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[P3–021]: THE ROLE OF CARDIOVASCULAR HEALTH IN MODERATING THE EFFECTS OF POSTMENOPAUSAL HORMONE THERAPY ON NEUROIMAGING OUTCOMES
Author(s) -
Dowling Maritza,
Miller Virginia M.,
Jack Clifford R.,
Gunter Jeffrey L.,
Shuster Lynne T.,
Zuk Samantha M.,
Bailey Kent R.,
Gleason Carey E.,
Kantarci Kejal
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1834
Subject(s) - medicine , imputation (statistics) , placebo , menopause , hormone therapy , randomization , randomized controlled trial , physical therapy , missing data , breast cancer , cancer , alternative medicine , pathology , machine learning , computer science
determined by LC-MS/MS. Results:CSF Cytokines: majority were below-level-of-quantitation. CSF-IL8 was only cytokine quantifiable at all time-points. CSF-TNFa was quantifiable in approximately one-third of samples. Peak CSF-IL8 at EOT was significantly and inversely correlated (p1⁄40.008; r1⁄4.79)to plasma drug-exposure (AUC0-12); similar trend seen for CSF-TNFa (p1⁄40.08; r1⁄4.48). For both, reduction in levels was prominent at average plasma drug-concentration (CAVERAGE) >10 ng/mL, the target concentration for anti-inflammatory activity based on preclinical studies. CSF-Ab: Percent change in mean levels over 24hours was significantly correlated to AUC0-12 for each of CSF Ab38 (p1⁄40.03; r1⁄40.62), Ab40 (p1⁄40.012; r1⁄40.75), and Ab42 (p1⁄40.047; r1⁄40.58). For each, CSF-Ab levels were neutral or decreased at CAVERAGE < 8 ng/mL and increased at CAVERAGE > 10 ng/mL (see figure for Ab40). Conclusions:As one of the downstream effects of p38 inhibition is reduction of pro-inflammatory cytokine production, the PK-PD correlation between AUC0-12 and CSF-IL8/TNFa indicates target engagement. Further, the apparent relationship between anti-inflammatory effect and reduction in CSF amyloid beta levels at CAVERAGE > 10 ng/mL, and the known requirement of p38 MAPK for microglial-mediated uptake of amyloid-beta (Adolfsson, 2012), suggests that the increase in CSF amyloid-beta at high concentrations may be due to high-level p38 MAPK inhibition within microglia.