Amelia Elaine Cannon1†
Wolfgang Emanuel Zürrer1†
Charlotte Zejlon2Zsolt Kulcsar3
Sebastian Lewandowski4
Fredrik Piehl4,5
Tobias Granberg2,4
Benjamin Victor Ineichen1,3,4*‡- 1Center for Reproducible Science, University of Zurich, Zurich, Switzerland
- 2Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden
- 3Department of Neuroradiology, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- 4Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- 5Center of Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden
Background and objectives: Animal models for motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS) are commonly used in preclinical research. However, it is insufficiently understood how much findings from these model systems can be translated to humans. Thus, we aimed at systematically assessing the translational value of MND animal models to probe their external validity with regards to magnetic resonance imaging (MRI) features.
Methods: In a comprehensive literature search in PubMed and Embase, we retrieved 201 unique publications of which 34 were deemed eligible for qualitative synthesis including risk of bias assessment.
Results: ALS animal models can indeed present with human ALS neuroimaging features: Similar to the human paradigm, (regional) brain and spinal cord atrophy as well as signal changes in motor systems are commonly observed in ALS animal models. Blood-brain barrier breakdown seems to be more specific to ALS models, at least in the imaging domain. It is noteworthy that the G93A-SOD1 model, mimicking a rare clinical genotype, was the most frequently used ALS proxy.
Conclusions: Our systematic review provides high-grade evidence that preclinical ALS models indeed show imaging features highly reminiscent of human ALS assigning them a high external validity in this domain. This opposes the high attrition of drugs during bench-to-bedside translation and thus raises concerns that phenotypic reproducibility does not necessarily render an animal model appropriate for drug development. These findings emphasize a careful application of these model systems for ALS therapy development thereby benefiting refinement of animal experiments.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022373146.
1. Introduction
Preclinical neuroscience has advanced our understanding of the pathophysiology of neurological diseases, and research in animal models of these diseases has identified many putative treatment targets for human diseases. However, this progress stands in stark contrast to the high attrition rates in drug development, being among the highest in neuroscience (1–4). This gap in bench-to-bedside translation can be attributed to multiple factors (5, 6), some of them inherent to the challenge of developing innovative therapies (7). However, the inappropriate design and conduct of preclinical studies have been flagged as major concerns (8–10). To this end, some attention has focused on external validity (11), i.e., the extent to which an experimental finding can be extrapolated to other settings, e.g., translation from animals to humans (12, 13).
A neuroscience subfield with particularly low bench-to-bedside translation and only exiguous therapeutic options are motor neuron diseases (MND), including entities such as amyotrophic lateral sclerosis (ALS) (4, 14, 15). In these mostly fatal diseases, magnetic resonance imaging (MRI) has become among the most important paraclinical tools for diagnostic workup (16–19). Although unspecific to MND; MRI can present with certain patterns of brain and spinal cord atrophy as well as signal changes in the corticospinal tract and motor cortex (Figure 1).
Figure 1. Magnetic resonance imaging signs in human amyotrophic lateral sclerosis (ALS). Magnetic resonance imaging (MRI) from two amyotrophic lateral sclerosis (ALS) patients with the “motor band sign,” i.e., motor cortex hypointensities, on susceptibility weighted imaging [SWI, (A, D)] and T2 hyperintensities along the corticospinal tract on 3T 3D T2w-FLAIR (B, C, E, F). Image adjusted from (20). For comparison, T2 signal changes in rodent brain stem motor nuclei are shown in (21–23).
A variety of MND animal models are used for pathomechanistic investigations of these disorders, most prominently transgenic rodents with mutations in the SOD1 gene, thus mimicking familial ALS (24). However, it is insufficiently understood how well these animal models mimic human MND imaging phenotypes, i.e., what is external validity of these animal models in the neuroimaging domain? Improved understanding of the external validity of these animal models would not only benefit researchers using these models to assess putative drug candidates for MND, but it would also help to implement refinement strategies from the 3R—reduce, replace, refine—within the field (13, 25).
