Central pathology in painful diabetic peripheral neuropathy

Aims: A substantial proportion of patients with diabetic peripheral neuropathy (DPN) experience chronic neuropathic pain. This study aimed to assess brain alterations in patients with type 1 diabetes mellitus (T1DM) and painful DPN (pDPN) with surface-based morphometry.

Methods: This study utilized data from the MEDON study (Methods of Early Detection of Diabetic Neuropathy), a cross-sectional, case-control study in Aalborg, Denmark. 18 T1DM without DPN, 19 T1DM with painless DPN, 19 T1DM with pDPN, and 20 healthy controls (HC) were finally assessed. Participants were age and sex-matched at 1:1:1:1. DPN was defined according to the Toronto criteria and pDPN on DN4 score ³ 4. Magnetic resonance imaging was performed with a 3.0T GE scanner to obtain T1 weighted images with a 3D MPRAGE sequence. Following a rigorous image quality assessment protocol, surface-based morphometry was used to estimate cortical thickness (mm), sulcus depth (mm) and the gyrification index (a measurement of cortical folding as an indication of structural brain abnormalities).

Results: In patients with painless compared to patients without DPN, HbA1c (p=0.004) and diabetes duration were higher (p=0.007). In patients with painless DPN and pDPN compared to patients without DPN, sural nerve conduction velocity (p<0.01) and amplitude (p<0.01) were significantly lower but not between the DPN subgroups. In the T1DM group as a whole compared to HC, there was a significant reduction in cortical thickness both globally (p=0.007), and regionally in the frontal gyrus (L: p<0.001; and R: p=0.015), superior parietal lobule (L: p=0.018; and R: p=0.005), lingual gyrus (L only: p=0.012), supramarginal gyrus (L only: p=0.006), and  middle occipital gyrus (L only: p<0.001). Amongst T1DM subgroups, only pDPN patients compared to HC expressed significantly lower cortical thickness both globally (p=0.02), and regionally in the middle frontal gyrus (L: p=0.048; R: p=0.029), lingual gyrus (L: p=0.005; R: p=0.027), postcentral gyrus (R only: p=0.05), planum temporale (p=0.025), and superior parietal lobule (R only: p=0.008). Additionally, the pDPN subgroup compared to painless DPN, showed a significant reduction in sulcus depth in the right postcentral/supramarginal gyrus (p=0.006). There was a negative correlation in: age vs. global cortical thickness (p<0.001); age vs. postcentral gyrus (p < 0.001), sulcus depth vs. DN4 (p<0.05), sulcus depth vs. average and peak pain scores (p<0.05). There was a positive correlation in age vs. sulcus depth.   

Conclusions: Cortical thinning may be associated with neuropathic pain. Measurements of cortical morphometry are key to better understand the impact of central pathology on DPN, particularly pDPN.

Comments: T1DM is not considered a classical neurodegenerative disease, however there is ample evidence of widespread neurodegeneration across the central and peripheral nervous systems. This study underscores the importance of utilizing imaging and highlights the contribution of structural brain changes, such as cortical thinning and reduced sulcus depth, in pDPN. The present findings suggest that chronic neuropathic pain in diabetes is not solely peripheral but involves significant central changes, thus arguing for the inclusion of brain as a site of pathology in pDPN. Furthermore, with diabetes being a systemic disease, the alarming relationship between cortical morphometry and age raises a question about the potential impact of chronic hyperglycemia in the ageing brain, particularly cognitive impairment. Better understanding of the onset and progression of brain pathology in the context of DPN has the potential to aid diagnosis and pave the way for the identification of novel treatment targets. Further studies incorporating additional MRI modalities and objective imaging endpoints are warranted.

Ioannis N. Petropoulos

Reference: Hostrup SN, Croosu SS, Røikjer J, Mørch CD, Ejskjær N, Hansen TM, Frøkjær JB. Altered surface-based brain morphometry in type 1 diabetes and neuropathic pain. Neuroscience. 2025 Feb 6;566:39-48. doi: 10.1016/j.neuroscience.2024.12.033. Epub 2024 Dec 18. PMID: 39706517.

🔗 https://www.ibroneuroscience.org/article/S0306-4522(24)00740-1/fulltext