Parkinsons disease(PD)is a chronic,progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.Pain,a key component of PDs non-motor symptoms,was first documented by Charcot in 1872 as a ...Parkinsons disease(PD)is a chronic,progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.Pain,a key component of PDs non-motor symptoms,was first documented by Charcot in 1872 as a potential correlate of the disease.While pharmacological and surgical interventions have gained traction in managing PD-related pain,the therapeutic framework remains inconsistent.Understanding the pathogenesis and contributing factors of PD pain is crucial for developing novel therapies and refining disease identification and treatment protocols.This review examines the potential mechanisms and influencing factors of PD-associated pain,with the aim of identifying new therapeutic targets for PD pain.展开更多
Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson...Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.展开更多
Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include...Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include disturbances in sleep,gastrointestinal function,and olfaction.PD misdiagnosis rates have been reported to reach approximately 30%,partly owing to the heterogeneity of parkinsonism with non-PD pathologies,and the differential diagnosis of PD from neurodegenerative diseases such as multiple systemic atrophy(MSA)and progressive supranuclear palsy poses another unmet need.展开更多
Amyloid oligomers,a brief history:Amyloid diseases encompass a range of human neurological,systemic,a nd metabolic disorders,characterized by the common feature of amyloid fibril and plaque deposition,either intracell...Amyloid oligomers,a brief history:Amyloid diseases encompass a range of human neurological,systemic,a nd metabolic disorders,characterized by the common feature of amyloid fibril and plaque deposition,either intracellularly or extracellularly.Among them,Alzheimer's disease(AD)—manifested by memory loss and cognitive decline—and Parkinson's disease(PD)—underlined by impaired dopamine release and motor dysfunction—are the two most prevalent forms of neurodegenerative conditions that have rapidly become global epidemics.Type 2 diabetes,conversely,is a prevalent metabolic disorder underpinned by pancreatic beta cell loss,elicited primarily by the aggregation and toxicity of human islet amyloid peptide.展开更多
Neurodegenerative diseases are a growing burden on healthcare systems.Patients with Alzheimer’s or Parkinson’s diseases(AD or PD)are desperately waiting for innovative solutions that are slow to come,despite several...Neurodegenerative diseases are a growing burden on healthcare systems.Patients with Alzheimer’s or Parkinson’s diseases(AD or PD)are desperately waiting for innovative solutions that are slow to come,despite several decades of research worldwide.In 2021 and again in 2023,two monoclonal antibodies,aducanumab and lecanemab,have been approved by the U.S.Food and Drug Administration,and a third,donanemab,is currently under review.However,these treatments have very limited efficacy on cognitive functions and are accompanied by major side effects:amyloid-related imaging abnormalities,microhemorrhages,and accelerated brain volume loss(Høilund-Carlsen et al.,2024).展开更多
Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor...Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).展开更多
Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis...Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.展开更多
In recent years,rising life expectancy has led to a significant increase in the prevalence of neurodegenerative disorders,including Alzheimer’s disease(AD),Parkinson’s disease,and age-related cognitive decline.Addit...In recent years,rising life expectancy has led to a significant increase in the prevalence of neurodegenerative disorders,including Alzheimer’s disease(AD),Parkinson’s disease,and age-related cognitive decline.Additionally,other neurological conditions such as glioblastoma,the most common and aggressive brain tumor in adults have been more frequently reported in aging populations.The brain itself is highly vulnerable to age-related changes,particularly disruptions in homeostatic regulation,which further contribute to its functional decline and heightened susceptibility to disease.This has led to a surge of interest in understanding the cellular and molecular mechanisms driving these changes.展开更多
The loss of control over movement is one of the most devastating consequences of Parkinson’s disease(PD).The loss of control largely results from the gradual but inexorable destruction of dopamine-producing neurons i...The loss of control over movement is one of the most devastating consequences of Parkinson’s disease(PD).The loss of control largely results from the gradual but inexorable destruction of dopamine-producing neurons in the substantia nigra pars compacta.As dopamine levels fall,the ability to initiate,control,learn,and sustain actions declines.Treatment with the dopamine precursor levodopa can partly overcome motor impairments;however,years of use often leads to levodopa-induced dyskinesia(LID),a debilitating condition characterized by uncontrolled writhing and ballistic movements,making continued treatment difficult or impossible.While progress has been made towards unraveling the molecular and cellular processes driving the development of LID,far less is known about the changes in ongoing neuronal activity that contribute to LID expression.展开更多
