Katsutoshi Furukawa

MicroRNAs in plasma and cerebrospinal fluid as potential markers for Alzheimer's disease.

The development of Alzheimers disease (AD) biomarkers remains an unmet challenge, and new approaches that can improve current AD biomarker strategies are needed. Recent reports suggested that microRNA (miRNA) profiling of biological fluids has emerged as a diagnostic tool for several pathologic conditions. In this study, we measured six candidate miRNAs (miR-9, miR-29a, miR-29b, miR-34a, miR-125b, and miR-146a) in plasma and cerebrospinal fluid (CSF) of AD and normal subjects by using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to evaluate their potential usability as AD biomarkers. The qRT-PCR results showed that plasma miR-34a and miR-146a levels, and CSF miR-34a, miR-125b, and miR-146a levels in AD patients were significantly lower than in control subjects. On the other hand, CSF miR-29a and miR-29b levels were significantly higher than in control subjects. Our results provide a possibility that miRNAs detected in plasma and CSF can serve as biomarkers for AD.

Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population.

Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimers disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.

Soluble Amyloid Precursor Protein 770 Is Released from Inflamed Endothelial Cells and Activated Platelets: A NOVEL BIOMARKER FOR ACUTE CORONARY SYNDROME*

Background: Separate monitoring of the cleavage products of different amyloid β precursor protein (APP) variants may provide useful information. Results: We found that soluble APP770 (sAPP770) is released from inflamed endothelial cells and activated platelets as judged by ELISA. Conclusion: sAPP770 is an indicator for endothelial and platelet dysfunctions. Significance: How sAPP770 is released in vivo has been shown. Most Alzheimer disease (AD) patients show deposition of amyloid β (Aβ) peptide in blood vessels as well as the brain parenchyma. We previously found that vascular endothelial cells express amyloid β precursor protein (APP) 770, a different APP isoform from neuronal APP695, and produce Aβ. Since the soluble APP cleavage product, sAPP, is considered to be a possible marker for AD diagnosis, sAPP has been widely measured as a mixture of these variants. We hypothesized that measurement of the endothelial APP770 cleavage product in patients separately from that of neuronal APP695 would enable discrimination between endothelial and neurological dysfunctions. Using our newly developed ELISA system for sAPP770, we observed that inflammatory cytokines significantly enhanced sAPP770 secretion by endothelial cells. Furthermore, we unexpectedly found that sAPP770 was rapidly released from activated platelets. We also found that cerebrospinal fluid mainly contained sAPP695, while serum mostly contained sAPP770. Finally, to test our hypothesis that sAPP770 could be an indicator for endothelial dysfunction, we applied our APP770 ELISA to patients with acute coronary syndrome (ACS), in which endothelial injury and platelet activation lead to fibrous plaque disruption and thrombus formation. Development of a biomarker is essential to facilitate ACS diagnosis in clinical practice. The results revealed that ACS patients had significantly higher plasma sAPP770 levels. Furthermore, in myocardial infarction model rats, an increase in plasma sAPP preceded the release of cardiac enzymes, currently used markers for acute myocardial infarction. These findings raise the possibility that sAPP770 can be a useful biomarker for ACS.

Nobiletin-rich Citrus reticulata peels, a kampo medicine for Alzheimer's disease: A case series

to provide such consent. As medical consent has not been legally allowed for families or guardians, in December 2011 the Japan Federation of Bar Association proposed an outline of medical consent for the government. In this regard, advanced care planning that includes guardian selection should be promoted. Additionally, public guardian systems should be developed. Health professionals, especially care managers, should arrange for a guardian to meet their client’s needs. In conclusion, the present study showed a scarcity of guardians in long-term care settings, and also highlighted a fact that care managers often compensate for this lack of guardians.

Royal Jelly Prevents the Progression of Sarcopenia in Aged Mice In Vivo and In Vitro

Sarcopenia is characterized by the age-related loss of muscle mass and strength. One of the mechanisms of sarcopenia is the loss in the function and number of muscle satellite cells. Royal jelly (RJ) is a health food used worldwide. To obtain better digestion and absorption than RJ, protease-treated RJ (pRJ) has been developed. RJ and pRJ have been suggested to have potential pharmacological benefits such as prolonging the life span and reducing fatigue. Because these effects may improve sarcopenia and the functions of satellite cells, we examined the effects of RJ or pRJ treatment on the skeletal muscles in an animal model using aged mice. In vivo, RJ/pRJ treatment attenuated the decrease in the muscle weight and grip strength and increased the regenerating capacity of injured muscles and the serum insulin-like growth factor-1 levels compared with controls. In vitro, using isolated satellite cells from aged mice, pRJ treatment increased the cell proliferation rate, promoted cell differentiation, and activated Akt intracellular signaling pathway compared with controls. These findings suggest that RJ/pRJ treatment had a beneficial effect on age-related sarcopenia.

