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The therapeutic effect of in vivo direct reprogramming on ischemic stroke has not been evaluated. In the present study, a retroviral solution (1.5–2.0 × 107 /ul) of mock pMX-GFP (n = 13) or pMX-Ascl1/Sox2/NeuroD1 (ASN) (n = 14) was directly injected into the ipsilateral striatum and cortex 3 days after 30 min of transient cerebral ischemia. The reprogrammed cells first expressed neuronal progenitor marker Dcx 7 and 21 days after viral injection, then expressed mature neuronal marker NeuN. This was accompanied by morphological changes, including long processes and synapse-like structures, 49 days after viral injection. Meanwhile, therapeutic improvement was not detected both in clinical scores or infarct volume. The present study provides a future novel self-repair strategy for ischemic stroke with beneficial modifications of the inducer-suppressor balance.

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.

BACKGROUND: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX). METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry. RESULTS: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; #P < .05 and ##P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; #P < .05, and ##P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group. CONCLUSIONS: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.

The relationship between stroke etiology and clot pathology remains controversial.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.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.A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

Aim We compared the behavioral and psychological symptoms of Alzheimer's disease (AD) and Parkinson's disease (PD) in order to determine the characteristic features of each disorder. Methods For this retrospective cohort study, we compared the behavioral and psychological symptoms of 288 AD patients and 189 PD patients (mean age, 74.6 ± 5.9 and 73.0 ± 8.7 years respectively). Symptoms were evaluated using the geriatric depression scale (GDS), apathy scale (AS), and Abe's behavioral and psychological symptoms of dementia score (ABS). Results AD patients had higher AS and ABS scores than PD patients. A gender-dependent comparison showed that ABS scores were worse in female AD patients than in female PD patients (p = 0.001). A subscale analysis of ABS scores revealed that male AD patients were only significantly different from male PD patients in 1 item, whereas female AD patients were significantly different from female PD patients in 4 items. Among patients with mild cognitive decline, no differences in affective scores were observed. Alternatively, among patients with moderate cognitive decline, affective scores on all 3 scales were worse in PD patients than in AD patients. Conclusions The present age- and gender-matched retrospective analysis identified greater behavioral and psychological disease severity in female AD patients relative to female PD patients, and greater affective severity in PD patients versus AD patients with a similar degree of cognitive decline.

Aim The coexistence of Alzheimer's disease (AD) and cerebrovascular disease pathology increases age-dependently. We comprehensively analyzed the clinical effects of galantamine or cilostazol monotherapy to the add-on combination therapy on three major factors of dementia, such as cognitive, affective and activities of daily living functions in AD patients with asymptomatic lacunar infarction. Methods We divided 101 AD patients with asymptomatic lacunar infarction into two subgroups: group A (n = 61, first treated with galantamine and then cilostazol added) and group B (n = 40, first treated with cilostazol and galantamine added). We compared the clinical effects before and after combination therapy of galantamine and cilostazol (i.e. 3 months [M] before (–3 M), baseline (0 M), 3 and 6 M after the add-on combination). Results Galantamine monotherapy increased cognitive Hasegawa dementia score-revised scores, which were further improved with add-on cilostazol. Cilostazol monotherapy also increased the cognitive tests, which were further improved with add-on galantamine. Add-on cilostazol significantly improved Geriatric Depression Scale and Abe's behavioral and psychological symptoms of dementia scores after galantamine monotherapy. Cilostazol monotherapy also significantly improved Geriatric Depression Scale scores, with further improvements in Geriatric Depression Scale, apathy scores and Abe's behavioral and psychological symptoms of dementia scores by add-on galantamine. Activities of daily living scores continuously improved with galantamine monotherapy and add-on cilostazol. Conclusions The present study provides a clinical possibility that galantamine or cilostazol monotherapy and the combination therapy maintained or even improved cognitive, affective, and activities of daily living functions in AD with asymptomatic lacunar infarction. Geriatr Gerontol Int 2017; 17: 1384–1391.

Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action.

