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IntroductionImpaired awareness of hypoglycemia (IAH) is a common complication in patients with type-1 diabetes (T1D). IAH is a major risk factor for severe hypoglycemic events, leading to adverse clinical consequences and cerebral damage. Non-invasive, cost-effective, and logistically efficient biomarkers for this condition have not been validated. Here, we propose plasma neurofilament light chain (NfL) levels as a biomarker of neuroaxonal damage in patients with T1D-IAH.Research design and methods54 patients were included into the study (18 T1D-IAH, 18 T1D with normal awareness of hypoglycemia (NAH) and 18 healthy controls). We measured plasma NfL levels and studied cerebral gray matter alterations on MRI.ResultsWe found that NfL levels were increased in patients with T1D-IAH compared with patients with T1D-NAH and healthy controls. Importantly, increased NfL levels correlated with reduced cerebral gray matter volume and increased IAH severity in patients with T1D-IAH.ConclusionOverall, our findings identify plasma NfL levels as a potential biomarker of cerebral damage in this population, motivating further confirmatory studies with potential implications in clinical trials.

Context Type 1 Diabetes (T1D) is associated with an increased risk of cognitive decline, where severe hypoglycaemia (SH) and impaired awareness of hypoglycaemia (IAH) may play a role. While there is evidence of a possible association between IAH and brain damage, the potential brain changes remain poorly characterized by magnetic resonance imaging (MRI). Objective To investigate whether there are structural brain differences in a group of T1D patients with IAH compared with normal awareness of hypoglycaemia (NAH). Design General practice, population-based, cross-sectional study. (July 2018 to July 2019) Setting Endocrinology Department, Hospital Santa Creu i Sant Pau. Participants A total of 40 T1D patients (20 each with IAH and NAH) matched for age, sex, T1D duration and education level. Main Outcome Measures: Using different neuroimaging techniques, we compared whole-brain grey matter (GM) and white matter (WM) differences. We used voxel-based morphometry (VBM) and cortical surface area analysis methods to assess GM differences, and fractional anisotropy (FA) to assess WM differences. Results Compared to patients with T1D-NAH, patients with T1D-IAH had reduced GM volumes and cortical surface areas, especially in frontal and parietal regions (p<0.05 corrected), and also showed reduced FA values in major WM tracts. The observed MRI differences correlated with both SH frequency and IAH severity. Conclusions MRI for patients with T1D show that IAH is associated with brain changes involving both GM and WM. Further research is needed to elucidate whether the observed differences are and cause of a consequence of increased SH episode frequency and increased IAH severity.