Publications by authors named "Yasuto Higashi"

11 Publications

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Early detection of cognitive decline in mild cognitive impairment and Alzheimer's disease with a novel eye tracking test.

J Neurol Sci 2021 Jun 3;427:117529. Epub 2021 Jun 3.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. Electronic address:

Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening.
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http://dx.doi.org/10.1016/j.jns.2021.117529DOI Listing
June 2021

Tocilizumab-induced Leukoencephalopathy with a Reversible Clinical Course.

Intern Med 2020 Nov 30;59(22):2927-2930. Epub 2020 Sep 30.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Japan.

Tocilizumab (TCZ; Actemra/RoActemra) is an anti-interleukin (IL)-6 receptor antibody for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases and cytokine storms. The present case is a 63-year-old female well-controlled RA patient, who presented with a progressive cognitive impairment after 34 months of TCZ administration. Brain magnetic resonance imaging (MRI) showed leukencephalopathy with a lactic acid peak in magnetic resonance spectroscopy (MRS), a decreased blood flow in single photon emission computed tomography (SPECT), and a decreased accumulation in fluorodeoxyglucose positron emission tomography (FDG-PET). The discontinuation of TCZ improved her cognitive function and brain MRI findings at 3 months after drug cessation. The present case suggests that TCZ may sometimes cause leukoencephalopathy after long-term administration, and thus the early discontinuation of TCZ is recommended to achieve a good prognosis.
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http://dx.doi.org/10.2169/internalmedicine.5288-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725625PMC
November 2020

A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology.

J Alzheimers Dis 2020 ;73(1):217-227

Membrane Protein and Ligand Analysis Center, Protosera Inc., Osaka, Japan.

Background: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established.

Objective: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology.

Methods: With only 1.5μl of serum, we examined a new target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains.

Results: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains.

Conclusion: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.
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http://dx.doi.org/10.3233/JAD-191016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029318PMC
April 2021

Clinical Benefits of Antioxidative Supplement Twendee X for Mild Cognitive Impairment: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Prospective Interventional Study.

J Alzheimers Dis 2019 ;71(3):1063-1069

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer's disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. Seventy-eight subjects with MCI were randomized into placebo (n = 37) and TwX (n = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI.
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http://dx.doi.org/10.3233/JAD-190644DOI Listing
November 2020

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development.

Dement Geriatr Cogn Disord 2016 2;41(1-2):55-67. Epub 2015 Dec 2.

Department of Neuropsychiatry, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Background/aims: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision.

Methods: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres.

Results: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed.

Conclusion: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.
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http://dx.doi.org/10.1159/000441443DOI Listing
September 2016

High Incidence of Dementia Conversion than Stroke Recurrence in Poststroke Patients of Late Elder Society.

J Stroke Cerebrovasc Dis 2015 Jul 22;24(7):1621-8. Epub 2015 Apr 22.

Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address:

Background: This study investigated the incidence of current poststroke dementia (PSD), the annual conversion ratio into PSD, and the risk factors for conversion.

Methods: In a 4.8-year follow-up period, 112 poststroke patients (ischemic stroke and intracerebral hemorrhage) were retrospectively investigated in cognitive examinations. They were categorized into 3 subgroups: converters into PSD, nonconverters who maintained their normal cognitive functions, and reverters who recovered to the normal mentality range. The clinical and demographic characteristics of these 3 subgroups were analyzed.

Results: Among all 112 poststroke patients (61.6% male, 73.6 ± 10.4 years old), 16.1% had PSD. During the follow-up period, a part of the normal baseline mentality group (83.9% of 112 original patients) newly developed PSD (subdivided into converters) with an annual conversion rate of 7.6%. The reversion rate from the baseline PSD group was 11.3%. There were significant differences in age (P < .05), baseline mini-mental state examination scores (P < .05), body mass index (P < .05), and periventricular and deep white matter hyperintensity grades (P < .05 and P = .01, respectively) between converters and nonconverters. The annual rate of stroke recurrence was only 2.2% in all stroke subtypes.

Conclusions: In comparison with stroke recurrence (2.2%), 7.6% of the annual PSD conversion rate was very high. Therefore, prevention of direct conversion into PSD without stroke recurrence may be another important aspect of poststroke clinics, especially in late elder society.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.03.037DOI Listing
July 2015

Functional independence measure scores predict level of long-term care required by patients after stroke: a multicenter retrospective cohort study.

Disabil Rehabil 2015 15;37(4):331-7. Epub 2014 May 15.

Department of Stroke Medicine, Kawasaki Medical School , Kurashiki, Okayama , Japan .

Purpose: To examine whether Functional Independence Measure (FIM) scores on admission can predict the future care levels of patients after acute stroke.

Methods: In this multicenter retrospective cohort study, we enrolled post-acute stroke patients and assessed stroke subtypes, self-care abilities using FIM scores, and discharge destination. Patients' care levels were assessed according to the Long-Term Care Insurance (LTCI) system (0-5: slight impairment to bedridden), the national insurance plan for care in Japan, at discharge. We divided patients into two groups according to LTCI care levels (0-2 versus 3-5) to compare their clinical characteristics using multivariate logistic regression analysis. The trial was registered with the UMIN Clinical Trials Registry (UMIN000012653).

