Correlation Between TCM Syndromes, Olfactory And Biomarkers And The Outcome Of Mild Cognitive Impairment

ObjectiveMild cognitive impairment(MCI)is the characterization of transition between normal cognitive(NC)aging and the earlest manifestations of dementing disorders,which may reverse to NC,remain stable or progress to dementia.The purpose of this research is to investigate the characteristic and predictive utility of Traditional Chinese Medicine(TCM)syndromes elements,plasma biomarkers and odor identification deficits as indicators for MCI conversion.Method(1)Volunteers from clinical patient of Dongzhimen Hostipal and community nearby during Sep,2015 to Dec,2017,were assessed by neuropsychology test,TCM syndromes elements scoring and smell identification test.Blood samples were collected from the eligible subjects to detect genotype of Apolipoprotein E(APOE)gene and concentration of three plasma proteins,including Transthyretin(TTR),β-amyloid 1-40(AP40)and β-amyloid 1-42(Aβ42).Paticipants were classified as NC,MCI and dementia according to the results of neuropsychological assessment.The characteristics of TCM syndrome,plasma protein concentrations,polymorphism of the APOE gene,and the difference of olfactory score were compared among the three groups.The correlation between cognitive function and biomarkers&olfactory were analysesed.(2)On the basis of cross-sectional study,94 cases of MCI patients were followed up for 12 months.Scoring of TCM syndromes were performed every 3 months after baseline.Neuropsychological assessment and olfactory test were carried out every 6 months.The longitudinal variation of TCM syndrome and olfactory score in MCI patients was recorded,the correlation with the variation of cognitive function of them were analysesed.(3)According to the cognitive outcome over 12 months follow-up,MCI patients were divided into group R(reverse to NC),group S(remain stable)and group P(progression to dementia).The cognitive function,TCM syndrome,olfactory score,three plasma protein concentrations and the polymorphism of APOE gene were compared in group R,S and P,investigating the utility of them as indicators for MCI conversion.Result(1)490 participants(NC=149,MCI=189 and dementia =152)were enrolled.The results showed that TCM syndromes in MCI patients were mainly distributed in phlegm turbidity(32.28%),kidney deficiency(28.57%),and marrow depletion(26.46%).Olfactory test and blood collection were administrated in 162 subjects(NC=33,MCI=94 and dementia =35).The results showed that the olfactory score in the MCI group(6.24 ＋ 1.79)was significantly higher than that in the dementia group(4.40± 1.52)(P<0.01),and was significantly lower than that in the NC group(8.94±1.32)(P<0.01).Choosing olfaction score as an indicator of distinguish MCI from NC,the area under the ROC curve is 0.8732.When the cut-off is 7,the sensitivity was 0.78 and the specificity was 0.88.As an indicator of distinguish MCI from dementia,the area under the ROC curve is 0.7556 for olfaction score,the cut-off is 6 and the sensitivity was 0.66 and the specificity was 0.77.In MCI patients,the olfactory score was positively correlated with Mini-mental state examination(MMSE)(=0.278,P=0.007)and MCI-activity of daily living(MCI-ADL)(r=0.337,P=0.002).When comes to the proteins in plasma,there were no notable difference for TTR、Aβ40、Aβ42、Aβ40/Aβ42、TTR/Aβ42 among the 3 groups(P>0.05).Regarding MCI patients,TTR concentration(r=-0.218,P=0.038)and TTR/Aβ42(r=-0.228,P=0.040)are negatively correlated with ADL level.Aβ40 concentration is positively correlated with Activity of Daily Living(ADL)score(r=0.222,P=0.035),and Clinical dementia rating scale-sum boses(CDR-SB)score(r=0.210,P=0.047).104 subjects(NC=18,MCI=51,and dementia =35)tested successfully for the APOE gene.The carrying rates of the ε2,s3,and ε4 alleles in MCI group were 5.88%,70.59%,23.53%,while 2.86%,57.14%,40%in dementia group,and 13.89%、77.78%、8.33%in NC group,carrying rates of the ε4 alleles of dementia group was the highest(P=0.001),there showed no significant difference of cognitive function between ε4 carriers and non s4 carriers in MCI group(P>0.05).(2)78 of 94(82.98%)patients with MCI completed the 12-month followed-up.Over the follow up,kidney deficiency(P<0.01),marrow depletion(P<0.01)and phlegm turbidity(P<0.01)were all higher than the baseline.At 6th month and 12th month,the variation of marrow depletion(P<0.01)and phlegm turbidity(P<0.05)score were positively correlated with the variation of CDR-SB.The variation of phlegm turbidity score(P<0.05)was positively correlated with the variation of ADL at 6th month and 12th month.Olfactory scores did not show significant changes during follow-up(P>0.05).In MCI group,the variation of ADL(1.27±1.19,P =0.026)and CDR-SB(1.09±1.11,P =0.035)score of s4 carriers were higher than those of the non,s4 carriers(0.45±0.76,0.46±0.58).Compared with non-ε2 carriers(-1.00± 1.44),the variation of MMSE(0.75±1.26,P =0.027)score of ε2 carriers was less.