Publications by authors named "Nozomi Hishikawa"

161 Publications

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

Author Correction: Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis.

Sci Rep 2021 Jun 14;11(1):12828. Epub 2021 Jun 14.

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

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http://dx.doi.org/10.1038/s41598-021-91963-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203677PMC
June 2021

4-Hydroxyl-2-Nonenal Localized Expression Pattern in Retrieved Clots is Associated with Large Artery Atherosclerosis in Stroke Patients.

J Stroke Cerebrovasc Dis 2021 Mar 4;30(3):105583. Epub 2021 Jan 4.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan. Electronic address:

Objectives: The relationship between stroke etiology and clot pathology remains controversial.

Materials And Methods: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed.

Results: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots.

Conclusions: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105583DOI Listing
March 2021

A Unique Case of Encephalopathy with an Elevated IgG-4 and Extremely High Interleukin-6 Level and Delayed Myelodysplastic Syndrome.

Intern Med 2021 Jul 29;60(13):2125-2128. Epub 2020 Dec 29.

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

We herein report a 75-year-old man who developed disturbed consciousness with polynuclear cell dominant pleocytosis and low glucose and extremely high interleukin (IL)-6 levels in his cerebrospinal fluid. The biopsy specimen from his right supraclavicular lymph node showed the infiltration of inflammatory cells positive for IgG, IgG4 and IL-6. Prednisolone and azathioprine administered under suspicion of IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD) successfully remitted the symptoms. However, he developed myelodysplastic syndrome (MDS) and died 18 months later. The extremely high IL-6 may have been related to the rare neurological manifestations and development of MDS in the present case.
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http://dx.doi.org/10.2169/internalmedicine.6098-20DOI Listing
July 2021

Hypoxic stress visualized in the cervical spinal cord of ALS patients.

Neurol Res 2021 Jun 30;43(6):429-433. Epub 2020 Dec 30.

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

: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Hypoxic stress is suspected as the pathogenesis of ALS, however, no positron emission tomography (PET) study for hypoxic stress has been conducted in the spinal cord of ALS patients.: In the present study, we examined cervical spinal hypoxic stress of nineALS patients with upper extremity (U/E) atrophy byF-fluoromisonidazole (FMISO) PET.: On the ipsilateral side of C1 and C5 levels, F-FMISO uptake increased significantly compared with the contralateral side (* < 0.05) and the control subject (** < 0.01). In addition, a strong correlation was found between F-FMISO uptake of the C5 level and the rate of progression of the ALS FRS-R score (R = 0.781, * = 0.013).: These results indicate that hypoxic stress increased in the spinal cord of ALS patients with a close link to ALS progression. Both hypoxic stress and a compromised response to hypoxia, which may lead to subsequent motor neuron death, could be a potential therapeutic target for ALS.
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http://dx.doi.org/10.1080/01616412.2020.1866383DOI Listing
June 2021

Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer's disease with chronic cerebral hypoperfusion.

J Cereb Blood Flow Metab 2021 06 26;41(6):1437-1448. Epub 2020 Oct 26.

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

White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer's disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.
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http://dx.doi.org/10.1177/0271678X20968927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142121PMC
June 2021

Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis.

Sci Rep 2020 10 13;10(1):17102. Epub 2020 Oct 13.

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

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 10 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.
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http://dx.doi.org/10.1038/s41598-020-74216-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554047PMC
October 2020

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

Repeat sizes of NOP56 gene in a Japanese Asidan (SCA36) family with clinical anticipation.

J Neurol Sci 2020 11 21;418:117150. Epub 2020 Sep 21.

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

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http://dx.doi.org/10.1016/j.jns.2020.117150DOI Listing
November 2020

The Oldest Japanese Case of Combined Central and Peripheral Demyelination, which Developed Nine Years After the First Instance of Optic Neuritis.

Intern Med 2021 Jan 12;60(2):305-308. Epub 2020 Sep 12.

