Regular ArticleIn vivo quantification of spinal and bulbar motor neuron degeneration in the G93A-SOD1 transgenic mouse model of ALS by T2 relaxation time and apparent diffusion coefficient
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the spinal cord, brainstem, and motor cortex, which occurs in familial (fALS) and sporadic (sALS) form. While the etiology of sALS is largely unknown, 20% of fALS is associated with a dominantly inherited mutation in the gene that encodes the Cu/Zn-superoxide dismutase 1, SOD1. How the mutated SOD1 causes the selective motor neuron loss remains unclear, even though various mechanisms are discussed (reviewed in Bruijn et al., 2004).
For an independent evaluation of putative therapeutic approaches, sensitive and specific markers for the progression of the disease are crucial prerequisites (Karitzky and Ludolph, 2001). An optimal progression marker should reflect major pathological features of ALS, be easily detectable, and allow for a serial examination in an individual animal. So far, the progression of ALS is diagnosed from behavioral tests (Weydt et al., 2003) or more directly by counting neurons in affected regions (Kaspar et al., 2003). However, so far, no quantitative in vivo progression marker for longitudinal studies is available.
Recently, non-invasive magnetic resonance imaging (MRI) revealed disease-related alterations in brain structure and function in longitudinal human studies (Basak et al., 2002, Ellis et al., 2001). In the most prevalent ALS model, the transgenic G93A-SOD1 mouse (Gurney, 1994), neuronal degeneration of brainstem motor nuclei was recently visualized by T2-weighted MRI (Angenstein et al., 2004, Zang et al., 2004). Although disease progression was mirrored by a relative increase in signal intensity, the previous approaches did not allow for an absolute quantification of changes. Furthermore, the spinal cord–a highly relevant area for the development of ALS–was not assessed. In this study, we examined whether the measurement of T2 and the apparent diffusion coefficient (ADC) can be utilized for a quantitative assessment of disease progression in ALS. Both parameters are influenced by changes in water mobility and allow for an absolute quantification of structural alterations. However, the two parameters do not necessarily change the same way and may, therefore, yield complementing information (Bernarding et al., 2000).
Section snippets
Transgenic mice
Two lines of transgenic mice expressing multiple copies of human SOD1 were employed in this study. Male B6SJL-Tg(G93A-SOD1)1GurJ mice (G93A-SOD1 mice) originally obtained from Jackson Laboratories (Bar Harbor, USA) were bred with non-transgenic B6SJL mice in the animal facility of the Department of Neurology, University of Ulm, Germany. As a second type of transgenic human SOD1 mice, male B6SJL-Tg(SOD1)2Gur/J mice (tg-SOD1 mice), i.e., transgenic mice over-expressing non-mutated human SOD1,
T2 mapping
In the presented work, mapping of T2 and ADC was used to obtain progression markers for the development of ALS in G93A-SOD1 mice. Fig. 1 shows adjacent sagittal T2-weighted MR images and T2 maps of a G93A-SOD1 mouse, a wild-type mouse, and an age-matched tg-SOD1 mouse 110 days after birth. In addition, ADC maps are shown for all animal groups 90 days after birth. In the T2-weighted MR images, signal alterations in motor nuclei Nc. XII (Fig. 1A), V, and VII (both in Fig. 1J) in the brain stem
Discussion
In this report, we used quantitative T2 and ADC mapping to non-invasively study the disease development and to identify potential biomarkers in the G93A-SOD1 mouse model of ALS. Consistent with disease progression, we found significantly increased T2 values in brainstem motor nuclei Nc. V, VII, and XII and spinal cord, but not in cortex or thalamus. The ADC showed differences in Nc. VII and XII. A significant correlation of T2 values of the brain stem nuclei and between the brain stem nuclei
Acknowledgments
The authors received support from the Center of Advanced Imaging Magdeburg (CAI, BMBF-grants 01GO0202 and 01GO0504), the German Research Council (SFB/TR3 TP A7), and the Foundation of Medical Research, Frankfurt (to S.V. and H.J.H).
References (32)
- et al.
Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice
Brain Res.
(2005) - et al.
Imaging and neurochemical markers for diagnosis and disease progression in ALS
J. Neurol. Sci.
(2001) - et al.
Diffusion tensor imaging detects age-dependent white matter changes in a transgenic mouse model with amyloid deposition
Neurobiol. Dis.
(2004) Nuclear magnetic resonance (NMR) measurement of the apparent diffusion coefficient (ADC) of tissue water and its relationship to cell volume changes in pathological states
Neurochem. Int.
