Abstract
Glycosylated hemoglobin A1c (HbA1c) has been considered as a key contributor to impaired cognition in type 2 diabetes mellitus (T2DM) brains. However, how does it affect the brain and whether the glucose controlling can slow down the process are still unknown. In the current study, T2DM patients with high glycosylated hemoglobin level (HGL) and controls with normal glycosylated hemoglobin level (NGL) were enrolled to investigate the relationships between HbA1c, brain imaging characteristics and cognitive function. First, a series of cognitive tests including California Verbal Learning Test (CVLT) were conducted. Then, the functional irregularity based on resting state functional magnetic resonance imaging data was evaluated via a new data-driven brain entropy (BEN) mapping analysis method. We found that the HGLs exhibited significantly increased BEN in the right precentral gyrus (PreCG.R), the right middle frontal gyrus (MFG.R), the triangular and opercular parts of the right inferior frontal gyrus (IFGtriang.R and IFGoperc.R). The strengths of the functional connections of PreCG.R with the brainstem/cerebellum were decreased. Partial correlation analysis showed that HbA1c had a strong positive correlation to regional BEN and negatively correlated with some CVLT scores. Negative correlations also existed between the BEN of PreCG.R/IFGoperc.R and some CVLT scores, suggesting the correspondence between higher HbA1c, increased BEN and decreased verbal memory function. This study demonstrated the potential of BEN in exploring the functional alterations affected by HbA1c and interpreting the verbal memory function decline. It will help understanding the neurophysiological mechanism of T2DM-induced cognitive decline and taking effective prevention or treatment measures.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ajilore, O., Narr, K., Rosenthal, J., Pham, D., Hamilton, L., Watari, K., Elderkin-Thompson, V., Darwin, C., Toga, A., & Kumar, A. (2010). Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression. Psychiatry Research, 184(2), 63–70. https://doi.org/10.1016/j.pscychresns.2010.07.003.
Avadhani, R., Fowler, K., Barbato, C., Thomas, S., Wong, W., Paul, C., Aksakal, M., Hauser, T. H., Weinger, K., & Goldfine, A. B. (2015). Glycemia and cognitive function in metabolic syndrome and coronary heart disease. The American Journal of Medicine, 128(1), 46–55. https://doi.org/10.1016/j.amjmed.2014.08.025.
Chen, Y. C., Jiao, Y., Cui, Y., Shang, S. A., Ding, J., Feng, Y., Song, W., Ju, S. H., & Teng, G. J. (2014). Aberrant brain functional connectivity related to insulin resistance in type 2 diabetes: A resting-state fMRI study. Diabetes Care, 37(6), 1689–1696. https://doi.org/10.2337/dc13-2127.
Chen, G. Q., Zhang, X., Xing, Y., Wen, D., Cui, G. B., & Han, Y. (2017). Resting-state functional magnetic resonance imaging shows altered brain network topology in type 2 diabetic patients without cognitive impairment. Oncotarget, 8(61), 104560–104570. https://doi.org/10.18632/oncotarget.21282.
Cheng, G., Huang, C., Deng, H., & Wang, H. (2012). Diabetes as a risk factor for dementia and mild cognitive impairment: A meta-analysis of longitudinal studies. Internal Medicine Journal, 42(5), 484–491. https://doi.org/10.1111/j.1445-5994.2012.02758.x.
Climie, R. E., Srikanth, V., Beare, R., Keith, L. J., Fell, J., Davies, J. E., & Sharman, J. E. (2014). Aortic reservoir characteristics and brain structure in people with type 2 diabetes mellitus; a cross sectional study. Cardiovascular Diabetology, 13, 143. https://doi.org/10.1186/s12933-014-0143-6.
Cui, X., Abduljalil, A., Manor, B. D., Peng, C. K., & Novak, V. (2014a). Multi-scale glycemic variability: A link to gray matter atrophy and cognitive decline in type 2 diabetes. PLoS One, 9(1), e86284. https://doi.org/10.1371/journal.pone.0086284.
Cui, Y., Jiao, Y., Chen, Y. C., Wang, K., Gao, B., Wen, S., et al. (2014b). Altered spontaneous brain activity in type 2 diabetes: A resting-state functional MRI study. Diabetes, 63(2), 749–760. https://doi.org/10.2337/db13-0519.
Cui, Y., Jiao, Y., Chen, H. J., Ding, J., Luo, B., Peng, C. Y., Ju, S. H., & Teng, G. J. (2015). Aberrant functional connectivity of default-mode network in type 2 diabetes patients. European Radiology, 25(11), 3238–3246. https://doi.org/10.1007/s00330-015-3746-8.
