title: The fornix provides multiple biomarkers to characterize circuit disruption in a mouse model of Alzheimer's disease.
abstract: Multivariate biomarkers are needed for detecting Alzheimer's disease (AD), understanding its etiology, and quantifying the effect of therapies. Mouse models provide opportunities to study characteristics of AD in well-controlled environments that can help facilitate development of early interventions. The CVN-AD mouse model replicates multiple AD hallmark pathologies, and we identified multivariate biomarkers characterizing a brain circuit disruption predictive of cognitive decline. In vivo and ex vivo magnetic resonance imaging (MRI) revealed that CVN-AD mice replicate the hippocampal atrophy (6%), characteristic of humans with AD, and also present changes in subcortical areas. The largest effect was in the fornix (23% smaller), which connects the septum, hippocampus, and hypothalamus. In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%) and axial diffusivity (2%), in detecting pathological changes. These findings were strengthened by optical microscopy and ultrastructural analyses. Ultrastructual analysis provided estimates of axonal density, diameters, and myelination-through the g-ratio, defined as the ratio between the axonal diameter, and the diameter of the axon plus the myelin sheath. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller g-ratios). CD68 staining showed that white matter pathology could be secondary to neuronal degeneration, or due to direct microglial attack. In conclusion, these findings strengthen the hypothesis that the fornix plays a role in AD, and can be used as a disease biomarker and as a target for therapy.
authors: Center for In Vivo Microscopy, Duke University Medical Center, Department of Radiology, Durham, NC 27710, USA. Electronic address: alexandra.badea@duke.edu.
authors: Alexandra
authors: A
authors: Badea
authors: Trinity College of Arts & Sciences, Duke University, Durham, NC 27710, USA.
authors: Lauren
authors: L
authors: Kane
authors: Center for In Vivo Microscopy, Duke University Medical Center, Department of Radiology, Durham, NC 27710, USA.
authors: Robert J
authors: RJ
authors: Anderson
authors: Center for In Vivo Microscopy, Duke University Medical Center, Department of Radiology, Durham, NC 27710, USA.
authors: Yi
authors: Y
authors: Qi
authors: Center for In Vivo Microscopy, Duke University Medical Center, Department of Radiology, Durham, NC 27710, USA.
authors: Mark
authors: M
authors: Foster
authors: Center for In Vivo Microscopy, Duke University Medical Center, Department of Radiology, Durham, NC 27710, USA.
authors: Gary P
authors: GP
authors: Cofer
authors: Department of Pathology, and Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
authors: Neil
authors: N
authors: Medvitz
authors: Department of Pathology, and Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
authors: Anne F
authors: AF
authors: Buckley
authors: Center for In Vivo Microscopy, Duke University Medical Center, Department of Radiology, Durham, NC 27710, USA.
authors: Andreas K
authors: AK
authors: Badea
authors: Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
authors: William C
authors: WC
authors: Wetsel
authors: Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Carol A
authors: CA
authors: Colton
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000473:pathology*; D000818:Animals; D001284:Atrophy / Q000473:pathology; D015415:Biomarkers; D056324:Diffusion Tensor Imaging / Q000379:methods*; D004195:Disease Models, Animal; D020712:Fornix, Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron / Q000379:methods*; D066127:White Matter / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D015415:Biomarkers
keywords: Alzheimer's disease; Diffusion tensor imaging; Electron microscopy; Fornix; Mouse models