Increased retinal venule diameter as a prognostic indicator for recurrent cerebrovascular events:a prospective observational study

Microvasculature of the retina is considered an alternative marker of cerebral vascular risk in healthy populations.However,the ability of retinal vasculature changes,specifically focusing on retinal vessel diameter,to predict the recurrence of cerebrovascular events in patients with ischemic stroke has not been determined comprehensively.While previous studies have shown a link between retinal vessel diameter and recurrent cerebrovascular events,they have not incorporated this information into a predictive model.Therefore,this study aimed to investigate the relationship between retinal vessel diameter and subsequent cerebrovascular events in patients with acute ischemic stroke.Additionally,we sought to establish a predictive model by combining retinal veessel diameter with traditional risk factors.We performed a prospective observational study of 141 patients with acute ischemic stroke who were admitted to the First Affiliated Hospital of Jinan University.All of these patients underwent digital retinal imaging within 72 hours of admission and were followed up for 3 years.We found that,after adjusting for related risk factors,patients with acute ischemic stroke with mean arteriolar diameter within 0.5-1.0 disc diameters of the disc margin(MAD_(0.5-1.0DD))of≥74.14μm and mean venular diameter within 0.5-1.0 disc diameters of the disc margin(MVD_(0.5-1.0DD))of≥83.91μm tended to experience recurrent cerebrovascular events.We established three multivariate Cox proportional hazard regression models:model 1 included traditional risk factors,model 2 added MAD_(0.5-1.0DD)to model 1,and model 3 added MVD0.5-1.0DD to model 1.Model 3 had the greatest potential to predict subsequent cerebrovascular events,followed by model 2,and finally model 1.These findings indicate that combining retinal venular or arteriolar diameter with traditional risk factors could improve the prediction of recurrent cerebrovascular events in patients with acute ischemic stroke,and that retinal imaging could be a useful and non-invasive method for identifying high-risk patients who require closer monitoring and more aggressive management.

Insight into endoplasmic reticulum-mitochondria contacts in human amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS) is a fastprogressing fatal neurodegenerative disease and the most common form of motor neuron disease.There is currently no cure and approximately 90% of cases are sporadic.ALS shares genetic causes,clinical and neuropathological features with frontotemporal dementia,the second most common form of presenile dementia.ALS and frontotemporal dementia are therefore considered a disease spectrum(Abramzon et al.,2020).

Synaptopathy in CHMP2B frontotemporal dementia highlights the synaptic vesicle cycle as a therapeutic target

Amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD)are both devastating neurodegenerative conditions.Despite affecting different regions of the nervous system(FTD affecting primarily the frontal and temporal lobes,whilst ALS presents with motor neuron loss),there is significant overlap between these conditions in terms of genetics,pathology,and disease mechanisms,and they are therefore often grouped as a spectrum of symptoms under the heading FTD/ALS(Abramzon et al.,2020).Significantly,there is currently no cure for ALS or FTD.However,recent mechanistic insight points to a novel pathway to target for potential therapeutic intervention.

Alexander disease:the road ahead

Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.

Deep learning-based activity recognition and fine motor identification using 2D skeletons of cynomolgus monkeys

Video-based action recognition is becoming a vital tool in clinical research and neuroscientific study for disorder detection and prediction.However,action recognition currently used in non-human primate(NHP)research relies heavily on intense manual labor and lacks standardized assessment.In this work,we established two standard benchmark datasets of NHPs in the laboratory:Monkeyin Lab(Mi L),which includes 13 categories of actions and postures,and MiL2D,which includes sequences of two-dimensional(2D)skeleton features.Furthermore,based on recent methodological advances in deep learning and skeleton visualization,we introduced the Monkey Monitor Kit(Mon Kit)toolbox for automatic action recognition,posture estimation,and identification of fine motor activity in monkeys.Using the datasets and Mon Kit,we evaluated the daily behaviors of wild-type cynomolgus monkeys within their home cages and experimental environments and compared these observations with the behaviors exhibited by cynomolgus monkeys possessing mutations in the MECP2 gene as a disease model of Rett syndrome(RTT).Mon Kit was used to assess motor function,stereotyped behaviors,and depressive phenotypes,with the outcomes compared with human manual detection.Mon Kit established consistent criteria for identifying behavior in NHPs with high accuracy and efficiency,thus providing a novel and comprehensive tool for assessing phenotypic behavior in monkeys.