A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of Nav1.6 and AnkG beyond the primary nodal region in the corpus callosum. Such abnormal neuropathological processes were retrieved with galantamine treatment. The present study demonstrated that cerebral HP strongly disrupted white matter integrity (WMI) at intermodal, paranodal, and Ranvier's nodal sites which may be associated with cognitive decline. Galantamine treatment significantly protected such WMI probably by allosterically potentiating ligand action.

Objective To compare age-dependent changes in cognitive and affective functions related to white matter changes between patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Methods We retrospectively compared age-dependent cognitive and affective functions in 216 AD patients, 153 PD patients, and 103 healthy controls with cerebral white matter lesions (WMLs), periventricular hyperintensity (PVH), deep white matter hyperintensity (DWMH), micro-bleeds (MBs), and lacunar infarcts (LIs). Results The average mini-mental state examination (MMSE) scores were 19.6 ± 6.1 and 26.8 ± 3.6 in AD and PD patients, respectively. Significant decreases were found in the MMSE score, Hasegawa's dementia scale-revised (HDS-R) score, frontal assessment battery score, and Abe's BPSD score (ABS) among the age-dependent AD subgroups and in the MMSE, HDS-R, Montreal cognitive assessment, geriatric depression scale, and ABS scores among the age-dependent PD subgroups; they were worse in AD patients. White matter changes were observed in > 88% and > 72% of patients with AD and PD, respectively. An age-dependent direct comparison of AD and PD showed significant differences in the PVH and DWMH grades, and numbers of MBs and LIs. Conclusion WML-related cognitive and affective functions worsen with age in AD and PD patients; however, the abnormalities were more frequent and stronger in AD patients.

AIM: The number of people with dementia is rapidly increasing as populations around the world age. It is important to grasp the characteristic features of mild cognitive impairment (MCI) for early detection and prevention of dementia. METHODS: We examined 408 individuals recruited from a health checkup for metabolic syndrome, which comprised three groups: normal (n = 325), MCI (n = 55) and apparent cognitive decline (ACD; n = 28). We compared cognitive/affective functions and exercise/hobby habits with assessments of vascular risk factors and results from computerized touch-panel tests. RESULTS: Among the 408 individuals, 93.1% showed normal scores on the Mini-Mental State Examination, and 6.9% had ACD. Among the normal Mini-Mental State Examination participants, 14.5% had MCI (13.5% of all participants). The three groups of participants showed significant differences in age, education, systolic blood pressure, glycosylated hemoglobin and high-density lipoprotein cholesterol level. Even within the normal range, those in the MCI group showed significantly lower cognitive function than those in the normal group. Scores on the Geriatric Depression Scale were greater in the MCI group, and "day-night reversal" was worse in the ACD group. Scores on touch-panel screening tests were significantly worse in the MCI and ACD groups than in the normal group. Participants showed better cognitive and affective function if they exercised regularly or had hobbies. CONCLUSIONS: Incidental MCI and ACD had prevalences of 13.5% and 6.9%, respectively, in the population-based study. Participants with these conditions showed cognitive/affective decline and impairment on computerized touch-panel tests in relation to vascular risk factors and exercise/hobbies. Geriatr Gerontol Int 2017; 17: 722-729.

Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p = 0.013 and 8.6±4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in “orientation to place” tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients’ lower average scores for “repetition” (MMSE), “recent memory” (HDS-R), and “lexical fluency” (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients’ poorer average subscale scores of “orientation to place” (MMSE) and “similarities”, “conflicting instructions”, and “go-no go” (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.

AIMS: The world is rapidly aging, and is facing an increase of late-elderly dementia patients. It is important to investigate the characteristic features of late-elderly dementia in a super-aged country. METHODS: We examined 1554 patients with cognitive decline in Department of Neurology, Okayama University Hospital, Okayama, Japan, divided into three subgroups according to the age: young-elderly (age ≤64 years), middle-elderly (age 65-74 years) and late-elderly (age 75 years), and investigated the cognitive, affective and activities of daily living functions (ADL), especially in late-elderly patients compared with young-elderly and middle-elderly patients. RESULTS: Among 1554 patients, Alzheimer's disease dominated at 62%, and age-dependently increased up to 69% in the late-elderly group. The total scores of four cognitive tests were significantly worse with aging for specific subscales of orientation, recall, visual retention, word fluency and so on. In contrast, total scores of the affective tests showed only an increase in the apathy scale in the late-elderly group. Each subgroup showed depressive/depression in 63.2-55.2%, and apathy in 44.2-54.8%. Furthermore, instrumental ADL items significantly deteriorated in the late-elderly group, which statistically correlated with Mini-Mental State Examination score. CONCLUSIONS: These results show that the late-elderly group is characterized by significant cognitive declines, increasing apathy, and instrumental ADL decrease. The cognitive decline may be related to such affective and ADL declines.

