Biomarkers for Early Diagnostic of Mild Cognitive Impairment in Type 2 Diabetes Patients: A Multicentre, Retrospective, Nested Case Control Study
Background Both type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are common age associated disorders and T2DM patients show an increased risk to suffer from AD, however, there is currently no marker to identify who in T2DM populations will develop AD. Since glycogen synthase kinase 3b (GSK 3b) activity, ApoE genotypes and olfactory function are involved in both T2DM and AD pathogenesis, we investigate whether alterations of these factors can identify cognitive impairment in T2DM patients. Methods The cognitive ability was evaluated using Minimum Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) and the mild cognitive impairment (MCI) was diagnosed by Petersen's criteria. GSK 3b activity in platelet, ApoE genotypes in leucocytes and the olfactory function were detected by Western/dot blotting, the amplification refractory mutation system (ARMS) PCR and the Connecticut Chemosensory Clinical Research Center (CCCRC) test, respectively. The odds ratio (OR) and 95% confidence intervals (95% CI) of the biomarkers for MCI diagnosis were calculated by logistic regression. The diagnostic capability of the biomarkers was evaluated by receiver operating characteristics (ROC) analyses. Findings We recruited 694 T2DM patients from Jan. 2012 to May. 2015 in 5 hospitals (Wuhan) and 646 of them met the inclusion criteria and were included in this study. 345 patients in 2 hospitals were assigned to the training set, and 301 patients in another 3 hospitals assigned to the validation set. Patients in each set were randomly divided into two groups: T2DM without MCI (termed T2DM nMCI) or with MCI (termed T2DM MCI) There were no significant differences for sex, T2DM years, hypertension, hyperlipidemia, coronary disease, complications, insulin treatment, HbA1c, ApoE e2, ApoE e3, tGSK3b and pS9GSK3b between the two groups. Compared with the T2DM nMCI group, T2DM MCI group showed lower MMSE score with older age, ApoE e4 allele, higher olfactory score and higher rGSK 3b (ratio of total GSK 3b to Ser9 phosphorylated GSK 3b) in the training set and the validation set. The OR values of age, ApoE e4 gene, olfactory score and rGSK 3b were 1.09, 2.09, 1.51, 10.08 in the training set, and 1.06, 2.67, 1.47, 7.19 in the validation set, respectively. The diagnostic accuracy of age, ApoE e4 gene, olfactory score and rGSK 3b were 0.76, 0.72, 0.66, 0.79 in the training set, and 0.70, 0.68, 0.73, 0.79 in the validation set, respectively. These four combined biomarkers had the area under the curve (AUC) of 82% and 86% diagnostic accuracy of 83% and 81% in the training set and the validation set, respectively. Interpretation Aging, activation of peripheral circulating GSK 3b, expression of ApoE e4 and increase of olfactory score are diagnostic for the mild cognitive impairment in T2DM patients, and combination of these biomarkers can improve the diagnostic accuracy.
EBioMedicine