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

Combined central and peripheral demyelination (CCPD) causes demyelination in both the central and peripheral nervous systems. Anti-neurofascin 155 antibody plays an important pathogenic role in CCPD, but evidence concerning an association between this antibody and CCPD remains inconclusive. Although there have been no reports of precedent optic neuritis developing into CCPD, we herein report a Japanese man in whom optic neuritis recurred four times over nine years and who developed CCPD without positive anti-neurofascin 155 antibody. This case suggests the possibility of developing CCPD after optic nerve neuritis and the existence of an unknown antibody that induces CCPD.
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http://dx.doi.org/10.2169/internalmedicine.5536-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872801PMC
January 2021

-Related Cerebral Small Vessel Disease: A Review of the Literature.

Front Neurol 2020 3;11:545. Epub 2020 Jul 3.

Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is clinically characterized by early-onset dementia, stroke, spondylosis deformans, and alopecia. In CARASIL cases, brain magnetic resonance imaging reveals severe white matter hyperintensities (WMHs), lacunar infarctions, and microbleeds. CARASIL is caused by a homozygous mutation in (). Recently, it was reported that several heterozygous mutations in also cause cerebral small vessel disease (CSVD). Although patients with heterozygous -related CSVD (symptomatic carriers) are reported to have a milder form of CARASIL, little is known about the clinical and genetic differences between the two diseases. Given this gap in the literature, we collected clinical information on -related CSVD from a review of the literature to help clarify the differences between symptomatic carriers and CARASIL and the features of both diseases. Forty-six symptomatic carriers and 28 patients with CARASIL were investigated. Twenty-eight mutations in symptomatic carriers and 22 mutations in CARASIL were identified. Missense mutations in symptomatic carriers are more frequently identified in the linker or loop 3 (L3)/loop D (LD) domains, which are critical sites in activating protease activity. The ages at onset of neurological symptoms/signs were significantly higher in symptomatic carriers than in CARASIL, and the frequency of characteristic extraneurological findings and confluent WMHs were significantly higher in CARASIL than in symptomatic carriers. As previously reported, heterozygous -related CSVD has a milder clinical presentation of CARASIL. It seems that haploinsufficiency can cause CSVD among symptomatic carriers according to the several patients with heterozygous nonsense/frameshift mutations. However, the differing locations of mutations found in the two diseases indicate that distinct molecular mechanisms influence the development of CSVD in patients with -related CSVD. These findings further support continued careful examination of the pathogenicity of mutations located outside the linker or LD/L3 domain in symptomatic carriers.
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http://dx.doi.org/10.3389/fneur.2020.00545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351529PMC
July 2020

Clinical anticipation of disease onset in a Japanese Asidan (SCA36) family.

J Neurol Sci 2020 09 16;416:117043. Epub 2020 Jul 16.

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

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http://dx.doi.org/10.1016/j.jns.2020.117043DOI Listing
September 2020

The Efficacy of Sertraline, Escitalopram, and Nicergoline in the Treatment of Depression and Apathy in Alzheimer's Disease: The Okayama Depression and Apathy Project (ODAP).

J Alzheimers Dis 2020 ;76(2):769-772

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

Background: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer's disease (AD) are associated with a lower quality of life.

Objective: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients.

Methods: In the present study, we evaluated the efficacy of sertraline (n = 11; average dose = 31.8 mg), escitalopram (n = 13; average dose = 7.3 mg), and nicergoline (n = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) (>5) or a high Apathy Scale (AS) (>16) scores.

Results: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p = 0.05); however, no significant changes were noted in patients receiving nicergoline.

Conclusion: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD.
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http://dx.doi.org/10.3233/JAD-200247DOI Listing
May 2021

Direct arterial damage and neurovascular unit disruption by mechanical thrombectomy in a rat stroke model.

J Neurosci Res 2020 10 18;98(10):2018-2026. Epub 2020 Jun 18.

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

Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke that could cause hemorrhagic complications. We aimed to evaluate the pathology of MT-induced arterial damage and neurovascular unit (NVU) disruption in relation to tissue-type plasminogen activator (tPA) injection for acute ischemic stroke. We induced transient middle cerebral artery occlusion in male SHR/Izm rats for 2 hr. This was followed by reperfusion with/without tPA (3 mg/kg) and "rough suture" insertion that mimicked MT once or thrice (MT1 or MT3). Compared with the control group, the tPA + MT3 group presented with an increase in the cerebral infarct and hemorrhage with severer IgG leakage. Moreover, structural damage reaching the tunica media was detected in the MT3 and tPA + MT3 groups. The tPA + MT3 group presented with increased matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression with some MMP9-positive cells expressing a neutrophil marker myeloperoxidase. Furthermore, basal lamina detachment from astrocyte foot processes was observed in the tPA + MT1 and tPA + MT3 groups. These findings suggest that MT causes direct arterial damage, as well as VEGF and MMP9 upregulation, which results in NVU disruption and hemorrhagic complications in acute ischemic stroke, especially when combined with tPA.
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http://dx.doi.org/10.1002/jnr.24671DOI Listing
October 2020