We recently experienced 2 young adult patients who developed ischemic stroke after regular intravenous immunoglobulin (IVIg) therapy for agammaglobulinemia with diagnosis of common variable immunodeficiency (CVID) in their childhood. Patient 1 was 26-year-old woman, who developed Wallenberg's syndrome 6 days after the last IVIg therapy, but had no further stroke recurrence with cilostazol later. Patient 2 was 37-year-old man, who developed recurrent cerebral infarction in the territory of bilateral lenticulostriate branches like branch atheromatous disease (BAD) several days after the IVIg therapy. However, he had no further stroke recurrence after bone marrow transplantation (BMT) therapy for his lymphoproliferative disorder. It was suggested that IVIg therapy was associated to these different types of ischemic stroke in our 2 young adult patients with minimal vascular risk factors. Although IVIg therapy is widely used as a relatively safe medication for immunodeficiency disorders or autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy.

Clinical data from Japan on the safety and real-world outcomes of alteplase (tPA) thrombolysis in the extended therapeutic window are lacking. The aim of this study was to assess the safety and real-world outcomes of tPA administered within 3-4.5 h of stroke onset. The study comprised consecutive acute ischemic stroke patients (n = 177) admitted across five hospitals between September 2012 and August 2014. Patients received intravenous tPA within

Background: Although changes to gait are an important clinical feature of progressive supranuclear palsy (PSP), systematic analyses have not been well examined, especially in comparison to Parkinson's disease (PD). Methods: The characteristics of gait in 20 PSP patients (14 males and 6 females) were evaluated in comparison to 124 PD patients (64 males and 60 females) and 24 controls, that is, healthy age-matched adults (5 males and 19 females). Gait in patients was recorded in a 10-m walking test at a self-selected speed. During this time, patients felt most comfortable while wearing a new portable triaxial accelerometer rhythmogram device. Gait variables among the 3 groups were compared. Results: Both PSP and PD patients shared the following similar hypokinetic gait characteristics: decreased velocity, step length, cadence and mean acceleration. Step time and variability in step time were mutually related. However, among the 3 groups, PSP patients showed characteristically low vertical displacement and a higher acceleration than PD patients at the same cadence. Conclusion: Although PSP and PD patients showed similar hypokinetic gait, a reduced vertical displacement characterized walking in PSP patients, differing substantially from the characteristics of walking displayed by PD patients.

A pituitary abscess is a rare intracranial infection, and a direct transsphenoidal surgery is a common for the therapy. Intracranial rupture of the pituitary abscess is usually fatal. Here, we report a 76-years-old woman with a pituitary abscess who showed headaches, left eyelid ptosis, periorbital swelling, and external eye movement disturbances in the left eye. Although her symptoms initially improved after therapy with systemic antibiotics, the pituitary abscess suddenly developed an intraventricular rupture on admission day 27. However, emergency ventricular drainage in combination with different antibiotics gradually improved her condition. The present case suggests that the combination of emergency ventricular drainage and systemic antibiotic administration could serve as an alternative choice to manage pituitary abscesses of ventricular ruptures, especially in elderly patients. This article is protected by copyright. All rights reserved.

As the number of elderly people increases, Alzheimer's disease (AD) and hypertension have become more common. This is an important case report that shows severe hyponatremia induced by a combination of angiotensin II receptor blocker (ARB) and thiazide, causing the deterioration of cognitive functions in an elderly patient. In rapidly aging societies around the world, more attention should be paid to hyponatremia under combination therapy of ARB plus thiazide to assist elderly patients. This article is protected by copyright. All rights reserved.