(3)Over the 12-month followed-up,16 subjects reversed to NC(group R),62 remained stable(group S),16 progressed to dementia(group P),according to the last cognitive assessment of 94 patients with MCI.The rate of dementia-conversion in 1 year was 17.02%.The results showed that there was no significant difference in TCM syndrome scores between the three groups at baseline.During the follow-up process,the increase of the score of kidney deficiency,marrow depletion and phlegm turbidity in group P was higher than that in the S group,also higher than that in the group R(P<0.05).The score of olfactory scorein group R(7.69± 1.30)was higher than that in group S(5.97±1.90),and higher than that in group P(4.69±1.62)(P<0.01).There were no significant changes of the olfactory score in the three groups during the follow-up.Meanwhile,it showed the highest plasma concentration of TTR in group S,the lowest level in group P(P<0.001).51 of 94 subject with MCI detected APOE gene successfully,including 4 in group R,39 in group S,and 8 in group P.The carrying rate of ε2,ε3,and s4 were 6.25%、50.00%、37.50%in group P,while 3.85%、75.64%、19.23%in group S and 25.00%,62.50%,12.50%in group R.With "group P" and“group S" as the dependent variables,a single factor and Logistic analysis of TCM syndrome score,cognitive function,olfactory score,three plasma protein concentrations and ratios and APOE gene polymorphism at baseline were carried out.The results showed that the plasma TTR concentration(OR=0.981,95%CI:0.965-0.998,P=0.029),delayed story recall(DSR)score(OR=0.727,95%CI:0.574～0.921,P=0.008)and MMSE score(OR=0.151,95%CI:0.041-0.551,P=0.004)were independent influencing factors of progressing to dementia in 1 year of MCI group.The model buit for predicting risk of MCI group progressing to dementia in 1 year is:p=ex/(1+ex),x= x=55.2294-(0.3185×DSR)-(0.0190×TTR)-(1.8902×MMSE).These three factors were defined as indicators of judging the progression to dementia in 1 year of MCI group,3 ROC curves were drawn respectively.The area under the curve of plasama TTR concentration was 0.7339(95%CI:0.5853-0.8824),when the cut-off was 225.75 μg/mL,the sensitivity was 0.81,the specificity was 0.67,the area under the curve of DSR score was 0.7535(95%CI:0.6114-0.8957)when the cut-off was 2,the sensitivity was 0.63 and the specificity was 0.89.At last,the area under the curve of the MMSE score was 0.8669(95%CI:0.7872-0.9467),when the cut-off was 26 points,the sensitivity was 0.88,while the specificity was 0.76;With " group R " and "non group R " as the dependent variables,a single factor and Logistic analysis were carried out with the same facoters as previous.The results showed that the olfactory score(OR=2.048,95%CI 1.220-3.437,P=0.007),MCI-ADL(OR=1.236,95%CI:1.008-1.516,P=0.042)and DSR score(OR=1.104,95%CI:1.015～1.201,P=0.020)were independent influencing factors of reversing to NC in 1 year of MCI group.The model buit for predicting risk of MCI group conversing to NC in 1 year is:p=ex/(l+ex),x=x=-19.3913-(0.2120×MCI-ADL)+(0.7166×olfactory score)+(0.0991×DSR).These 3 factors were defined as indicators of judging reversing to NC in 1 year of MCI group,3 ROC curves were drawn.The area under the ROC curve of the olfactory score was0.8088(95%CI:0.7144-0.9032).When the cut-off was 7 points,the sensitivity was 0.81,the specificity was 0.68;the area under the curve of the MCI-ADL score was 0.8031(95%CI 0.6830-0.9232),and the cut-off was 58 points,the sensitivity was 0.63,and the specificity was 0.87.The area under the curve of the DSR score was 0.7488(95%CI:0.6140-0.8836),and the cut-off was 10 points,the sensitivity was 0.75,and the specificity was 0.68.Conclusion(1)The major TCM syndromes elements of MCI patients are kidney deficiency,marrow depletion and phlegm turbidity.The faster the increase of marrow depletion and phlegm turbidity,the more likely it is to develop into dementia in 1 years for MCI;(2)Olfactory score could be used for the differential diagnosis for MCI group;(3)In MCI group,plasama TTR concentration,MMSE,DSR are indicators for predicting the progression to dementia in 1 year.Olfactory score,MCI-ADL,DSR are indicators for predicting the convertion to NC in 1 year.(4)Carrying APOE ε4 allele may be a risk factor for cognitive impairment,while APOE s2 allele may be a protective factor for cognitive.