Prior Menopausal Hormone Treatments And Association of Peripheral Markers of Neurovascular Unit Integrity And β‐amyloid in The Brains of Menopausal Women

Abstract

BackgroundBreak down of the blood brain barrier and activation of brain cells are implicated in progression of deposition of β‐amyloid that is associated with the pathophysiology of Alzheimer's disease. A previous study from our group indicated that deposition of β‐amyloid may be reduced in the brains of menopausal women treated with transdermal 17β‐estradiol. This study aimed to determine the association of peripheral microvesicles carrying markers of cells of the neurovascular unit with β‐amyloid in the brains of menopausal women and if the association was affected by prior menopausal hormone treatments (MHT).MethodsMenopausal women previously enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic underwent β‐amyloid positron emission tomography (PET) imaging of their brains 3 years following treatment with either placebo (PL, n=29), transdermal 17β‐estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17) for 4 years. Microvesicles (MV) were isolated from peripheral venous blood by differential centrifugation and analyzed by flow cytometry using fluorophore conjugated antibodies directed toward total tau, β‐amyloid 1‐42 (Ab1‐42), neuron specific class III β‐tubulin (Tuj1), microglia ionized calcium adaptor molecule 1(Iab‐1), glial fibrillar acid protein (GFAP), and low density lipoprotein receptor‐related protein 1. Principal components analysis was used to reduce the dimensionality of the 6 brain markers to 2 principal components (PCs). Proportional odds ordinal logistic regression analysis was used to regress deposition of β‐amyloid on the 2 PCs with and without adjustment for MHT group.ResultsNumber of blood MV positive for Ab1‐42 differed significantly among MHT groups (median [IQR]: 6.06 [2.11, 12.55] in the PL; 2.49 [0.73, 3.59] in the tE2 and 4.96 [0.83, 10.31] in the oCEE; P=0.036). The first 2 PCs explain 58% of the variance of the 6 markers. PC#1 represented a contrast between MV‐Iab‐1 and the MV‐GFAP and MV‐Tuj1. In multivariable models, brain β‐amyloid load positively associated with the first PC after adjustment for MHT (P= 0.006).ConclusionMV derived from cells of the neurovascular unit can be detected in peripheral blood, and, when combined into summary scores, showed an association with deposition of β‐amyloid in the brain that is independent of MHT.Support or Funding InformationSupported by grants from NIH P50 AG044170 and the Mayo FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.