BACKGROUND Older adults with mild cognitive impairment(MCI)often show motor dysfunction,including slower gait and impaired handwriting.While gait and handwriting parameters are promising for MCI screening,their combin...BACKGROUND Older adults with mild cognitive impairment(MCI)often show motor dysfunction,including slower gait and impaired handwriting.While gait and handwriting parameters are promising for MCI screening,their combined potential to distinguish MCI from cognitively normal adults is unclear.AIM To assess gait and handwriting differences and their potential for screening MCI in older adults.METHODS Ninety-five participants,including 34 with MCI and 61 cognitively normal controls,were assessed for gait using the GAITRite^(R)system and handwriting with a dot-matrix pen.Five machine learning models were developed to assess the discriminative power of gait and handwriting data for MCI screening.RESULTS Compared to the cognitively normal group,the MCI group had slower gait velocity(Z=-2.911,P=0.004),shorter stride and step lengths(t=-3.005,P=0.003;t=2.863,P=0.005),and longer cycle,standing,and double support times(t=-2.274,P=0.025;t=-2.376,P=0.018;t=-2.717,P=0.007).They also had reduced cadence(t=2.060,P=0.042)and increased double support time variability(Z=-2.614,P=0.009).In handwriting,the MCI group showed lower average pressure(all tasks:Z=-2.135,P=0.033)and decreased accuracy(graphic task:Z=-2.447,P=0.014;Chinese character task:Z=-3.078,P=0.002).In the graphic task,they demonstrated longer time in air(Z=-2.865,P=0.004),reduced X-axis maximum velocities(Z=-3.237,P=0.001),and lower accelerations(X-axis:Z=-2.880,P=0.004;Y-axis:Z=-1.987,P=0.047)and maximum accelerations(X-axis:Z=-3.998,P<0.001;Y-axis:Z=-2.050,P=0.040).The multimodal analysis achieved the highest accuracy(74.4%)with the Gradient Boosting Classifier.CONCLUSION Integrating gait and handwriting kinematics parameters provides a viable method for distinguishing MCI,potentially supporting large-scale screening,especially in resource-limited settings.展开更多
Insulin secretion is mainly regulated by two electrophysiological events,depolarization initiated by the closure of adenosine triphosphate(ATP)-sensitive K^(+)(K_(ATP))channels and repolarization mediated by K^(+)effl...Insulin secretion is mainly regulated by two electrophysiological events,depolarization initiated by the closure of adenosine triphosphate(ATP)-sensitive K^(+)(K_(ATP))channels and repolarization mediated by K^(+)efflux.Quinine,a natural component commonly used for the treatment of malaria,has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting K_(ATP)channels.In this study,we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets.We also revealed that low-dose quinine(<20μM)did not directly provoke Ca^(2+)spikes or insulin secretion under low-glucose conditions but potentiated Ca^(2+)influx and insulin secretion induced by high glucose,which cannot be explained by K_(ATP)inhibition.KCNH6(hERG2)is a voltage-dependent K^(+)(Kv)channel that plays a critical role in the repolarization of pancreaticβcells.Patch clamp experiments showed that quinine inhibited hERG channels at low micromolar concentrations.However,whether quinine can target KCNH6 to potentiate glucose-induced insulin secretion remains unclear.Here,we showed that in vivo administration of low-dose quinine(25 mg/kg)improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout(βKO)mice.Consistently,in vitro treatment of primary isletβcells with low-dose quinine(10μM)prolonged action potential duration and augmented glucose-induced Ca^(2+)influx in the wild-type control group but not in the Kcnh6-βKO group.Our results demonstrate that KCNH6 plays an important role in low-dose quinine-potentiated insulin secretion and provide new insights into KCNH6-targeted drug development.展开更多
基金Supported by National Natural Science Foundation of China,No.72174061 and No.71704053Key Research and Development Program of Zhejiang Province,No.2025C02106+1 种基金China Scholarship Council Foundation,No.202308330251Health Science and Technology Project of Zhejiang Provincial Health Commission,No.2022KY370。
文摘BACKGROUND Older adults with mild cognitive impairment(MCI)often show motor dysfunction,including slower gait and impaired handwriting.While gait and handwriting parameters are promising for MCI screening,their combined potential to distinguish MCI from cognitively normal adults is unclear.AIM To assess gait and handwriting differences and their potential for screening MCI in older adults.METHODS Ninety-five participants,including 34 with MCI and 61 cognitively normal controls,were assessed for gait using the GAITRite^(R)system and handwriting with a dot-matrix pen.Five machine learning models were developed to assess the discriminative power of gait and handwriting data for MCI screening.RESULTS Compared to the cognitively normal group,the MCI group had slower gait velocity(Z=-2.911,P=0.004),shorter stride and step lengths(t=-3.005,P=0.003;t=2.863,P=0.005),and longer cycle,standing,and double support times(t=-2.274,P=0.025;t=-2.376,P=0.018;t=-2.717,P=0.007).They also had reduced cadence(t=2.060,P=0.042)and increased double support time variability(Z=-2.614,P=0.009).In handwriting,the MCI group showed lower average pressure(all tasks:Z=-2.135,P=0.033)and decreased accuracy(graphic task:Z=-2.447,P=0.014;Chinese character task:Z=-3.078,P=0.002).In the graphic task,they demonstrated longer time in air(Z=-2.865,P=0.004),reduced X-axis maximum velocities(Z=-3.237,P=0.001),and lower accelerations(X-axis:Z=-2.880,P=0.004;Y-axis:Z=-1.987,P=0.047)and maximum accelerations(X-axis:Z=-3.998,P<0.001;Y-axis:Z=-2.050,P=0.040).The multimodal analysis achieved the highest accuracy(74.4%)with the Gradient Boosting Classifier.CONCLUSION Integrating gait and handwriting kinematics parameters provides a viable method for distinguishing MCI,potentially supporting large-scale screening,especially in resource-limited settings.
基金supported by grants from the National Natural Science Foundation of China(82070890 to J.L.and 81930019 to J.-K.Y.)Beijing Natural Science Foundation(7232230 to J.L.).
文摘Insulin secretion is mainly regulated by two electrophysiological events,depolarization initiated by the closure of adenosine triphosphate(ATP)-sensitive K^(+)(K_(ATP))channels and repolarization mediated by K^(+)efflux.Quinine,a natural component commonly used for the treatment of malaria,has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting K_(ATP)channels.In this study,we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets.We also revealed that low-dose quinine(<20μM)did not directly provoke Ca^(2+)spikes or insulin secretion under low-glucose conditions but potentiated Ca^(2+)influx and insulin secretion induced by high glucose,which cannot be explained by K_(ATP)inhibition.KCNH6(hERG2)is a voltage-dependent K^(+)(Kv)channel that plays a critical role in the repolarization of pancreaticβcells.Patch clamp experiments showed that quinine inhibited hERG channels at low micromolar concentrations.However,whether quinine can target KCNH6 to potentiate glucose-induced insulin secretion remains unclear.Here,we showed that in vivo administration of low-dose quinine(25 mg/kg)improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout(βKO)mice.Consistently,in vitro treatment of primary isletβcells with low-dose quinine(10μM)prolonged action potential duration and augmented glucose-induced Ca^(2+)influx in the wild-type control group but not in the Kcnh6-βKO group.Our results demonstrate that KCNH6 plays an important role in low-dose quinine-potentiated insulin secretion and provide new insights into KCNH6-targeted drug development.