A 18F-Labeled BF-227 Derivative as a Potential Radioligand for Imaging Dense Amyloid Plaques by Positron Emission Tomography

PurposeThe aims of this study were to evaluate the binding and pharmacokinetics of novel 18F-labeled ethenyl-benzoxazole derivatives (i.e., [18F] fluorinated amyloid imaging compound of Tohoku university ([18F]FACT)) as amyloid positron emission tomography (PET) tracers and to assess [18F]FACT efficacy in imaging of Alzheimer’s disease (AD).ProceduresBinding assay was conducted using synthetic amyloid-β (Aβ) fibrils, fluorescence microscopy, and autoradiogram in three postmortem AD brains. Pharmacokinetics of [18F]FACT was assessed using 12 Crj:CD-1 (ICR) mice. In vivo binding ability with brain amyloid was investigated using amyloid precursor protein (APP) transgenic mouse. Clinical PET scanning using [18F]FACT was performed in ten healthy controls and ten mild cognitive impairment and ten AD patients.Results[18F]FACT showed high binding affinity for synthetic Aβ fibrils, preferential binding to dense cored plaques in brain sections, and excellent brain uptake and rapid clearance in mice. Injection in APP mice resulted in specific in vivo labeling of amyloid deposits in the brain. PET scans of AD patients showed significantly higher [18F]FACT uptake in the neocortex compared to controls (Pu2009<u20090.05, Kruskal–Wallis test).Conclusion[18F]FACT is a promising agent for imaging dense Aβ plaques in AD.

Coffee treatment prevents the progression of sarcopenia in aged mice in vivo and in vitro.

Sarcopenia is characterized by the age-related loss of muscle mass and strength, which results in higher mortality in aged people. One of the mechanisms of the sarcopenia is the loss in the function and number of muscle satellite cells. Chronic low-grade inflammation plays a central role in the pathogenesis of age-related sarcopenia. Accumulating evidence suggests that coffee, one of the most widely consumed beverages in the world, has potential pharmacological benefits such as anti-inflammatory and anti-oxidant effects. Since these effects may improve sarcopenia and the functions of satellite cells, we examined the effects of coffee on the skeletal muscles in an animal model using aged mice. In vivo, coffee treatment attenuated the decrease in the muscle weight and grip strength, increased the regenerating capacity of injured muscles, and decreased the serum pro-inflammatory mediator levels compared to controls. In vitro, using satellite cells isolated from aged mice, coffee treatment increased the cell proliferation rate, augmented the cell cycle, and increased the activation level of Akt intra-cellular signaling pathway compared to controls. These findings suggest that the coffee treatment had a beneficial effect on age-related sarcopenia.

Cortical Laminar Binding of PET Amyloid and Tau Tracers in Alzheimer Disease

Neurofibrillary tau pathology and amyloid β (Aβ) plaques, characteristic lesions of Alzheimer disease (AD), show different neocortical laminar distributions. Neurofibrillary-tangle tau pathology tends to be closer to the gray matter–white matter boundary, whereas Aβ is dispersed throughout the width of the cortical ribbon. Methods: Using PET radiotracers for tau and Aβ lesions, we developed an image analysis tool to measure the distance of tracer-positive voxels from the gray matter–white matter boundary. We studied 5 AD and 5 healthy subjects with both 18F-THK5117 (tau) and 11C-Pittsburgh compound B (Aβ) PET. Results: On average, tau-positive voxels were closer to the white matter than were Aβ-positive voxels. This effect was found for all AD subjects and for all regions, both before and after regionally adjusting for the nonspecific white matter binding of both tracers. The differential laminar pattern was validated through postmortem examination. Conclusion: Within cortical lamina, distance measures may be of value in testing PET tracers for their anatomic selectivity.

Aggravation of Alzheimer's disease symptoms after the earthquake in Japan: A comparative analysis of subcategories

We recently reported that patients with Alzheimer’s disease (AD) experienced a significant worsening of symptoms after the earthquake and tsunami that occurred in Japan on 11 March 2011. Our previous analysis showed that patients with AD who experienced the disaster had deteriorated with regard to both cognitive functions, and behavioral and psychological symptoms of dementia (BPSD) compared with those

Evaluation of the biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe [18F]FACT in humans

BackgroundThe biodistribution and radiation dosimetry of the 18F-labelled amyloid imaging probe ([18F] FACT) was investigated in humans.MethodsSix healthy subjects (three males and three females) were enrolled in this study. An average of 160.8 MBq of [18F] FACT was intravenously administered, and then a series of whole-body PET scans were performed. Nineteen male and 20 female source organs, and the remainder of the body, were studied to estimate time-integrated activity coefficients. The mean absorbed dose in each target organ and the effective dose were estimated from the time-integrated activity coefficients in the source organs. Biodistribution data from [18F] FACT in mice were also used to estimate absorbed doses and the effective dose in human subjects; this was compared with doses of [18F] FACT estimated from human PET data.ResultsThe highest mean absorbed doses estimated using human PET data were observed in the gallbladder (333 ± 251 μGy/MBq), liver (77.5 ± 14.5 μGy/MBq), small intestine (33.6 ± 30.7 μGy/MBq), upper large intestine (29.8 ± 15.0 μGy/MBq) and lower large intestine (25.2 ± 12.6 μGy/MBq). The average effective dose estimated from human PET data was 18.6 ± 3.74 μSv/MBq. The highest mean absorbed dose value estimated from the mouse data was observed in the small intestine (38.5 μGy/MBq), liver (25.5 μGy/MBq) and urinary bladder wall (43.1 μGy/MBq). The effective dose estimated from the mouse data was 14.8 μSv/MBq for [18F] FACT.ConclusionsThe estimated effective dose from the human PET data indicated that the [18F] FACT PET study was acceptable for clinical purposes.