We report mother-daughter cases of AxD type 2 with a novel GFAP gene mutation. The mother (proband) began to show slowly progressive gait disturbance. However, after an incidental medical checkup, it took only 9 months for the diagnosis. Different from the previous reports, she showed a unique phenotype in points of scoliosis without palatal myoclonus, decreased regional cerebral blood flow in the frontal lobe, and mild cognitive impairment. Her second daughter showed mild intellectual disability. Genetic analysis of the mother and the second daughter showed the same novel GFAP gene mutation (c.371_372insAGA). This article is protected by copyright. All rights reserved.

Patients with progressive supranuclear palsy (PSP) often suffer from dysphagia, and percutaneous endoscopic gastrostomy (PEG) is a treatment option for the advanced stage of this disease. The present PSP patient had slightly impaired glucose tolerance (IGT), but the condition became considerably worse with normal nutrients due to limited activity and an infection after PEG, resulting in a non-ketoic hyperosmolar coma (NKHC). After receiving supplementary fluid, intravenous insulin, antibiotics and endotracheal intubation, the patient recovered from the NKHC state. PEG placement at an advanced stage of a neurodegenerative disorder such as PSP should have a careful follow-up, especially when glucose tolerance worsens. This article is protected by copyright. All rights reserved.

A 72-year-old woman developed a subacute series of encephalitis, cerebellar ataxia, and combined symptoms of both myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS). Seven different neuronal antibodies (Ab) were detected for Hu, glutamic acid decarboxylase (GAD), acetylcholine receptor, P/Q-type voltage-gated calcium-channels, Zic4, Titin, and SOX1 in her serum with intrathecal synthesis of GAD-Ab. Although she showed classical manifestations with onconeural antibodies, she was diagnosed with not paraneoplastic but autoimmune neurological syndrome because of no underlying tumor and good response to immunotherapies. Our present case is very unique and rare for complexed neurological disorders including MG and LEMS overlap syndrome with multiple neuronal antibodies. This article is protected by copyright. All rights reserved.

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

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, Ne-(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.

A 46-year-old woman developed slowly progressive tongue weakness with a pseudohypertrophic change on the right side of her tongue. She subsequently developed weakness in her proximal lower extremities, skin erythema and a sustained increase of muscle enzymes at 11 M after the onset. A biopsy of the quadriceps muscle showed necrotizing myopathy and a skin biopsy showed erythema nodosum. The present case showed characteristic clinical manifestations that may represent a rare variant of sarcoidosis.

Klinefelter syndrome is a chromosomal disorder with a typical karyotype of 47, XXY, accompanied by various neurological symptoms. We herein report the first case of Klinefelter syndrome with a rare mosaic form of 47, XXY and 48, XXXY, combined with both spastic paraplegia and peripheral motor neuropathy. This case showed spasticity and hyperreflexia with pathological reflexes and ankle clonus as well as muscle weakness in all extremities. A motor nerve conduction study and the magnetic motor evoked potential suggested motor axonal neuropathy and corticospinal tract disorders. The present case suggests that Klinefelter syndrome can present with both upper and lower motor neuron degeneration.

Oxidative stress is associated with the degeneration of both motor neurons and skeletal muscles in amyotrophic lateral sclerosis (ALS). A free radical scavenger edaravone has been proven as a therapeutic drug for ALS patients, but the neuroprotective mechanism for the oxidative stress of ALS has not been fully investigated. In this study, we investigated oxidative stress in ALS model mice bearing both oxidative stress sensor nuclear erythroid 2-related factor 2 (Nrf2) and G93A-human Cu/Zn superoxide dismutase (Nrf2/G93A) treated by edaravone. In vivo Nrf2 imaging analysis showed the accelerated oxidative stress both in spinal motor neurons and lower limb muscles of Nrf2/G93A mice according to disease progression in addition to the enhancement of serum oxidative stress marker dROMS. These were significantly alleviated by edaravone treatment accompanied by clinical improvements (rotarod test). The present study suggests that in vivo optical imaging of Nrf2 is useful for detecting oxidative stress in ALS, and edaravone alleviates the degeneration of both motor neurons and muscles related to oxidative stress in ALS patients.

