Cerebrovascular mechanisms between type 2 diabetes and Alzheimer's disease: Insights from ultrasound localization microscopy

BACKGROUND: Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two major global health challenges, both associated with increased incidence and mortality. Although their pathologies differ, mounting evidence points to a shared vascular dysfunction that may drive the onset and progression of both conditions. Ultrasound localization microscopy (ULM) offers a promising approach for high-resolution imaging and quantification of cerebral microvasculature. PURPOSE: To investigate changes in cerebral micro-vessels induced by T2DM, AD, and their coexistence, aiming to uncover the underlying interactions between the two diseases. METHODS: Twenty-four Sprague Dawley (SD) rats were randomly assigned into four groups: (1) normal, (2) DM combined with AD, (3) DM, and (4) AD. Cerebral vascular density in the caudate putamen (CPu), thalamus (TH), and hippocampus (HIP) was quantified using ULM. Statistical analysis was conducted using one-way ANOVA followed by Tukey's honestly significant difference (HSD) post-hoc test, after confirming normality and homogeneity of variance (Shapiro-Wilk and Levene's tests). A p-value < 0.05 was considered statistically significant. To validate the model and examine the relationship between T2DM and AD, pathological staining was performed to assess cellular and neuronal changes, as well as Aβ deposition. RESULTS: Both single diseases and their combination led to a reduction in cerebral vascular density across all three brain regions. The blood glucose-vessel density distributions in the DM and DM&AD groups showed substantial overlap, indicating similar patterns of cerebrovascular changes. In the CPu region, vascular density in diabetic rats decreased by 34.13% compared to controls (p = 0.003), while in the HIP of the DM&AD group, vascular density was reduced by 29.98% (p = 0.002). CONCLUSION: T2DM triggers an increased risk of AD. ULM provides the possibility to be used as an emerging technological tool to detect early cerebral microangiopathy.