects and vasodilative and immunomodulatory actions that is widely distributed throughout the vascular system of the brain.

OBJECTIVE: To investigate mid-regional proADM (MR-proADM), a stable fragment of the ADM precursor, and cerebral deep white matter lesions (DWMLs) in association with cognitive decline.

METHODS: The study participants were 288 patients (194 men, 94 women) who gave consent to participate in a 5-year longitudinal survey on arteriosclerosis from 2008 to 2013. The Fazekas classification system (Grade [G] 0 [normal] to G3 [severe]) was used for the evaluation of DWMLs on brain magnetic resonance imaging (MRI). In addition, all participants were asked to undergo cognitive function tests regarding word/letter fluency, the results of which were assessed for correlations with MR-proADM levels.

RESULTS: MR-proADM levels significantly increased with DWML grade progression. The odds ratio for high MR-proADM levels was 3.08 (95% confidence interval: 1.49-5.17) in the groups graded G3 on brain MRI, suggesting that a high level of MR-proADM is an independent risk factor for DWMLs. A significant inverse correlation was observed between MR-proADM levels and cognitive test scores. MR-proADM levels were significantly increased in the G3 group in 2013 compared with 2008.

CONCLUSION: MR-proADM levels were significantly different between the DWML groups and inversely correlated with cognitive function test scores, suggesting that high MR-proADM levels and DWMLs are associated with cognitive decline. Therefore, the MR-proADM level may be an effective candidate as a potential diagnostic surrogate marker of cognitive decline.

%B J Alzheimers Dis %V 56 %P 1253-1262 %8 2017 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/28234256?dopt=Abstract %R 10.3233/JAD-160901