Strain-dependent alpha-synuclein spreading in Parkinson's disease and multiple system atrophy

Parkinson's disease(PD) and atypical Parkinsonian syndromes,such as multiple system atrophy(MSA) and Dementia with Lewy bodies,are neurodegenerative movement disorders characterized by the accumulation of alphasynuclein(a-syn) aggregates.These a-syn aggregates propagate throughout the brain in a prion-like manner,where pathological a-syn recruits endogenous a-syn to form insoluble aggregates.Oligomeric forms representing intermediates on the way to insoluble aggregates result in the most pronounced neurotoxic effects.

Machine learning-based decision tool for selecting patients with idiopathic acute pancreatitis for endosonography to exclude a biliary aetiology

BACKGROUND Biliary microlithiasis/sludge is detected in approximately 30%of patients with idiopathic acute pancreatitis(IAP).As recurrent biliary pancreatitis can be prevented,the underlying aetiology of IAP should be established.AIM To develop a machine learning(ML)based decision tool for the use of endosonography(EUS)in pancreatitis patients to detect sludge and microlithiasis.METHODS We retrospectively used routinely recorded clinical and laboratory parameters of 218 consecutive patients with confirmed AP admitted to our tertiary care hospital between 2015 and 2020.Patients who did not receive EUS as part of the diagnostic work-up and whose pancreatitis episode could be adequately explained by other causes than biliary sludge and microlithiasis were excluded.We trained supervised ML classifiers using H_(2)O.ai automatically selecting the best suitable predictor model to predict microlithiasis/sludge.The predictor model was further validated in two independent retrospective cohorts from two tertiary care centers(117 patients).RESULTS Twenty-eight categorized patients’variables recorded at admission were identified to compute the predictor model with an accuracy of 0.84[95%confidence interval(CI):0.791-0.9185],positive predictive value of 0.84,and negative predictive value of 0.80 in the identification cohort(218 patients).In the validation cohort,the robustness of the prediction model was confirmed with an accuracy of 0.76(95%CI:0.673-0.8347),positive predictive value of 0.76,and negative predictive value of 0.78(117 patients).CONCLUSION We present a robust and validated ML-based predictor model consisting of routinely recorded parameters at admission that can predict biliary sludge and microlithiasis as the cause of AP.

Lithium beyond psychiatric indications:the reincarnation of a new old drug

Lithium has been used in the treatment of bipolar disorders for decades,but the exact mechanisms of action remain elusive to this day.Recent evidence suggests that lithium is critically involved in a variety of signaling pathways affecting apoptosis,inflammation,and neurogenesis,all of which contributing to the complex pathophysiology of various neurological diseases.As a matter of fact,preclinical work reports both acute and longterm neuroprotection in distinct neurological disease models such as Parkinson’s disease,traumatic brain injury,Alzheimer’s disease,and ischemic stroke.Lithium treatment reduces cell injury,decreasesα‑synuclein aggregation and Tau protein phosphorylation,modulates inflammation and even stimulates neuroregeneration under experimental conditions of Parkinson’s disease,traumatic brain injury,and Alzheimer’s disease.The therapeutic impact of lithium under conditions of ischemic stroke was also studied in numerous preclinical in vitro and in vivo studies,giving rise to a randomized double-blind clinical stroke trial.The preclinic data revealed a lithium-induced upregulation of anti-apoptotic proteins such as B-cell lymphoma 2,heat shock protein 70,and activated protein 1,resulting in decreased neuronal cell loss.Lithium,however,does not only yield postischemic neuroprotection but also enhances endogenous neuroregeneration by stimulating neural stem cell proliferation and by regulating distinct signaling pathways such as the RE1-silencing transcription factor.In line with this,lithium treatment has been shown to modulate postischemic cytokine secretion patterns,diminishing microglial activation and stabilizing blood-brain barrier integrity yielding reduced levels of neuroinflammation.The aforementioned observations culminated in a first clinical trial,which revealed an improved motor recovery in patients with cortical stroke after lithium treatment.Beside its well-known psychiatric indications,lithium is thus a promising neuroprotective candidate for the aforementioned neurological diseases.A detailed understanding of the lithium-induced mechanisms,however,is important for prospective clinical trials which may pave the way for a successful benchto-bedside translation in the future.In this review,we will give an overview of lithiuminduced neuroprotective mechanisms under various pathological conditions,with special emphasis on ischemic stroke.

