Fibrinogen’s potential role in connecting cerebrovascular abnormalities with glymphatic dysfunction in Alzheimer’s disease

Alzheimer’s disease(AD)stands out as the primary manifestation of age-related dementia,portraying a chronic neurodegenerative disorder distinguished by the accumulation of fibrillar amyloid-β(Aβ)plaques and neurofibrillary tangles of hyperphosphorylated tau.However,from a clinical standpoint,AD presents itself as a complex condition with a spectrum of dysfunctions rather than a singular pathological mechanism.An often-overlooked aspect of the disease is the presence of extensive cerebrovascular abnormalities,given that the majority of AD patients experience altered cerebral blood flow,damaged vasculature,increased microinfarcts and microhemorrhages.Animal models of AD further support this observation,showing cerebrovascular dysfunction such as impaired cerebral blood flow and altered cerebrovascular reactivity(Tataryn et al.,2021;Gareau et al.,2023).

Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

Deep magnetic stimulation targeting the medial prefrontal and anterior cingulate cortices for methamphetamine use disorder:a randomised,double-blind,sham-controlled study

Craving is a key component of substance use disorders(SUDs).1 In recent decades,repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising treatment for individuals with SUDs by reducing their drug cravings and drug-associated cues,including methamphetamine,heroin,cocaine,nicotine and alcohol.2–7 Recently,the transdiagnostic consistency of the medial prefrontal cortex(MPFC)8 and anterior cingulate cortex(ACC)9 as neural substrates underlying cue reactivity was proposed.

A novel model of drug cue-induced behaviours in rhesus macaque subjected to chronic ketamine exposure

To the Editor,Non-human primate(NHP)models are advantageous for mimicking human addiction with high behavioural validity.1 However,current NHP drug addiction models(eg,self-administration)often require a comprehensive behavioural training paradigm,relatively expensive apparatus and invasive surgical procedures.

Using machine learning to identify factors related to nitrous oxide(laughing gas)relapse among adolescents

Introduction Nitrous oxide(N2O/laughing gas)has been used in medical practice as an inhalational anaesthetic and analgesic for more than 150 years.1 In the past decades,N2O exhibited increasing popularity among recreational drug users for its euphoric effects,potentially through its interaction with the endogenous opioid system.2 Recreational use of N2O emerged as the seventh most used drug globally in the past decade.3 The use of N2O can cause myelopathy,myocardial injury,anaemia,severe mood disorders,sensory and motor neuropathy,and psychotic symptoms.45 Prolonged N2O intake results in vitamin B12 deficiency and inhibits methionine synthetase,folate and DNA production,leading to plasma homocysteine(HCY)level elevation and bone marrow haematopoietic dysfunction.6 This study aimed to investigate the neurological symptoms of nitrous oxide use and then explore the relapse trajectory and risk factors for relapse.

Liver-brain axis with alcohol:Role of fibroblast growth factor 21(FGF21)

Fibroblast growth factor21(FGF21)is a hormone that can balance nutrient fluctuations,control metabolic processes,and maintain energy homeostasis.Endogenous FGF21 is produced by a variety of cell types,including hepatocytes,adipocytes,bone cells,myocardial cells,and pancreas cells,and act on various effector tissues such as brain,adipose tissue,liver,heart,and skeletal muscle.1 The target that FGF21 interacts with is the cell-surface receptor composed of FGF receptors in complex with the single-pass transmembrane proteinβ-Klotho.These receptors are abundantly expressed,both in peripheral tissues and some regions of the CNS,such as the hypothalamus and amygdala and the locus coeruleus(LC).2 Physiologically,FGF21 can be induced by various metabolic stresses,including hunger,protein deficiency,monosaccharides,and alcohol,by acting onβ-Klotho receptor in corresponding tissues,ultimately exerting regulatory effects(Fig.1)

CHIT1-positive microglia act as culprits for spinal motor neuron aging

Aging is one of the primary factors in spinal cord-associated disorders(Roberts,1990).However,the effects of aging on the spinal cord and the age-specific mechanisms underlying this relationship remain unclear.Motor neurons(MNs)are essential for regulating motor,autonomic,and sensory modalities(Arber,2012).

