Skip to main content Accessibility help
×
Home

Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients

  • Jian-Hui Zhang (a1), Hong-Zeng Xu (a1), Qi-Feng Shen (a1), Yong-Zhong Lin (a1), Chang-Kai Sun (a2), Lin Sha (a3), Yu-Song Ge (a1), Ying Liu (a1) and Chun Wang (a1)...

Abstract

Objective: To study the relationship of Nε-(carboxymethyl)-lysine level (CML) with microstructure changes of white matter (WM), and cognitive impairment in patients with type 2 diabetes mellitus (T2DM) and to discuss the potential mechanism underlying T2DM-associated cognitive impairment. Methods: The study was performed in T2DM patients (n=22) with disease course ≥5 years and age ranging from 65 to 75 years old. A control group consisted of 25 sex- and age-matched healthy volunteers. Fractional anisotropy (FA) of several WM regions was analyzed by diffusion tensor imaging scan. Plasma CML levels were measured by enzyme-linked immunosorbent assay, and cognitive function was assessed by Mini-Mental State Examination and Montreal cognitive assessment (MoCA). Results: The total Mini-Mental State Examination score in the patient group (25.72±3.13) was significantly lower than the control group (28.16±2.45) (p<0.05). In addition, the total MoCA score in the patient group (22.15±3.56) was significantly lower than the control group 25.63±4.12) (p<0.01). In the patient group, FA values were significantly decreased in the corpus callosum, cingulate fasciculus, inferior fronto-occipital fasciculus, parietal WM, hippocampus, and temporal lobes relative to corresponding regions of healthy controls (p<0.05). Plasma CML level was negatively correlated with average FA values in the global brain (r=−0.58, p<0.01) and MoCA scores (r=−0.47, p<0.05). Conclusions: In T2DM, WM microstructure changes occur in older patients, and elevations in CML may play a role in the development of cognitive impairment.

Nɛ-(carboxyméthyl)-lysine, substance blanche et fonction cognitive chez des patients diabétiques. Objectif: Le but de l’étude était d’examiner la relation entre le niveau de Nɛ-(carboxyméthyl)-lysine (CML) et les changements dans la microstructure de la substance blanche (SB) et l’atteinte cognitive chez des diabétiques de type 2 (DT2), et de discuter des mécanismes possibles sous-jacents à l’atteinte cognitive associée au DT2. Méthode: L’étude a porté sur des patients atteints de DT2 (n=22) dont la maladie évoluait depuis 5 ans ou plus et qui étaient âgés de 65 à 75 ans. Le groupe témoin était constitué de 25 volontaires sains appariés pour le sexe et l’âge. L’anisotropie fractionnaire (AF) de plusieurs régions de la SB a été analysée par IRM du tenseur de diffusion. Les niveaux de CML ont été mesurés par dosage immuno-enzymatique et la fonction cognitive a été évaluée par le mini-examen de l’état mental et le Montreal cognitive assessment (MoCA). Résultats: Le score total au mini-examen de l’état mental du groupe de patients (25,72±3,13) était significativement plus bas que celui du groupe témoin (28,16±2,45) (p<0,05). De plus, le score total au MoCA du groupe de patients (22,15±3,56) était significativement plus bas que celui du groupe témoin (25,63±4,12) (p<0,01). Dans le groupe de patients, les valeurs d’AF étaient significativement diminuées dans le corps calleux, le faisceau cingulaire, le faisceau fronto-occipital inférieur, la SB pariétale, l’hippocampe et les lobes temporaux par rapport aux régions correspondantes chez les sujets témoins en bonne santé (p<0,05). Le niveau de CML plasmatique était corrélé négativement aux valeurs moyennes d’AF dans le cerveau total (r=-0,58 ; p<0,01) et les scores au MoCA (r=-0,47; p<0,05). Conclusions: Dans le DT2, des changements se produisent dans la microstructure de la SB chez les patients plus âgés et l’augmentation de CML pourrait jouer un rôle dans l’apparition de troubles cognitifs.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients
      Available formats
      ×

Copyright

Corresponding author

Correspondence to: Yong-Zhong Lin, Department of Neurology, Second Hospital, Dalian Medical University, Dalian 116027, China; or Chang-Kai Sun, Institute for Brain Disorder and Disease, Dalian Medical University, Dalian 116044, China. Email: lin19671024@163.com or cksun110@vip.sina.com.

