The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”...Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”to date,yields over 33,000 publications.From fundamental biology to potential therapeutic applications,BDNF has clearly garnered extensive and significant attention in the field of neurobiology research.展开更多
Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms...Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.展开更多
In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, n...In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.展开更多
The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipidbilayer vesicles ...The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipidbilayer vesicles secreted by cells that play a crucial role in intercellular communication due to their diverse cargo.Among these,brain-derived extracellular vesicles,which are secreted by various brain cells such as neurons,glial cells,and Schwann cells,have garnered increasing attention.They serve as a promising tool for elucidating Parkinson's disease pathogenesis and for advancing diagnostic and therapeutic strategies.This review highlights the recent advancements in our understanding of brain-derived extracellular vesicles released into the blood and their role in the pathogenesis of Parkinson's disease,with specific emphasis on their involvement in the aggregation and spread of alpha-synuclein.Brain-derived extracellular vesicles contribute to disease progression through multiple mechanisms,including autophagy-lysosome dysfunction,neuroinflammation,and oxidative stress,collectively driving neurodegeneration in Parkinson's disease.Their application in Parkinson's disease diagnosis is a primary focus of this review.Recent studies have demonstrated that brainderived extracellular vesicles can be isolated from peripheral blood samples,as they carryα-synuclein and other key biomarkers such as DJ-1 and various micro RNAs.These findings highlight the potential of brain-derived extracellular vesicles,not only for the early diagnosis of Parkinson's disease but also for disease progression monitoring and differential diagnosis.Additionally,an overview of explorations into the potential therapeutic applications of brain-derived extracellular vesicles for Parkinson's disease is provided.Therapeutic strategies targeting brain-derived extracellular vesicles involve modulating the release and uptake of pathological alpha-synuclein-containing brain-derived extracellular vesicles to inhibit the spread of the protein.Moreover,brain-derived extracellular vesicles show immense promise as therapeutic delivery vehicles capable of transporting drugs into the central nervous system.Importantly,brain-derived extracellular vesicles also play a crucial role in neural regeneration by promoting neuronal protection,supporting axonal regeneration,and facilitating myelin repair,further enhancing their therapeutic potential in Parkinson's disease and other neurological disorders.Further clarification is needed of the methods for identifying and extracting brain-derived extracellular vesicles,and large-scale cohort studies are necessary to validate the accuracy and specificity of these biomarkers.Future research should focus on systematically elucidating the unique mechanistic roles of brain-derived extracellular vesicles,as well as their distinct advantages in the clinical translation of methods for early detection and therapeutic development.展开更多
α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indice...Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9%)and 0.759(with an accuracy of 65.3%),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3%).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.展开更多
BACKGROUND Parkinson’s disease(PD)is commonly accompanied by neuropsychiatric symptoms,such as anxiety and depression,which can significantly impair patients’cognitive function,social engagement,and quality of life....BACKGROUND Parkinson’s disease(PD)is commonly accompanied by neuropsychiatric symptoms,such as anxiety and depression,which can significantly impair patients’cognitive function,social engagement,and quality of life.Psychological resilience has been identified as a critical factor influencing the severity of these emotional disturbances.AIM To explore the relationship between anxiety-depression status and psychological resilience in patients with PD and to identify associated risk factors.METHODS A total of 188 consecutive patients with PD treated at our institution between January 2023 and December 2024 were enrolled.Anxiety was assessed using the Beck Anxiety Inventory(BAI),depressive symptoms were measured with the Geriatric Depression scale(GDS),and psychological resilience was evaluated using the Connor-Davidson Resilience Scale(CD-RISC).Pearson correlation analysis was conducted to examine the relationships among these variables.Furthermore,clinical and sociodemographic characteristics-including gender,age,disease duration,disease severity,comorbidity burden,marital status,gross monthly household income,and educational attainment-were analyzed using univariate analysis and multivariate binary logistic regression to identify the factors influencing psychological resilience.RESULTS The mean BAI score was 22.05±10.52(indicative of moderate anxiety),the mean GDS score was 15.81±5.49(mild depression),and the mean CD-RISC score was 51.03±9.32(moderate resilience).Correlational analysis revealed an inverse relationship between psychological resilience and both anxiety and depression scores,whereas anxiety and depression were positively correlated.Univariate analysis identified disease duration,disease severity,comorbidity burden,gross monthly household income,educational attainment,BAI scores,and GDS scores as variables significantly associated with psychological resilience.Multivariate regression analysis showed that advanced disease stage,a high comorbidity burden,lower gross monthly household income,lower educational attainment,and elevated anxiety and depression scores were independent predictors of reduced psychological resilience.CONCLUSION The findings highlight the prevalence of anxiety and depression among patients with PD and the presence of moderate psychological resilience.Patients with advanced disease stages,multiple comorbidities,lower socioeconomic status,limited education,and higher anxiety and depression scores are particularly vulnerable to diminished psychological resilience.展开更多
BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a...BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a common site for MS plaques,and the medial olivocochlear(MOC)system is located in the superior olivary complex(SOC)of the brainstem.The cochlear nuclei are also involved in the MOC reflex arc.Additionally,the temporal cortex can modulate the SOC and cochlear nucleus,so lesions in the brainstem or temporal cortex may affect the MOC reflex in MS.AIM To investigate efferent auditory system activity in patients with multiple sclerosis via the MOC reflex.METHODS The study included 50 patients with MS and 50 healthy controls.Patients with MS were divided into three subgroups according to cranial magnetic resonance imaging findings:Patients with brainstem lesions(Group 1,n=20);patients with temporal cortex lesions without brainstem involvement(Group 2,n=20);and patients without any lesions in the brainstem or temporal cortex(Group 3,n=10).Tympanometry,acoustic stapedial reflex thresholds,pure-tone audiometry,and transientevoked otoacoustic emission(TEOAE)tests(with and without contralateral noise)were performed for all participants.RESULTS There was no significant difference in pure-tone hearing thresholds or baseline TEOAE amplitudes between the MS and control groups,indicating normal cochlear function in patients with MS;however,MOC reflex suppression was significantly reduced in patients with MS compared to controls(P=0.021).In particular,Group 1(MS with brainstem lesions)showed the lowest mean suppression values,which was significantly lower than that of Group 2 and the control group(P=0.002).By contrast,Group 2 and Group 3 did not significantly differ from controls.Additionally,patients with MS exhibited a sex difference in MOC function:Male patients had significantly lower suppression compared to female patients both within Group 1 and in the MS group as a whole.CONCLUSION The findings indicate that the efferent auditory system(specifically the MOC reflex)is affected by MS.MOC reflex activity was most significantly decreased in patients with MS with brainstem lesions,while temporal cortex lesions alone did not appear to notably impair the MOC reflex.Diminished MOC activity may underlie various auditory difficulties in patients with MS(e.g.,hearing in noise),and loss of efferent suppression could contribute to symptoms such as hyperacusis or tinnitus in this population.Further studies are needed to better understand the relationship between MOC dysfunction and auditory symptoms in MS,as well as the potential diagnostic value of MOC testing in MS.展开更多
Objectives:Anxiety represents one of the most frequently observed non-motor manifestations in patients diagnosed with Parkinson’s disease(PD),yet its neurobiological mechanisms remain largely unclear.The lateral habe...Objectives:Anxiety represents one of the most frequently observed non-motor manifestations in patients diagnosed with Parkinson’s disease(PD),yet its neurobiological mechanisms remain largely unclear.The lateral habenular nucleus(LHb),an essential part of the limbic-monoaminergic system,plays a vital role in emotional regulation and houses serotonin 5-HT_(6)receptors,which are considered promising candidates for anxiolytic therapies.This research aimed to clarify the role of LHb 5-HT_(6)receptors in modulating anxiety-like behaviors within Parkinsonian contexts.Methods:To model PD,rats underwent unilateral 6-hydroxydopamine(6-OHDA)lesions targeting the medial forebrain bundle(MFB),while control animals received sham operations.Anxiety-related responses were examined utilizing the open field test(OFT)and elevated plus maze(EPM).Pharmacological modulation of LHb 5-HT_(6)receptors was achieved via microinjection of either the agonist WAY208466 or the antagonist SB258585.To account for potential locomotor confounds,spontaneous locomotor activity was measured.Results:Animals subjected to MFB lesions exhibited pronounced anxiety-related behaviors.This was evidenced by a reduction in center zone occupancy in the OFT,along with fewer entries into and less time spent within the open arms of the EPM.In the sham-operated rats,administering WAY208466 into the LHb induced anxiety-like behaviors,whereas SB258585 exhibited anxiolytic effects.Interestingly,lesioned rats responded to WAY208466 with anxiolytic effects,while SB258585 elicited anxiety-like behaviors.Notably,both compounds showed efficacy at lower doses among the lesioned rats compared to the sham controls.These behavioral changes occurred without notable alterations in locomotor activity.Conclusion:This study demonstrates that 5-HT_(6)receptors in the LHb exert bidirectional modulatory effects on anxiety-like behavior.In the PD model,the pharmacological actions of 5-HT_(6)receptor agents diverged from those observed in intact animals,suggesting that PD pathology may alter LHb 5-HT_(6)receptor function or sensitivity.These findings indicate that LHb 5-HT_(6)receptors may represent a promising therapeutic target for managing anxiety symptoms in PD.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
文摘Brain-derived neurotrophic factor(BDNF)exerts pleiotropic effects on brain processes including psychiatric disorders,aging,neurodegeneration,and metabolic homeostasis.A simple PubMed search using the key word“BDNF,”to date,yields over 33,000 publications.From fundamental biology to potential therapeutic applications,BDNF has clearly garnered extensive and significant attention in the field of neurobiology research.
