| Brain aging refers to the degenerative changes of brain tissue in structure and function with age increasing.Along with the brain aging progression,learning and memory ability declined in healthy elderly,especially connection memory.Concurrently,endocrine function decreased with ageing.Endocrine dysfunction is related to abnormal thyroid hormone secretion and blood lipid regulation disorder.The level of Thyroid hormone is regulated by the hypothalamus-pituitary-thyroid axis(HPT).The thyroid stimulating hormone(TSH)increased after HPT axis activation,then increase the secretion of thyroid hormone via a positive feedback.Thyroid hormone promotes lipids degradation.Some research reported that the level of TSH may be positively correlated with cognition.Patients with hyperlipidemia have higher risk of Alzheimer's disease(AD)and vascular dementia(VD)after middle-age,Increased blood lipid will further aggravate the damage of cognitive function.Therefore,Study on blood lipid control and increase TSH has great importance for improving cognitive function the elderly.How to prevent brain aging and delay dementia is a hot topic of current neuroscience.Repetitive transcranial magnetic stimulation(rTMS),a painless and noninvasive cortex stimulation method,has the advantages of convenient operation,safe and reliable,is widely used in clinical in recent years.Our previous study revel that rTMS can improve aging related cognitive dysfunction in aging mice.At the same time,we found that cholesterol levels decreased in prefrontal area after a whole brain rTMS intervention to the aged mice.The decrease of cholesterol level were positively correlated with cognitive function.r TMS stimulation may change the cell membrane potential,then result in the changes in cell function and initiate the changes of cell metabolism.Neural plasticity may be involved in this progress.Our recent study using resting-state functional magnetic resonance imaging(fMRI)showed that the brain plasticity of the elderly were modulated by the rTMS.Although brain plasticity retains in the elderly,the level of plasticity decreased with aging,suggested that early intervention is necessary.However,there is no systematic study about the effect of rTMS intervention on the healthy elderly,and early intervention in brain aging also is less.Little study had focus on the effects of rTMS on endocrine and the results were inconsistent.Whether blood lipid and peripheral endocrine change are relate to the cognition impairment in the elderly and whether the metabolism of the brain is adjusted by changing the synaptic plasticity to act on the HPT axis has not been reported.In this study,we aimed:(1)to observe whether the rTMS intervention can improve cognitive function in the elderly and explore its potential endocrine mechanism.(2)to discuss the mechanisms of rTMS on brain aging related cognitive impairment by detect hippocampal synaptic related protein and mRNA.This study can provide an theoretical support for the opinion that change of peripheral endocrine may be involve in the regulation of brain plasticity.Part one The effect of repetitive transcranial magnetic stimulation oncongition in older adultsObjective: To explore the effect of the rTMS on the associative memory(especially connection memory)in healthy older adults.Methods:1 50 elderly subjects were recruited after screened,then were randomly assigned to magnetic stimulation intervention group(rTMS group)and the control group(Sham group)according to random number table method,25 cases in each group.rTMS group was given 10 Hz rTMS applied to subjects of right DLPFC,intervention cycle is 2 weeks,five times a week,and intervention for 20 minutes at a time.In Sham group,the parameter was set the same as the rTMS group,subjects were treated by the perpendicular side of the coil for a sham purpose.2 Before r TMS intervention,cognitive function were assessed by neuropsychological test(pretest)as a baseline record.3 Two groups of the elderly participate in neuropsychological test after rTMS to assess the effect of intervention.2 cases in rTMS group and 3 cases in the Sham group quited after the whole schedule.Results:1 No significantly difference between two groups were found in the age,gender,education,complaint