SSK1-Loaded Neurotransmitter-Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells.

Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging-associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti-AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by ß-gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of ß-gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1-loaded neurotransmitter -derived lipid nanoparticles are herein developed (SSK1-NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1-NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid-beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1-NPs, a novel nanomedicine displaying potent anti-AD activity and excellent safety profile, provides a promising strategy for AD therapy.

Memantine ameliorates cognitive deficit in AD mice via enhancement of entorhinal-CA1 projection.

BACKGROUND: Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve cognitive functions in animal models of Alzheimer's disease (AD). Here we treated APP/PS1 AD mice with a therapeutic dose of memantine (20 mg/kg/day) and examined its underlying mechanisms in ameliorating cognitive defects. METHODS: Using behavioral, electrophysiological, optogenetic and morphology approaches to explore how memantine delay the pathogenesis of AD. RESULTS: Memantine significantly improved the acquisition in Morris water maze (MWM) in APP/PS1 mice without affecting the speed of swimming. Furthermore, memantine enhanced EC to CA1 synaptic neurotransmission and promoted dendritic spine regeneration of EC neurons that projected to CA1. CONCLUSIONS: Our study reveals the underlying mechanism of memantine in the treatment of AD mice.

Purkinje cells of vestibulocerebellum play an important role in acute vestibular migraine.

Both the central and peripheral vestibular systems contribute to the pathogenesis of vestibular migraine, although the mechanism of vestibular migraine remains unclear. To assess central and peripheral vestibular system damage in vestibular migraine and explore the underlying mechanism we performed vestibular function tests, including a caloric test, spontaneous, gaze-evoked nystagmus and saccadic, pursuit and optokinetic eye movements to evaluate the involvement of the central and/or peripheral vestibular system in subjects with acute vestibular migraine episodes. It was found that both peripheral and central vestibular systems were damaged in vestibular migraine patients with the number of subjects with central deficits significantly larger than those with peripheral deficits. The cerebellum, especially the vestibule cerebellum, is the most important part of the central vestibular system. Locculus and paraflocculus are essential structures of cerebellar circuitry controlling vestibular nuclei and oculomotor functions and are anatomically linked with the "migraine pathway". Purkinje cells are the only source of cerebellar output and it innervates inhibitory action. Therefore, we examined the effect of the electric stimulation on paraflocculus Purkinje cells by using a specific electrical stimulation of trigeminal ganglia to induce a migraine-like phenomenon in animal part. Moreover, electrophysiological recordings showed that parafloccular Purkinje cells of rats underwent electrical stimulation of trigeminal ganglia resulted in partial inhibition. It is suggested that Purkinje cells in the paraflocculus could be inhibited after the occurrence of migraine episode and this inhibition may be an important factor leading to vestibular migraine.

Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances.

Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers.

[Management of bilateral benign paroxysmal positional vertigo with Dix-Hallpike test].

OBJECTIVE: To explore the diagnosis and treatment of benign paroxysmal positional vertigo (BPPV) with bilateral positive Dix-Hallpike test. METHODS: This is a retrospective study based on the clinical data of BPPV patients diagnosed in the Dizziness Clinic of Changzheng Hospital from January 2012 to December 2012. Totally 490 patients with vertigo and nystagmus provoked by Dix-Hallpike maneuver were included in the present analysis. RESULTS: Among all the patients, 55 (11.2%) of them presented with bilateral nystagmus by the provocative test. According to the type of nystagmus provoked by Dix-Hallpike maneuver, the 55 patients can be divided into the following four categories. (1) Bilateral geotropic (n = 16) and apogeotropic nystagmus (n = 5): all these patients were diagnosed with horizontal canal BPPV and free of vertigo after head side-shaking exercise in supine position and Barbecue maneuver. (2) Bilateral predominant down-beating nystagmus (n = 2): patients in this group were diagnosed with anterior canal BPPV, and got recovered after Kim maneuver. (3) Bilateral torsional up-beating geotropic nystagmus (n = 20): after a lying-down test, 6 of the patients manifested as vertical up-beating nystagmus and 14 patients remained torsional up-beating nystagmus. The former were diagnosed with bilateral posterior canal BPPV, and were cured after bilateral PRM therapy, and the latter were diagnosed with horizontal canal BPPV, who were cured after Barbecue maneuver. (4) Torsional up-beating geotropic nystagmus on one side and down-beating nystagmus on the other side (n = 12). The down-beating nystagmus on the other side disappeared when the patients was firstly seated up with head down in 30 degrees for half an hour before second Dix-Hallpike maneuver. These patients were diagnosed with unilateral posterior canal BPPV and cured by PRM therapy. CONCLUSIONS: It is common for vertigo patients with bilateral nystagmus induced by Dix-Hallpike test. The diagnoses should be made by the types of nystagmus provoked step by step before maneuver therapy.