Cukierman-Yaffe, T., Gerstein, H. C., Williamson, J. D., Lazar, R. M., Lovato, L., Miller, M. E., Coker, L. H., Murray, A., Sullivan, M. D., Marcovina, S. M., Launer, L. J., & Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) Investigators. (2009). Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: The action to control cardiovascular risk in diabetes-memory in diabetes (ACCORD-MIND) trial. Diabetes Care, 32(2), 221–226. https://doi.org/10.2337/dc08-1153.
Fang, P., An, J., Tan, X., Zeng, L. L., Shen, H., Qiu, S., & Hu, D. (2017). Changes in the cerebellar and cerebro-cerebellar circuit in type 2 diabetes. Brain Research Bulletin, 130, 95–100. https://doi.org/10.1016/j.brainresbull.2017.01.009.
Hoogenboom, W. S., Marder, T. J., Flores, V. L., Huisman, S., Eaton, H. P., Schneiderman, J. S., et al. (2014). Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes. Diabetes, 63(2), 728–738. https://doi.org/10.2337/db13-1219.
Hsu, J. L., Chen, Y. L., Leu, J. G., Jaw, F. S., Lee, C. H., Tsai, Y. F., Hsu, C. Y., Bai, C. H., & Leemans, A. (2012). Microstructural white matter abnormalities in type 2 diabetes mellitus: A diffusion tensor imaging study. Neuroimage, 59(2), 1098–1105. https://doi.org/10.1016/j.neuroimage.2011.09.041.
Judas, M., & Cepanec, M. (2007). Adult structure and development of the human fronto-opercular cerebral cortex (Broca's region). Clinical Linguistics & Phonetics, 21(11–12), 975–989. https://doi.org/10.1080/02699200701617175.
LaBerge, D. (1997). Attention, awareness, and the triangular circuit. Consciousness and Cognition, 6(2–3), 149–181. https://doi.org/10.1006/ccog.1997.0305.
Li, W., Risacher, S. L., Huang, E., Saykin, A. J., & Alzheimer's Disease Neuroimaging, I. (2016). Type 2 diabetes mellitus is associated with brain atrophy and hypometabolism in the ADNI cohort. Neurology, 87(6), 595–600. https://doi.org/10.1212/WNL.0000000000002950.
Liu, F., Guo, W. B., Liu, L., Long, Z. L., Ma, C. Q., Xue, Z. M., et al. (2013). Abnormal amplitude low-frequency oscillations in medication-naive, first-episode patients with major depressive disorder: A resting-state fMRI study. Journal of Affective Disorders, 146(3), 401–406. https://doi.org/10.1016/j.jad.2012.10.001.
Liu, F., Guo, W. B., Fouche, J. P., Wang, Y. F., Wang, W. Q., Ding, J. R., et al. (2015). Multivariate classification of social anxiety disorder using whole brain functional connectivity. Brain Structure & Function, 220(1), 101–115. https://doi.org/10.1007/s00429-013-0641-4.
Liu, F., Wang, Y. F., Li, M. L., Wang, W. Q., Li, R., Zhang, Z. Q., et al. (2017). Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic-clonic seizure. Human Brain Mapping, 38(2), 957–973. https://doi.org/10.1002/hbm.23430.
Liu, D., Duan, S., Zhou, C., Wei, P., Chen, L., Yin, X., Zhang, J., & Wang, J. (2018). Altered brain functional hubs and connectivity in type 2 diabetes mellitus patients: A resting-state fMRI study. Frontiers in Aging Neuroscience, 10, 55. https://doi.org/10.3389/fnagi.2018.00055.
Longo, C. A., Fried, P. A., Cameron, I., & Smith, A. M. (2014). The long-term effects of prenatal nicotine exposure on verbal working memory: An fMRI study of young adults. Drug and Alcohol Dependence, 144, 61–69. https://doi.org/10.1016/j.drugalcdep.2014.08.006.
Marden, J. R., Mayeda, E. R., Tchetgen Tchetgen, E. J., Kawachi, I., & Glymour, M. M. (2017). High hemoglobin A1c and diabetes predict memory decline in the health and retirement study. Alzheimer Disease and Associated Disorders, 31(1), 48–54. https://doi.org/10.1097/WAD.0000000000000182.
