title: Latrepirdine increases cerebral glucose utilization in aged mice as measured by [18F]-fluorodeoxyglucose positron emission tomography.
abstract: Latrepirdine is hypothesized to exert a unique mechanism of action involving stabilization of mitochondria that may have utility in treating Alzheimer's disease. However, the ability of latrepirdine to improve cognition in Alzheimer's disease (AD) is controversial due to a discrepancy between the positive signal reported in the multi-site phase II clinical trial where latrepirdine met all primary and secondary endpoints [Doody et al. (2008) Lancet 372:207-215], and the subsequent null effect observed in a multicenter, phase III trial. While dysfunction of mitochondria and abnormal energy metabolism has been linked to AD pathology, no studies have been reported that investigate latrepirdine's effect on cerebral glucose utilization (CGU). Glucose metabolism, following acute latrepirdine administration, can be used to help dose selection in Phase I dose-ranging studies. The aim of the current study was to assess changes in CGU in young and aged mice in vivo using [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) after acute treatment with latrepirdine. Two ages of B6SJLF2 mice (5 and 20 months old) were tested. Three test-retest FDG-PET baseline scans were assessed across all subjects. As CGU was heterogeneous in aged mice, compared to young mice, aged subjects were rank ordered and then counterbalanced into two CGU homogenous groups. In Studies 1 and 2, latrepirdine (1.0 mg/kg) significantly enhanced CGU in aged mice. In contrast, Study 3 revealed that latrepirdine did not modulate CGU in young mice. Monitoring changes in CGU in response to acute drug administration may represent an imaging biomarker for dose selection in AD. Further studies that would establish the translation from mice to non-human primates to humans need to be investigated to confirm the utility of FDG-PET in dose-selection for mitochondrial modulators.
authors.affiliation: Translational Imaging and Biochemical Biomarkers/Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mark.day@abbott.com
authors.forename: M
authors.initials: M
authors.lastname: Day
authors.forename: P
authors.initials: P
authors.lastname: Chandran
authors.forename: F
authors.initials: F
authors.lastname: Luo
authors.forename: N R
authors.initials: NR
authors.lastname: Rustay
authors.forename: S
authors.initials: S
authors.lastname: Markosyan
authors.forename: D
authors.initials: D
authors.lastname: LeBlond
authors.forename: G B
authors.initials: GB
authors.lastname: Fox
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals
chemical_list: D007211:Indoles; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D005947:Glucose; C010119:latrepirdine