Background Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both thrombolytic and anti-inflammatory effects, but its neuroprotective effects on cerebral ischemia are still unclear. The present study assessed the antioxidative and neurovascular unit (NVU) protective effects of SMTP-7 using transient middle cerebral artery occlusion (tMCAO) mice. Methods After 60 minutes tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA + SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24 hours after reperfusion. We histologically assessed the hemorrhage and expressive changes of antioxidative markers in brains. Results SMTP-7 treatment showed a similar antithrombotic effect to tPA, but significantly decreased the hemorrhage volumes and the number of 4-HNE, 3-NT and 8-OHdG positive cells, meanwhile, ameliorated the decrease of collagen IV in the ischemic brains. However, tPA + SMTP-7 treatment did not decrease hemorrhage volumes nor showed NVU protective effect. Conclusions The present study suggested that SMTP-7 provided therapeutic benefits for ischemic stroke through antioxidative and NVU protective effects unlike tPA alone or tPA + SMTP-7.

Facioscapulohumeral muscular dystrophy (FSHD) 2 is caused by a combination of heterozygous structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) mutation plus DNA hypomethylation on D4Z4. Here we report two Japanese FSHD2 siblings (brother and sister) with a new SMCHD1 nonsense mutation (a heterogeneous c. 1654C > T substitution, leading to a stop codon Arg552∗). They showed the typical phenotype of FSHD2 such as asymmetric muscle weakness and atrophy in bilateral facial, scapular and humeral muscles, but different clinicopathological features between them. The brother and asymptomatic mother showed normal D4Z4 methylation plus the same SMCHD1 mutation, but the sister showed the SMCHD1 mutation plus D4Z4 hypomethylation, suggesting an interesting correlation of the new SMCHD1 nonsense mutation and D4Z4 hypomethylation.

Background Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both potentials of thrombolytic and neuroprotective effects, but its detailed neuroprotective mechanisms in ischemic stroke are still unclear. Here, we assessed the neuroprotective effects of SMTP-7 for anti-inflammatory and antiapoptosis mechanisms after 60 minutes of transient middle cerebral artery occlusion (tMCAO) in mice. Methods After 60minutes of tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA+SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24hours after reperfusion. We histologically assessed the antineuroinflammatory effect of SMTP-7 on the expressive changes of inflammatory markers in ischemic mouse brains. Results Compared with the vehicle and tPA groups, SMTP-7 treatment significantly improved clinical scores and decreased the infarct volume and the numbers of TNF-α, nuclear factor-κB (NF-κB), nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), and cleaved caspase-3-positive cells in the brain of mice at 24hours after tMCAO but not p62-positive cells. However, tPA+SMTP-7 treatment did not show such effects. Conclusions The present study suggested that SMTP-7 provides a therapeutic benefit for ischemic stroke mice through anti-inflammatory and antiapoptotic effects but not antiautophagic effect.

Sigma-1 receptor (Sig-1R) is expressed at endoplasmic reticulum (ER) membranes, where it regulates a variety of specific physiological functions. However, the profile and exact roles of ER stress-related molecules after Sig-1R agonist treatment in an in vivo stroke model are largely unknown. The aim of this study is to investigate the effect of a novel Sig-1R agonist, aniline derivative compound (Comp-AD), on the ER stress response following ischemic stroke. Male C57BL/6J mice received transient middle cerebral artery occlusion for 90 min, and were then treated with vehicle saline or Comp-AD at reperfusion. At 3 hr, 1 day, and 7 days after reperfusion, immunohis- tochemistry was performed for Sig-1R and ER stress-related proteins including phospho protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), phospho inositol requiring enzyme 1α (p- IRE1α), and activating transcription factor 6 (ATF6). Neurobehavioral analysis showed improved functional recovery at 1 day and 7 days after reperfusion, and the infarct volume was significantly smaller at 7 days (p < .05), in the Comp-AD group compared with the vehicle group. Comp-AD treatment upregulated Sig-1R immunoreactivity at 3 hr and 1 day (p < .05), and reduced p-PERK and p-IRE1α expression at 1 day (p < .05, respectively), in the peri-ischemic region compared with the vehicle group. Treatment with the novel Sig-1R agonist Comp-AD was neuroprotective after transient middle cerebral artery occlusion, and was associated with upregulation of Sig-1R and a reduction of ER stress.