and MoCA(P>0.05).2 The overall cognitive function assessment showed that the scores of cognitive function between two groups had no statistical difference before rTMS intervention(P>0.05).After rTMS,the scores of Face-name and PALT significantly improved in r TMS group(P<0.05).In Sham group,compared to the data before rTMS,the scores of Face-name,PALT,DSF were increased after rTMS,but no statistical difference was found(P>0.05).Compared the score difference of cognitive function between the two groups after intervention,DSB and Face-name have significant statistical difference(P< 0.05),the rest of the cognitive function score had no significant statistical difference(P>0.05).Part two The endocrine mechanisms of repetitive transcranial magneticstimulation on improving the cognition in older adultsObjective: To discuss the underlying endocrine mechanisms of rTMS on improving the cognition in older adults through detecting the change of peripheral blood lipid,serum thyroid hormone after rTMS intervention.Methods:1 43 cases of the elderly subjects who were recruited and screened,then were randomly assigned to magnetic stimulation intervention group(r TMS group)and the control group(Sham group)according to random number table method,22 cases in rTMS group,21 cases in Sham group.rTMS group was given 10 Hz rTMS applied to subjects of right DLPFC,intervention cycle is 2 weeks,five times a week,and intervention for 20 minutes at a time.In Sham group,the parameter was set the same as the rTMS group,subjects were treated by the perpendicular side of the coil for a sham purpose.2 All subjects were draw blood at 8:00 am before rTMS intervention,the blood samples were collected to detect the blood lipids and thyroid hormone.3 All subjects were draw blood at 8:00 am after rTMS intervention,the blood samples were collected to detect the blood lipids and thyroid hormone.In whole experiment process,8 cases in rTMS group and 5 cases in the Sham group were lost.Results:1 No significantly difference between two groups was found in age,gender,education,complaint and MoCA(P>0.05).2 Serum TH level between two groups had no statistical difference before rTMS intervention(P>0.05),After the rTMS intervention,TSH,T4 were significantly higher than that of before intervention in rTMS group(P<0.05,P<0.01).After intervention,T3,T4,TSH level were decreased compared with that of before intervention in the Sham group,but no significant difference was found(P>0.05).After the intervention,the difference value of serum TH were no significantly different between two groups(P>0.05).3 The blood lipid level between two groups had no statistical difference before rTMS intervention(P>0.05).In rTMS group,CHO,TG,Apo-B were significantly lower after rTMS intervention(P<0.05).In sham group,after rTMS intervention,the CHO,TG,HDL,LDL-C,Apo-A1 showed a tendency of increase compared with the level before intervention,but no significant statistical difference was shown(P>0.05).The Apo-B was increased after intervention,as well as the difference was statistically significant(P<0.05).After intervention,the difference value of each index,i.e.CHO,TG,LDL-C,Apo-A1,Apo-B have significant statistical difference between two groups(P<0.05).However,no significance was found in HDL-C between two groups(P>0.05).4 The overall cognitive function assessment showed that the scores of cognitive function between two groups had no statistical difference before rTMS intervention(P>0.05).After rTMS,the scores of Face-name,PALT,DSF and DSB were significantly improved in rTMS group(P<0.05).In Sham group,compared to the data before rTMS,the scores of Face-name,PALT and DSF were increased after rTMS,but no statistical difference was found(P>0.05).Compared the score difference of cognitive function between the two groups after intervention,the cognitive function score had no significant statistical difference(P>0.05).5 The Correlation analysis between blood lipids,serum TH and cognitive function showed: CHO values rTMS group decreased within a certain range,meanwhile Face-name score increased.TSH level increased,accompanied by PLAT score decreased.CHO values and Face-name score in rTMS group was significantly negative correlated(r=-0.628,P=0.016).In rTMS group TSH values and