A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative...A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.展开更多
Parkinson’s disease(PD)is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic(DA)neurons in the substantia nigra pars compacta.Thes...Parkinson’s disease(PD)is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic(DA)neurons in the substantia nigra pars compacta.These neurons are characterized by the presence of the cytoplasmic pigment neuromelanin(NM),and their degeneration is closely associated with the accumulation ofα-synuclein(α-syn)into intraneuronal inclusions known as Lewy bodies(LBs),which represent a neuropathological hallmark of PD.展开更多
Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highli...Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highlights the selective vulnerability of neurons to the insults of reactive oxygen species.The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra.These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism(Watanabe et al.,2024).展开更多
Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson'...Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).展开更多
Nuclear receptor subfamily 2 group F member 1(NR2F1,also called COUP-TF1)is a transcription factor and part of the steroid/thyroid hormone receptor superfamily(Gay et al.,2002).NR2F1 is an orphan receptor that dimeriz...Nuclear receptor subfamily 2 group F member 1(NR2F1,also called COUP-TF1)is a transcription factor and part of the steroid/thyroid hormone receptor superfamily(Gay et al.,2002).NR2F1 is an orphan receptor that dimerizes to bind DNA and acts as a repressor as well as an activator of the target genes(Gay et al.,2002;Bertacchi et al.,2019;Bonzano et al.,2023).展开更多
Deep brain stimulation(DBS)is an established therapeutic intervention for people with Parkinson’s disease(PwPD)and is increasingly being utilized for other neurological disorders.Although effective in alleviating mot...Deep brain stimulation(DBS)is an established therapeutic intervention for people with Parkinson’s disease(PwPD)and is increasingly being utilized for other neurological disorders.Although effective in alleviating motor symptoms and reducing medication requirements,DBS has undergone minimal conceptual evolution and still relies on continuous high-frequency electrical stimulation.In Parkinson’s disease(PD),this persistent stimulation may cause adverse effects,including dysarthria,stimulation-induced dyskinesia,impulsivity,and mood alterations.Additionally,the continuous energy demand of current DBS systems accelerates battery depletion,necessitating more frequent battery charging or battery replacement surgeries,increasing risks,burden,and costs.Basic neuroscience research has long demonstrated that exogenous electrical stimulation can induce persistent changes to synaptic connections,known as long-term plasticity.展开更多
Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticula...Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).展开更多
The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzh...The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.展开更多
N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory lo...N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.展开更多
Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as ...Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.展开更多
文摘Parkinsons disease(PD)is a chronic,progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.Pain,a key component of PDs non-motor symptoms,was first documented by Charcot in 1872 as a potential correlate of the disease.While pharmacological and surgical interventions have gained traction in managing PD-related pain,the therapeutic framework remains inconsistent.Understanding the pathogenesis and contributing factors of PD pain is crucial for developing novel therapies and refining disease identification and treatment protocols.This review examines the potential mechanisms and influencing factors of PD-associated pain,with the aim of identifying new therapeutic targets for PD pain.
基金supported by the Spanish Ministry of Science and Innovation via a doctoral grant[FPU22/03656].supported by the Spanish Ministry of Science and Innovation(PID2022-137963OB-I00)Generalitat de Catalunya(2021-SGR-00635 AGAUR)+1 种基金CERCA Programme(Generalitat de Catalunya)by ICREA,ICREA-Academia 2020(to SV)。
文摘Alpha-synuclein and Parkinson's disease:Neuronal damage and inflammation caused by the aggregation of alpha-synuclein(α-syn)are central to a group of disorders known as synucleopathies,which includes Parkinson's disease(PD),dementia with Lewy bodies,and multiple system atrophy,among others.PD,the most common synucleinopathy,is the second most prevalent neurodegenerative disease after Alzheimer's disease,and it is the fastest growing.Its primary hallmark is the degeneration of dopaminergic neurons in the substantia nigra pars compacta,disrupting the communication with the striatum.
