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
Time: March 18-21, 2020Venue: SingaporeWebsite: https://adi2020.org/The 34th International Conference of Alzheimer's Disease International (ADI) will take place in Singapore on March 18-21,2020. This unique, multi...Time: March 18-21, 2020Venue: SingaporeWebsite: https://adi2020.org/The 34th International Conference of Alzheimer's Disease International (ADI) will take place in Singapore on March 18-21,2020. This unique, multi⁃disciplinary event brings together all those with an interest in dementia, including researchers, scientists,clinicians, allied healthcare professionals, people living with dementia, family members, care professionals, and staff and volunteersof Alzheimer associations.ADI is proud that its international conference is the longest running and one of the largest international conferences ondementia, attracting over 1, 000 delegates from over 100 countries.展开更多
BACKGROUND New therapies are urgently needed for Alzheimer disease(AD). Sodium oligomannate(GV-971) is a marine-derived oligosaccharide that has been shown to decrease amyloid deposition, reduce neuroinflammation, rec...BACKGROUND New therapies are urgently needed for Alzheimer disease(AD). Sodium oligomannate(GV-971) is a marine-derived oligosaccharide that has been shown to decrease amyloid deposition, reduce neuroinflammation, reconstitute gut microbiota, and improve cognition in animal models of AD. A Phase 3 trial was conducted to assess efficacy and safety of GV-971. METHODS We conducted a Phase 3, double-blind placebo-controlled trial in patients with mild-to-moderate AD. Participants were randomized to receive placebo or GV-971(900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer′s Disease Assessment Scale(ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician′s Interview-Based Impression of Change(CIBIC+), Alzheimer′s Disease Cooperative Study-Activities of Daily Living(ADCS-ADL) scale, and Neuropsychiatric Inventory(NPI). The effect of GV-971 on the cerebral glucose metabolic rate was examined by 18 Fluorine-FDG PET in a subgroup. Safety and tolerability were monitored. RESULTS 818 participants were randomized, of which 408 were assigned to GV-971 and 410 to placebo. A significant drug-placebo difference in favor of GV-971 was present at each measurement time-point on the ADAS-Cog12. The difference between groups with regard to the change from baseline was-2.15 points(95% confidence interval,-3.07 to-1.23;P<0.0001;effect size 0.531) after 36 weeks treatment. There was a trend towards benefit on CIBIC+(P=0.0588) but not on the ADCS-ADL(P=0.5712), NPI(P=0.8004), or the CMRglu. TEAE incidence77% and 76%, comparable between the two groups. Two deaths occurred in the GV-971 group;these were determined not to be related to GV-971. CONCLUSION GV-971 demonstrated significant efficacy in improving cognition and showed sustained improvement across al observation periods. GV-971 was safe and well tolerated.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.
文摘Time: March 18-21, 2020Venue: SingaporeWebsite: https://adi2020.org/The 34th International Conference of Alzheimer's Disease International (ADI) will take place in Singapore on March 18-21,2020. This unique, multi⁃disciplinary event brings together all those with an interest in dementia, including researchers, scientists,clinicians, allied healthcare professionals, people living with dementia, family members, care professionals, and staff and volunteersof Alzheimer associations.ADI is proud that its international conference is the longest running and one of the largest international conferences ondementia, attracting over 1, 000 delegates from over 100 countries.
文摘BACKGROUND New therapies are urgently needed for Alzheimer disease(AD). Sodium oligomannate(GV-971) is a marine-derived oligosaccharide that has been shown to decrease amyloid deposition, reduce neuroinflammation, reconstitute gut microbiota, and improve cognition in animal models of AD. A Phase 3 trial was conducted to assess efficacy and safety of GV-971. METHODS We conducted a Phase 3, double-blind placebo-controlled trial in patients with mild-to-moderate AD. Participants were randomized to receive placebo or GV-971(900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer′s Disease Assessment Scale(ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician′s Interview-Based Impression of Change(CIBIC+), Alzheimer′s Disease Cooperative Study-Activities of Daily Living(ADCS-ADL) scale, and Neuropsychiatric Inventory(NPI). The effect of GV-971 on the cerebral glucose metabolic rate was examined by 18 Fluorine-FDG PET in a subgroup. Safety and tolerability were monitored. RESULTS 818 participants were randomized, of which 408 were assigned to GV-971 and 410 to placebo. A significant drug-placebo difference in favor of GV-971 was present at each measurement time-point on the ADAS-Cog12. The difference between groups with regard to the change from baseline was-2.15 points(95% confidence interval,-3.07 to-1.23;P<0.0001;effect size 0.531) after 36 weeks treatment. There was a trend towards benefit on CIBIC+(P=0.0588) but not on the ADCS-ADL(P=0.5712), NPI(P=0.8004), or the CMRglu. TEAE incidence77% and 76%, comparable between the two groups. Two deaths occurred in the GV-971 group;these were determined not to be related to GV-971. CONCLUSION GV-971 demonstrated significant efficacy in improving cognition and showed sustained improvement across al observation periods. GV-971 was safe and well tolerated.
