TY - JOUR
T1 - Diffusion-weighted magnetic resonance imaging detection of basal forebrain cholinergic degeneration in a mouse model
AU - Kerbler, Georg M.
AU - Hamlin, Adam S.
AU - Pannek, Kerstin
AU - Kurniawan, Nyoman D.
AU - Keller, Marianne D.
AU - Rose, Stephen E.
AU - Coulson, Elizabeth J.
N1 - Funding Information:
This project was funded by the Queensland State Government National and International Research Alliances Program . Adam S. Hamlin and Elizabeth J. Coulson were supported by National Health and Medical Research Council of Australia fellowships. Georg Kerbler was supported by an ANZ Trustees PhD Scholarship. We thank Zoran Boskovic and Sally Martin for assistance with experiments, Maree Smith, Ian Brereton, Andrew Whittaker and Dr Andrew Janke for helpful discussions, and Rowan Tweedale for editorial assistance. The authors acknowledge the facilities, scientific and technical assistance of the Queensland NMR Network, and National Imaging Facility Node at the Centre for Advanced Imaging, The University of Queensland, a facility funded by the University, Queensland State and Australian Commonwealth Governments.
PY - 2013/2/1
Y1 - 2013/2/1
N2 - 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 (r2=0.72), followed by MD (r2=0.64), AD (r2=0.64) and RD (r2=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.
AB - 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 (r2=0.72), followed by MD (r2=0.64), AD (r2=0.64) and RD (r2=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.
KW - Alzheimer's disease
KW - Cholinergic basal forebrain
KW - Diffusion tensor imaging
KW - MRI
KW - Neurodegeneration
KW - Tractography
UR - https://www.scopus.com/pages/publications/84869784887
U2 - 10.1016/j.neuroimage.2012.10.075
DO - 10.1016/j.neuroimage.2012.10.075
M3 - Article
C2 - 23128077
AN - SCOPUS:84869784887
SN - 1053-8119
VL - 66
SP - 133
EP - 141
JO - NeuroImage
JF - NeuroImage
ER -