A rare case report of bilateral vestibulopathy due to otosyphilis.

RATIONALE: Bilateral vestibulopathy is an important cause of imbalance. There are multiple etiologies of bilateral vestibulopathy (BVP), but reports of BVP due to otosyphilis are rare. PATIENT CONCERNS: A 39-year-old male was referred to our medical center due to vertigo, persistent dizziness and gait disturbance for 2 months. DIAGNOSES: Bilateral vestibulopathy due to otosyphilis was considered in this case, as confirmed through analyses of vestibular function, laboratory tests, and penicillin treatment. INTERVENTIONS: The patient was was treated with a high dose of penicillin G (24 × 106 IU/d) for 14 days. OUTCOMES: The patient's symptoms had improved greatly following treatment, with dizziness and gait disturbance having completely resolved at 3 months following hospital discharge. LESSONS: Bilateral vestibulopathy should be considered when evaluating patients with acute or subacute persistent dizziness. Clinicians should also be aware of the potential for otosyphilis among patients who report BVP.

Exploring the Occurrence Mechanism and Early-Warning Model of Phlebitis Induced by Aescinate Based on Metabolomics in Cerebral Infarction Patients.

Objective: This study aims to explore the mechanism underlying the induction of phlebitis by aescinate and create an early-warning model of phlebitis based on metabolomics. Methods: Patients with cerebral infarction enrolled had been treated with aescinate. Plasma samples were collected either before administration of aescinate, upon the occurrence of phlebitis, or at the end of treatment. Non-targeted metabolomics and targeted amino acid metabolomics were carried out to analyze metabolic profiles and quantify the metabolites. Results: Untargeted metabolomics revealed six differential metabolites in baseline samples versus post-treatment samples and four differential metabolites in baseline samples from patients with or without phlebitis. Pathways of these differential metabolites were mainly enriched in amino acid metabolism. Ten differential amino acids with a VIP value of >1 were identified in the baseline samples, enabling us to distinguish between patients with or without phlebitis. A logistic regression model was constructed (AUC 0.825) for early warning of phlebitis of grade 2 or higher. Conclusion: The occurrence of aescinate-induced phlebitis, which can be predicted early during onset, may be associated with perturbations of the endogenous metabolic profile, especially the metabolism of amino acids.

Systemic Administration of Neurotransmitter-Derived Lipidoids-PROTACs-DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis-targeting chimera (PROTAC), a novel protein-degradation technique that mediates degradation of target proteins via the ubiquitin-proteasome system, and a neurotransmitter-derived lipidoid (NT-lipidoid) nanoparticle delivery system with high blood-brain barrier-penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau-targeting PROTAC is loaded onto the positively charged nanoparticles using DNA-intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood-brain barrier-penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.

Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease.

With the increase of population aging, the number of Alzheimer's disease (AD) patients is also increasing. According to current estimates, approximately 11% of people over 65 suffer from AD, and that percentage rises to 42% among people over 85. However, no effective treatment capable of decelerating or stopping AD progression is available. Furthermore, AD-targeted drugs composed of synthetic molecules pose concerns regarding biodegradation, clearance, immune response, and neurotoxicity. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are essential intercellular communication mediators holding great promise as AD therapeutics owing to their biocompatibility, versatility, effortless storage, superior safety, and the ability to transport messenger and noncoding RNAs, proteins, lipids, DNAs, and other bioactive compounds derived from cells. The functionalisation and engineering strategies of MSC-EVs are highlighted (e.g. preconditioning, drug loading, surface modification, and artificial EV fabrication), which could improve AD treatment by multiple therapeutic effects, including clearing abnormal protein accumulation and achieving neuroprotection and immunomodulatory effects. Herein, this review summarises state-of-the-art strategies to engineer MSC-EVs, discusses progress in their use as AD therapeutics, presents the perspectives and challenges associated with the related clinical applications, and concludes that engineered MSC-EVs show immense potential in AD therapy.

