Beginning from the end:the presynaptic terminal as a pathomechanism hub in frontotemporal dementia and amyotrophic lateral sclerosis

Frontotemporal dementia and amyotrophic lateral sclerosis:Frontotemporal dementia(F T D)and amyo t rophic lateral sclerosis(ALS)are neurodegenerative diseases with significant overlapping attributes.While these neurodegenerative diseases affect different neuronal populations(with FTD affecting neurons of the frontal and temporal lobes,and ALS affecting upper and lower motor neurons),these two diseases are complexly intertwined.FTD and ALS exist on a disease spectrum,with shared genetic causes,clinical presentations,and pathologies.

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.

Targeting muscle to treat Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease(CMT)is a hereditary peripheral neuropathy causing muscle weakness/wasting and sensory dysfunction predominantly in limb extremities.CMT patients display gait abnormalities,foot deformities,loss of sensation and decreased/absent deep tendon reflexes,with motor symptoms usually being more prominent than sensory.

Cilostazol and isosorbide mononitrate for the prevention of progression of cerebral small vessel disease:baseline data and statistical analysis plan for the Lacunar Intervention Trial-2(LACI-2)(ISRCTN14911850)

Background Cerebral small vessel disease(SVD)causes lacunar strokes(25%of all ischaemic strokes),physical frailty and cognitive impairment and vascular and mixed dementia.There is no specific treatment to prevent progression of SVD.Methods The LACunar Intervention Trial-2 is an investigator-initiated prospective randomised open-label blinded-endpoint phase II feasibility study assessing cilostazol and isosorbide mononitrate for preventing SVD progression.We aimed to recruit 400 patients with clinically evident lacunar ischaemic stroke and randomised to cilostazol,isosorbide mononitrate,both or neither,in addition to guideline secondary ischaemic stroke prevention,in a partial factorial design.The primary outcome is feasibility of recruitment and adherence to medication;key secondary outcomes include:drug tolerability;recurrent vascular events,cognition and function at 1 year after randomisation;and safety(bleeding,falls,death).Data are number(%)and median(IQR).Results The trial commenced on 5 February 2018 and ceased recruitment on 31 May 2021 with 363 patients randomised,with the following baseline characteristics:average age 64(56.0,72.0)years,female 112(30.9%),stroke onset to randomisation 79.0(27.0,244.0)days,hypertension 267(73.6%),median blood pressures 143.0(130.0,157.0)/83.0(75.0,90.0)mm Hg,current smokers 67(18.5%),educationally achieved end of school examinations(A-level)or higher 118(32.5%),modified Rankin scale 1.0(0.0,1.0),National Institutes Health stroke scale 1.0(1.4),Montreal Cognitive Assessment 26.0(23.0,28.0)and total SVD score on brain imaging 1.0(0.0,2.0).This publication summarises the baseline data and presents the statistical analysis plan.Summary The trial is currently in follow-up which will complete on 31 May 2022 with results expected in October 2022.Trial registration number ISRCTN14911850.

Transcriptional regulation analysis reveals the complexity of metamorphosis in the Pacific oyster(Crassostrea gigas)

Many marine invertebrate phyla are characterized by indirect development.These animals transit from planktonic larvae to benthic spats via settlement and metamorphosis,which contributes to their adaption to the marine environment.Studying the biological process of metamorphosis is,thus,key to understanding the origin and evolution of indirect development.Although numerous studies have been conducted on the relationship between metamorphosis and the marine environment,microorganisms,and neurohormones,little is known about gene regulation network(GRN)dynamics during metamorphosis.Metamorphosis-competent pediveligers of the Pacific oyster Crassostrea gigas were assayed in this study.By assaying gene expression patterns and open chromatin region changes of different samples of larvae and spats,the dynamics of molecular regulation during metamorphosis were examined.The results indicated significantly different gene regulation networks before,during and post-metamorphosis.Genes encoding membrane-integrated receptors and those related to the remodeling of the nervous system were upregulated before the initiation of metamorphosis.Massive biogenesis,e.g.,of various enzymes and structural proteins,occurred during metamorphosis as inferred from the comprehensive upregulation of the protein synthesis system post epinephrine stimulation.Hierarchical downstream gene networks were then stimulated.Some transcription factors,including homeobox,basic helix–loop–helix and nuclear receptors,showed different temporal response patterns,suggesting a complex GRN during the transition stage.Nuclear receptors,as well as their retinoid X receptor partner,may participate in the GRN controlling oyster metamorphosis,indicating an ancient role of the nuclear receptor regulation system in animal metamorphosis.

