title: Diffusion-weighted magnetic resonance imaging detection of basal forebrain cholinergic degeneration in a mouse model.
abstract: Loss of basal forebrain cholinergic neurons is an early and key feature of Alzheimer's disease, and magnetic resonance imaging (MRI) volumetric measurement of the basal forebrain has recently gained attention as a potential diagnostic tool for this condition. The aim of this study was to determine whether loss of basal forebrain cholinergic neurons underpins changes which can be detected through diffusion MRI using diffusion tensor imaging (DTI) and probabilistic tractography in a mouse model. To cause selective basal forebrain cholinergic degeneration, the toxin saporin conjugated to a p75 neurotrophin receptor antibody (mu-p75-SAP) was used. This resulted in ~25% loss of the basal forebrain cholinergic neurons and significant loss of terminal cholinergic projections in the hippocampus, as determined by histology. To test whether lesion of cholinergic neurons caused basal forebrain, hippocampal, or whole brain atrophy, we performed manual segmentation analysis, which revealed no significant atrophy in lesioned animals compared to controls (Rb-IgG-SAP). However, analysis by DTI of the basal forebrain area revealed a significant increase in fractional anisotropy (FA; +7.7%), mean diffusivity (MD; +6.1%), axial diffusivity (AD; +8.5%) and radial diffusivity (RD; +4.0%) in lesioned mice compared to control animals. These parameters strongly inversely correlated with the number of choline acetyl transferase-positive neurons, with FA showing the greatest association (r(2)=0.72), followed by MD (r(2)=0.64), AD (r(2)=0.64) and RD (r(2)=0.61). Moreover, probabilistic tractography analysis of the septo-hippocampal tracts originating from the basal forebrain revealed an increase in streamline MD (+5.1%) and RD (+4.3%) in lesioned mice. This study illustrates that moderate loss of basal forebrain cholinergic neurons (representing only a minor proportion of all septo-hippocampal axons) can be detected by measuring either DTI parameters of the basal forebrain nuclei or tractography parameters of the basal forebrain tracts. These findings provide increased support for using DTI and probabilistic tractography as non-invasive tools for diagnosing and/or monitoring the progression of conditions affecting the integrity of the basal forebrain cholinergic system in humans, including Alzheimer's disease.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072 Qld., Australia.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Kerbler
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072 Qld., Australia.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Hamlin
authors.affiliation: Centre for Clinical Research, The University of Queensland, Brisbane, 4072 Qld., Australia; Centre for Advanced Imaging, The University of Queensland, Brisbane, 4072 Qld., Australia.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Pannek
authors.affiliation: Centre for Advanced Imaging, The University of Queensland, Brisbane, 4072 Qld., Australia.
authors.forename: Nyoman D
authors.initials: ND
authors.lastname: Kurniawan
authors.affiliation: Centre for Advanced Imaging, The University of Queensland, Brisbane, 4072 Qld., Australia.
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Keller
authors.affiliation: Centre for Clinical Research, The University of Queensland, Brisbane, 4072 Qld., Australia; Centre for Advanced Imaging, The University of Queensland, Brisbane, 4072 Qld., Australia.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Rose
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, 4072 Qld., Australia. Electronic address: e.coulson@uq.edu.au.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Coulson
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D066187:Basal Forebrain / Q000473:pathology*; D059329:Cholinergic Neurons / Q000473:pathology*; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000473:pathology*
keywords: Alzheimer's disease; Cholinergic basal forebrain; Diffusion tensor imaging; MRI; Neurodegeneration; Tractography