T₂-weighted MRI detects presymptomatic pathology in the SOD1 mouse model of ALS.
Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1)(G93A) transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T₂-weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural (T₂, T₁, apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T₂-weighted images from as early as 60 days (P<0.05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T₂-weighted changes. Significant reductions in ADC (P<0.01) and MTR (P<0.05) were found at 120 days in the same brainstem nuclei. No changes in T₁ relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T₂-weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents.
1] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK [2] CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK.
Matthew C
MC
Evans
CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK.
Sébastien
S
Serres
CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK.
Alexandre A
AA
Khrapitchev
1] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK [2] Department of Pharmacology, University of Oxford, Oxford, UK.
Helen B
HB
Stolp
Department of Pharmacology, University of Oxford, Oxford, UK.
Daniel C
DC
Anthony
1] Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK [2] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
Kevin
K
Talbot
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Martin R
MR
Turner
CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK.
Nicola R
NR
Sibson
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity; D009154:Mutation; D010539:Permeability; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D015431:Weight Loss
C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1