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Non-invasive characterization of amyotrophic lateral sclerosis in a hTDP-43 A315T mouse model: A PET-MR study

Authors
  • Weerasekera, Akila1, 2
  • Crabbé, Melissa3, 4
  • Tomé, Sandra O.5
  • Gsell, Willy1
  • Sima, Diana6, 7
  • Casteels, Cindy3, 4
  • Dresselaers, Tom8
  • Deroose, Christophe3, 4
  • Van Huffel, Sabine7
  • Rudolf Thal, Dietmar5, 9
  • Van Damme, Philip10, 11, 12
  • Himmelreich, Uwe1
  • 1 Biomedical MRI Unit/MoSAIC, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
  • 2 A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School (MGH/HMS), Boston, MA, USA
  • 3 Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven, Belgium
  • 4 MoSAIC - Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium
  • 5 Laboratory for Neuropathology, Department of Neurosciences, KU Leuven, Leuven, Belgium
  • 6 Icometrix, R&D department, Leuven, Belgium
  • 7 Department of Electrical Engineering (ESAT), STADIUS Center for Dynamical Systems, Signal Processing and Data Analytics, KU Leuven, Leuven, Belgium
  • 8 Division of Radiology, Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium
  • 9 Department of Pathology, University Hospitals Leuven, Leuven, Belgium
  • 10 Laboratory of Neurobiology, Department of Neurosciences, KU Leuven, Leuven, Belgium
  • 11 Center for Brain & Disease Research, VIB, Leuven, Belgium
  • 12 Department of Neurology, University Hospitals Leuven, Leuven, Belgium
Type
Published Article
Journal
NeuroImage Clinical
Publisher
Elsevier
Publication Date
Jun 25, 2020
Volume
27
Identifiers
DOI: 10.1016/j.nicl.2020.102327
PMID: 32653817
PMCID: PMC7352080
Source
PubMed Central
Keywords
License
Unknown

Abstract

Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo . For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43A315T disease pathogenesis and may prove useful for clinical management of ALS.

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