Revisiting the role of beta-amyloid precursor protein immunoreactivity in the neuropathological diagnosis of hypoglycaemia.

The neuropathological diagnosis of hypoglycaemia has long relied on demonstrating the classical pattern of selective neuronal necrosis in affected brain regions. This approach is heavily limited, as hypoglycaemic injury is often indistinguishable from hypoxia-ischaemia. We demonstrate a distinct pattern of beta-amyloid precursor protein (β-APP) immunoreactivity in hypoglycaemic deaths (n = 6), contrasting them with non-hypoglycaemic deaths (n = 8). We also address the temporal relationship between hypoglycaemia and β-APP immunoreactivity. The sample comprised neuropathologically examined medico-legal autopsy cases from Helsinki, Finland, during the years 2023-2025. Hypoglycaemic deaths comprised one accidental and five suicidal insulin intoxications. Non-hypoglycaemic deaths comprised two diabetic ketoacidoses, two other deaths in insulin-treated diabetics, two cases of traumatic axonal injury, and two cases of vascular axonal injury. Detailed characteristics of each case were collected (background information; autopsy, neuropathology, and toxicology findings; photomicrographs of β-APP immunoreactivity in the corpus callosum, capsula interna, pons, and thalamus). Estimates of temporal relationships between hypoglycaemia and β-APP immunoreactivity were based on continuous glucose monitoring records and previous hospitalisations due to insulin intoxications. In our sample, utilisation of β-APP appeared more beneficial for the neuropathological diagnosis of hypoglycaemia than classical assessment of selective neuronal injury. In β-APP, hypoglycaemic deaths consistently exhibited positivity of thalamic and pontine axonal fibres. In contrast, non-hypoglycaemic cases were immunonegative or demonstrated immunoreactivity that was predominantly localised elsewhere. Estimates of temporal relationships suggested that β-APP immunoreactivity developed within a few hours of hypoglycaemia (~2.5-3 h) and was not retained after remote episodes (≥ 1 month). On the basis of our preliminary findings, β-APP immunoreactivity appears to be a promising adjunct marker for hypoglycaemic brain injury. Future studies are needed to corroborate the present findings and further explore potential caveats.