A commentary of“Unravelling the mechanisms of human genomic‘dark matter’in driving aging”:Top 10 Scientific Advances of 2023,China

Aging is related to physiological decline and the development of chronic diseases,yet molecular changes and mechanisms underlying the aging process remain unclear.Could certain“dark matter”,such as transposable elements with viral origins in the genome,be activated and participate in the aging process?Excitingly,a study by Liu and colleagues revealed that the reactivation of endogenous retroviruses(ERVs)during aging enhances senescence[1].By using cross-species models and multiple techniques,the team uncovered the unusual role of ERV reactivation as a hallmark and driver of aging.The authors identified that ERV expression is associated with cellular and tissue aging(Fig.1).They found that the accumulation of human ERV group K(HERVK)retrovirus-like particles(RVLPs)mediates aging-promoting effects in recipient cells.

miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1- containing AMPA receptors in a mouse model of Alzheimer’s disease

Alzheimer ’s disease(AD) is a leading cause of dementia in the elderly.Mitogen-activated protein kinase phosphatase 1(MKP-1) plays a neuroprotective role in AD.However,the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied.MicroRNAs(miRNAs) regulate gene expression at the post-transcriptional level,thereby repressing mRNA translation.Here,we reported that the microRNA-429-3p(miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPPAD model cells.We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3’-untranslated region(3’ UTR).Inhibition of miR-429-3p by its antagomir(A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation.More importantly,intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase(ERK1/2)-mediated GluAl hyperphosphorylation at Ser831 site,thereby increasing the surface expression of GluAl-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors(AMPARs).Together,these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice,suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

光干预降低可卡因记忆消退后复吸行为的神经环路机制

毒品成瘾已经成为一个严峻挑战,特别是因滥用造成的可卡因高复吸率给社会带来严重负担。尽管我们在神经生物学层面对成瘾的理解取得了显著进展,但仍缺乏有效降低复吸的戒断手段.在这项研究中,我们发现在可卡因戒断期实施亮光干预(BLT)并结合消退训练可防止可卡因驱动的复吸行为,该效应是通过丘脑-外侧核通路所介导。实验证实,在可卡因戒断进程中,外侧核(LHb)被激活,而通过BLT抑制LHb可减少可卡因驱动的复吸行为:本文阐明了BLT的作用是通过激活投射至LHb的腹外侧膝状体和膝状体间小叶(VLGN/IGL)神经元或抑制该通路中突触后LHb神经元实现。此外,BLT可以改善药物戒断引起的负性情绪。本研究结果表明在可卡因戒断期间施加BLT可能成为一种实现药物戒除的有效手段.

Neuroimaging and neuroendocrine insights into foodcravings and appetite interventions in obesity

This article reviews the previous studies on the distinction between food cravings and appetite,and how they are regulated by hor-mones and reflected in brain activity.Based on existing research,food cravings are defined as individual preferences influenced by hormones and psychological factors,which differ from appetite,as they are not necessarily related to hunger or nutritional needs.The article also evaluates the neuroimaging findings about food cravings,and interventions to reduce food cravings,such as mindfulness training,alternative sweeteners,non-invasive brain stimulation techniques,cognitive-behavioral therapy,and imaginal retraining,and points out their advantages,disadvantages,and limitations.Furthermore,the article delves into the potential future directions in the field,emphasizing the need for a neuroendocrine perspective,considerations for associated psychiatric disorders,innovative clinical interventions,and emerging therapeutic frontiers in obesity management.The article outlines the neuro-endocrine basis of food cravings,including ghrelin,leptin,melanocortin,oxytocin,glucagon-like peptide-1,baclofen,and other hormones and their brain regions of action.The article argues that food cravings are an important target for obesity,and more research is needed to explore their complex characteristics and mechanisms,and how to effectively interact with their neuro-endocrine pathways.The article provides a new perspective and approach to the prevention and treatment of obesity.