TTN missense variants in two siblings with asymmetric facial and limb weakness.

J Neurol Sci 2020 08 7;415:116885. Epub 2020 May 7.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.116885DOI Listing
August 2020

Neuroprotective effect of CuATSM in mice stroke model by ameliorating oxidative stress.

Neurosci Res 2021 May 24;166:55-61. Epub 2020 May 24.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan. Electronic address:

Cu-diacetyl-bis (N4-methylthiosemicarbazone) (CuATSM) has both anti-oxidative and anti-inflammatory activities, but its therapeutic efficacy for oxidative stress has not been thoroughly investigated in acute ischemic stroke. Here, the present study was designed to assess the efficacies of CuATSM in acute ischemic stroke by comparing with the standard neuroprotective reagent edaravone. Mice were subjected to transient middle cerebral occlusion (tMCAO) for 60 min, and then intravenously administrated with CuATSM (1.5 mg/kg) or edaravone (3 mg/kg) just after the reperfusion, and examined at 1 and 3 d. Compared with the vehicle group, CuATSM treatment decreased infarct volumes and oxidative stress at 3d after tMCAO, which was further enhanced by combined CuATSM + edaravone treatment as compared with single CuATSM group, but not improve neurobehaviors. The present study demonstrated that CuATSM showed strong antioxidative and neuroprotective effects in acute ischemic stroke, which was enhanced by the combination with edaravone.
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http://dx.doi.org/10.1016/j.neures.2020.05.009DOI Listing
May 2021

Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients.

J Neurol Sci 2020 Aug 15;415:116906. Epub 2020 May 15.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Electronic address:

Background: The free radical scavenger edaravone is a proven neuroprotective drug for patients with amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the therapeutic effects of edaravone for oxidative stress and anti-oxidative activity in ALS patients.

Methods: Twenty-two ALS patients with a disease duration of 2 years, treated by edaravone, and 25 control participants were evaluated according to their clinical scores, including ALS functional rating scale-revised (ALSFRS-R), and serum and cerebrospinal fluid (CSF) markers of oxidative stress dROM and anti-oxidative activity OXY.

Results: Serum and CSF markers of anti-oxidative activity OXY were significantly decreased in ALS patients at pre-treatment compared with controls (p < .01), which was improved in the course of edaravone treatment. Both serum and CSF OXY were significantly correlated with ALS clinical scores including ALSFRS-R (*p < .05, **p < .01, ***p < .001). Furthermore, serum OXY at pre-treatment was significantly correlated with a change in the ALSFRS-R score in the sixth cycle of edaravone treatment (*p < .05).

Conclusions: The present study suggests significant correlations between anti-oxidative activity and ALS clinical severity, and the therapeutic efficacy of edaravone for decreased anti-oxidative activity in ALS.
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http://dx.doi.org/10.1016/j.jns.2020.116906DOI Listing
August 2020

Antioxidative effects of a novel dietary supplement Neumentix in a mouse stroke model.

J Stroke Cerebrovasc Dis 2020 Aug 19;29(8):104818. Epub 2020 May 19.

Departments of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Dentistry and Pharmacy, 2-5-1 Shikata-cho, Okayama Okayama Japan. Electronic address:

Background: During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear.

Methods: Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO.

Results: Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice.

Conclusion: The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104818DOI Listing
August 2020

A Polyphenolic Complex Attenuates Inflammatory Response and Blood- Brain Barrier Disruption.

