Protective effect of scallop-derived plasmalogen against vascular dysfunction, via the pSTAT3/PIM1/NFATc1 axis, in a novel mouse model of Alzheimer's disease with cerebral hypoperfusion.

A strong relationship between Alzheimer's disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

Human Cord Blood-Endothelial Progenitor Cells Alleviate Intimal Hyperplasia of Arterial Damage in a Rat Stroke Model.

Human cord blood-endothelial progenitor cells (hCB-EPCs) isolated from the human umbilical cord can be used to repair damaged arteries. In this study, we used an animal model with pathological changes that mimics artery wall damage caused by stent retrievers in humans. We injected hCB-EPCs to investigate their effect on endothelial hyperplasia and dysfunction during intimal repair. Four groups were established based on the length of reperfusion (3 and 28 days), as well as the presence or absence of hCB-EPC therapy. Damage to the internal carotid artery was evaluated by hematoxylin-eosin and immunohistochemical staining. Stroke volume was not significantly different between non-EPC and EPC groups although EPC treatment alleviated intimal hyperplasia 28 days after intimal damage. Vascular endothelial growth factor (VEGF) and eNOS expression were significantly higher in the EPC-treated group than in the non-EPC group 3 days after intimal damage. In addition, MMP9 and 4HNE expression in the EPC-treated group was significantly lower than in the non-EPC group. Ultimately, this study found that venous transplantation of hCB-EPCs could inhibit neointimal hyperplasia, alleviate endothelial dysfunction, suppress intimal inflammation, and reduce oxidative stress during healing of intimal damage.

A Unique Case of Sarcoid-associated Myelopathy Accompanied by Lung Cancer.

The differential diagnosis of myelopathy in patients with malignancies may be challenging, as a spinal biopsy is not always applicable. A 66-year-old woman who had shown transient double vision and nausea developed spasticity and impaired deep sensation in both feet. Magnetic resonance imaging showed abnormal gadolinium enhancement of the brainstem, spinal meninges, and nerve root. Cerebrospinal fluid (CSF) revealed mild pleocytosis and elevated protein and decreased glucose levels, although CSF cytology was normal. Lung carcinoma was simultaneously detected, and noncaseating granuloma was detected from the hilar and axillary lymph nodes, so she was diagnosed with sarcoid-associated myelopathy. Her symptoms were kept stable by intravenous methylprednisolone, oral prednisolone, and methotrexate. This is the first case of sarcoid-associated myelopathy accompanied by lung cancer, suggesting the importance of clinical course, repetitive CSF cytology, and a biopsy of the lymph nodes to distinguish sarcoid-associated myelopathy from meningeal metastasis in patients with malignancies.

Neuroprotective effects of carnosine in a mice stroke model concerning oxidative stress and inflammatory response.

Carnosine (ß-alanyl-L-histidine) is a natural dipeptide with multiple neuroprotective properties. Previous studies have advertised that carnosine scavenges free radicals and displays anti-inflammatory activity. However, the underlying mechanism and the efficacies of its pleiotropic effect on prevention remained obscure. In this study, we aimed to investigate the anti-oxidative, anti-inflammative, and anti-pyroptotic effects of carnosine in the transient middle cerebral artery occlusion (tMCAO) mouse model. After a daily pre-treatment of saline or carnosine (1000 mg / kg / day) for 14 days, mice (n = 24) were subjected to tMCAO for 60 min and continuously treated with saline or carnosine for additional 1 and 5 days after reperfusion. The administration of carnosine significantly decreased infarct volume 5 days after the tMCAO (*p < 0.05) and effectively suppressed the expression of 4-HNE, 8-OHdG, Nitrotyrosine 5 days, and RAGE 5 days after tMCAO. Moreover, the expression of IL-1ß was also significantly suppressed 5 days after tMCAO. Our present findings demonstrated that carnosine effectively relieves oxidative stress caused by ischemic stroke and significantly attenuates neuroinflammatory responses related to IL-1ß, suggesting that carnosine can be a promising therapeutic strategy for ischemic stroke.