Hemodynamic investigations in intracranial aneurysms:a commentary

Intracranial aneurysms(IAs)are abnormal bulges in a blood vessel in the brain that have a potential to rupture and even causing a stroke,which can lead to lasting brain damage,long-term disability,or even loss of life.It has been widely acknowledged that hemodynamic factors,e.g.,instantaneous wall shear stress,time-averaged wall shear stress,wall shear stress gradient,gradient oscillatory number,oscillatory shear index,pulsatile blood flow waveform(flow rate magnitude and shape,physical flow period),relative residence time/turnover time,blood pressure.

The emerging role of autophagic-lysosomal dysfunction in Gaucher disease and Parkinson's disease

Gaucher disease(GD),the commonest lysosomal storage disorder,results from the lack or functional deficiency of glucocerebrosidase(GCase) secondary to mutations in the GBA1 gene.There is an established association between GBA1 mutations and Parkinson's disease(PD),and indeed GBA1 mutations are now considered to be the greatest genetic risk factor for PD.Impaired lysosomal-autophagic degradation of cellular proteins,including α-synuclein(α-syn),is implicated in the pathogenesis of PD,and there is increasing evidence for this also in GD and GBA1-PD.Indeed we have recently shown in a Drosophila model lacking neuronal GCase,that there are clear lysosomal-autophagic defects in association with synaptic loss and neurodegeneration.In addition,we demonstrated alterations in mechanistic target of rapamycin complex 1(mTORC1) signaling and functional rescue of the lifespan,locomotor defects and hypersensitivity to oxidative stress on treatment of GCase-deficient flies with the mT OR inhibitor rapamycin.Moreover,a number of other recent studies have shown autophagy-lysosomal system(ALS) dysfunction,with specific defects in both chaperone-mediated autophagy(CMA),as well as macroautophagy,in GD and GBA1-PD model systems.Lastly we discuss the possible therapeutic benefits of inhibiting mT OR using drugs such as rapamycin to reverse the autophagy defects in GD and PD.

Brain delivering RNA-based therapeutic strategies by targeting mTOR pathway for axon regeneration after central nervous system injury

Injuries to the central nervous system(CNS)such as stroke,brain,and spinal cord trauma often result in permanent disabilities because adult CNS neurons only exhibit limited axon regeneration.The brain has a surprising intrinsic capability of recovering itself after injury.However,the hostile extrinsic microenvironment significantly hinders axon regeneration.Recent advances have indicated that the inactivation of intrinsic regenerative pathways plays a pivotal role in the failure of most adult CNS neuronal regeneration.Particularly,substantial evidence has convincingly demonstrated that the mechanistic target of rapamycin(mTOR)signaling is one of the most crucial intrinsic regenerative pathways that drive axonal regeneration and sprouting in various CNS injuries.In this review,we will discuss the recent findings and highlight the critical roles of mTOR pathway in axon regeneration in different types of CNS injury.Importantly,we will demonstrate that the reactivation of this regenerative pathway can be achieved by blocking the key mTOR signaling components such as phosphatase and tensin homolog(PTEN).Given that multiple mTOR signaling components are endogenous inhibitory factors of this pathway,we will discuss the promising potential of RNA-based therapeutics which are particularly suitable for this purpose,and the fact that they have attracted substantial attention recently after the success of coronavirus disease 2019 vaccination.To specifically tackle the blood-brain barrier issue,we will review the current technology to deliver these RNA therapeutics into the brain with a focus on nanoparticle technology.We will propose the clinical application of these RNA-mediated therapies in combination with the brain-targeted drug delivery approach against mTOR signaling components as an effective and feasible therapeutic strategy aiming to enhance axonal regeneration for functional recovery after CNS injury.

FUS-mediated HypEVs: Neuroprotective effects against ischemic stroke

Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sEVs in the onset and progression of ischemic stroke remains an unresolved question. Our study systematically identified the characteristics of sEVs derived from neurons under hypoxic conditions (HypEVs) by physical characterization, sEV absorption, proteomics and transcriptomics analysis. The effects of HypEVs on neurites, cell survival, and neuron structure were assessed in vitro and in vivo by neural complexity tests, magnetic resonance imaging (MRI), Golgi staining, and Western blotting of synaptic plasticity-related proteins and apoptotic proteins. Knockdown of Fused in Sarcoma (FUS) small interfering RNA (siRNA) was used to validate FUS-mediated HypEV neuroprotection and mitochondrial mRNA release. Hypoxia promoted the secretion of sEVs, and HypEVs were more easily taken up and utilized by recipient cells. The MRI results illustrated that the cerebral infarction volume was reduced by 45% with the application of HypEVs, in comparison to the non- HypEV treatment group. Mechanistically, the FUS protein is necessary for the uptake and neuroprotection of HypEVs against ischemic stroke as well as carrying a large amount of mitochondrial mRNA in HypEVs. However, FUS knockdown attenuated the neuroprotective rescue capabilities of HypEVs. Our comprehensive dataset clearly illustrates that FUS-mediated HypEVs deliver exceptional neuroprotective effects against ischemic stroke, primarily through the maintenance of neurite integrity and the reduction of mitochondria-associated apoptosis.