基金supported by Swiss Center for Applied Human Toxicology(SCAHT AP22-01)(to RN)。
文摘Parkinson's disease(PD)is the second most common neurodegenerative disorder.The clinical manifestations of PD include motor symptoms,such as bradykinesia,resting tremor,rigidity,and nonmotor symptoms,which include disturbances in sleep,gastrointestinal function,and olfaction.PD misdiagnosis rates have been reported to reach approximately 30%,partly owing to the heterogeneity of parkinsonism with non-PD pathologies,and the differential diagnosis of PD from neurodegenerative diseases such as multiple systemic atrophy(MSA)and progressive supranuclear palsy poses another unmet need.
基金National Key Research and Development Program of China(2021YFA1200900 and 2022YFC2409700)the Distinguished Visiting Scholar Program with the University of Macao(to PCK)。
文摘Amyloid oligomers,a brief history:Amyloid diseases encompass a range of human neurological,systemic,a nd metabolic disorders,characterized by the common feature of amyloid fibril and plaque deposition,either intracellularly or extracellularly.Among them,Alzheimer's disease(AD)—manifested by memory loss and cognitive decline—and Parkinson's disease(PD)—underlined by impaired dopamine release and motor dysfunction—are the two most prevalent forms of neurodegenerative conditions that have rapidly become global epidemics.Type 2 diabetes,conversely,is a prevalent metabolic disorder underpinned by pancreatic beta cell loss,elicited primarily by the aggregation and toxicity of human islet amyloid peptide.
文摘Neurodegenerative diseases are a growing burden on healthcare systems.Patients with Alzheimer’s or Parkinson’s diseases(AD or PD)are desperately waiting for innovative solutions that are slow to come,despite several decades of research worldwide.In 2021 and again in 2023,two monoclonal antibodies,aducanumab and lecanemab,have been approved by the U.S.Food and Drug Administration,and a third,donanemab,is currently under review.However,these treatments have very limited efficacy on cognitive functions and are accompanied by major side effects:amyloid-related imaging abnormalities,microhemorrhages,and accelerated brain volume loss(Høilund-Carlsen et al.,2024).
基金supported by the DGIST start-up funds from the Ministry of Science and ICT(2024010330)a National Research Foundation of Korea(NRF)grant funded by the Korea Government(MSIT)(No.RS-2024-00351442)(to TWK).
文摘Parkinson’s disease(PD)is the second most common neurodegenerative disorder.The progressive degeneration of dopamine(DA)producing neurons in the midbrain is the pathological hallmark,which leads to debilitating motor symptoms,including tremors,rigidity,and bradykinesia.Drug treatments,such as levodopa,provide symptomatic relief.However,they do not halt disease progression,and their effectiveness diminishes over time(reviewed in Poewe et al.,2017).
基金supported by the Spanish Ministerio de Ciencia e Innovación/Agencia Española de Investigación(PID2021-124096OB-I00)(to JLV)JGR was granted by Demensfonden,The Royal Physiografic Society of Lund,Neurofonden,The Greta och Johan Kocks stiftelser,and Bertil och Ebon Norlins stiftelse.
文摘Different forms of programmed cell death have been described to participate in the degeneration of dopaminergic neurons in Parkinson’s disease(PD).Given the critical role that disturbance of mitochondrial homeostasis plays in the pathogenesis of PD,apoptosis can be reasonably considered as one of the cell death pathways involved in neuronal loss(Schon and Przedborski,2011).Multiple lines of evidence support that proposal such as the observations in postmortem human brain samples of PD patients including mitochondrial complex I deficiency,reactive oxygen species generation,and oxidative damage to lipids,proteins,and DNA,among others.
基金supported by the Swedish ResearchCouncil and the Swedish Brain Foundation,theCancer Research Funds of Radiumhemmet,theStrategic Research Area in Cancer(StratCan),the Strategic Research Area in Neuroscience(StratNeuro),the Swedish Cancer Society,theSwedish Childhood Cancer Foundation,theKarolinska Institutet Foundation,the InnoHKinitiative of the Innovation and TechnologyCommission of the Hong Kong SpecialAdministrative Region Government(to BJ).Openaccess funding is provided by the KarolinskaInstitute.