Curr Neurovasc Res 2020 ;17(3):286-293

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

Background: Cerebral ischemia causes a strong inflammatory response. Neumentix is a dietary supplement containing 14.9% rosmarinic acid and 29.9% total phenolic content, which has been proved to be beneficial against inflammatory response. Therefore, Neumentix's effect on anti-inflammatory and blood brain barrier (BBB) disruption in transient middle cerebral artery occlusion (tMCAO) model mice is investigated in this study.

Methods: After the pretreatment of vehicle or Neumentix 134 mg/kg/d, intraperitoneal injection (i.p.) (containing rosmarinic acid 20 mg/kg/d) for 14 days, mice were subjected to tMCAO for 60 min and kept receiving vehicle or Neumentix daily 5 days afterward.

Results: Neumentix treatment ameliorated neurobehavioral impairment in the corner test (5d after tMCAO, **P<0.01), reduced infarct volume (#P<0.05), suppressed expression of ionized calciumbinding adapter molecule-1 (Iba-1), tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) (###P<0.001), and improved the integrity of BBB (§P<0.05) at 5 days after tMCAO.

Conclusion: The present study provided an evidence of Neumentix's anti-inflammatory and neuroprotection effect against BBB disruption on experimental tMCAO model mice, suggesting that Neumentix could be a potential therapeutic agent for stroke.
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http://dx.doi.org/10.2174/1567202617666200517105727DOI Listing
January 2020

Dynamic changes and mislocalizations of neurodegenerative disease-related proteins in mice stroke model.

Brain Res 2020 09 28;1742:146862. Epub 2020 Apr 28.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kitaku, Okayama 700-8558, Japan. Electronic address:

The aggregation and cellular mislocalization of several RNA-binding proteins (RBPs) have been identified as the major hallmarks of neurodegenerative diseases such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, it remains obscure whether these pathological changes also occur during cerebral ischemia. In this study, we report that RBPs increased significantly compared with the sham group (*p < 0.05 and p < 0.01 vs sham), with nuclear depletion and cytoplasmic deposition in neurons in the acute phase of cerebral ischemia. On the other hand, such nucleocytoplasmic mislocalization were not observed in astrocytes. We provide evidence of the alteration of these neurodegeneration-related RBPs after cerebral ischemia, suggesting a potential association between cerebral ischemia and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.brainres.2020.146862DOI Listing
September 2020

Up-regulation of sphingosine-1-phosphate receptors and sphingosine kinase 1 in the peri-ischemic area after transient middle cerebral artery occlusion in mice.

Brain Res 2020 07 9;1739:146831. Epub 2020 Apr 9.

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

There is thought to be a strong relationship between sphingosine-1-phosphate (S1P) signaling and pathophysiolosy of cerebral ischemia. We examined the change of expression and distribution of S1P receptors (S1PRs) and sphingosine kinases (SphKs) after cerebral ischemia in male C57BL6/J mice using immunohistochemical analysis at 1, 5, 14, and 28 days after 30 min of transient middle cerebral artery occlusion (tMCAO). S1PR1, 3, and 5 were transiently induced in the cells, which were morphologically similar to neurons in the peri-infarct lesion with a peak seen at 1 day after tMCAO (p < 0.01 vs. sham control). S1PR2 appeared in the inner layer of vessels in the ischemic core (p < 0.01 vs. sham control) and the peri-infarct lesion (p < 0.01 vs. sham control) at the acute phase after tMCAO. However, SphK1 was strongly induced at 1 and 5 days after tMCAO (p < 0.01 vs. sham control) in the peri-infarct lesion, whereas SphK2 expression did not change. Western blot analysis at 1 and 5 days after 30 min of tMCAO revealed that the expression of S1PRs were transiently enhanced at the acute phase, which was consistent with the immunohistochemical results. Double immunofluorescent analysis revealed S1PR2/NG2- and S1PR2/CD31-, S1PR3/CD31-, and S1PR5/CD31-double positive cells in the peri-infarct lesion 1 day after tMCAO. The present results suggest that S1PRs and SphK1 may be important therapeutic targets for rescuing the peri-infarct lesion.
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http://dx.doi.org/10.1016/j.brainres.2020.146831DOI Listing
July 2020

Bone Marrow Stromal Cell Transplantation Drives Molecular Switch from Autophagy to the Ubiquitin-Proteasome System in Ischemic Stroke Mice.