PLAT scores were significantly positively correlated(r=0.600,P=0.023).Part three The effect of rTMS on cognition and synaptic plasticity relatedmarkers in SAMP8 miceObjective: To examine whether 5Hz rTMS with 30% maximum output could improve cognitive functions in SAMP8 mice and explore the mechanisms.Methods:1 SAMP8 and senescence-accelerated-prone mouse/resistant 1(SAMR1)(7-month old male)mice were randomly divided into 3 groups: SAMP8 rTMS group(P8-rTMS),SAMP8 sham-r TMS group(P8-sham),and SAMR1 sham-rTMS group(R1-sham).The P8-rTMS group was treated daily with 5Hz r TMS with 30% maximum output for 14 consecutive days,whereas the other two groups were controls without rTMS stimulation.n=20/group.2 Morris water maze(MWM)experiment was performed after rTMS or sham treatment to assess the effect of rTMS on cognitive function in mice among different groups.3 The hippocampus were dissected on ice and stored at-80 ?after two weeks rTMS intervention.4 The expression of SYN,PSD95,BDNF and TrKB in hippocampus of mice were analyzed by western blotting.5 The expression of SYN,PSD95,BDNF and TrKB in hippocampus of mice were analyzed by reverse transcription-polymerase chain reaction.Results:1 The mean escape latency of each mouse finding the platform from the four quarters was recorded in each of the five days.The mean escape latency of the mice became shorter with time during the course of the trials.The mean escape latency of P8-rTMS group was significantly shorter than that of P8-sham group(P=0.022<0.05).The mean escape latency was markedly shorter in R1-sham group than in P8-rTMS group or P8-sham group(P<0.01).Differences among groups were clearly shown at day 6(R1-sham Vs P8-sham or P8-rTMS,P<0.01,and P8-rTMS Vs P8-sham,P=0.019<0.05).The number of platform crossings was markedly higher in R1-sham group than those in P8-rTMS group or P8-sham group(P<0.01).The number of platform crossings for the P8-rTMS group was significantly higher than those for P8-sham groups(P<0.01).These results suggest that 14 days of rTMS could significantly reverse the impairments of learning and memory in SAMP8 mice,but could not recover to levels as in SAMR1 mice.2 To evaluate the effect of rTMS on synaptic plasticity,we examined the expressions of SYN,PSD95,BDNF and TrkB in the hippocampus of P8-rTMS,P8-sham,and R1-sham mice at protein level.Our results showed that 14 days of rTMS significantly upregulated the protein expression of SYN,PSD95,BDNF and TrkB in the hippocampus of p8-rTMS mice compared to those in P8-sham mice(P<0.05),yet it was lower than the normal level shown in R1-sham control mice(P<0.05).3 RT-PCR was performed on hippocampal samples collected from P8-rTMS,P8-sham,and R1-sham mice.The mRNA expression levels of Syn,Psd95,Bdnf and TrkB in the different groups were consistent with those of the corresponding proteins.In addition,the highest mRNA levels of Syn,Psd95,Bdnf and Trk B were in the R1-sham group,significantly higher than those in the P8-Sham group and P8-rTMS group(P<0.05).Results from the semiRT-PCR and relative mRNA expression analyses revealed that rTMS significantly upregulated the mRNA expression of SYN,PSD95,BDNF and TrkB in p8-rTMS mice compared to those in the P8-sham mice(P<0.05).Conclusion:1 RTMS improved associative memory,ameliorated the cognitive function in healthy elderly.This experiment provides an effective intervention for the treatment of age-related cognitive dysfunction.2 RTMS improved the blood lipid levels in healthy elderly.T3,T4,TSH increased after rTMS intervention.HPT axis regulating TH might be involved as a mechanism.3 Compared with the SAMR1 mice,learning and memory ability reduced in the 7 months of SAMP8 mice,however,14-day rTMS(5Hz,30% maximum output intensity)may ameliorate the learning and memory dysfunction in SAMP8 mice.4 After 14-day rTMS(5Hz,30%maximum output intensity)intervention,the protein and mRNA expression of SYN,PSD95,BDNF and Trk B in the hippocampus were increased in SAMP8 mice,it may be a potential mechanism of rTMS improve cognitive function in SAMP8 mice.We speculate that the change of peripheral blood lipids and HT may be related to the regulation of brain plasticity in elderly,then regulated the HPT. |
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