文摘In recent years,rising life expectancy has led to a significant increase in the prevalence of neurodegenerative disorders,including Alzheimer’s disease(AD),Parkinson’s disease,and age-related cognitive decline.Additionally,other neurological conditions such as glioblastoma,the most common and aggressive brain tumor in adults have been more frequently reported in aging populations.The brain itself is highly vulnerable to age-related changes,particularly disruptions in homeostatic regulation,which further contribute to its functional decline and heightened susceptibility to disease.This has led to a surge of interest in understanding the cellular and molecular mechanisms driving these changes.
基金supported by Arizona Biomedical Research Commission[ADHS18-198846]the National Institute of Health NINDS[R56-NS109608 and R01-NS122805]Davies,Robert and Peyton,Parkinson’s Disease Research Fund to TF.
文摘The loss of control over movement is one of the most devastating consequences of Parkinson’s disease(PD).The loss of control largely results from the gradual but inexorable destruction of dopamine-producing neurons in the substantia nigra pars compacta.As dopamine levels fall,the ability to initiate,control,learn,and sustain actions declines.Treatment with the dopamine precursor levodopa can partly overcome motor impairments;however,years of use often leads to levodopa-induced dyskinesia(LID),a debilitating condition characterized by uncontrolled writhing and ballistic movements,making continued treatment difficult or impossible.While progress has been made towards unraveling the molecular and cellular processes driving the development of LID,far less is known about the changes in ongoing neuronal activity that contribute to LID expression.
文摘A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.
基金This work was supported by PID2022-138285OB-I00financiado por MCIN/AEI/10.13039/501100011033/FEDER,UE to AGO and MCTAsociación de Amigos fellowship grant to MGG.
文摘Parkinson’s disease(PD)is a progressive age-related neurodegenerative disorder clinically defined by motor symptoms and pathologically by the loss of dopaminergic(DA)neurons in the substantia nigra pars compacta.These neurons are characterized by the presence of the cytoplasmic pigment neuromelanin(NM),and their degeneration is closely associated with the accumulation ofα-synuclein(α-syn)into intraneuronal inclusions known as Lewy bodies(LBs),which represent a neuropathological hallmark of PD.
基金supported by OHSU Neurology Foundation Funds and NIH Grant R01NS119226 to IM.
文摘Oxidative stress has long been implicated as a driving force in neurodegenerative disease,with studies of human brain tissue and animal models revealing its important role.Parkinson’s disease(PD),in particular,highlights the selective vulnerability of neurons to the insults of reactive oxygen species.The motor symptoms of PD are caused by degeneration of dopamine neurons in the substantia nigra.These neurons experience increased oxidative stress due in part to highly active mitochondria that support their high bioenergetic demand and the generation of reactive oxygen species by dopamine metabolism(Watanabe et al.,2024).
基金supported by grants from the Deutsche Forschungsgemeinschaft(HU 2614/1-1(Project No.462650276))the Fritz Thyssen Foundation(10.21.1.021MN)the Medical faculty of the University of Saarland(HOMFOR2016,HOMFORexzellent2017,HOMFOR2024 Anschubfinanzierung)to WH。
文摘Neuroinflammation,the inflammatory response of the central nervous system(CNS),is a common feature of many neurological disorders such as sepsis-associated encephalopathy(SAE),multiple sclerosis(MS),and Parkinson's disease(PD).Prior studies identified cytokines(e.g.,tumor necrosis factor[TNF],interleukin[IL]-1,and IL-6)delivered by resident glial cells and brain-invading peripheral immune cells as the major contributor to neuroinflammation(Becher et al.,2017).In addition to pro-inflammatory cytokines,elevated levels of extracellular purine molecules such as adenosine triphosphate(ATP)and adenosine can be detected upon any pathological insults(e.g.,injury,ischemia,and hypoxia),contributing to the progression of neurological disorders(Borea et al.,2017).