文摘Huntington’s disease(HD)is a genetic disease characterized by the progressive degeneration of the striatum and cortex.Patients can present with a variety of symptoms that can broadly be classified into motor symptoms,inclusive of choreatic movements and rigidity,mood and psychiatric symptoms,such as depression and apathy,and cognitive symptoms,such as cognitive decline.The causal mutation underlying HD results from an expansion of a CAG repeat sequence on the IT15 gene,resulting in the formation and accumulation of a mutant huntingtin protein.
文摘In 1872, George Huntington presented his essay “On Chorea” to the Meigs and Mason Academy of Medicine and, in doing so, detailed a disease that would later bear his name. Huntington's disease(HD) is a genetic, neurodegenerative disease that manifests as the loss of motor control,cognitive impairment,and mood and psychiatric changes in paents.
基金supported by the National Natural Science Foundation of China,No.822712782019 Wuhan Huanghe Talents Program+3 种基金2020 Wuhan Medical Research Project,No.20200206010123032021 Hubei Youth Top-notch Talent Training Program2022 Outstanding Youth Project of Natural Science Foundation of Hubei Province,No.2022CFA106Medical Research Program of Huatongguokang,No.2023HT036(all to NX)。
文摘The misfolding,aggregation,and deposition of alpha-synuclein into Lewy bodies are pivotal events that trigger pathological changes in Parkinson's disease.Extracellular vesicles are nanosized lipidbilayer vesicles secreted by cells that play a crucial role in intercellular communication due to their diverse cargo.Among these,brain-derived extracellular vesicles,which are secreted by various brain cells such as neurons,glial cells,and Schwann cells,have garnered increasing attention.They serve as a promising tool for elucidating Parkinson's disease pathogenesis and for advancing diagnostic and therapeutic strategies.This review highlights the recent advancements in our understanding of brain-derived extracellular vesicles released into the blood and their role in the pathogenesis of Parkinson's disease,with specific emphasis on their involvement in the aggregation and spread of alpha-synuclein.Brain-derived extracellular vesicles contribute to disease progression through multiple mechanisms,including autophagy-lysosome dysfunction,neuroinflammation,and oxidative stress,collectively driving neurodegeneration in Parkinson's disease.Their application in Parkinson's disease diagnosis is a primary focus of this review.Recent studies have demonstrated that brainderived extracellular vesicles can be isolated from peripheral blood samples,as they carryα-synuclein and other key biomarkers such as DJ-1 and various micro RNAs.These findings highlight the potential of brain-derived extracellular vesicles,not only for the early diagnosis of Parkinson's disease but also for disease progression monitoring and differential diagnosis.Additionally,an overview of explorations into the potential therapeutic applications of brain-derived extracellular vesicles for Parkinson's disease is provided.Therapeutic strategies targeting brain-derived extracellular vesicles involve modulating the release and uptake of pathological alpha-synuclein-containing brain-derived extracellular vesicles to inhibit the spread of the protein.Moreover,brain-derived extracellular vesicles show immense promise as therapeutic delivery vehicles capable of transporting drugs into the central nervous system.Importantly,brain-derived extracellular vesicles also play a crucial role in neural regeneration by promoting neuronal protection,supporting axonal regeneration,and facilitating myelin repair,further enhancing their therapeutic potential in Parkinson's disease and other neurological disorders.Further clarification is needed of the methods for identifying and extracting brain-derived extracellular vesicles,and large-scale cohort studies are necessary to validate the accuracy and specificity of these biomarkers.Future research should focus on systematically elucidating the unique mechanistic roles of brain-derived extracellular vesicles,as well as their distinct advantages in the clinical translation of methods for early detection and therapeutic development.
