| Objective:To explore the characteristics of plasma biomarkers,hippocampal volume,and the clinical effect of kidney medicine therapy in patients with amnestic mild cognitive impairment(aMCI),so as to provide evidence for early diagnosis and early treatment of Alzheimer’s disease(AD).Methods:Study 1:110 subjects were divided into normal control group(NC,n=40),aMCI group(n=40)and AD group(n=30).Plasma was extracted from the collected fasting peripheral blood.The levels of plasma β-amyloid protein(Aβ,including Aβ40,Aβ42,Aβ38)and neurofilament light chain protein(NFL)were detected by electrochemiluminescence(ECL),and enzyme-linked immunoassay(ELISA)was used to detect plasma monocyte chemoattractant protein 1(MCP-1)level,and the differences of the above indicators in different groups were analyzed.Receiver operating characteristic curve(ROC)was used to analyze the performance of plasma biomarkers alone or in combination(ratio or logistic regression model)in the diagnosis of aMCI and AD,and analyzed their correlation with cognitive function.Study 2:75 subjects were divided into NC group(n=40)and aMCI group(n=35),the hippocampal body area was manually delineated on the magnetic resonance image(MRI),and the hippocampal volume(HV)was measured by software.The differences in HV between the two groups were analyzed.ROC curve was used to analyze the performance of HV in the identification of aMCI and NC,and to analyze its correlation with cognitive function.Study 3:A 24-week randomized,double-blind,placebo-controlled clinical trial was conducted,in which 59 aMCI subjects were divided into kidney-tonifying treatment group(n=29)and placebo control group(n=30),and the intervention period was 24 weeks.Intention to treat-last observation carry forward(ITT-LOCF)and Per-protocal set(PPS)methods were used to assess the treatment effect.Safety analysis was performed.Results:1.Plasma biomarkers:(1)Differences between groups:The plasma Aβ40 level in AD group was significantly higher than NC(P=0.003)and aMCI(P=0.035),and the plasma A(342 level in AD group was significantly lower than NC(P=0.006).The plasma Aβ42/Aβ40 ratio gradually decreased between the NC,aMCI and AD groups,and there were significant differences between any two groups(P<0.05).Plasma NFL level in AD group was significantly higher than NC(P=0.000)and aMCI(P＝0.000).Compared with NC,plasma Aβ40 and NFL levels in the cognitive impairment group(aMCI+AD)were significantly increased(P=0.020,P=0.001),plasma Aβ42 level and Aβ42/Aβ40 ratio were significantly reduced(P=0.044,P=0.000).There was no significant difference in plasma MCP-1 level between any two groups.(2)Correlation between plasma biomarker level and cognitive function(age controlled):In the cognitive impairment group(aMCI+AD),plasma NFL level was significantly negatively correlated with global cognition(MMSE)(β=-0.259,P=0.024)and significantly positively associated with the severity of dementia(CDR-SB)(β=0.240,P=0.046).In all subjects(NC+aMCI+AD),plasma Aβ40 and NFL levels were significantly negatively correlated with MMSE and episodic memory(DSR)scores(P<0.05),and significantly positively associated with CDR-SB(β＝0.211,P=0.022;β=0.323,P=0.000).Plasma Aβ42/Aβ40 ratio was significantly positively correlated with MMSE and DSR scores(β=0.269,P=0.004;β=0.267,P＝0.005)and significantly negatively correlated with the CDR-SB(β＝-0.289 P=0.003).(3)Diagnostic performance of plasma biomarkers:The area under the curve(AUC)of plasma biomarkers alone or in combination for the identification of AD and NC were:AUCNFL=0.831,AUCAβ42/Aβ40=0.858,AUCLogistic(Aβ40,Aβ42)=0.867,AUCLogistic(Aβ42,NFL)=0.889.The accuracy of combination of Aβ40,Aβ42 and NFL[Logistic(Aβ40,Aβ42,NFL)]in identifying NC and AD was the best(AUC=0.914),with a sensitivity of 0.867 and a specificity of 0.825.However,the above plasma biomarkers had lower accuracy in identifying aMCI and NC,aMCI and AD,(aMCI+AD)and NC(AUC<0.789).2.Hippocampal volume on MRI:(1)The left,right and total HV of aMCI were significantly lower than those of NC(P<0.05).The total HV of NC and aMCI were(6958.62±1154.78)and(6226.93± 1135.80)mm3.(2)In NC,aMCI and(NC+aMCI)subjects,the left,right and total HV were significantly negatively correlated with age(P<0.01).In the aMCI group,the left and right HV were significantly positively correlated with the orientation in MMSE(β=0.333,P=0.009;β＝0.323,P=0.007)after controlling age.The total HV was significantly positively correlated with DSR and orientation in MMSE(β＝0.244,P＝0.047;β＝0.339,P=0.005).(3)The accuracy of left,right and total HV for identifying NC and aMCI was low(AUC＝0.640,0.646,0.641;P<0.05).3.Clinical effect of kidney-tonifying treatment:Both ITT-LOCF and PPS analysis showed that the cognitive endpoint(ADAS-cog)scores of the test group at week 12 and 24 were significantly lower than that of the baseline(P<0.05),and the cognitive improvement of the test group at week 24 was significantly better than that of the control group(PITT-LOCF=0.026,PPPS=0.040).ITT-LOCF analysis showed that the improvement of ADAS-cog comprehension in the test group was significantly better than that in the control group at each observation point(Pweek4=0.021,Pweek 12=0.045,Pweek24=0.016).PPS analysis of MMSE scores showed that the experimental group was significantly higher than the baseline at week 24(P=0.034)and the improvement was better than the control group(P=0.047).ITT-LOCF and PPS analysis showed that at week 12 and 24,the improvement of MMSE delayed word recall in the experimental group was significantly better than that in the control group(PITT-LOCF<0.05,PPPs<0.05).Kidney deficiency syndrome(CGIS-KDS)score in test group was significantly lower than that in the control group(PITT-LOCF=0.033,PPPS=0.040)at week 24,and the improvement rate of kidney deficiency subjects in the test group was significantly higher than that in the control group(ITT-LOCF:15/27 vs 9/29,P=0.000;PPS:14/23 vs 8/25,P=0.000).There was no significant difference in the incidence of adverse events between the two groups(P=0.807).Conclusion:1.The plasma Aβ42/Aβ40 ratio in aMCI is significantly lower than that of NC.The plasma Aβ40 and NFL level in AD are significantly higher and plasma Aβ42 level,Aβ42/Aβ40 ratio lower than that in NC.Plasma Aβ42/Aβ40 ratio and the combination of Aβ 40,Aβ 42 and NFL(Logistic regression model of Aβ 40,Aβ42 and NFL)show high accuracy in the diagnosis of AD.Elevated plasma Aβ40 and NFL and decreased Aβ42/Aβ40 ratio are associated with poor cognitive function.2.The quantitative measurement value of hippocampus volume in aMCI patients decreases compared with NC,and it is associated with age and memory decline,but the accuracy of distinguishing aMCI from normal elderly is low.3.Tonifying kidney is probably effective and safe in the treatment of cognitive function and kidney deficiency in patients with aMCI. |
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