Optimizing vestibular neuritis management with modular strategies.

Objective: This study proposes a "modular management" approach for vestibular neuritis (VN) to reduce chronicization and improve patient prognosis. The approach involves multi-factor grading and hierarchical intervention and was found to be more effective than traditional treatment strategies. Methods: This retrospective analysis compared two groups of VN patients from two medical institutions. The intervention group of 52 patients received "modular management," while the control group of 51 patients did not receive this kind of management. Analyzed the early treatment strategies, 6-month prognosis, and other indicators of the two groups of patients, compared and analyzed their overall prognosis, and identified the risk factors affecting the chronicization. Results: The modular management group had lower dizziness severity, better balance, lower anxiety, and higher video head impulse testing (v-HIT) gain after 6 months of onset. Analysis of factors related to persistent postural-perceptual dizziness (PPPD) in patients with VN showed positive correlations between the time from onset to diagnosis and PPPD, and Vertigo Symptom Scale (VSS), Dizziness Handicap Inventory (DHI), anxiety, and depression. Normalized vestibular rehabilitation was negatively correlated with PPPD, while gender, age, and early steroid use had no significant correlation. The multi-factor logistic regression model correctly classified 93.20% of the study subjects with a sensitivity of 87.50% and specificity of 94.90%. Conclusion: The proposed "modular management" scheme for VN is a comprehensive and dynamic approach that includes health education, assessment, rehabilitation, therapy, evaluation, and prevention. It can significantly improve patient prognosis and reduce chronicization by shifting from simple acute treatment to continuous management.

Cell primitive-based biomimetic nanomaterials for Alzheimer's disease targeting and therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is not just confined to the older population. Although developments have been made in AD treatment, various limitations remain to be addressed. These are partly contributed by biological hurdles, such as the blood-brain barrier and peripheral side effects, as well as by lack of carriers that can efficiently deliver the therapeutics to the brain while preserving their therapeutic efficacy. The increasing AD prevalence and the unavailability of effective treatments have encouraged researchers to develop improved, convenient, and affordable therapies. Functional materials based on primitive cells and nanotechnology are emerging as attractive therapeutics in AD treatment. Cell primitives possess distinct biological functions, including long-term circulation, lesion site targeting, and immune suppression. This review summarizes the challenges in the delivery of AD drugs and recent advances in cell primitive-based materials for AD treatment. Various cell primitives, such as cells, extracellular vesicles, and cell membranes, are presented together with their distinctive biological functions and construction strategies. Moreover, future research directions are discussed on the basis of foreseeable challenges and perspectives.

Sleep Parameters and Plasma Biomarkers for Cognitive Impairment Evaluation in Patients With Cerebral Small Vessel Disease.

OBJECTIVES: Cognitive impairment caused by cerebrovascular disease accounts for more than half of vascular dementia. However, neuropsychological tests are limited by their subjectivity. Additional effective approaches to evaluate cognitive impairment in patients with cerebrovascular disease are necessary. METHOD: One hundred and thirty-two patients with cerebrovascular disease were recruited. One hundred participants met the criteria and completed neuropsychological scales. Sixty-nine participants proceeded with polysomnography, and 63 of them had their peripheral blood biomarkers measured. According to Mini-Mental State Examination scores, patients were divided into cognitively impaired and cognitively normal groups. The differences in biomarkers and sleep parameters between the groups were compared, and decision tree models were constructed to evaluate the evaluation ability of these indicators on cognitive decline. RESULTS: The integrated decision tree model of sleep parameters yielded an area under curve (AUC) of 0.952 (95% confidence interval [CI]: 0.911-0.993), while that of plasma biomarkers yielded an AUC of 0.872 (95% CI: 0.810-0.935) in the assessment of cognition status. Then the participants were automatically clustered into mild and severe cognitive impairment groups by multiple neuropsychological test results. The integrated plasma biomarker model showed an AUC of 0.928 (95% CI: 0.88-0.977), and the integrated sleep parameter model showed an AUC of 0.851 (95% CI: 0.783-0.919) in the assessment of mild/severe cognitive impairment. DISCUSSION: Integrated models which consist of sleep parameters and plasma biomarkers can accurately evaluate dementia status and cognitive impairment in patients with cerebral small vessel disease. This innovative study may facilitate drug development, early screening, clinical diagnosis, and prognosis evaluation of the disease.