The authors report a man who developed oral dyskinesia at 46 years of age, followed by slowly progressive choreic movement and mild cognitive impairment over 20 years. He showed caudate atrophy and four types of intracranial calcification in the hippocampus (dot-like), cerebellar white matter (vague-mass), occipital cortices (laminar), and cerebral white matter (linear). Linear-calcification in the corona radiata seems to be deposition along small veins, which may be related to the white matter changes and to the decreased regional cerebral blood flow in the frontal and parietal lobes. The present case shows a slowly progressive disease with caudate atrophy and characteristic brain calcifications.

Background and purpose A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously. Methods Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control). Results Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon. Conclusion The present unique 2-bp deletion (CT) in codon 178 induced a ‘PrP systemic deposition disease’ such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology.

Background and purpose The influence of metabolic syndrome (MetS) on cognitive and affective functions in patients with Alzheimer's disease (AD) was examined. Methods A total of 570 AD patients were divided into two subgroups depending on waist circumference (WC) (normal versus achieving Japanese diagnostic criteria of MetS). Afterwards, the AD control subgroup was defined as those normal WC patients with no vascular risk factors (VRFs). The AD with MetS (AD-MetS) subgroup was defined as the MetS WC group who had two or more VRFs to qualify as having MetS. Cognitive and affective functions, insulin resistance, vascular endothelial function and white matter changes between AD-MetS and AD controls were compared. Results Scores on the Mini-Mental State Examination, Hasegawa Dementia Score – Revised, Frontal Assessment Battery and Montreal Cognitive Assessment were worse in the AD-MetS group than in AD controls, but the difference was not significant. Some analyses were conducted twice, once including all patients and once including only late-elderly patients. Scores on the Geriatric Depression Scale were found to be significantly higher for AD-MetS than for AD controls (all ages, late-elderly), as were those for apathy (late-elderly). Furthermore, both the homeostasis model assessment of insulin resistance and reactive hyperemia index scores were significantly worse in AD-MetS than in AD controls, whilst white matter changes showed a tendency to be worse. Conclusions Greater cognitive and affective decline occurs in patients with AD-MetS than in those without. Further, insulin resistance and vascular endothelial dysfunction are strongly correlated with AD-MetS before pathological white matter changes can be observed.

Background Subacute myelo-optico neuropathy was the first epidemic drug intoxication that affected many people in Japan in the 1970s. Aim More than 40 years later, we assessed the real conditions of subacute myelo-optico neuropathy patients. Methods The present study examined current cognitive and affective functions, activities of daily living, and vascular endothelial function in aged subacute myelo-optico neuropathy patients (n = 28) compared with age-, sex-, body mass index- and years of schooling-matched normal controls (n = 141). Results Mini-Mental State Examination, Hasegawa Dementia Scale-Revised, Montreal Cognitive Assessment and Frontal Assessment Battery scores were not significantly lower in subacute myelo-optico neuropathy patients, but the Geriatric Depression Scale was significantly higher without apathy. Computerized touch-panel tests showed poor performance in the flipping cards game, arranging pictures game and beating devils game, whereas activities of daily living and vascular endothelial function were within normal limits. Conclusion The present study shows that subacute myelo-optico neuropathy patients showed essentially normal cognitive function using standard cognitive assessments, although the touch-panel tests detected some decline in subacute myelo-optico neuropathy patients. Subacute myelo-optico neuropathy patients presented a higher depression score without evident apathy, activities of daily living decline or vascular endothelial dysfunction.