Hyperdense artery sign, symptomatic infarct swelling and effect of alteplase in acute ischaemic stroke

Background Alteplase improves functional outcomes of patients with acute ischaemic stroke,but its effects on symptomatic infarct swelling,an adverse complication of stroke and the influence of CT hyperdense artery sign(HAS)are unclear.This substudy of the Third International Stroke Trial aimed to investigate the association between HAS and symptomatic infarct swelling and effect of intravenous alteplase on this association.Methods We included stroke patients whose prerandomisation scan was non-contrast CT.Raters,masked to clinical information,assessed baseline(prerandomisation)and follow-up(24-48 hours postrandomisation)CT scans for HAS,defined as an intracranial artery appearing denser than contralateral arteries.Symptomatic infarct swelling was defined as clinically significant neurological deterioration≤7 days after stroke with radiological evidence of midline shift,effacement of basal cisterns or uncal herniation.Results Among 2961 patients,HAS presence at baseline was associated with higher risk of symptomatic infarct swelling(OR 2.21;95% CI 1.42 to 3.44).Alteplase increased the risk of swelling(OR 1.69;95% CI 1.11 to 2.57),with no difference between patients with and those without baseline HAS(p=0.49).In patients with baseline HAS,alteplase reduced the proportion with HAS at follow-up(OR 0.67;95% CI 0.50 to 0.91),where HAS disappearance was associated with reduced risk of swelling(OR 0.25,95% CI 0.14 to 0.47).Conclusion Although alteplase was associated with increased risk of symptomatic infarct swelling in patients with or without baseline HAS,it was also associated with accelerated clearance of HAS,which in return reduced swelling,providing further mechanistic insights to underpin the benefits of alteplase.

Clinical management of cerebral small vessel disease:a call for a holistic approach

Cerebral small vessel disease(SVD)is a common global brain disease that causes cognitive impairment,ischemic or hemorrhagic stroke,problems with mobility,and neuropsychiatric symptoms.The brain damage,seen as focal white and deep grey matter lesions on brain magnetic resonance imaging(MRI)or computed tomography(CT),typically accumulates"covertly"and may reach an advanced state before being detected incidentally on brain scanning or causing symptoms.Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation,perhaps explaining a lack of awareness,until recently,of the full range and complexity of SVD.In this review,we discuss the varied clinical presentations,established and emerging risk factors,relationship to SVD features on MRI or CT,and the current state of knowledge on the effectiveness of a wide range of pharmacological and lifestyle interventions.The core message is that effective assessment and clinical management of patients with SVD,as well as future advances in diagnosis,care,and treatment,will require a more"joined-up"’approach.This approach should integrate clinical expertise in stroke neurology,cognitive,and physical dysfunctions.It requires more clinical trials in order to improve pharmacological interventions,lifestyle and dietary modifications.A deeper understanding of the pathophysiology of SVD is required to steer the identification of novel interventions.An essential prerequisite to accelerating clinical trials is to improve the consistency,and standardization of clinical,cognitive and neuroimaging endpoints.

Measures of intracranial compartments in acute intracerebral haemorrhage:data from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial(RIGHT-2)

Background and purpose Intracerebral haemorrhage volume(ICHV)is prognostically important but does not account for intracranial volume(ICV)and cerebral parenchymal volume(CPV).We assessed measures of intracranial compartments in acute ICH using computerised tomography scans and whether ICHV/ICV and ICHV/CPV predict functional outcomes.We also assessed if cistern effacement,midline shift,old infarcts,leukoaraiosis and brain atrophy were associated with outcomes.Methods Data from 133 participants from the Rapid Intervention with Glyceryl Trinitrate in Hypertensive Stroke-2 Trial trial were analysed.Measures included ICHV(using ABC/2)and ICV(XYZ/2)(by independent observers);ICHV,ICV and CPV(semiautomated segmentation,SAS);atrophy(intercaudate distance,ICD,Sylvian fissure ratio,SFR);midline shift;leukoaraiosis and cistern effacement(visual assessment).The effects of these measures on death at day 4 and poor functional outcome at day 90(modified Rankin scale,mRS of>3)was assessed.Results ICV was significantly different between XYZ and SAS:mean(SD)of 1357(219)vs 1420(196),mean difference(MD)62 mL(p<0.001).There was no significant difference in ICHV between ABC/2 and SAS.There was very good agreement for ICV measured by SAS,CPV,ICD,SFR,leukoaraiosis and cistern score(all interclass correlations,n=10:interobserver 0.72-0.99,intraobserver 0.73-1.00).ICHV/ICV and ICHV/CPV were significantly associated with mRS at day 90,death at day 4 and acute neurological deterioration(all p<0.05),similar to ICHV.Midline shift and cistern effacement at baseline were associated with poor functional outcome but old infarcts,leukoaraiosis and brain atrophy were not.Conclusions Intracranial compartment measures and visual estimates are reproducible.ICHV adjusted for ICH and CPV could be useful to prognosticate in acute stroke.The presence of midline shift and cistern effacement may predict outcome but the mechanisms need validation in larger studies.