Effect of the Shanghai Stroke Service System (4S) on the quality of stroke care and outcomes: A prospective quality improvement project.

BACKGROUND: In China, disparities in the quality of stroke care still exist and implementing quality improvement is still a challenge. AIM: The aim of the study was to determine whether the intervention by Shanghai Stroke Service System (4S) has helped improve adherence to stroke care guidelines and patient outcome. METHODS: The 4S is a regional stroke network with real-time data extraction among its 61 stroke centers in Shanghai. A total of 11 key performance indicators (KPIs) were evaluated. The primary outcomes were a composite measure and an all-or-none measure of adherence to 11 KPIs. The secondary outcomes were length of hospital stay and in-hospital mortality. RESULTS: The study enrolled 92,395 patients (mean age 69.0 ± 12.5 years, 65.2% men) with acute ischemic stroke hospitalized within 7 days of onset in Shanghai from January 2015 to December 2020. More patients received guideline recommended care between 2018 and 2020 than those between 2015 and 2017 (composite measure 87.1% vs 83.6%; absolute difference 2.9%, 95% confidence interval (CI) = [2.7%, 3.2%], p < 0.001; all-or-none measure 49.2% vs 44.8% patients; absolute difference 3.5%, 95% CI = [2.7%, 4.2%], p < 0.001). Further analysis of individual KPIs showed an absolute increase in six KPIs ranging from 3.4% to 8.9% (p < 0.001 for all comparisons). Compared with 2015-2017, hospital length of stay was shorter (10.95 vs 11.90 days; absolute difference -1.08, 95% CI = [-1.18, -0.99], p < 0.001), and in-hospital mortality was significantly reduced (risk ratio (RR) = 0.88, 95% CI = [0.79, 0.98], p = 0.01) in 2018-2020. CONCLUSION: The 4S intervention was associated with increased adherence to the stroke care guidelines, which further translated to improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02735226.

[Analysis of misdiagnosed cases with benign paroxysmal positional vertigo].

OBJECTIVE: To analyze the misdiagnosed cases with benign paroxysmal positional vertigo (BPPV). METHODS: During October 2010 to January 2011, a total of 287 patients with dizziness visited the Dizziness Clinic at Changzheng Hospital, Second Military Medical University. Forty-eight misdiagnosed cases with BPPV were collected and their clinical data were analyzed. All 48 cases were diagnosed by the Dix-Hallpike or Roll test maneuver. RESULTS: (1) CLINICAL FEATURES: there were 38 females and 10 males with an average age of 54 ± 12 years old (range: 31 - 87). Posterior semicircular canal was involved in 75.0% (36/48) whereas the horizontal semicircular and multiple canals in 20.8% (10/48) and 4.2% (2/48) respectively. All patients were treated successfully. And 41 cases (85.4%) were cured on the first visiting day. Recurrences of BPPV occurred in 6 cases during the follow-up. (2) The initial visiting departments consisted of the department of general internal medicine 43.8% (21/48), department of neurology 27.1% (13/48), department of osteology 18.7% (9/48), ear, nose & throat (ENT) department 2.1% (1/48) and other departments 8.3% (4/48). In addition, 68.7% (33/48) of them frequented the general out-patient clinics during their initial visits and the other 31.3% (15/48) used the emergency services. (3) The initial diagnoses included vertebrobasilar insufficiency/cerebral circulation insufficiency 27.1% (13/48), cervical spondylosis 27.1% (13/48), cerebral infarction 4.2% (2/48), Meniere's disease 2.1% (1/48) and others 10.4% (5/48); Besides, 29.1% (14/48) of them had no diagnosis. (4) The average clinic visits per patient were 3.4 times (164 visits/48 cases). (5) The most commonly performed tests included brain computed tomography (CT) (28 person-times), cervical magnetic resonance imaging (MRI) (19 person-times), brain MRI (18 person-times), cervical radiography (18 person-times) and cervical CT (8 person-times). CONCLUSION: In these misdiagnosed cases of BPPV, most of them were middle-aged women. They were most likely to have their first consultations in the departments of general internal medicine and neurology. Therefore these two departments should pay more attention to applying the maneuver of Dix-Hallpike or Roll test so as to reduce the misdiagnosis of BPPV and the waste of healthcare resources.