AIMS: The world is rapidly aging, and is facing an increase of late-elderly dementia patients. It is important to investigate the characteristic features of late-elderly dementia in a super-aged country. METHODS: We examined 1554 patients with cognitive decline in Department of Neurology, Okayama University Hospital, Okayama, Japan, divided into three subgroups according to the age: young-elderly (age ≤64 years), middle-elderly (age 65-74 years) and late-elderly (age 75 years), and investigated the cognitive, affective and activities of daily living functions (ADL), especially in late-elderly patients compared with young-elderly and middle-elderly patients. RESULTS: Among 1554 patients, Alzheimer's disease dominated at 62%, and age-dependently increased up to 69% in the late-elderly group. The total scores of four cognitive tests were significantly worse with aging for specific subscales of orientation, recall, visual retention, word fluency and so on. In contrast, total scores of the affective tests showed only an increase in the apathy scale in the late-elderly group. Each subgroup showed depressive/depression in 63.2-55.2%, and apathy in 44.2-54.8%. Furthermore, instrumental ADL items significantly deteriorated in the late-elderly group, which statistically correlated with Mini-Mental State Examination score. CONCLUSIONS: These results show that the late-elderly group is characterized by significant cognitive declines, increasing apathy, and instrumental ADL decrease. The cognitive decline may be related to such affective and ADL declines.

AIM: The aim of the present study was to compare the effects of a galantamine only therapy and a combination therapy with galantamine plus ambulatory cognitive rehabilitation for Alzheimer's disease patients. METHODS: For this retrospective cohort study, we enrolled 86 patients with Alzheimer's disease, dividing them into two groups - a galantamine only group (group G, n = 45) and a combination with galantamine plus ambulatory rehabilitation group (group G + R, n = 41). The present cognitive rehabilitation included a set of physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. We compared the Mini-Mental State Examination and Frontal Assessment Battery for cognitive assessment, and Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia score for affective assessment in two groups over 6 months. RESULTS: The baseline Mini-Mental State Examination score was 20.2 and 18.7 in groups G and G + R, respectively. Other baseline data (Frontal Assessment Battery, Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia) were not different between the two groups. Although group G kept all the scores stable until 6 months of the treatment, the Apathy Scale score showed a significant improvement in group G + R as early as 3 months, followed by the Mini-Mental State Examination and Frontal Assessment Battery improvements at 6 months (*P = 0.04 and *P = 0.02, respectively). The Geriatric Depression Scale and Abe's Behavioral and Psychological Symptoms of Dementia did not show any changes. CONCLUSION: The combination therapy of galantamine plus ambulatory cognitive rehabilitation showed a superior benefit both on cognitive and affective functions than galantamine only therapy in Alzheimer's disease patients.

Cognitive impairment and affective dysfunction of multiple system atrophy (MSA) and cortical cerebellar atrophy (CCA) have not been simultaneously examined comparing standard test batteries and a sensitive tool to detect subtle cognitive decline in patients. In the present study, we simultaneously examined cognitive and affective ability in MSA with predominant cerebellar ataxia (MSA-C, n = 25), MSA with predominant parkinsonism (MSA-P, n = 8), and CCA (n = 14) patients using computerized touch panel screening tests. Mini-mental state examination (MMSE), Hasegawa dementia scale-revised (HDS-R), frontal assessment battery (FAB), and Montreal cognitive assessment (MoCA) scores were significantly lower in MSA-C patients than in age-and gender-matched normal controls. One MSA-C patient showed a decrease in the regional cerebral blood flow (rCBF) of the frontal lobe. MSA-P patients showed no such cognitive decline. Only FAB and MoCA scores were significantly lower in the CCA patients. MSA and CCA patients also showed a mild to moderate depressive state. Touch-panel screening tests demonstrated a significant decline of beating devils game in all three disease groups including MSA-P patients, and a significant extension of the flipping cards game only in MSA-C patients. The present study demonstrated different cognitive and affective functions among MSA-C, MSA-P, and CCA patients, and a sensitive screening method for cognitive assessment using touch-panel tests.

Background/objective To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years). Methods The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total). Results The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions. Conclusions The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months.

Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit ( N -acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV–positive basement membrane and progressive increases of MMP-9–positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.

In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This study was designed for a new simple assessment of BPSD. We first employed a clinical survey for the local community with sending an inquiry letter to all members (n=129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliability was examined comparing scores between main and second caregivers (n=70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe's BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r=0.716, **p

An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an antihypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.