Gender difference in network relationship between inter-temporal decisions and prefrontal activation levels in internet gaming disorder

Background:Impulsivity and decision-making are key factors in addiction.However,little is known about how gender and time sensitivity affect impulsivity in internet gaming disorder(IGD).Objective:To investigate the gender difference of impulsive decision-making and relevant brain responses in IGD.Methods:We conducted a functional magnetic resonance imaging(fMRI)study with 123 participants,including 59 IGD individuals(26 females)and 64 matched recreational game users(RGUs,23 females).Participants performed a delay-discounting task during fMRI scanning.We examined gender-by-group effects on behavioral and neural measures to explore the preference for immediate over delayed rewards and the associated brain activity.We also investigated the network correlations between addiction severity and behavioral and neural measures,and analyzed the mediating role of brain activity in the link between delay discounting parameters and IGD severity.Results:We found significant gender-by-group interactions.The imaging results revealed gender-by-group interactions in the dor-solateral prefrontal cortex,medial frontal gyrus,and inferior frontal gyrus(IFG).Post hoc analysis indicated that,for females,RGUs showed higher activity than IGD individuals in these brain regions,while for males IGD individuals exhibited higher activity than RGUs.The activation in the left IFG mediated the relation between Internet Addiction Test score and discount rate in females.In males,the activation in the right dlPFC mediated the relation between IAT score and time sensitivity.Discussion:Our findings imply that male IGD participants demonstrate impaired intertemporal decisions associated with neural dysfunction.Influencing factors for impulsive decision-making in IGD diverge between males(time sensitivity)and females(discount rate).These findings augment our comprehension of the neural underpinnings of gender differences in IGD and bear significant implications for devising effective intervention strategies for treating people with IGD.

Connections Between Insomnia and Cognitive Aging

Insomnia is a common sleep disorder among older adults,and a risk factor for poor physical and mental health.However,the relationship between insomnia and cognitive health is not well understood.Here,we review observational studies that have investigated whether insomnia is associated with deficits in objective cognitive performance and an increased risk of dementia,magnetic resonance imaging studies that have assessed grey matter volumes and white matter microstructure,and interventional studies that have explored whether the treatment of insomnia can improve cognitive outcomes.There are inconsistent findings regarding impaired performance in objective cognitive tests and reduced grey matter volumes,and limited,emerging,evidence that suggests that insomnia is associated with an increased risk of dementia and reduced white matter integrity.Although the interventional literature is still in its infancy,there is some indication that treatment may have an impact on vigilance.Well-powered studies examining sources of heterogeneity are warranted.

Current Alzheimer disease research highlights: evidence for novel risk factors

Alzheimer disease(AD)is the most common type of dementia characterized by the progressive cognitive and social decline.Clinical drug targets have heavily focused on the amyloid hypothesis,with amyloid beta(Aβ),and tau proteins as key pathophysiologic markers of AD.However,no effective treatment has been developed so far,which prompts researchers to focus on other aspects of AD beyond Aβ,and tau proteins.Additionally,there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous.In the past decades,new risk factors or potential etiologies have been widely studied.Here,we review several novel epidemiologic and clinical research developments that focus on sleep,hypoxia,diet,gut microbiota,and hearing impairment and their links to AD published in recent years.At the frontiers of AD research,these findings and updates could be worthy of further attention.

Clusterin transduces Alzheimer-risk signals to amyloidogenesis

Dear Editor,Deposition of amyloid-β(Aβ)to form neuritic plaque(NP)is the hallmark of Alzheimer’s Disease(AD).Major non-genetic risk factors such as ageing,stroke,diabetes and other conditions facilitate AD pathogenesis via unclear mechanisms.Furthermore,the mechanism underlying NP formation is unclear.Increasing Aβcauses NP in familial AD patients and in transgenic AD mice robustly expressing Aβ,but the NP formation requires long-term Aβaccumulation.