A young female case of asymptomatic immune-mediated necrotizing myopathy: a potential diagnostic option of antibody testing for rhabdomyolysis.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) is a neuromuscular disorder that presents muscle weakness in proximal extremities and/or the trunk with an elevation of creatine kinase (CK). Young and asymptomatic anti-HMGCR IMNM patients are very rare and a treatment regimen has not been established. The present case, a 17-year-old woman without any muscular symptoms, only showed hyperCKemia that was detected by chance. After close examinations, including a muscle biopsy and antibody search, she was diagnosed as anti-HMGCR IMNM, and initial treatment with methotrexate and continuous intravenous immunoglobulin seemed to be effective. The present case is the unusually young asymptomatic case of anti-HMGCR IMNM. The diagnosis was successfully made, leading to the early introduction of a treatment. Given the course of this case, we believe that the preceding antibody testing is one of the diagnostic option for rhabdomyolysis.

Actual Telemedicine Needs of Japanese Patients with Neurological Disorders in the COVID-19 Pandemic.

Objective During the coronavirus disease 2019 (COVID-19) pandemic, many social activities have moved online using applications for digital devices (e.g. computers, smartphones). We investigated the needs of telemedicine and trends in medical status and social care situations of Japanese patients with neurological disorders in order to estimate their affinity for an online telemedicine application. Methods We designed an original questionnaire for the present study that asked participants what problems they had with hospital visits, how the COVID-19 pandemic had affected their lives, and whether or not they would like to receive telemedicine. Patients The present study included volunteer caregivers, participants with Parkinson's disease (PD), epilepsy, stroke, dementia, immune-mediated neurological disease (IMMD), spinocerebellar degeneration (SCD), amyotrophic lateral sclerosis (ALS), headache, myopathy, and other neurological diseases from Okayama University Hospital. Results A total of 29.6% of patients wanted to use telemedicine. Patients with headaches (60.0%) and epilepsy (38.1%) were more likely to want to use telemedicine than patients with PD (17.8%) or stroke (19.0%). Almost 90% of patients had access to a digital device, and there was no association between favoring telemedicine, ownership of a digital device, hospital visiting time, or waiting time at the hospital, although age was associated with motivation to telemedicine use (52.6 vs. 62.2 years old, p<0.001). Conclusion We can contribute to the management of the COVID-19 pandemic and the medical economy by promoting telemedicine, especially for young patients with headaches or epilepsy.

Tocovid Attenuated Oxidative Stress and Cognitive Decline by Inhibiting Amyloid-ß-Induced NOX2 Activation in Alzheimer's Disease Mice.

BACKGROUND: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer's disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. OBJECTIVE: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. METHODS: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aß-overexpressed transgenic AD mice model (APP23, n = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n = 9) was assessed. RESULTS: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aß deposition after 16 months. CONCLUSION: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment.

Clinical and Pathological Benefits of Scallop-Derived Plasmalogen in a Novel Mouse Model of Alzheimer's Disease with Chronic Cerebral Hypoperfusion.

BACKGROUND: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer's disease (AD) patients. OBJECTIVE: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20-30% among the dementia society, were still elusive. METHODS: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH. RESULTS: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-ß pathology, regulated neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M. CONCLUSION: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH.

Efficacy and safety of spot heating and ultrasound irradiation on in vitro and in vivo thrombolysis models.

The feasibility of transcranial sonothrombolysis has been demonstrated, although little is known about the relationships between thermal or mechanical mechanisms and thrombolytic outcomes. Therefore, the present study aims to reveal the effect and safety of temperature and ultrasound through in vitro and in vivo thrombolysis models. Artificial clots in microtubes were heated in a water bath or sonicated by ultrasound irradiation, and then clots weight decrease with rising temperature and sonication time was confirmed. In the in vitro thrombotic occlusion model, based on spot heating, clot volume was reduced and clots moved to the distal side, followed by recanalization of the occlusion. In the in vivo study, the common carotid artery of rats was exposed to a spot heater or to sonication. No brain infarct or brain blood barrier disruption was shown, but endothelial junctional dysintegrity and an inflammatory response in the carotid artery were detected. The present spot heating and ultrasound irradiation models seem to be effective for disintegrating clots in vitro, but the safety of the in vivo model was not fully supported by the data. However, the data indicates that a shorter time exposure could be less invasive than a longer exposure.

