Kazunori Kawaguchi

Reduction of Alzheimer's disease amyloid-β in plasma by hemodialysis and its relation to cognitive functions.

Background/Aims: Rapid removal of plasma amyloid-β (Aβ) by blood purification may serve as a peripheral Aβ sink from the brain for Alzheimer’s disease therapy. We investigated the reduction of plasma Aβ during hemodialysis and cognitive states. Methods: Aβ concentrations and Mini-Mental State Examinations (MMSE) were investigated in 37 hemodialysis patients (68.9 ± 4.1 years). Results: The dialyzers effectively removed Aβ1–40 and Aβ1–42, 63.9 ± 14.4 and 51.6 ± 17.0% at 4 h dialysis, resulting in the reduction of Aβs in whole-body circulation by 51.1 ± 8.9 and 32.7 ± 12.0%, respectively. Although the plasma Aβs before dialysis (750.8 ± 171.3 pg/ml for Aβ1–40) were higher than those reported for Alzheimer’s disease patients, the cognitive states of hemodialysis patients were relatively normal, especially of longer dialysis vintages. Conclusions: Dialyzers effectively reduced Aβs in whole-body circulation. Repeated rapid decrease of plasma Aβs might maintain cognitive state.

Patients that have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer’s Disease by Removal of Blood Amyloid

As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimers disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining. Our findings suggest that removal of blood Aβ by hemodialysis results in lower accumulation of Aβ in the brain.

Removal of Blood Amyloid As a Therapeutic Strategy for Alzheimer’s Disease: The Influence of Smoking and Nicotine

Accumulation of amyloid β protein (Aβ) in the brain causes cognitive impairment in Alzheimer’s disease (AD). The nature of the relationship between smoking and AD or dementia has been controversial. However, a recent meta-analysis revealed that smoking is a risk factor for AD. With regard to nicotinic acetylcholinergic receptors (nAChRs), both AD and control patients that smoke have been reported to show an increase in 3H-cytisine (an α4β4 nAChR agonist) binding in the temporal cortex. The α7 nAChR is also a key factor in AD pathology, particularly in relation to internalization of Aβs. Furthermore, there are many reports showing the neuroprotective effects of nicotine. The internalization of Aβ may lead to Aβ clearance in the brain.

REMOVAL OF Aβ OLIGOMERS FROM THE BLOOD USING HOLLOW FIBERS: A POTENTIAL THERAPEUTIC SYSTEM FOR ALZHEIMER’S DISEASE

antibodies generated, we selected a molecule showing a KD value of 6 nM for isoAsp7-Ab and displaying w 500fold selectivity over non-modified Ab. Immunohistochemical staining of tissue from human post mortem brain showed exclusive labelling of amyloid plaques. This pattern was also observed in brain samples from transgenic mice, where we observed a characteristic increase of isoAsp detection beginning with onset of plaque deposition and increasing with age and amyloid pathology. Based on Ab extraction and ELISA quantification, we conclude that the isoAsp content is low in micewith onset of pathology (4%) and increases with ageing of 5xFAD mice. A 12weeks treatment of transgenic mice led to a reduction of isoAsp-modified and total Ab load, suggesting that selective opsonization of modified amyloid is eliciting phagocytosis of non-modified peptides. In a second trial, we observed an amelioration of a behavioral phenotype in elevated plus maze upon treatment with the antibody. Conclusions:In addition to previous studies applying antibodies directed against pGlu-modified Ab, we show here that also isoAsp-modified Ab represents a vital target for immunotherapy. The results support the general concept that targeting modified Ab peptides, which might be underrepresented compared to full-length Ab, are attractive anchor points for a more directed approach of immunotherapy in order to reduce common side effects.

POTENTIAL THERAPEUTIC SYSTEM FOR ALZHEIMER’S DISEASE BY REMOVING BLOOD Aβ: EFFECTS OF BLOOD PURIFICATION PERIOD ON Aβ REMOVAL EFFICIENCIES IN HEMODIALYSIS PATIENTS

active (VR with no treadmill, treadmill with non-specific cognitive stimulation) and one passive (waitlist) control conditions in a single-blind, parallel group, randomized controlled design. Participants in active groups train for 45 min. twice/week for 12 weeks. Primary outcomes are changes in memory performance and cerebral blood flow (CBF; MRI arterial spin labeling) immediately following training and at 6 months. Results:Baseline (mean6SD) demographic, clinical and cognitive characteristics of the first 10 participants: age 57.467.2 years, education: 15.862.9 years, 4 female; MMSE 28.561.1. On SF36 health status scales (scale:0-100; 1001⁄4no disability), mean6SD ranged from 62.0618.1 (energy/fatigue) to 95.068.2 (physical functioning). Memory scores: RAVLT Trial 1 6.861.9, Trial 5 11.262.4, Delayed recall: 10.263.2; Logical Memory I: 14.663.8, Logical Memory II: 13.664.1. Scores were within the normal range using accepted norms. Conclusions:Non-pharmacologic trainingmay be administered prior to symptom onset when prevention may be possible. An ecologically valid VR setting that mimics complex demands of everyday life may prove an ideal cognitive training environment that augments transfer. Though VR training has benefited clinical cohorts, benefit in asymptomatic high-risk individuals is relatively unknown. Further, CBF may be a key marker of cognitive benefits, as it has shown sensitivity to cognitive training in healthy seniors and hypoperfusion in individuals with AD family history. This trial may define a new prophylactic paradigm for AD, adaptable for home-based application in high risk individuals. By AAIC 2017 we anticipate demographic, cognitive and CBF data for 30 participants.