Caregiver burden and its associated factors among family caregivers of persons with dementia in Shanghai, China: a cross-sectional study.

OBJECTIVE: To assess the level of caregiver burden and factors associated with it among family caregivers of persons with dementia (PWD) living in communities of Shanghai, China. DESIGN: Cross-sectional study. SETTING: Communities in Hongkou District of Shanghai, China. PARTICIPANTS: A random sample of 109 older adults with dementia and their primary family caregivers. MAIN OUTCOME MEASURE: Caregiver burden measured by the Caregiver Burden Inventory (CBI), and the Caregivers' depressive symptom measured by the simplified Chinese version of Self-rating Depression Scale was the outcome variable of the study. The independent variables, including the cognitive function (measured by Montreal Cognitive Assessment (MoCA), sleep quality assessed by the Pittsburgh Sleep Quality Index, abilities of daily life assessed by the Activities of Daily Living Scale, and behavioural and psychological symptoms assessed by the Neuropsychiatric Inventory of PWDs, the community service utilisation (measured by the Community Service Utilisation Measurement), perceived social support (assessed by three questions), positive aspects of caregiving (PAC) (assessed by the PAC) of dementia caregivers, were analysed. Multivariate linear regression was employed to determine the factors related to caregiver burden. RESULTS: The average level of CBI was 65.92±16.74. The score of MoCA, PAC and perceived social support of caregivers were negatively associated with caregiver burden (ß=-0.84, p<0.001, ß=-3.61, p=0.03 and ß=-1.22, p=0.001, respectively). Community service utilisation was positively associated (ß=3.46, p<0.001) with caregiver burden. Perceived social support by the caregiver moderated the relationship between caregiver burden and caregivers' depression symptoms. CONCLUSION: Dementia caregivers experienced a high level of caregiver burden. The cognitive function of PWD, PAC, social support and community service utilisation were factors associated with caregiver burden. Strengthening social support, providing more high-quality home care services, promoting PAC are imperative to reduce caregiver burden.

Recent Advancements in Strategies for Abnormal Protein Clearance in Alzheimer's Disease.

Alzheimer's disease (AD) is an intricate neurodegenerative disease with chronic and progressive development whose typical neuropathological features encompass senile plaques and neurofibrillary tangles, respectively formed by the extracellular deposition of amyloid-beta (Aß) and the intracellular accumulation of hyperphosphorylated tau protein in the brain, particularly in limbic and cortical regions. The pathological changes are considered to be caused by the loss of Aß and tau protein clearance mechanisms under pathological conditions, which leads to an imbalance between the rates of clearance and production. Consequently, the main strategies for treating AD aim to reduce the production of Aß and hyperphosphorylated tau protein in the brain, inhibit their accumulation, or accelerate their clearance. Although drugs utilizing these therapeutic strategies have been studied successively, their therapeutic effects have generally been less than ideal. Fortunately, recent advances have been made in clearance strategies for these abnormally expressed proteins, including immunotherapies and nanomedicines targeting Aß or tau, which could represent an important breakthrough for treating AD. Here, we review recent development of the strategies for the removal of abnormal proteins and provide new ideas and methods for treating AD.

WNK3-PER1 interactions regulate the circadian rhythm in the suprachiasmatic nucleus in rats.

PER1 is a core component of the internal time-keeping system. In the suprachiasmatic nucleus, it serves as the primary circadian pacemaker in mammalian brains. PER1 functions with other clock components to generate a feedback loop involving the transcriptional repression of gene expression to produce a circadian rhythm with an approximately 24-hour cycle. Post-transcriptional modifications (PTMs) are a basic regulatory mechanism that both perpetuate self-sustained oscillations and interpret metabolic input into circadian physiology by affecting factors such as protein stability, interactions, localization, and activity. Here we examined whether the serine/threonine protein kinase WNK3, which is expressed in a circadian rhythm, can interact and colocalize with PER1 in the SCN. In rats, WNK3 knockdown in the SCN is associated with altered sleep patterns. Moreover, WNK3 can phosphorylate PER1 to promote its degradation and is associated with circadian oscillations when PER1 is expressed in vitro.