Matsuo, K., Chen, S. H., Liu, C. M., Liu, C. C., Hwang, T. J., Hsieh, M. H., et al. (2013). Stable signatures of schizophrenia in the cortical-subcortical-cerebellar network using fMRI of verbal working memory. Schizophrenia Research, 151(1–3), 133–140. https://doi.org/10.1016/j.schres.2013.10.028.
Mayeda, E. R., Whitmer, R. A., & Yaffe, K. (2015). Diabetes and cognition. Clinics in Geriatric Medicine, 31(1), 101–115, ix. https://doi.org/10.1016/j.cger.2014.08.021.
Moran, C., Phan, T. G., Chen, J., Blizzard, L., Beare, R., Venn, A., Münch, G., Wood, A. G., Forbes, J., Greenaway, T. M., Pearson, S., & Srikanth, V. (2013). Brain atrophy in type 2 diabetes: Regional distribution and influence on cognition. Diabetes Care, 36(12), 4036–4042. https://doi.org/10.2337/dc13-0143.
Peters, F., Collette, F., Degueldre, C., Sterpenich, V., Majerus, S., & Salmon, E. (2009). The neural correlates of verbal short-term memory in Alzheimer's disease: An fMRI study. Brain, 132(Pt 7), 1833–1846. https://doi.org/10.1093/brain/awp075.
Reijmer, Y. D., van den Berg, E., Ruis, C., Kappelle, L. J., & Biessels, G. J. (2010). Cognitive dysfunction in patients with type 2 diabetes. Diabetes/Metabolism Research and Reviews, 26(7), 507–519. https://doi.org/10.1002/dmrr.1112.
Rosenberg, J., Lechea, N., Pentang, G. N., & Shah, N. J. (2019). What magnetic resonance imaging reveals - a systematic review of the relationship between type II diabetes and associated brain distortions of structure and cognitive functioning. Frontiers in Neuroendocrinology, 52, 79–112. https://doi.org/10.1016/j.yfrne.2018.10.001.
Roy, S., Kim, N., Desai, A., Komaragiri, M., Baxi, N., Jassil, N., Blessinger, M., Khan, M., Cole, R., Desai, N., Terrigno, R., & Hunter, K. (2015). Cognitive function and control of type 2 diabetes mellitus in young adults. North American Journal of Medical Sciences, 7(5), 220–226. https://doi.org/10.4103/1947-2714.157627.
Sakurai, Y., Furukawa, E., Kurihara, M., & Sugimoto, I. (2018). Frontal phonological Agraphia and Acalculia with impaired verbal short-term memory due to left inferior Precentral Gyrus lesion. Case Reports in Neurology, 10(1), 72–82. https://doi.org/10.1159/000487849.
Saxe, G. N., Calderone, D., & Morales, L. J. (2018). Brain entropy and human intelligence: A resting-state fMRI study. PLoS One, 13(2), e0191582. https://doi.org/10.1371/journal.pone.0191582.
Shaw, J. E., Sicree, R. A., & Zimmet, P. Z. (2010). Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Research and Clinical Practice, 87(1), 4–14. https://doi.org/10.1016/j.diabres.2009.10.007.
Sokunbi, M. O., Fung, W., Sawlani, V., Choppin, S., Linden, D. E., & Thome, J. (2013). Resting state fMRI entropy probes complexity of brain activity in adults with ADHD. Psychiatry Research, 214(3), 341–348. https://doi.org/10.1016/j.pscychresns.2013.10.001.
Sun, Q., Chen, G. Q., Wang, X. B., Yu, Y., Hu, Y. C., Yan, L. F., Zhang, X., Yang, Y., Zhang, J., Liu, B., Wang, C. C., Ma, Y., Wang, W., Han, Y., & Cui, G. B. (2018). Alterations of white matter integrity and hippocampal functional connectivity in type 2 diabetes without mild cognitive impairment. Frontiers in Neuroanatomy, 12, 21. https://doi.org/10.3389/fnana.2018.00021.
Wang, C. X., Fu, K. L., Liu, H. J., Xing, F., & Zhang, S. Y. (2014a). Spontaneous brain activity in type 2 diabetics revealed by amplitude of low-frequency fluctuations and its association with diabetic vascular disease: A resting-state FMRI study. PLoS One, 9(10), e108883. https://doi.org/10.1371/journal.pone.0108883.
Wang, Z., Li, Y., Childress, A. R., & Detre, J. A. (2014b). Brain entropy mapping using fMRI. PLoS One, 9(3), e89948. https://doi.org/10.1371/journal.pone.0089948.
Wang, B., Niu, Y., Miao, L., Cao, R., Yan, P., Guo, H., Li, D., Guo, Y., Yan, T., Wu, J., Xiang, J., & Zhang, H. (2017). Decreased complexity in Alzheimer's Disease: Resting-state fMRI evidence of brain entropy mapping. Frontiers in Aging Neuroscience, 9, 378. https://doi.org/10.3389/fnagi.2017.00378.
Xia, W., Wang, S., Sun, Z., Bai, F., Zhou, Y., Yang, Y., Wang, P., Huang, Y., & Yuan, Y. (2013). Altered baseline brain activity in type 2 diabetes: A resting-state fMRI study. Psychoneuroendocrinology, 38(11), 2493–2501. https://doi.org/10.1016/j.psyneuen.2013.05.012.
Xia, W., Wang, S., Spaeth, A. M., Rao, H., Wang, P., Yang, Y., Huang, R., Cai, R., & Sun, H. (2015). Insulin resistance-associated Interhemispheric functional connectivity alterations in T2DM: A resting-state fMRI study. BioMed Research International, 2015, 719076. https://doi.org/10.1155/2015/719076.
Yang, A. C., Hong, C. J., Liou, Y. J., Huang, K. L., Huang, C. C., Liu, M. E., Lo, M. T., Huang, N. E., Peng, C. K., Lin, C. P., & Tsai, S. J. (2015). Decreased resting-state brain activity complexity in schizophrenia characterized by both increased regularity and randomness. Human Brain Mapping, 36(6), 2174–2186. https://doi.org/10.1002/hbm.22763.
Yau, P. L., Kluger, A., Borod, J. C., & Convit, A. (2014). Neural substrates of verbal memory impairments in adults with type 2 diabetes mellitus. Journal of Clinical and Experimental Neuropsychology, 36(1), 74–87. https://doi.org/10.1080/13803395.2013.869310.
Zhang, Y. W., Zhang, J. Q., Liu, C., Wei, P., Zhang, X., Yuan, Q. Y., Yin, X. T., Wei, L. Q., Cui, J. G., & Wang, J. (2015). Memory dysfunction in type 2 diabetes mellitus correlates with reduced hippocampal CA1 and subiculum volumes. Chinese Medical Journal, 128(4), 465–471. https://doi.org/10.4103/0366-6999.151082.
Zhou, F., Huang, S., Gao, L., Zhuang, Y., Ding, S., & Gong, H. (2016a). Temporal regularity of intrinsic cerebral activity in patients with chronic primary insomnia: A brain entropy study using resting-state fMRI. Brain and Behavior: A Cognitive Neuroscience Perspective, 6(10), e00529. https://doi.org/10.1002/brb3.529.
Zhou, F., Zhuang, Y., Gong, H., Zhan, J., Grossman, M., & Wang, Z. (2016b). Resting state brain entropy alterations in relapsing remitting multiple sclerosis. PLoS One, 11(1), e0146080. https://doi.org/10.1371/journal.pone.0146080.
Zilliox, L. A., Chadrasekaran, K., Kwan, J. Y., & Russell, J. W. (2016). Diabetes and cognitive impairment. Current Diabetes Reports, 16(9), 87. https://doi.org/10.1007/s11892-016-0775-x.
Funding
This work was funded by the National Natural Science Foundation of China (grant numbers 61603399, 81571656, 81771815), the Fundamental Research Funds for the Central Universities (grant number 31020190QD002), the Major Project of Medicine Science and Technology of PLA (grant number AWS17J012) and the Innovation Foundation of Tangdu Hospital (grant number 2016LCYJ011).
Author information
Authors and Affiliations
Contributions
WW, GBC and XZ conceived and designed the study. ZSS, KX, JHF and ZYL collected the data. YY (Yang Yang), JZ, QS and BH performed data preprocessing. XZ, YY (Ying Yu), XNZ and SNC did statistical analysis and interpretation of results. XZ drafted the manuscript. WW, GBC and LFY reviewed and edited the manuscript. All authors read and approved the manuscript.
Corresponding authors
Ethics declarations
All procedures performed in the current study involving human participants were in accordance with the ethical standards of the Ethics Committee of Tangdu Hospital and this study has been registered to ClinicalTrials.gov (NCT02420470, http://www.clinicaltrials.gov).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 37 kb)
Rights and permissions
About this article
Cite this article
Zhang, X., Yu, Y., Shi, ZS. et al. Increased resting state functional irregularity of T2DM brains with high HbA1c: sign for impaired verbal memory function?. Brain Imaging and Behavior 15, 772–781 (2021). https://doi.org/10.1007/s11682-020-00285-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11682-020-00285-8