Management Recommendations on Sleep Disturbance o Patients with Parkinson's Disease

INTRODUCTION Sleep disturbance is one of the most common nonmotor symptoms in Parkinson's disease (PD).Sleep disturbance affects 40-98% of PD patients in the world. In China, the prevalence of PD patients with sleep disturbance ranges from 47.66% to 89.10%. Sleep disturbance usually has adverse impact on the quality of life of PD patients. Apossible pathogenesis of PD with sleep disturbance include thalamocortical pathway degeneration and changes of neurotransmitter systems. The etiology of sleep disturbance is multifactorial,involving degeneration of areas regulating sleep,sleep structure affected by drugs,sleep disturbance induced by drug,and sleep fragmentation by multiple factors.

布美他尼治疗3至6岁孤独症谱系障碍儿童后症状改善:一项随机、双盲、安慰剂对照的临床试验

孤独症谱系障碍是一大类婴幼儿期起病、以社交沟通和感知觉障碍为主要特征的神经发育障碍性疾病.目前治疗以康复为主,无有效药物.本研究采用随机、双盲、安慰剂对照临床试验策略,探索布美他尼干预对低龄孤独症患儿的疗效、安全性及潜在的神经生物学机制.研究结果显示,与安慰剂对照组相比,为期3个月的布美他尼药物干预可安全、有效改善低龄孤独症患儿核心症状,药效可能与其调节岛叶皮层GABA功能有关.本研究为目前国际上单站点最大样本量的随机双盲临床试验,研究结果为低龄孤独症患儿提供了潜在的药物治疗方案.

Adult neurogenesis and pattern separation in rodents： A critical evaluation of data, tasks and interpretation

当在存储器的不同代表被认为依靠进程，区别并且存储类似的输入的能力在马头鱼尾的怪兽的有牙齿的回转叫了模式分离。最近的计算、实验的调查结果支持为在空间模式分离的成年人出生的小粒神经原的一个角色。我们考察了操作了两海马趾的成年神经发生并且估计了模式分离的啮齿类动物研究。研究的多数在在行为的水平测量了的模式分离报导成年出生的神经原的一个配角。然而，出版调查结果的更靠近的评估在两项模式分离任务并且在行为的性能的解释揭示变化，一起拿，建议在模式分离的海马趾的成年神经发生的角色可以是比的建立的更少当前被假定。对在通过立即的早基因表示的使用的网络水平的模式分离的评价， optogenetic， pharmacogenetic 或在 vivo electrophysiology，研究能在进一步进一步在模式分离证实成年出生的神经原的一个角色是有帮助的。最后，海马趾的成年神经发生和模式分离不是独占的对，作为为贡献在记忆的事件的时间的分离的海马趾的成年神经发生的证据，忘记，认知灵活性也被发现了。我们断定而为在模式分离的海马趾的成年神经发生的参与的当前的实验证据似乎支持，对行为的调查结果的小心的解释和成年出生的神经原的各种各样的建议功能的集成有需要。

Computational fluid dynamics simulation of intracranial aneurysms-comparing size and shape

Objective:To study the hemodynamics of an anatomic internal carotid artery aneurysm derived from a patient-specific model and then manipulate into two phantom morphologies:one growing uniformly by size and the other changing shape unevenly.Methods:The computational model of the saccular,internal carotid artery,aneurysm was constructed from 3D rotational,digitally subtracted,catheter angiography images.Computational fluid dynamics simulations were performed under pulsatile cardiac flow conditions.Velocity vectors,streamlines,pressure,and wall shear stress(WSS)and its variance distributions were quantitatively visualized.Results:The maximum pressure and WSS from the time-averaged distribution on the inside saccular surface of the original case are 415.38 and 17.61 Pa.In contrast,the bi-lobed shape gives rise to higher peak values of pressure(461.00 Pa)and WSS(33.20 Pa)on the saccular dome.Conversely,the evenly enlarged aneurysm actually results in a slightly lower peak pressure(399.58 Pa)and drastically decreased WSS(9.81 Pa).Conclusions:The current study indicates that the size of the aneurysm should not be the only determining factor for the rupture risk consideration,the irregularity of the aneurysm shape and the corresponding aberrant hemodynamics might be a more important factor to consider for risk assessment.