J Stroke Cerebrovasc Dis 2020 May 1;29(5):104743. Epub 2020 Mar 1.

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

Background: Bone marrow stromal cell (BMSC) transplantation is a promising therapeutic approach for cerebral ischemia, as it elicits multiple neuroprotective effects. However, it remains unclear how BMSC transplantation modulates the ubiquitin-proteasome system (UPS) and autophagy under cerebral ischemia.

Methods: In the present study, an intermediate level of cerebral ischemia (30 minutes) was chosen to examine the effect of BMSC transplantation on the molecular switch regulating UPS and autophagy. BMSC or vehicle was stereotactically injected into the penumbra 15 minutes after sham operation or transient middle cerebral artery occlusion (tMCAO).

Results: Thirty minutes of tMCAO artery occlusion significantly increased TUNEL-, ubiquitin-, and p62-positive cells (which peaked at 72 hours, 2 hours, and 2 hours after reperfusion, respectively) and ratios of both BAG3/BAG1 and LC3-II/LC3-I at 24 hours after reperfusion. However, intracerebral injection of BMSCs significantly reduced infarct volume and numbers of TUNEL- and p62-positive cells, and improved BAG3/BAG1 and LC3-II/LC3-I ratios. In addition, observed increases in ubiquitin-positive cells 2 hours after reperfusion were slightly suppressed by BMSC transplantation.

Conclusions: These data suggest a protective role of BMSC transplantation, which drove the molecular switch from autophagy to UPS in a murine model of ischemic stroke.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104743DOI Listing
May 2020

Discrepancy of subjective and objective sleep problems in Alzheimer's disease and mild cognitive impairment detected by a home-based sleep analysis.

J Clin Neurosci 2020 Apr 30;74:76-80. Epub 2020 Jan 30.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Electronic address:

There is a strong relationship between Alzheimer's disease (AD) and sleep problems, and a sleep condition is informative for evaluating the AD status. In the present study, we evaluated subjective sleep problems in AD and mild cognitive impairment (MCI) with self-check questionnaires and objective sleep problems with a convenient home-based portable device, WatchPAT. A total of 63 subjects with normal cognition (NC) (n = 22), MCI (n = 20), and AD (n = 21) were cross-sectionally investigated. AD patients showed a better self-check Pittsburgh sleep quality index (PSQI) score (*p < 0.05) than NC and MCI patients. On the other hand, WatchPAT analysis showed a significantly reduced rapid eye movement (REM) sleep (*p < 0.05) and increased light sleep in AD patients (*p < 0.05) compared with NC subjects, and mildly reduced REM and increased light sleep in MCI subjects. The present study revealed a gap between the subjective self-check sleep questions and the objective WatchPAT analysis in AD patients. Thus, a home-based sleep study with WatchPAT is a useful tool to detect an objective sleep problem in AD and the risk of MCI conversion into AD.
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http://dx.doi.org/10.1016/j.jocn.2020.01.085DOI Listing
April 2020

Different clinical and neuroimaging features of Japanese dementia siblings with a new N-terminal mutation (Val225Ala) of APP gene.

J Clin Neurosci 2020 Feb 11;72:482-484. Epub 2020 Jan 11.

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

Autosomal dominant amyloid precursor protein (APP) mutations in familial Alzheimer's disease accelerate the amyloid beta (Aβ) pathology. Here we describe Japanese siblings with a new N-terminal mutation (a heterogeneous c.674T>C, p.Val225Ala) of the APP gene, developing a progressive dementia at 57 years and Aβ and tau pathologies in cerebrospinal fluid studies. However, the brother and sister showed different clinical and neuroimaging features, suggesting different Aβ pathologies for each sibling.
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http://dx.doi.org/10.1016/j.jocn.2019.11.009DOI Listing
February 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

Early Emergence of Neuropsychiatric Symptoms in Cognitively Normal Subjects and Mild Cognitive Impairment.