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
基金supported by the National Natural Science Foundation of China,No.82071909(to GF)the Natural Science Foundation of Liaoning Province,No.2023-MS-07(to HL)。
文摘Freezing of gait is a significant and debilitating motor symptom often observed in individuals with Parkinson's disease.Resting-state functional magnetic resonance imaging,along with its multi-level feature indices,has provided a fresh perspective and valuable insight into the study of freezing of gait in Parkinson's disease.It has been revealed that Parkinson's disease is accompanied by widespread irregularities in inherent brain network activity.However,the effective integration of the multi-level indices of resting-state functional magnetic resonance imaging into clinical settings for the diagnosis of freezing of gait in Parkinson's disease remains a challenge.Although previous studies have demonstrated that radiomics can extract optimal features as biomarkers to identify or predict diseases,a knowledge gap still exists in the field of freezing of gait in Parkinson's disease.This cross-sectional study aimed to evaluate the ability of radiomics features based on multi-level indices of resting-state functional magnetic resonance imaging,along with clinical features,to distinguish between Parkinson's disease patients with and without freezing of gait.We recruited 28 patients with Parkinson's disease who had freezing of gait(15 men and 13 women,average age 63 years)and 30 patients with Parkinson's disease who had no freezing of gait(16 men and 14 women,average age 64 years).Magnetic resonance imaging scans were obtained using a 3.0T scanner to extract the mean amplitude of low-frequency fluctuations,mean regional homogeneity,and degree centrality.Neurological and clinical characteristics were also evaluated.We used the least absolute shrinkage and selection operator algorithm to extract features and established feedforward neural network models based solely on resting-state functional magnetic resonance imaging indicators.We then performed predictive analysis of three distinct groups based on resting-state functional magnetic resonance imaging indicators indicators combined with clinical features.Subsequently,we conducted 100 additional five-fold cross-validations to determine the most effective model for each classification task and evaluated the performance of the model using the area under the receiver operating characteristic curve.The results showed that when differentiating patients with Parkinson's disease who had freezing of gait from those who did not have freezing of gait,or from healthy controls,the models using only the mean regional homogeneity values achieved the highest area under the receiver operating characteristic curve values of 0.750(with an accuracy of 70.9%)and 0.759(with an accuracy of 65.3%),respectively.When classifying patients with Parkinson's disease who had freezing of gait from those who had no freezing of gait,the model using the mean amplitude of low-frequency fluctuation values combined with two clinical features achieved the highest area under the receiver operating characteristic curve of 0.847(with an accuracy of 74.3%).The most significant features for patients with Parkinson's disease who had freezing of gait were amplitude of low-frequency fluctuation alterations in the left parahippocampal gyrus and two clinical characteristics:Montreal Cognitive Assessment and Hamilton Depression Scale scores.Our findings suggest that radiomics features derived from resting-state functional magnetic resonance imaging indices and clinical information can serve as valuable indices for the identification of freezing of gait in Parkinson's disease.
文摘BACKGROUND Parkinson’s disease(PD)is commonly accompanied by neuropsychiatric symptoms,such as anxiety and depression,which can significantly impair patients’cognitive function,social engagement,and quality of life.Psychological resilience has been identified as a critical factor influencing the severity of these emotional disturbances.AIM To explore the relationship between anxiety-depression status and psychological resilience in patients with PD and to identify associated risk factors.METHODS A total of 188 consecutive patients with PD treated at our institution between January 2023 and December 2024 were enrolled.Anxiety was assessed using the Beck Anxiety Inventory(BAI),depressive symptoms were measured with the Geriatric Depression scale(GDS),and psychological resilience was evaluated using the Connor-Davidson Resilience Scale(CD-RISC).Pearson correlation analysis was conducted to examine the relationships among these variables.Furthermore,clinical and sociodemographic characteristics-including gender,age,disease duration,disease severity,comorbidity burden,marital status,gross monthly household income,and educational attainment-were analyzed using univariate analysis and multivariate binary logistic regression to identify the factors influencing psychological resilience.RESULTS The mean BAI score was 22.05±10.52(indicative of moderate anxiety),the mean GDS score was 15.81±5.49(mild depression),and the mean CD-RISC score was 51.03±9.32(moderate resilience).Correlational analysis revealed an inverse relationship between psychological resilience and both anxiety and depression scores,whereas anxiety and depression were positively correlated.Univariate analysis identified disease duration,disease severity,comorbidity burden,gross monthly household income,educational attainment,BAI scores,and GDS scores as variables significantly associated with psychological resilience.Multivariate regression analysis showed that advanced disease stage,a high comorbidity burden,lower gross monthly household income,lower educational attainment,and elevated anxiety and depression scores were independent predictors of reduced psychological resilience.CONCLUSION The findings highlight the prevalence of anxiety and depression among patients with PD and the presence of moderate psychological resilience.Patients with advanced disease stages,multiple comorbidities,lower socioeconomic status,limited education,and higher anxiety and depression scores are particularly vulnerable to diminished psychological resilience.