Ex vivo 100 μm isotropic diffusion MRI-based tractography of connectivity changes in the end-stage R6/2 mouse model of Huntington's disease

Background:Huntington's disease is a progressive neurodegenerative disorder.Brain atrophy,as measured by volumetric magnetic resonance imaging(MRI),is a downstream consequence of neurodegeneration,but microstructural changes within brain tissue are expected to precede this volumetric decline.The tissue microstructure can be assayed non-invasively using diffusion MRI,which also allows a tractographic analysis of brain connectivity.Methods:We here used ex vivo diffusion MRI(11.7 T)to measure microstructural changes in different brain regions of end-stage(14 weeks of age)wild type and R6/2 mice(male and female)modeling Huntington's disease.To probe the microstructure of different brain regions,reduce partial volume effects and measure connectivity between different regions,a 100μm isotropic voxel resolution was acquired.Results:Although fractional anisotropy did not reveal any difference between wild-type controls and R6/2 mice,mean,axial,and radial diffusivity were increased in female R6/2 mice and decreased in male R6/2 mice.Whole brain streamlines were only reduced in male R6/2 mice,but streamline density was increased.Region-to-region tractography indicated reductions in connectivity between the cortex,hippocampus,and thalamus with the striatum,as well as within the basal ganglia(striatum—globus pallidus—subthalamic nucleus—substantia nigra—thalamus).Conclusions:Biological sex and left/right hemisphere affected tractographic results,potentially reflecting different stages of disease progression.This proof-of-principle study indicates that diffusion MRI and tractography potentially provide novel biomarkers that connect volumetric changes across different brain regions.In a translation setting,these measurements constitute a novel tool to assess the therapeutic impact of interventions such as neuroprotective agents in transgenic models,as well as patients with Huntington's disease.

A phase 1b randomized clinical trial of CT1812 to measure Aβoligomer displacement in Alzheimer’s disease using an indwelling CSF catheter

Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet promising dis-ease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta(Aβ)is a toxic species contributing to AD through synaptic damage and neuronal toxicity[1].

Acute cerebral small vessel disease:Classification,mechanism,and therapeutic implications

Cerebral small vessel disease(CSVD)is a significant cause of stroke and dementia.CSVD causes up to 30% of ischemic strokes and 80% of spontaneous intraparenchymal hemorrhages.[1]Compared with data from developed countries,Asian populations exhibit a heavier burden of strokes caused by CSVD.[2]The clinical manifestations of CSVD can vary.

Pathophysiological subtypes of mild cognitive impairment due to Alzheimer’s disease identified by CSF proteomics

The number of patients with Alzheimer’s disease(AD)is increasing worldwide due to extended life expectancy,with AD being the most common cause of dementia.AD pathological hallmarks consist of brain depositions of aggregated amyloid beta(Aβ)into neuritic plaques and neurofibrillary tangles of hyperphosphorylated tau,lead-ing to synaptic dysfunction and neuronal loss[1].Prot-eomic studies of cerebrospinal fluid(CSF)have shown that several biological processes are dysregulated in AD,such as the innate immune system,inflammatory response,hemostasis,lipid processing,oxidative stress response and synaptic functioning[2].

The relation of synaptic biomarkers with Aβ,tau,glial activation,and neurodegeneration in Alzheimer’s disease

Main text Synaptic degeneration is a prominent feature of vari-ous neurodegenerative diseases and represents an early pathogenic event in Alzheimer’s disease(AD)[1,2].Multiple synapse-specific proteins involved in distinct synaptic pathways can be measured in the cerebrospi-nal fluid(CSF)and have been implicated as promising biomarkers of synaptic degeneration.Among them,the most extensively studied ones include the presynaptic proteins synaptosomal-associated protein-25(SNAP25),growth-associated protein-43(GAP43)and synaptotag-min-1(SYT1)and postsynaptic protein neurogranin(NRGN)[3,4].