J Alzheimers Dis 2020 ;73(1):209-215

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

The world is rapidly aging and facing an increase in the number of dementia patients, so it is important to detect the preclinical stage of dementia in such countries. We examined both cognitive and affective functions among cognitively normal control (n = 218), mild cognitive impairment (MCI, n = 146), and Alzheimer's disease (AD, n = 305) subjects using two evaluation tools for behavioral and psychological symptoms of dementia (BPSD) [Abe's BPSD score (ABS) and mild behavioral impairment (MBI)]. BPSD were present in 12.4% (ABS) and 9.6% (MBI) of cognitively normal people, 34.9% and 32.2% in MCI subjects, and 66.2% and 51.1% in AD patients. Both ABS (§p<0.05) and MBI (§§p < 0.01) score showed worse score with cognitive decline of the Mini-Mental State Examination in the AD group in BPSD-positive participants. Similar correlations were found in all participants in AD group (||||p < 0.01 versus ABS and MBI). Among the subscales in BPSD-positive participants, an apathy/indifference score of ABS and a decreased motivation of MBI showed significant differences in AD patients compared to the control and MCI subjects (**p<0.01). In addition, subscale analyses further showed a downward trend from the control to MCI and AD subjects in four ABS subscales and three MBI subscales. The present study showed the preclinical presence of BPSD in cognitively normal people, more so in MCI subjects, and ABS detected BPSD more sensitively than MBI in all three groups.
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http://dx.doi.org/10.3233/JAD-190669DOI Listing
April 2021

A novel homoplasmic mitochondrial DNA mutation (m.13376T>C, p.I347T) of MELAS presenting characteristic medial temporal lobe atrophy.

J Neurol Sci 2020 01 25;408:116460. Epub 2019 Oct 25.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2019.116460DOI Listing
January 2020

Yoga-plus exercise mix promotes cognitive, affective, and physical functions in elderly people.

Neurol Res 2019 Nov 5;41(11):1001-1007. Epub 2019 Oct 5.

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

: Increased attention is being paid to Asian medicine in balanced total health care. We investigated the effects of mixed exercise including yoga ('Yoga-plus') among elderly individuals. : A total of 385 subjects (72 males and 313 females, 75.5 ± 8.7 years old) participated in a 12-month (M) exercise program at a health and welfare center, a day service center, and a nursing home. Cognitive, affective, and physical functions, and activities of daily living (ADL), were compared at baseline (0M), 6M and 12M of exercise intervention. : Mean scores on the frontal assessment battery, clock drawing test, cube copying test, letter fluency, and category fluency significantly improved after the Yoga-plus intervention, while mini-mental state examination, Hasegawa dementia score-revised, and trail-making test performance were relatively stable. Affective scores on the geriatric depression scale (GDS), apathy scale (AS) and Abe's behavioral and psychological symptoms of dementia were not significantly affected by exercise therapy, but subgroups with higher baseline GDS (GDS ≥ 5) and AS (AS ≥ 16) scores showed a significant improvement after intervention. One-leg standing time and 3-m timed up and go test performance significantly improved after 12M intervention. : Yoga-plus improved cognitive, affective, ADL, and physical functions in a local elderly population, particularly among below-baseline individuals, indicating the benefits of dementia prevention among elderly individuals.
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http://dx.doi.org/10.1080/01616412.2019.1672380DOI Listing
November 2019

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

Female dominant association of sarcopenia and physical frailty in mild cognitive impairment and Alzheimer's disease.

J Clin Neurosci 2019 Dec 20;70:96-101. Epub 2019 Aug 20.

Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Electronic address:

Associations of sarcopenia and physical frailty in cognitive and affective (depression, apathy, and behavioral and psychological symptoms of dementia) functions of mild cognitive impairment (MCI) and Alzheimer's disease (AD) were not fully evaluated previously, especially not for gender differences. 165 AD, 84 MCI, and 48 control participants (175 female, 122 male) were evaluated for cognitive, affective, activities of daily living (ADL), and physical functions associated with sarcopenia and physical frailty. In both sexes, cognitive and affective functions, ADL, and physical functions worsened in MCI and AD compared to control subjects. Physical dysfunctions, especially slow gait speed (3 m up and go test), were significantly associated with cognitive, affective, and ADL declines in participants (control subjects, MCI, and AD) of each gender, which were especially noticeable in females. The present study may be the first to suggest significant associations of sarcopenia and physical frailty with cognitive and affective functions of MCI and AD, especially in females.
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http://dx.doi.org/10.1016/j.jocn.2019.08.062DOI Listing
December 2019
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