文摘BACKGROUND Multiple sclerosis(MS)is known to affect many sensory systems,yet most auditory research in MS has focused on the afferent pathways,with relatively few studies examining efferent function.The brainstem is a common site for MS plaques,and the medial olivocochlear(MOC)system is located in the superior olivary complex(SOC)of the brainstem.The cochlear nuclei are also involved in the MOC reflex arc.Additionally,the temporal cortex can modulate the SOC and cochlear nucleus,so lesions in the brainstem or temporal cortex may affect the MOC reflex in MS.AIM To investigate efferent auditory system activity in patients with multiple sclerosis via the MOC reflex.METHODS The study included 50 patients with MS and 50 healthy controls.Patients with MS were divided into three subgroups according to cranial magnetic resonance imaging findings:Patients with brainstem lesions(Group 1,n=20);patients with temporal cortex lesions without brainstem involvement(Group 2,n=20);and patients without any lesions in the brainstem or temporal cortex(Group 3,n=10).Tympanometry,acoustic stapedial reflex thresholds,pure-tone audiometry,and transientevoked otoacoustic emission(TEOAE)tests(with and without contralateral noise)were performed for all participants.RESULTS There was no significant difference in pure-tone hearing thresholds or baseline TEOAE amplitudes between the MS and control groups,indicating normal cochlear function in patients with MS;however,MOC reflex suppression was significantly reduced in patients with MS compared to controls(P=0.021).In particular,Group 1(MS with brainstem lesions)showed the lowest mean suppression values,which was significantly lower than that of Group 2 and the control group(P=0.002).By contrast,Group 2 and Group 3 did not significantly differ from controls.Additionally,patients with MS exhibited a sex difference in MOC function:Male patients had significantly lower suppression compared to female patients both within Group 1 and in the MS group as a whole.CONCLUSION The findings indicate that the efferent auditory system(specifically the MOC reflex)is affected by MS.MOC reflex activity was most significantly decreased in patients with MS with brainstem lesions,while temporal cortex lesions alone did not appear to notably impair the MOC reflex.Diminished MOC activity may underlie various auditory difficulties in patients with MS(e.g.,hearing in noise),and loss of efferent suppression could contribute to symptoms such as hyperacusis or tinnitus in this population.Further studies are needed to better understand the relationship between MOC dysfunction and auditory symptoms in MS,as well as the potential diagnostic value of MOC testing in MS.
文摘Objectives:Anxiety represents one of the most frequently observed non-motor manifestations in patients diagnosed with Parkinson’s disease(PD),yet its neurobiological mechanisms remain largely unclear.The lateral habenular nucleus(LHb),an essential part of the limbic-monoaminergic system,plays a vital role in emotional regulation and houses serotonin 5-HT_(6)receptors,which are considered promising candidates for anxiolytic therapies.This research aimed to clarify the role of LHb 5-HT_(6)receptors in modulating anxiety-like behaviors within Parkinsonian contexts.Methods:To model PD,rats underwent unilateral 6-hydroxydopamine(6-OHDA)lesions targeting the medial forebrain bundle(MFB),while control animals received sham operations.Anxiety-related responses were examined utilizing the open field test(OFT)and elevated plus maze(EPM).Pharmacological modulation of LHb 5-HT_(6)receptors was achieved via microinjection of either the agonist WAY208466 or the antagonist SB258585.To account for potential locomotor confounds,spontaneous locomotor activity was measured.Results:Animals subjected to MFB lesions exhibited pronounced anxiety-related behaviors.This was evidenced by a reduction in center zone occupancy in the OFT,along with fewer entries into and less time spent within the open arms of the EPM.In the sham-operated rats,administering WAY208466 into the LHb induced anxiety-like behaviors,whereas SB258585 exhibited anxiolytic effects.Interestingly,lesioned rats responded to WAY208466 with anxiolytic effects,while SB258585 elicited anxiety-like behaviors.Notably,both compounds showed efficacy at lower doses among the lesioned rats compared to the sham controls.These behavioral changes occurred without notable alterations in locomotor activity.Conclusion:This study demonstrates that 5-HT_(6)receptors in the LHb exert bidirectional modulatory effects on anxiety-like behavior.In the PD model,the pharmacological actions of 5-HT_(6)receptor agents diverged from those observed in intact animals,suggesting that PD pathology may alter LHb 5-HT_(6)receptor function or sensitivity.These findings indicate that LHb 5-HT_(6)receptors may represent a promising therapeutic target for managing anxiety symptoms in PD.