Nanoparticles-based anti-aging treatment of Alzheimer's disease.

Age is the strongest risk factor for Alzheimer's disease (AD). In recent years, the relationship between aging and AD has been widely studied, with anti-aging therapeutics as the treatment for AD being one of the mainstream research directions. Therapeutics targeting senescent cells have shown improvement in AD symptoms and cerebral pathological changes, suggesting that anti-aging strategies may be a promising alternative for AD treatment. Nanoparticles represent an excellent approach for efficiently crossing the blood-brain barrier (BBB) to achieve better curative function and fewer side effects. Thereby, nanoparticles-based anti-aging treatment may exert potent anti-AD therapeutic efficacy. This review discusses the relationship between aging and AD and the application and prospect of anti-aging strategies and nanoparticle-based therapeutics in treating AD.

Molecular Mediators of Estrogen Reduction-induced Otolith Shedding.

OBJECTIVE: Previous study suggested that estradiol (E2) plays an important role in otolith shedding by regulating the expression of otoconin 90 (OC90). The purpose of this article is to provide further data on the effect and mechanism of E2 on the morphology of otolith. METHODS: The rats receiving bilateral ovariectomy (OVX) were used as animal models. Co-immunoprecipitation was used to observe the relationship between estrogen receptor (ER) and estrogen-related receptor α (ERRα). The morphology of otolith was observed under the scanning electron microscopy. Western blotting and qPCR were used for quantitative analysis of the roles of ER and ERRα in regulating OC90 expression. RESULTS: The looser otoliths were observed in rats receiving bilateral OVX, which could be reversed by supplementation with E2. The level of ERRα was decreased in bilateral OVX rats. ER and ERRα interacted with each other on the regulation of the expression of OC90. CONCLUSION: Our results suggest ER and ERRα are both important downstream receptors involved in regulating OC90 expression in utricles of rats, and ERRα probably functions by interacting with ER. This provides evidence for the mechanism of otolith shedding. And it may be significant for future studies of targeted prevention and therapies for benign paroxysmal positional vertigo.

[The efficacy of topiramate and flunarizine hydrochloride for prophylactic treatment of vestibular migraine].

Objective:To evaluate the efficacy and safety of topiramate and flunarizine hydrochloride in the prophylactic treatment of vestibular migraine prophylaxis. Methods:47 patients with confirmed or probable vestibular migraine（VM） treated at the vertigo clinic of our neurology department from August 2020 to April 2021 were reviewed, and 42 patients were finally included. They were divided into topiramate group （n=22） and flunarizine hydrochloride group （n=20）. The two groups were treated with topiramate 50 mg daily and flunarizine hydrochloride 10 mg daily, respectively. The visual analogue scale, vertigo duration, vertigo frequency, and Dizziness Handicap Inventory （DHI） scores of patients with VM before and 3 months after treatment were compared. The anxiety screening scale （GAD-7） and depression screening scale （PHQ-9） were recorded to assess the improvement of patients' anxiety and depression, and the occurrence of adverse events. Results:Topiramate and flunarizine hydrochloride effectively reduced vertigo intensity, vertigo duration, and vertigo frequency in VM patients （P<0.05）. Meanwhile, total DHI score, DHI physical （DHI-P）, DHI emotional （DHI-E）, DHI functional （DHI-F）, PHQ-9 and GAD-7 were significantly decreased（P<0.05）. Furthermore, topiramate was superior to flunarizine hydrochloride in reducing vertigo intensity, vertigo duration, vertigo frequency, DHI-P, and DHI-F, while there was no significant difference between two drugs in improving patients' mood（P>0.05）. No serious adverse events were reported in either group. Conclusion:This study suggests that topiramate and flunarizine hydrochloride are safe and effective in the prevention of VM, and the daily dose of topiramate 50 mg is superior to the daily dose of flunarizine hydrochloride 10 mg. However, there was no significant difference between the two drugs in terms of mood improvement.