Results: Of the 1261 patients (47% female, mean age 75 years), 492 (39%) fulfilled LTCI care levels 0-2. FIM scores on admission were significantly correlated with LTCI care levels (p < 0.001). On multivariate analysis, age and FIM scores on admission were found to be independent predictors of LTCI care levels 0-2.

Conclusions: FIM scores on admission after stroke can independently predict later care requirements. Early prediction of LTCI care levels may contribute to the early supported discharge and improve the efficiency of healthcare planning. Implications for Rehabilitation There is a clear relationship between Functional Independence Measure (FIM) scores and the care levels certified by the Long-Term Care Insurance (LTCI) system, a national healthcare and insurance system in Japan. FIM scores on admission can predict future LTCI care levels required for patients after acute stroke. Early prediction of LTCI care levels may contribute to early supported discharge, improve the efficiency of stroke management and assist healthcare planning.
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http://dx.doi.org/10.3109/09638288.2014.918195DOI Listing
October 2015

The clinical characteristics of spinocerebellar ataxia 36: a study of 2121 Japanese ataxia patients.

Mov Disord 2012 Aug 2;27(9):1158-63. Epub 2012 Jul 2.

Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.

Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes.
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http://dx.doi.org/10.1002/mds.25092DOI Listing
August 2012

Effects of edaravone on muscle atrophy and locomotor function in patients with ischemic stroke: a randomized controlled pilot study.

Drugs R D 2010 ;10(3):155-63

Senri Chuo Hospital, Toyonaka, Japan.

Background And Objective: Stroke patients with severe leg paralysis are often bedridden in the acute and subacute phase, which increases the risk of disuse muscle atrophy in the chronic phase. The evidence to date indicates that oxidative stress plays an important role in the mechanism of disuse muscle atrophy. Therefore, the aim of this study was to determine if long-term radical scavenger treatment with edaravone following an acute stroke prevents the progression of disuse muscle atrophy and improves leg locomotor function in the chronic phase.

Methods: This randomized controlled pilot study was conducted at 19 acute stroke and rehabilitation centers across Japan. Forty-seven ischemic stroke patients with at least leg motor weakness admitted within 24 hours of onset were randomly assigned to receive continuous intravenous infusions of edaravone 30 mg twice daily for 3 days (short-term group) or 10-14 days (long-term group). The primary endpoints of the study included the degree of leg disuse muscle atrophy, as measured by the percentage change from baseline in femoral muscle circumference 15 cm above the knee, and the improvement in leg locomotor function, as assessed by the maximum walking speed over 10 m, 3 months after the onset of stroke.

Results: Three-month follow-up was completed by a total of 41 patients (21 in the short-term group and 20 in the long-term group). On admission, there was no significant difference in the severity of stroke or the grade of leg paresis between the two treatment groups. The grade of disuse muscle atrophy and incidence of gait impairment 3 weeks after stroke onset were also similar between the short- and long-term groups. However, disuse muscle atrophy of the paretic and non-paretic legs was significantly less severe in the long-term versus the short-term treatment group (3.6 ± 5.9% and 1.5 ± 6.0% vs 8.3 ± 5.2% and 5.7 ± 6.4%; p < 0.01 and p < 0.05) 3 months after stroke onset. Additionally, the maximum walking speed over a distance of 10 m was significantly greater in the long-term group (98 ± 67 vs 54 ± 55 cm/sec; p < 0.05).

Conclusion: Edaravone treatment for up to 14 days suppresses the progression of disuse muscle atrophy and improves leg locomotor function to a greater extent than shorter-term treatment in acute stroke patients. This suggests that the management of stroke may be improved with long-term edaravone therapy by providing myoprotective effects that ameliorate functional outcome in the chronic phase.
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http://dx.doi.org/10.2165/11586550-000000000-00000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585769PMC
November 2011

Necessity of a uniform start for scanning after FDG injection in brain PET study.

Ann Nucl Med 2006 May;20(4):329-31

Department of Radiology and Nuclear Medicine, Hyogo Brain and Heart Center, Himeji Central Hospital, Japan.

Unlabelled: The authors' goal was to show the importance of starting scanning at a uniform time after F-18 fluorodeoxyglucose injection in positron emission tomography (PET) brain study.

Method: Fifteen healthy normal subjects underwent FDG-PET to obtain glucose metabolic images starting 60 min and 70 min after FDG injection, respectively. The two sets of images were compared in a voxel-by-voxel analysis.

Results: In the bilateral posterior cingulate gyrus, parietal and frontal association cortices, the FDG uptakes were larger on the 70 min scan images than on the 60 min scan images; the 60 min scans resembled Alzheimer's metabolic reduction area. Similarly the FDG uptakes were larger in the pons and vermis on the 60 min scan image than on the 70 min scan image.

Conclusions: Regional FDG uptake is different depending on the time scanning starts after FDG injection, even with a 10 minute difference in start time and different scanning time may lead to misdiagnosis. It is important to standardize the start time of FDG PET after FDG injection in brain PET.
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http://dx.doi.org/10.1007/BF02984652DOI Listing
May 2006

A 25-year-old woman with multiple brain tumors who died after a course of 1 year and 6 months.

Neuropathology 2003 Dec;23(4):364-6

Division of Neuropathology, Kawasaki Medical School, Matsushima, Kurashiki, Japan.

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http://dx.doi.org/10.1046/j.1440-1789.2003.00518.xDOI Listing
December 2003