PMID- 27077117
OWN - NLM
STAT- MEDLINE
DCOM- 20161230
LR  - 20220410
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 5
DP  - 2016 Mar
TI  - Biomarkers for Early Diagnostic of Mild Cognitive Impairment in Type-2 Diabetes 
      Patients: A Multicentre, Retrospective, Nested Case-Control Study.
PG  - 105-13
LID - 10.1016/j.ebiom.2016.02.014 [doi]
AB  - 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-3beta (GSK-3beta) 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-3beta 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 epsilon2, ApoE epsilon3, tGSK3beta and pS9GSK3beta between the two groups. Compared 
      with the T2DM-nMCI group, T2DM-MCI group showed lower MMSE score with older age, 
      ApoE epsilon4 allele, higher olfactory score and higher rGSK-3beta (ratio of total GSK-3beta 
      to Ser9-phosphorylated GSK-3beta) in the training set and the validation set. The OR 
      values of age, ApoE epsilon4 gene, olfactory score and rGSK-3beta 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 epsilon4 gene, olfactory score and 
      rGSK-3beta 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-3beta, expression of ApoE epsilon4 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.
FAU - Xu, Zhi-Peng
AU  - Xu ZP
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China; Department of Neurology, Wuhan 
      General Hospital of Guangzhou Command, Wuhan 430070, China.
FAU - Yang, Su-Lian
AU  - Yang SL
AD  - School of Public Health, Tongji Medical College, Huazhong University of Science 
      and Technology, Wuhan 430030, China.
FAU - Zhao, Shi
AU  - Zhao S
AD  - Department of Endocrinology, The Central Hospital of Wuhan, Wuhan 430014, China.
FAU - Zheng, Cheng-Hong
AU  - Zheng CH
AD  - Department of Endocrinology, Wuhan Hospital of Traditional Chinese Medicine, 
      Wuhan 430014, China.
FAU - Li, Hong-Hua
AU  - Li HH
AD  - Department of Neurology, Wuhan General Hospital of Guangzhou Command, Wuhan 
      430070, China.
FAU - Zhang, Yao
AU  - Zhang Y
AD  - Li-Yuan Hospital, Tongji Medical College, Huazhong University of Science and 
      Technology, Wuhan 430077, China.
FAU - Huang, Rong-Xi
AU  - Huang RX
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Li, Meng-Zhu
AU  - Li MZ
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Gao, Yuan
AU  - Gao Y
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Zhang, Shu-Juan
AU  - Zhang SJ
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Zhan, Pei-Yan
AU  - Zhan PY
AD  - Department of Neurology, The Central Hospital of Wuhan, Wuhan 430014, China.
FAU - Zhang, Li-Fang
AU  - Zhang LF
AD  - Department of Endocrinology, Wuhan Hospital of Traditional Chinese Medicine, 
      Wuhan 430014, China.
FAU - Deng, Lin
AU  - Deng L
AD  - Department of Endocrinology, The Central Hospital of Wuhan, Wuhan 430014, China.
FAU - Wei, Sheng
AU  - Wei S
AD  - School of Public Health, Tongji Medical College, Huazhong University of Science 
      and Technology, Wuhan 430030, China.
FAU - Liu, Yan-Chao
AU  - Liu YC
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Ye, Jing-Wang
AU  - Ye JW
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Ren, Hu-Jun
AU  - Ren HJ
AD  - Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan 
      430070, China.
FAU - Li, Na
AU  - Li N
AD  - Department of Endocrinology, The Central Hospital of Wuhan, Wuhan 430014, China.
FAU - Kong, Cai-Xia
AU  - Kong CX
AD  - Department of Endocrinology, The First Hospital of Wuhan, Wuhan 430022, China.
FAU - Wang, Xin
AU  - Wang X
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Fang, Lin
AU  - Fang L
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Zhou, Qiu-Zhi
AU  - Zhou QZ
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China.
FAU - Jiang, Hong-Wei
AU  - Jiang HW
AD  - School of Public Health, Tongji Medical College, Huazhong University of Science 
      and Technology, Wuhan 430030, China.
FAU - Li, Jing-Rong
AU  - Li JR
AD  - Health Service Center of Jianghan District, Wuhan 430014, China.
FAU - Wang, Qun
AU  - Wang Q
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China; Co-innovation Center of 
      Neuroregeneration, Nantong University, Nantong 226000, China.
FAU - Ke, Dan
AU  - Ke D
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China; Co-innovation Center of 
      Neuroregeneration, Nantong University, Nantong 226000, China.
FAU - Liu, Gong-Ping
AU  - Liu GP
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China; Co-innovation Center of 
      Neuroregeneration, Nantong University, Nantong 226000, China.
FAU - Wang, Jian-Zhi
AU  - Wang JZ
AD  - Department of Pathophysiology, School of Basic Medicine and the Collaborative 
      Innovation Center for Brain Science, Key Laboratory of Ministry of Education of 
      China for Neurological Disorders, Tongji Medical College, Huazhong University of 
      Science and Technology, Wuhan 430030, China; Co-innovation Center of 
      Neuroregeneration, Nantong University, Nantong 226000, China.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20160206
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Apolipoprotein E4)
RN  - 0 (Biomarkers)
RN  - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
SB  - IM
MH  - Aged
MH  - Alleles
MH  - Alzheimer Disease/*blood/etiology/pathology
MH  - Apolipoprotein E4/*blood
MH  - Biomarkers/blood
MH  - Blood Platelets/metabolism
MH  - Case-Control Studies
MH  - Cognitive Dysfunction/*blood/etiology/pathology
MH  - Diabetes Mellitus, Type 2/blood/*complications/pathology
MH  - Female
MH  - Genotype
MH  - Glycogen Synthase Kinase 3 beta/*blood
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Retrospective Studies
PMC - PMC4816853
OTO - NOTNLM
OT  - AD, Alzheimer's disease
OT  - ARMS, amplification refractory mutation system
OT  - AUC, the area under the curve
OT  - Alzheimer's disease
OT  - ApoE gene
OT  - ApoE, apolipoprotein E
OT  - CCCRC, Connecticut Chemosensory Clinical Research Center
OT  - CDR, clinical dementia rating
OT  - CI, confidence intervals
OT  - GSK-3beta, glycogen synthase kinase-3beta
OT  - Glycogen synthase kinase-3beta
OT  - HbA1c, hemoglobin A1c
OT  - MCI, mild cognitive impairment
OT  - MMSE, minimum mental state examination
OT  - Mild cognitive impairment
OT  - OR, odds ratio
OT  - Olfactory score
OT  - ROC, receiver operating characteristics
OT  - T2DM, type 2 diabetes mellitus
OT  - Type 2 diabetes mellitus
EDAT- 2016/04/15 06:00
MHDA- 2016/12/31 06:00
PMCR- 2016/02/06
CRDT- 2016/04/15 06:00
PHST- 2016/01/05 00:00 [received]
PHST- 2016/02/05 00:00 [revised]
PHST- 2016/02/05 00:00 [accepted]
PHST- 2016/04/15 06:00 [entrez]
PHST- 2016/04/15 06:00 [pubmed]
PHST- 2016/12/31 06:00 [medline]
PHST- 2016/02/06 00:00 [pmc-release]
AID - S2352-3964(16)30045-7 [pii]
AID - 10.1016/j.ebiom.2016.02.014 [doi]
PST - epublish
SO  - EBioMedicine. 2016 Feb 6;5:105-13. doi: 10.1016/j.ebiom.2016.02.014. eCollection 
      2016 Mar.