References

Hide All
1. McCrimmon, RJ, Ryan, CM, Frier, BM. Diabetes and cognitive dysfunction. Lancet. 2012;379:2291-2299.
2. Munshi, M, Grande, L, Hayes, M, et al. Cognitive dysfunction is associated with poor diabetes control in older adults. Diabetes Care. 2006;29:1794-1799.
3. Biessels, GJ, Deary, IJ, Ryan, CM. Cognition and diabetes: a lifespan perspective. Lancet Neurol. 2008;7:184-190.
4. Biessels, GJ, Staekenborg, S, Brunner, E, Brayne, C, Scheltens, P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5:64-74.
5. Ryan, JP, Fine, DF, Rosano, C. Type 2 diabetes and cognitive impairment: contributions from neuroimaging. J Geriatr Psychiatry Neurol. 2014;27:47-55.
6. Bozzali, M, Cherubini, A. Diffusion tensor MRI to investigate dementias: a brief review. Magn Reson Imaging. 2007;25:969-977.
7. Hsu, JL, Chen, YL, Leu, JG, et al. Microstructural white matter abnormalities in type 2 diabetes mellitus: a diffusion tensor imaging study. Neuroimage. 2012;59:1098-1105.
8. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-820.
9. Southern, L, Williams, J, Esiri, MM. Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia. BMC Neurol. 2007;7:35.
10. Horie, K, Miyata, T, Yasuda, T, et al. Immunohistochemical localization of advanced glycation end products, pentosidine, and carboxymethyllysine in lipofuscin pigments of Alzheimer’s disease and aged neurons. Biochem Biophys Res Commun. 1997;236:327-332.
11. Ikeda, K, Higashi, T, Sano, H, et al. N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry. 1996;35:8075-8083.
12. Bar, KJ, Franke, S, Wenda, B, et al. Pentosidine and N(epsilon)-(carboxymethyl)-lysine in Alzheimer’s disease and vascular dementia. Neurobiol Aging. 2003;24:333-338.
13. Nasreddine, ZS, Phillips, NA, Bedirian, V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695-699.
14. Folstein, MF, Folstein, SE, McHugh, PR. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
15. Morris, JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412-2414.
16. Hu, S, He, W, Liu, Z, Xu, H, Ma, G. The accumulation of the glycoxidation product N(epsilon)-carboxymethyllysine in cardiac tissues with age, diabetes mellitus and coronary heart disease. Tohoku J Exp Med. 2013;230:25-32.
17. Jenkinson, M, Bannister, P, Brady, M, Smith, S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825-841.
18. Smith, SM. Fast robust automated brain extraction. Hum Brain Mapp. 2002;17:143-155.
19. van Deutekom, AW, Niessen, HW, Schalkwijk, CG, Heine, RJ, Simsek, S. Increased Nepsilon-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus. Eur J Endocrinol. 2008;158:655-660.
20. Genuth, S, Sun, W, Cleary, P, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes. 2005;54:3103-3111.
21. McCance, DR, Dyer, DG, Dunn, JA, et al. Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus. J Clin Invest. 1993;91:2470-2478.
22. Smith, SM, Jenkinson, M, Johansen-Berg, H, et al. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006;31:1487-1505.
23. Last, D, Alsop, DC, Abduljalil, AM, et al. Global and regional effects of type 2 diabetes on brain tissue volumes and cerebral vasoreactivity. Diabetes Care. 2007;30:1193-1199.
24. van Harten, B, de Leeuw, FE, Weinstein, HC, Scheltens, P, Biessels, GJ. Brain imaging in patients with diabetes: a systematic review. Diabetes Care. 2006;29:2539-2548.
25. Brownlee, M. Advanced protein glycosylation in diabetes and aging. Annu Rev Med. 1995;46:223-234.
26. Furth, AJ. Glycated proteins in diabetes. Br J Biomed Sci. 1997;54:192-200.
27. Yaffe, K, Lindquist, K, Schwartz, AV, et al. Advanced glycation end product level, diabetes, and accelerated cognitive aging. Neurology. 2011;77:1351-1356.
28. Takeuchi, M, Yamagishi, S. TAGE (toxic AGEs) hypothesis in various chronic diseases. Med Hypotheses. 2004;63:449-452.
29. Reijmer, YD, Brundel, M, de Bresser, J, et al. Microstructural white matter abnormalities and cognitive functioning in type 2 diabetes: a diffusion tensor imaging study. Diabetes Care. 2013;36:137-144.
30. Kodl, CT, Franc, DT, Rao, JP, et al. Diffusion tensor imaging identifies deficits in white matter microstructure in subjects with type 1 diabetes that correlate with reduced neurocognitive function. Diabetes. 2008;57:3083-3089.
31. Yau, PL, Javier, D, Tsui, W, et al. Emotional and neutral declarative memory impairments and associated white matter microstructural abnormalities in adults with type 2 diabetes. Psychiatry Res. 2009;174:223-230.
32. Falvey, CM, Rosano, C, Simonsick, EM, et al. Macro- and microstructural magnetic resonance imaging indices associated with diabetes among community-dwelling older adults. Diabetes Care. 2013;36:677-682.
33. Gold, SM, Dziobek, I, Sweat, V, et al. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia. 2007;50:711-719.
34. Chen, HT, Lin, HD, Won, JG, et al. Cardiovascular autonomic neuropathy, autonomic symptoms and diabetic complications in 674 type 2 diabetes. Diabetes Res Clin Pract. 2008;82:282-290.
35. Hsu, WC, Chiu, YH, Chen, WH, Chiu, HC, Liou, HH, Chen, TH. Simplified electrodiagnostic criteria of diabetic polyneuropathy in field study (KCIS No. 14). Neuroepidemiology. 2007;28:50-55.

Keywords

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed