The Relationship Between Plasma DPP4 Activity to BDNF Ratio and Mild Cognitive Impairment in Elderly Population With Normal Glucose Tolerance

Abstract

Objective: Since decreased brain-derived neurotrophic factor (BDNF) and increased dipeptidyl peptidase-4 (DPP4) activity have both been implicated in the pathogenesis of mild cognitive impairment (MCI), the aim of our study was to evaluate the association of MCI with plasma DPP4 activity to BDNF ratio (DBR) in an elderly population with normal glucose tolerance. Methods: We cross-sectionally measured C-reactive protein, interleukin-6, nitrotyrosine, 8-iso-PGF2a, DPP4 activity BDNF and calculated the DBR in a total of 1,066 elderly participants in China. MCI was determined by the Montreal Cognitive Assessment and finally confirmed by neurologists. Results: An inverse correlation was found between DPP4 activity and BDNF ( r = -0.456, P < 0.001) and this inverse correlation was partly mediated by nitrotyrosine and 8-iso-PGF2a. Across rising quartiles of DBR, nitrotyrosine, 8-iso-PGF2a, C-reactive protein and interleukin-6 progressively increased, whereas the Montreal Cognitive Assessment score progressively decreased. Subjects in the lowest quartile of BDNF and highest quartiles of DBR and DPP4 activity, had higher MCI risk compared with subjects in the highest quartile of the BDNF and lowest quartiles of DBR and DPP4 activity, respectively (all P < 0.05). The odds ratio for MCI became more pronounced with decreased BDNF and increased DPP4. Conclusion: In conclusion, a negative correlation was found between DPP4 activity and BDNF, and this negative correlation was partly mediated by oxidative stress, not inflammation. The DBR was positively associated with MCI and thus may be used as a novel risk biomarker for MCI in an elderly population with normal glucose tolerance.

Neurobiological Highlights of Cognitive Impairment in Psychiatric Disorders

“…Although meta-analysis data showed a BDNF decrease in AD [199] and its concentration was associated with a reduction in hippocampal volume [200], other researchers believed that the possible biased use of plasma BDNF in MCI was critically risky [201]. [202] proposed the dipeptidyl peptidase-4 (DPP4) activity to BDNF ratio as a plasma biomarker. The Montreal Cognitive Assessment score decreased progressively when this ratio increased [203].…”

Association Between Dipeptidyl Peptidase-4 Inhibitor Use and Cognitive Functions, Brain-Derived Neurotrophic Factor, and Pentraxin-3 Levels in Patients With Type 2 Diabetes

“…In consideration of the lack of significant differences in sociodemographic characteristics and laboratory parameters (including HbA1c levels and fasting blood glucose levels) between study groups, these results of the present study can be interpreted as indicating that the protective effects of DPP-4 inhibitors against cognitive impairment may be independent of their glucose-lowering effects. Although an inverse correlation between DPP-4 activity and BDNF levels was reported in the elderly population with normal glucose tolerance [ 24 ], to the best of our knowledge, our work is the first study demonstrating higher serum BDNF levels in patients using DPP-4 inhibitors when compared with patients using only metformin treatment.…”

“…In a study conducted on a total of 420 participants (208 patients with type 2 diabetes and 212 controls), in addition to the lower cognitive test scores, lower levels of BDNF (p<0.001) were reported in patients with type 2 diabetes when compared to controls [ 23 ]. Additionally, in another study conducted on the elderly population with normal glucose tolerance, it was shown that there was an inverse correlation between DDP-4 activity and BDNF levels (r=-0.456, p<0.001) [ 24 ]. In our study, there was a remarkable difference in serum BDNF levels between patients using DPP-4±metformin treatment and patients using only metformin treatment (394.51±205.66 ng/ml vs. 180.63±297.94 ng/ml; p=0.001).…”

Effects of DPP4 Inhibitors as Neuroprotective Drug on Cognitive Impairment in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review

“…In our meta-analysis, DPP4 inhibitors showed an improved effect on cognitive impairment in T2D, and DPP4i has previously been shown to have an improved effect on cognitive impairment [ 31 ]. Of course, broader cognitive tests are needed to support this idea.…”