Blood-Based Microcirculation Markers in Alzheimer's Disease-Diagnostic Value of Midregional Pro-atrial Natriuretic Peptide/C-terminal Endothelin-1 Precursor Fragment Ratio

Background: There is evidence that vascular factors contribute substantially to Alzheimer's disease (AD). We have developed assays to reliably detect the circulation and microcirculation regulating factors C-terminal endothelin-1 precursor fragment (CT-proET-1), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP). We hypothesized that this set of blood-based (micro)circulation parameters is altered in AD. Methods: Prospectively recruited volunteer cohort (94 patients with probable AD, 53 healthy control subjects [HC]). In plasma, CT-proET-1, MR-proADIM, and MR-proANP were analyzed using sandwich luminescence immunoassays. Concentrations of plasma markers and their ratios (MR-proANP/CT-proET-1 and MR-proADM/CT-proET-1) were compared between groups. Diagnostic accuracy of the vasodilator/vasoconstrictor ratios were calculated in the training set (half of AD and HC groups, respectively) and the optimal cutoff was then applied to the test set (remaining half of the study population). Results: In AD patients, concentrations of MR-proADM and MR-proANP were significantly increased and levels of CT-proET-1 were significantly decreased compared with HC subjects. The ratios MR-proANP/CT-proET-1 and MR-proADM/CT-proET-1 improved group separation compared with the single markers. In a logistic regression analysis, the ratios of vasodilator/vasoconstrictor significantly contributed to group separation. The highest diagnostic accuracy was found for the MR-proANP/CT-proET-1 ratio. When applied to the training (test) set, specificity was 82% (80) and sensitivity was 81% (72). Conclusions: This indicates altered expression of microcirculation parameters and supports the hypothesis of a disturbed microvascular homeostasis in AD. We generated the hypothesis that the vasodilator/vasoconstrictor ratios hold promise as a diagnostic marker of AD. The best diagnostic accuracy was achieved for the MR-proANP/CT-proET-1 ratio.