Painful diabetic neuropathy, cognitive function and structural brain changes

Aims: Although diabetic peripheral neuropathy (DPN) is a disorder of the peripheral nervous system, emerging evidence indicates potential links to structural and functional changes in the central nervous system. This study aimed to investigate structural brain changes and cognitive outcomes in individuals with type 2 diabetes (T2D) with and without painful DPN.

Methods: A total of 105 participants were included: 37 healthy controls (HC), 26 patients with T2DM without DPN, and 42 patients with T2D and DPN, subdivided into painless (n=22) and painful (n=20) groups. DPN was defined as a Toronto Clinical Scoring System (TCSS) score ≥6 and at least two abnormal results from nerve conduction study of median, ulnar, peroneal, and tibial nerve. Painful DPN was defined as neuropathic pain lasting for at least 3 months and DN4 ≥4. DPN drugs were discontinued for at least one week. All participants underwent a cognitive assessment, using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), and brain high-resolution structural MRI (3 Tesla) applying voxel-based morphometry to analyse gray matter volume (GMV) and cortical thickness.

Results: Descriptive statistics revealed no differences in age, sex, BMI, educational level, lifestyle factors or lipid status between groups, while fasting plasma glucose and HbA1c was (as expected) significantly higher among individuals with T2D. There were no differences in global gray or white matter volumes across groups; however, compared with healthy controls (HC), individuals with T2D exhibited reduced average cortical thickness. Analyses of regional GMVs revealed group differences. Pairwise comparisons showed that individuals with painful DPN had reduced volumes in the cerebellum, putamen, pallidum, and right caudate, and instead increased brainstem volume when compared to HCs. When the painful and painless DPN groups were combined into a single DPN group, no significant differences were observed compared with HCs or T2D without DPN. Cognitive performance was significantly lower in T2D and in painful DPN groups in comparison with HCs.

Conclusions: In this study, painful DPN was associated with regional structural brain changes. Cognitive outcomes were less favourable in individuals with painful DPN.

Comments. The study explores brain changes in T2D and DPN providing similarities and few discrepancies with previous neuroimaging results. Painful DPN may be linked to structural brain changes as well as cognitive impairment. The observation of regional brain differences in participants with painful but not painless DPN suggests a potential pain-related effect. Results are well discussed in comparison with available literature with the attempt to provide a pathophysiological interpretation of the morphological changes associated with painful DPN. However, several limitations should be considered. The cross-sectional design with relatively small group sizes, heterogeneity within subgroups, and greater neuropathy severity in the painful DPN group mean these findings should be interpreted cautiously. Medication usage was not analysed. Cognitive differences were observed across groups; however, the presence of pain may have influenced cognitive outcomes, and this was not accounted for.

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Reference. He M, Yang J, Liu X, Zhou J, Zhang X, Li J, Shao X, Li W, Guan Y, Zhang W, Feng F. Brain morphological changes in type 2 diabetes patients with painful peripheral neuropathy. Metab Brain Dis. 2025 May 31;40(5):216. doi: 10.1007/s11011-025-01643-5. PMID: 40448742.

🔗 https://link.springer.com/article/10.1007/s11011-025-01643-5