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
文摘Nuclear receptor subfamily 2 group F member 1(NR2F1,also called COUP-TF1)is a transcription factor and part of the steroid/thyroid hormone receptor superfamily(Gay et al.,2002).NR2F1 is an orphan receptor that dimerizes to bind DNA and acts as a repressor as well as an activator of the target genes(Gay et al.,2002;Bertacchi et al.,2019;Bonzano et al.,2023).
文摘Deep brain stimulation(DBS)is an established therapeutic intervention for people with Parkinson’s disease(PwPD)and is increasingly being utilized for other neurological disorders.Although effective in alleviating motor symptoms and reducing medication requirements,DBS has undergone minimal conceptual evolution and still relies on continuous high-frequency electrical stimulation.In Parkinson’s disease(PD),this persistent stimulation may cause adverse effects,including dysarthria,stimulation-induced dyskinesia,impulsivity,and mood alterations.Additionally,the continuous energy demand of current DBS systems accelerates battery depletion,necessitating more frequent battery charging or battery replacement surgeries,increasing risks,burden,and costs.Basic neuroscience research has long demonstrated that exogenous electrical stimulation can induce persistent changes to synaptic connections,known as long-term plasticity.
基金funded by the Russian Science Foundation(grant No.23-74-10092)(to AIS)。
文摘Currently,our understanding of the pathogenesis of major neurodegenerative disorders,such as Alzheimer's,Parkinson's,and Huntington's diseases,is largely shaped by the amyloid cascade hypothesis.Pa rticularly,this hypothesis posits that in Alzheimer's disease,the aggregation of amyloid-beta peptide initiates a series of pathological processes leading to neuronal dysfunction and death(Zhang et al.,2024).
基金supported by ANR(ANR-21CE16-0008-01)ANR(ANR-21-CE16-0008-02 and ANR-23CE52-0007)+1 种基金UNADEV(A22018CS)(to HN)UNADEV(A22020CS)(to SB)。
文摘The mature central nervous system(CNS,composed of the brain,spinal cord,olfactory and optic nerves)is unable to regenerate spontaneously after an insult,both in the cases of neurodegenerative diseases(for example Alzheimer's or Parkinson's disease)or traumatic injuries(such as spinal cord lesions).In the last 20 years,the field has made significant progress in unlocking axon regrowth.
基金supported by the National Institute on Aging(Nos.AG000723 and AG000578)(to VAB)the Fondation Sante(No.19656),Greece 2.0+1 种基金the National Recovery and Resilience Plan’s flagship program TAEDR-0535850the European Research Council(No.101077374-Synapto Mitophagy)(to KP)。
文摘N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.
基金supported by STI2030-Major Project,No,2021ZD0204200(to LX).
文摘Neurodegenerative diseases,which are characterized by progressive neuronal loss and the lack of disease-modifying therapies,are becoming a major global health challenge.The existing neuromodulation techniques,such as deep brain stimulation and transcranial magnetic stimulation,show limitations such as invasiveness,restricted cortical targeting,and irreversible tissue effects.In this context,low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity.This review comprehensively assesses the therapeutic mechanisms,efficacy,and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases,with emphasis on its role in promoting neuronal regeneration,modulating neuroinflammation,and enhancing functional recovery.We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms,enhancing neural repair and regeneration,and alleviating symptoms associated with neurodegenerative diseases.Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors(e.g.,brain-derived neurotrophic factor),promote autophagy to clear protein aggregates,modulate microglial activation,and temporarily open the blood-brain barrier to facilitate targeted drug delivery.Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-βplaques,improve motor and cognitive deficits,and promote remyelination in various disease models.Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer’s disease and alleviate motor symptoms in Parkinson’s disease,all while demonstrating a favorable safety profile.Past studies support the notion that by integrating safety,precision,and reversibility,low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease.However,more advancements are necessary for future clinical application of low-intensity transcranial ultrasound,including optimizing parameters such as frequency,intensity,and duty cycle;considering individual anatomical differences;and confirming long-term efficacy.We believe establishing standardized protocols,conducting larger trials,and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard.Future research should focus on translating preclinical findings into clinical practice,addressing technical challenges,and exploring combination therapies with pharmacological or gene interventions.
