Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,n...Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.展开更多
目的为探讨1型糖尿病增高阿尔茨海默病(Alzhei mer disease,AD)发病风险的机制,采用1型糖尿病大鼠模型,研究tau蛋白过度磷酸化及其形成机制。方法以同龄Wistar大鼠为对照组(CTL),大剂量链脲佐菌素(strepto-zotocin,STZ)造成1型糖尿病大...目的为探讨1型糖尿病增高阿尔茨海默病(Alzhei mer disease,AD)发病风险的机制,采用1型糖尿病大鼠模型,研究tau蛋白过度磷酸化及其形成机制。方法以同龄Wistar大鼠为对照组(CTL),大剂量链脲佐菌素(strepto-zotocin,STZ)造成1型糖尿病大鼠模型(T1DM)。葡萄糖氧化酶法检测血糖,放射免疫法检测血浆胰岛素;蛋白质印迹分析海马内总tau蛋白及tau蛋白上部分位点(Ser199/202、Ser214、Ser396及Ser422)的磷酸化水平及胞质内总糖原合成激酶3β(glycogen synthase kinase 3β,GSK-3β)、磷酸化GSK-3β水平;免疫组化技术分析海马神经细胞内tau蛋白上位点Ser396磷酸化状态;蛋白磷酸酯酶2A(PP2A)、蛋白磷酸酯酶2B(PP2B)试剂盒检测PP2A、PP2B活性。结果T1DM组血糖水平较对照组(CTL)显著升高,血浆胰岛素水平显著下降。T1DM组大鼠海马总tau蛋白水平与CTL组比较差异无显著性意义,但tau蛋白上位点Ser199/202、Ser214、Ser396及Ser422上磷酸化程度有明显升高,Tau-1所检测的Ser199/202位点的非磷酸化水平较CTL组显著降低。免疫组化结果显示T1DM组海马区tau蛋白位点Ser396磷酸化水平显著高于CTL组。两组总GSK-3β水平差异无显著性意义,T1DM组磷酸化GSK-3β水平较CTL组下降,但差异无显著性意义。磷酸酯酶活性检测结果显示,T1DM组PP2A活性显著下降至CTL组的1/3,而PP2B活性不变。结论1型糖尿病大鼠海马中,主要由于PP2A活性下降导致tau蛋白呈Alzhei mer样过度磷酸化改变。展开更多
文摘Objective Repetitive transcranial magnetic stimulation(rTMS)has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease(AD),but the neurobiological mechanisms linking synaptic pathology,neural oscillatory dynamics,and brain network reorganization remain unclear.This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments,molecular profiling,and neurophysiological monitoring.Methods In this prospective double-blind trial,12 AD patients underwent a 14-day protocol of 20 Hz rTMS,with comprehensive multimodal assessments performed pre-and postintervention.Cognitive functioning was quantified using the mini-mental state examination(MMSE)and Montreal cognitive assessment(MOCA),while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living(ADL)scale and combined neuropsychiatric inventory(NPI)-Hamilton depression rating scale(HAMD).Peripheral blood biomarkers,specifically Aβ1-40 and phosphorylated tau(p-tau181),were analyzed to investigate the effects of rTMS on molecular metabolism.Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients,while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization.Furthermore,systematic assessment of correlations between cognitive scale scores,blood biomarkers,and network characteristics was performed to elucidate cross-modal therapeutic associations.Results Clinically,MMSE and MOCA scores improved significantly(P<0.05).Biomarker showed that Aβ1-40 level increased(P<0.05),contrasting with p-tau181 reduction.Moreover,the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores.Post-intervention analyses revealed significant modulations in oscillatory power,characterized by pronounced reductions in delta(P<0.05)and theta bands(P<0.05),while concurrent enhancements were observed in alpha,beta,and gamma band activities(all P<0.05).Network analysis revealed frequency-specific reorganization:clustering coefficients were significantly decreased in delta,theta,and alpha bands(P<0.05),while global efficiency improvement was exclusively detected in the delta band(P<0.05).The alpha band demonstrated concurrent increases in average nodal degree(P<0.05)and characteristic path length reduction(P<0.05).Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181.Additionally,the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band.However,the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands.Conclusion 20 Hz rTMS targeting dorsolateral prefrontal cortex(DLPFC)significantly improves cognitive function and enhances the metabolic clearance ofβ-amyloid and tau proteins in AD patients.This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation,which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks.These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales,blood biomarkers,and EEG——in understanding and monitoring the progression of AD.This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.