(2004)- et al.
Detection of age-dependent brain injury in a mouse model of brain amyloidosis associated with Alzheimer's disease using magnetic resonance diffusion tensor imaging
Exp. Neurol.
(2005) - et al.
An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria
Neuron
(1995) - et al.
Degeneration of corticospinal and bulbospinal systems in the superoxide dismutase 1 (G93A G1H) transgenic mouse model of familial amyotrophic lateral sclerosis
Neurosci. Lett.
(2002) - et al.
Age-dependent changes in MRI of motor brain stem nuclei in a mouse model of ALS
Neuroreport
(2004) - et al.
Magnetic resonance imaging in amyotrophic lateral sclerosis
Acta Neurol. Scand.
(2002) The basis of anisotropic water diffusion in the nervous system—A technical review
NMR Biomed.
(2002)
Histogram-based characterization of healthy and ischemic brain tissues using multiparametric MR imaging including apparent diffusion coefficient maps and relaxometry
Magn. Reson. Med.
Unraveling the mechanisms involved in motor neuron degeneration in ALS
Annu. Rev. Neurosci.
Age-dependent MRI-detected lesions at early stages of transient global ischemia in rat brain
Magma
Amyotrophic lateral sclerosis: current understanding
J. Neurosci. Nurs.
Diffusion changes in the aging human brain
AJNR Am. J. Neuroradiol.
Volumetric analysis reveals corticospinal tract degeneration and extramotor involvement in ALS
Neurology
Cited by (53)
Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1<sup>G93A</sup> mouse model of ALS
2019, Neurobiology of DiseaseCitation Excerpt :T2 lesions were also detected at 20 weeks in the cervical white matter. MRI diffusion metrics have been demonstrated to both decrease and increase when comparing SOD1.tg animals with wildtype controls (Evans et al., 2014; Kim et al., 2011; Niessen et al., 2006; Towner et al., 2013), possibly due to differences in diffusion imaging methodology among these studies. Here we found that mean diffusivity values are reduced in the hindbrain lesions (Fig. 6), where genotype differences were detected at 10 weeks for trigeminus, facial, and ambiguus nuclei; and 15 weeks in the hypoglossus nucleus and cervical gray matter.
Magnetic resonance imaging relaxation time in Alzheimer's disease
2018, Brain Research BulletinNon-invasive assessment of disease progression and neuroprotective effects of dietary coconut oil supplementation in the ALS SOD1<sup>G93A</sup> mouse model: A <sup>1</sup>H-magnetic resonance spectroscopic study
2018, NeuroImage: ClinicalCitation Excerpt :Consequently, it is reasonable to assume that neurometabolic changes occurring in those motor nuclei during the life-span of this mouse model (Kong et al., 1998). Using T2-weighted MR imaging Niessen et al. (2006) showed clear signal intensity enhancement compared with surrounding tissue in various motor nuclei within the brainstem of SOD1G93A mice, including the hypoglossal nucleus (Nc. Nv XII), nucleus ambiguus (Nc.
In vivo EPR pharmacokinetic evaluation of the redox status and the blood brain barrier permeability in the SOD1<sup>G93A</sup> ALS rat model
2017, Free Radical Biology and MedicineCitation Excerpt :Nevertheless, a number of studies reported histological evidence of compromised BBB and BSCB in both patients and transgenic rodent models of ALS [7–9]. Magnetic resonance imaging (MRI) studies were successfully employed to demonstrate neurodegenerative foci in the brain and spinal cord in patients and animal models [10–13], and iron accumulation in brains of patients [14,15]. However, MRI experiments focused on examining the state of the BBB gave ambiguous results.
Cognitive impairment in amyotrophic lateral sclerosis, clues from the SOD1 mouse
2016, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Patients with SOD1 mutations are less likely to have significant cognitive alterations (Wicks et al., 2009) compared to non-SOD1 fALS patients, although case reports of families developing ALS and FTD linked to SOD1 mutations have been reported (Katz et al., 2012; Nakamura et al., 2015) revealing that, even SOD1, although rarely, can cause FTD. Similarly the most relevant neuropathological traits of the mSOD1 mice seem to be restricted to the spinal and bulbar MN areas, with the cortical areas less affected (Ralph et al., 2005; Niessen et al., 2006). Nevertheless, the mSOD1 mice, particularly the SOD1G93A, have provided valuable insights into the degenerative processes happening in the cortical and subcortical brain areas throughout the course of the disease.