Modulating poststroke inflammatory mechanisms: Novel aspects of mesenchymal stem cells, extracellular vesicles and microglia

Inflammation plays an important role in the pathological process of ischemic stroke,and systemic inflammation affects patient prognosis.As resident immune cells in the brain,microglia are significantly involved in immune defense and tissue repair under various pathological conditions,including cerebral ischemia.Although the differentiation of M1 and M2 microglia is certainly oversimplified,changing the activation state of microglia appears to be an intriguing therapeutic strategy for cerebral ischemia.Recent evidence indicates that both mesenchymal stem cells(MSCs)and MSC-derived extracellular vesicles(EVs)regulate inflammation and modify tissue repair under preclinical stroke conditions.However,the precise mechanisms of these signaling pathways,especially in the context of the mutual interaction between MSCs or MSC-derived EVs and resident microglia,have not been sufficiently unveiled.Hence,this review summarizes the state-ofthe-art knowledge on MSC-and MSC-EV-mediated regulation of microglial activity under ischemic stroke conditions with respect to various signaling pathways,including cytokines,neurotrophic factors,transcription factors,and microRNAs.

Patterning inconsistencies restrict the true potential of dopaminergic neurons derived from human induced pluripotent stem cells

Human induced pluripotent stem cells(hiPSCs)are multipotent stem cells genetically reprogrammed using transcription factors,such as Sox2,c-Myc,Oct3/4 and Klf4(Takahashi and Yamanaka,2006)from fibroblasts,derived from either patient or control individuals.These factors are highly expressed in embryonic stem cells,and their overexpression can induce pluripotency in human somatic cells such as fibroblasts.Upon the generation of hiPSCs after reprogramming,these cells can be further differentiated into multiple neuronal cell types by using a strictly designed protocol.This process is known as patterning.Correct use of these hiPSCs derived neurons holds immense potential for researchers to uncover the underpinnings of disease pathophysiology and therefore is considered as a powerful tool.

ULK1 as a novel therapeutic target in neurodegeneration

Axonal degeneration is an early and key pathophysiological feature of many traumatic and neurodegenerative disorders of the central nervous system(CNS),such as spinal cord injury(SCI),Parkinson’s disease(PD),and amyotrophic lateral sclerosis(ALS).As the regenerative capacity of injured axons is severely restricted in the CNS,axonal degeneration frequently results in the irreversible loss of neuronal connections causing progressive neurological deficits and clinical disability.A better understanding of the mechanisms of axon degeneration is therefore hoped to unravel new therapeutic avenues to combat neurodegeneration(Lingor et al.,2012).

Role of cardiac magnetic resonance imaging in troponinemia syndromes

Cardiac magnetic resonance imaging(MRI)is an evolving technology,proving to be a highly accurate tool for quantitative assessment.Most recently,it has been increasingly used in the diagnostic and prognostic evaluation of conditions involving an elevation in troponin or troponinemia.Although an elevation in troponin is a nonspecific marker of myocardial tissue damage,it is a frequently ordered investigation leaving many patients without a specific diagnosis.Fortunately,the advent of newer cardiac MRI protocols can provide additional information.In this review,we discuss several conditions associated with an elevation in troponin such as myocardial infarction,myocarditis,Takotsubo cardiomyopathy,coronavirus disease 2019 related cardiac dysfunction and athlete’s heart syndrome.

Perspective on inflammatory cytokines in open spinal dysraphism

Myelomeningocele(MMC)is a severe form of spinal dysraphism.Due to the failure of neural tube closure during early embryonic development,the affected part of the spinal cord is left open like a book at the back of the affected child.This malformed part of the spinal cord is not covered by its protective mesodermal and ectodermal derived layers.Consequently,the exposed neural tissue(i.e.,the neural placode)is prone to injuryduring further intra-uterine development.

Ca^(2+) binding to the C_(2)E domain of otoferlin is required for hair cell exocytosis and hearing

Dear Editor,Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and Starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C_(2)-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein family involved in membrane trafficking and repair that are of major disease relevance(Pangršičet al.,2012),also see Supplementary Materials.Otoferlin is distributed broadly within IHCs(Fig.2Ai-Aiii;Pangrsic et al.,2010;Roux et al.,2006).

鞘内/脑室内注射抗生素和抗真菌药治疗中枢神经系统感染

血脑屏障和血脑脊液屏障可以保护中枢神经系统免受循环中内源性和外源性物质的影响,从而确保中枢神经系统的正常功能;但是这些屏障也限制了全身性应用抗感染药物后其在中枢神经系统的有效治疗浓度。多重耐药病原体引起的中枢神经系统感染,若全身给药无法达到有效治疗浓度,可采取鞘内/脑室内注射抗生素.

Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress

Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.

RBFOX2: a key factor in suppressing PDAC metastasis through regulation of alternative splicing events

A new study published in Nature by Jbara et al.has identified the splicing factor“RBFOX2,”which halts metastatic spread of pancreatic ductal adenocarcinoma(PDAC)through regulating alternative splicing events.1 The results of the study provide new insights into the molecular mechanisms underlying the start of metastatic spread of PDAC cells.The study also indicates that pathways involved in splicing modulation could be targeted for potential therapeutic interventions in an advanced-stage PDAC.

Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy

Background:Progressive accumulation ofα-synuclein is a key step in the pathological development of Parkinson’s disease.Impaired protein degradation and increased levels ofα-synuclein may trigger a pathological aggregation in vitro and in vivo.The chaperone-mediated autophagy(CMA)pathway is involved in the intracellular degradation processes ofα-synuclein.Dysfunction of the CMA pathway impairsα-synuclein degradation and causes cytotoxicity.Results:In the present study,we investigated the effects on the CMA pathway andα-synuclein aggregation using bioactive ingredients(Dihydromyricetin(DHM)and Salvianolic acid B(Sal B))extracted from natural medicinal plants.In both cell-free and cellular models ofα-synuclein aggregation,after administration of DHM and Sal B,we observed significant inhibition ofα-synuclein accumulation and aggregation.Cells were co-transfected with a Cterminal modifiedα-synuclein(SynT)and synphilin-1,and then treated with DHM(10μM)and Sal B(50μM)16 hours after transfection;levels ofα-synuclein aggregation decreased significantly(68%for DHM and 75%for Sal B).Concomitantly,we detected increased levels of LAMP-1(a marker of lysosomal homeostasis)and LAMP-2A(a key marker of CMA).Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A withα-synuclein inclusions after treatment with DHM and Sal B.We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo,along with decreased levels ofα-synuclein.Moreover,DHM and Sal B treatments exhibited anti-inflammatory activities,preventing astroglia-and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice.Conclusions:Our data indicate that DHM and Sal B are effective in modulatingα-synuclein accumulation and aggregate formation and augmenting activation of CMA,holding potential for the treatment of Parkinson’s disease.

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson’s disease: a study in LRRK2 mutation carriers

Background Asymptomatic carriers of leucine-rich repeat kinase 2(LRRK2)gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease(PD).In this study,we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers.Methods We measured the levels of CSF total-(t-),oligomeric(o-)and phosphorylated S129(pS129-)α-syn,total-tau(tTau),phosphorylated threonine 181 tau(pTau),amyloid-beta 40(Aβ-40),amyloid-beta-42(Aβ-42)and 40 inflammatory chemokines in symptomatic(n=23)and asymptomatic(n=51)LRRK2 mutation carriers,subjects with a clinical diagnosis of PD(n=60)and age-matched healthy controls(n=34).General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups.Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD.Results Discriminant function analysis revealed low levels of CSF t-α-syn,high levels of CSF o-α-syn and TNF-αbest discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls.Assessing the discriminative power using receiver operating curve analysis,an area under the curve>0.80 was generated.Conclusions The current study suggests that CSF t-,o-α-syn and TNF-αare candidate risk biomarkers for the detection of PD at the prodromal stage.Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers’panel approach for an accurate and timely diagnosis of PD.

No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors

Background:IgG-class autoantibodies to N-Methyl-D-Aspartate(NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis.Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results.We measured NMDA antibodies in a large,well phenotyped sample of Parkinson patients without and with cognitive impairment(n=296)and controls(n=295)free of neuropsychiatric disease.Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.Methods:NMDA antibodies were analysed in the serum of patients and controls using well established validated assays.We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.Results:The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients(13%)than in controls(22%)and higher than in previous studies in both groups.NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment,nor with quantitative indicators of disease severity and cognitive impairment.A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.Conclusion:It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g.to Parkinson disease with dementia,while NMDA IgG antibodies define a separate disease of its own.

Hypoalbuminemia: an underestimated, vital characteristic of hospitalized COVID-19 positive patients?

The COVID-19 pandemic has led to the greatest worldwide health crisis in decades.The number of infected patients with severe SARS-CoV-2(COVID-19)disease has overwhelmed the capacity of almost all health care systems around world.Hypoalbuminemia has now been reported in patients with severe disease seeking help in the emergency room because of COVID-19 infection.In the past,hypoalbuminemia was considered to be a negative prognostic marker,not only in patients with chronic liver disease,but also in patients with SARS and MERS infections.Albumin is the major serum protein synthesized by the liver.A low serum albumin level is an ominous clinical sign.Introduction of amino acids to a patient's diet is of fundamental importance to hepatic albumin synthesis in different clinical situations.This highlights the importance of nutritional support during the early phases of COVID-19-infection.Furthermore,albumin synthesis in the hepatocyte is downregulated at a pretranslational level by the direct interaction of the major acute-phase cytokines which are released into the circulation during the cytokine"storm"induced by the viral effects on the lungs.Both mechanisms contribute to severe hypoalbuminemia which,combined with massive fluid losses due to the fever,is responsible for severe hypovolemia and shock commonly observed in patients with COVID-19 in critical care settings.