Protective Effect of Rivaroxaban Against Amyloid Pathology and Neuroinflammation Through Inhibiting PAR-1 and PAR-2 in Alzheimer's Disease Mice.

BACKGROUND: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer's disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. OBJECTIVE: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. METHODS: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. RESULTS: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-ß deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. CONCLUSION: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

Chronic Beneficial Effect of Makeup Therapy on Cognitive Function of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software.

BACKGROUND: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. OBJECTIVE: To evaluate the therapeutic effect of makeup therapy. METHODS: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n = 16) or skin care plus makeup therapy (makeup therapy group, n = 18) once every 2 weeks for 3 months were assessed. RESULTS: Three months of makeup therapy significantly improved the Mini-Mental State Examination (MMSE) score compared with control patients (*p < 0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression (*p < 0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r = 0.43, *p < 0.05). CONCLUSION: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software.

Retinal Amyloid Imaging for Screening Alzheimer's Disease.

BACKGROUND: Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer's disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. OBJECTIVE: To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. METHODS: To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. RESULTS: Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. CONCLUSION: The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.

Immediate Beneficial Effect of Makeup Therapy on Behavioral and Psychological Symptoms of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software.

BACKGROUND: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients. OBJECTIVE: To evaluate the immediate effect of makeup therapy on dementia patients. METHODS: Female nursing home residents with dementia received either only skin care treatment (control group, n = 17) or skin care plus makeup therapy treatment (makeup therapy group, n = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software. RESULTS: Makeup therapy significantly improved Abe's behavioral and psychological symptoms of dementia (BPSD) score (ABS, *p < 0.05). AI software judged that makeup therapy significantly made the apparent age younger (*p < 0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy (*p < 0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r = 0.42, *p < 0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy (*p < 0.05). CONCLUSION: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance.

Accelerated accumulation of fibrinogen peptide chains with Aß deposition in Alzheimer's disease (AD) mice and human AD brains.

Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by the abnormal accumulation of intracellular and extracellular amyloid-ß (Aß) as well as disruption of the blood brain barrier (BBB). Fibrinogen plays an essential role in regulating thrombosis, wound healing, and other biological functions. In the present study, we investigated the relationship between three polypeptide chains α, ß, and γ (FGA, FGB, and FGG) and Aß deposition in the APP23 plus chronic cerebral hypoperfusion (CCH) mice model as well as the human AD brain. FGA, FGB, and FGG accumulated when Aß was deposited in neural cells and cerebral vessels. This deposition was significantly higher in AD plus CCH mice models relative to wild-type brains, and in human AD brains compared to control brains. The present study demonstrates that FGA, FGB, and FGG are associated with AD progress, and can thus be potential targets for the diagnosis and therapy of AD.

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

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.

Switching the Proteolytic System from the Ubiquitin-Proteasome System to Autophagy in the Spinal Cord of an Amyotrophic Lateral Sclerosis Mouse Model.

The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.

Cerebral Microbleeds in Patients with Parkinson's Disease and Dementia with Lewy Bodies: Comparison Using Magnetic Resonance Imaging and 99 mTc-ECD SPECT Subtraction Imaging.

BACKGROUND: Cerebral microbleeds (CMBs) in patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. OBJECTIVE: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 mTc-ECD SPECT subtraction images of these two diseases. METHODS: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 mTc-ECD SPECT subtraction imaging. RESULTS: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7-17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. CONCLUSION: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.

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

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%).

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

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.