Catquest-9SF functioning over a decade–a study from the Swedish National Cataract Register

Background:The Swedish National Cataract Register(NCR)collects data on cataract surgery outcomes during March,including patient-reported outcomes using the Catquest-9SF questionnaire for over 11 years.Previous studies from NCR have shown that the preoperative visual acuity has improved over time.The main purpose of this study was to evaluate the Catquest-9SF Rasch scoring performance in this changing environment.A second purpose was to describe clinical data over the same period for those who completed the questionnaire.Methods:The performance of the Catquest-9SF was analysed by a separate Rasch analysis for each year,resulting in a preoperative and postoperative score for each participating patient in the annual cohorts.The clinical data and questionnaire scoring were analysed for each year in the period 2008-2018 inclusive.Results:Data were available for 42,023 eyes for 11 annual cohorts(2008-2018).The psychometric properties of the questionnaire were stable during the study period.Person separation(precision)for the whole period was 2.58 and varied between 2.45 and 2.72.The person reliability was 0.87 and varied between 0.86 and 0.88.The targeting of question difficulty to person ability became less accurate over time meaning that the item activities became easier to carry out without difficulty.The average targeting for the whole period was−2.06 and changed from−1.92 in 2008 to−2.31 in 2018.The person score improved both before surgery and after surgery,indicating that patients are undergoing surgery at a more able level and getting better outcomes.The average improvement by surgery decreased from 3.41 logits in 2008 to 3.21 logits in 2018(p=0.003).Over time,patient age decreased from 75 to 74 years(p<0.001)and the proportion of women decreased from 63.9 to 57.9%(p<0.001).The mean preoperative visual acuity in both the operated eye and the better eye improved over time(0.47 to 0.40 logMAR,p<0.001 and 0.22 to 0.19 logMAR,p<0.001,respectively),as did the mean postoperative visual acuity in the operated eye(0.14 to 0.09 logMAR,p<0.001).Conclusions:The Catquest-9SF retained stable psychometric properties over this 11-year period although more recent cohorts included slightly younger patients with somewhat better vision.

Neurocognition in stimulant addiction: commentary on Kendrick et al (2021)

It would be easy to assume that that abusing stimulant drugs such as amphetamine,MDMA(‘Ecstasy’),and cocaine deleteriously impacts the brain and cognitive function.However,logically it could be the case that any neurobehavioural changes seen in drug abusers might have antedated drug taking,and so have been initially latent.An important issue is then to decide whether such changes might have been predisposing or causal factors for drug taking.They might even be considered as possible intermediate phenotypes or endophenotypes according to Gottesman’s original concept(Gottesman and Goulds,2003)—suggestive of possible constitutional or genetic factors leading to addiction.Such a hypothesis is commonly addressed by following the first degree relatives of the drug abuser to determine whether the neurobehavioural changes are also present in them.Of course,any such change might also be attributable to other familial factors,for example,the common environment,including possible stressful factors that may also contribute to neurobehavioural changes.

Why do‘OFF’periods still occur during continuous drug delivery in Parkinson’s disease?

Continuous drug delivery(CDD)is used in moderately advanced and late-stage Parkinson’s disease(PD)to control motor and non-motor fluctuations(‘OFF’periods).Transdermal rotigotine is indicated for early fluctuations,while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD.All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD.A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of‘OFF’periods.However,data suggest that despite their efficacy in reducing the number and duration of‘OFF’periods,these strategies still do not prevent‘OFF’periods in the middle to late stages of PD,thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation.Why these emergent‘OFF’periods still occur is unknown.In this review,we analyse the potential reasons for their persistence.The contribution of drug-and device-related involvement,and the problems related to site-specific drug delivery are analysed.We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent‘OFF’periods unresponsive to dopaminergic therapy delivered via CDD.

High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

Human monoamine oxidase B(hMAO-B)has emerged as a pivotal therapeutic target for Parkinson's disease.Due to adverse effects and shortage of commercial drugs,there is a need for novel,highly selective,and reversible hMAO-B inhibitors with good blood-brain barrier permeability.In this study,a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma,which resulted in the discovery of 75 active compounds,including phenolic acids,volatile oils,and phthalides,two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent,selective,reversible and had good blood‒brain permeability.Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism.Sedanolide(IC_(50)=103 nmol/L;SI=645)and neocnidilide(IC_(50)=131 nmol/L;SI=207)demonstrated their excellent potential as hMAO-B inhibitors.They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline.In SH-SY5Y cell assays,sedanolide(EC_(50)=0.962μmol/L)and neocnidilide(EC_(50)=1.161μmol/L)exhibited significant neuroprotective effects,comparable to the positive drugs rasagiline(EC_(50)=0.896μmol/L)and safinamide(EC_(50)=1.079μmol/L).These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.