POTENTIAL THERAPEUTIC SYSTEM FOR ALZHEIMER’S DISEASE BY REMOVAL OF BLOOD AB: EFFICIENT AB REMOVAL SYSTEM BY ENHANCING ADSORPTION ON HOLLOW FIBERS WITH HEMODIAFILTRATION

postmortem brains of 17 HD patients (mean age at death, 75. 7 6 10.4 years) and 16 age-matched non-HD subjects (79.0 6 12.6 years) were immunostained with the anti-Ab antibodies 4G8 (anti Ab17-24) and DE2 (anti Ab1-16); they were also subjected to silver staining by the periodic acid-methenamine-silver (PAM) and Gallyas-Braak (GB) methods, anti-phospho-PHF-Tau antibody (AT8), anti-glial-fibrillary-acidic-protein (GFAP) antibody for astrocytes, and anti-Iba1 antibody for microglial cells. Results: All cortices of the brains of HD patients exhibited significantly fewer senile plaques than those of non-HD subjects stained with antiAb antibodies. This significant difference was also observed by silver staining. The parietal lobes of HD patients contained significantly fewer plaques compared to those of non-HD subjects. The temporal, frontal, and occipital lobes of HD patients showed a similar tendency, although not significant. However, the hippocampus showed no clear tendency. The number of Iba1 positive cells in the brain significantly increased in HD patients. The results of AT8 immunostaining will be discussed. Conclusions: Ab deposition in the brain was significantly decreased in HD patients who underwent removal of blood Ab three times per week. Therefore, hemodialysis-induced Ab influx into the blood may at least partly be derived from the brain. It suggested that removal of blood Abmight reduce brain Ab burden. Acknowledgment: This work was partly supported by KAKENHI (20509008, 22500419 and 23500531) and Smoking Research Foundation.

Removal of blood beta-amyloid might reduce brain beta-amyloid deposition based on the study of hemodialysis patients: Extracorporeal beta-amyloid removal system (EARS) for Alzheimer's disease therapy

P4-279 REMOVAL OF BLOOD BETA-AMYLOID MIGHT REDUCE BRAIN BETA-AMYLOID DEPOSITION BASED ON THE STUDY OF HEMODIALYSIS PATIENTS: EXTRACORPOREAL BETA-AMYLOID REMOVAL SYSTEM (EARS) FOR ALZHEIMER’S DISEASE THERAPY Nobuya Kitaguchi, Kazuyoshi Sakai, Takao Senda, Kazunori Kawaguchi, Masao Kato, Makoto Kuroda, Shigeru Nakai, Ryuji Hata, Yukio Yuzawa, Yoshiyuki Hiki, Fujita Health University, Toyoake, Japan; Gifu University Graduate School of Medicine, Gifu, Japan. Contact e-mail: nkitaguc@fujita-hu.ac.jp

Toward therapeutic system for Alzheimer's Disease by removal of blood Aβ: Hemodialysis improved the impaired cognitive states of renal failure patients

Background: Active anti-amyloid immunotherapy is a strategy developed against Alzheimer’s disease.ApproacheswithAs1-42 orK6As1-30 immunogens in an adjuvant decrease amyloid-s burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of As1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop As plaques with age (Mestre-Franc es et al, 2000). Such a primate model may bemore predictive than rodents of human side effects.We studied, by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6As1-30 (n 1⁄4 4; 5.8 6 0.2years) and As1-42 (n1⁄4 4; 5.96 0.2years) immunogens in alum adjuvant. A second cohort was used to evaluateK6As1-30 (n1⁄4 6; 4.66 0.2years) compared to adjuvant alone (n 1⁄4 6; 4.7 6 0.3years). All the animals were followed-up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution 1⁄4 (234x234x234)Âmm3). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effect was performed with twenty other naive animals (1.5 to 4.9years). Results: TheT2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6As1-30 presented less microhemorrhages compared to those treated with As1-42 vaccine (Mann-Whitney, p< 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signal was detected on MRI and corresponded to iron deposits in the choroid plexus. Its volume increased with natural aging (r1⁄4 0.60; p< 0.001) and with As1-42 compared toK6As1-30 treatment (ANOVA, p< 0.05). No difference was detected between K6As1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6As1-30 strategy appears to be safer than the As1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus.

Toward the novel method of treatment for Alzheimer's disease: Extra-corporeal Aβ removal system (EARS)

butylcholinesterase with cognition (CNTB) were correlated; r1⁄40.56 and r1⁄40.65, respectively. 2. Three gamma secretases data include: a. 27 subjects were administered single doses of MK-0752. CSF Abeta declined over a 4-12 hour period in 18 of 19 subjects receiving >300 mg. Mean CSF Abeta40 was substantially reduced (>40%) at 12 hours after MK0752 > 500 mg. This effect was sustained over 24 hr at the highest dose of 1000 mg. b. BMS-708163 demonstrated a more than 25% reduction in CSF Abeta40 with single doses that approximate the concentration range for safe and tolerable multiple dosing regimens. c. In AD subjects, mean percent increases from baseline in CSF Abeta40 concentrations appeared to be less in elderly subjects receiving GSI-953 than in those receiving placebo at most time points. 4. An algorithm for power calculations to assess a proteomic change in with treatment will be provided. 5. These data demonstrate the improved reliability to detect a change in Abeta using an ’AUC’ vs. a single time point approach. Conclusions: Timed interval CSF sampling by indwelling catheterization can is a valuable corroborative biomarker for drug effect. CSF studies with drugs, which modify amyloid protein production or clearance, or inhibit acetylcholine esterase, can be instructive in selecting dosage for development. CSF also is useful in conducting pilot studies to investigate proteomic changes.