Thus, based on this shortcoming, we here aim at assessing the external validity of motor neuron disease animal models by systematically summarizing MRI features of MND animal models, and to compare these features with human MRI phenotypes. We focus our analysis on structural MRI as used in the clinical routine for MND diagnostic work-up. This study complements a recently published systematic review on structural neuroimaging findings in human MND (20).
2. Methods
2.1. Protocol registration
We registered a prospective study protocol in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42022373146, https://www.crd.york.ac.uk/PROSPERO/) and used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting (26).
2.2. Search strategy
We searched PubMed and Ovid EMBASE for relevant publications from inception up to December 19, 2022. See Supplementary Table 1 for the search strings in each of these databases.
2.3. Inclusion and exclusion criteria
We included original publications that reported on any structural brain or spinal cord MRI outcome in MND animal models. Conference abstracts, non-English articles, and publications which reiterated previously reported quantitative data were excluded. Reviews were excluded but retained as potential sources for additional records. Reference lists of these reviews were screened for additional eligible publications.
2.4. Study selection and data extraction
Titles and abstracts of studies were screened for their relevance in the web-based application Rayyan (27) by two independent reviewers followed by full-text screening. From eligible full texts, the following data was extracted by two independent reviewers: title, authors, publication year, journal, MND model, number of animals in the treatment and control groups, MRI static magnetic field strength, and main findings related to structural neuroimaging.
2.5. Quality assessment
Risk of bias was assessed against a 3-item checklist according to the consensus statement for good laboratory practice in the modeling of stroke (sample size calculations provided, reporting of animal welfare, statement of a potential conflict of interest) (28), as well as four items on reporting any measure of randomization or blinding (29).
3. Results
3.1. General study characteristics
3.1.1. Eligible publications
In total, 364 publications were retrieved from our database search, and an additional 2 publications from reference lists of reviews on related topics. After abstract and title screening, 46 publications were eligible for full-text search. After screening the full text of these records, 34 publications (17% of deduplicated references) were included for the qualitative synthesis (Figure 2).
Figure 2. PRISMA flow chart for study inclusion. A total of 34 publications were eligible for the qualitative synthesis. MND, motor neuron disease; MRI, magnetic resonance imaging.
3.1.2. Experimental parameters of eligible publications
The most frequently used MND animal model was the SOD1G93A transgenic model, mimicking familial ALS (26 publications, 76%, we will refer to these models as ALS animal models in the remainder of the manuscript). The B6SJL-Tg(SOD1G93A)1Gur/J was the most commonly used mutant (15 publications, 58%), the B6.Cg-Tg(SOD1G93A)1Gur/J was only used in one publication, the remaining publications did not further specify the mutant.
Only mice and rats were used in the eligible publications (30 [88%] and 4, [12%], respectively). The employed static magnetic field strengths ranged from 1.5T to 17.6T, with most publications employing 7T (16, 47%). The median sample size of animals was 10 and 5.5 animals for the experimental and control groups, respectively (interquartile range, IQR [7–21.75] and [0.75–7.75], respectively). Four publications did not report the number of used animals.
Seven publications (21%) tested a therapeutic intervention for MND, among them mostly stem cell-based approaches (4 publications, 12%) (21, 30–32). One study each investigated liposomal encapsulated glucocorticoid (33), davunetide (an intranasal neuropeptide therapy) (34), and deferiprone (an iron chelator) (35).
More detailed data on experimental parameters can be found in Supplementary Table 2.
3.1.3. Risk of bias assessment
Most publications showed a low risk of bias in the animal welfare (reported by 29/34 publications, 85%) and conflict of interest domain (19/34, 56%). Yet only few publications reported randomization (7/34, 21%), blinding (6/34, 18%) or sample size calculations for their study (3/34, 9%) (Supplementary Table 3).
3.2. Neuroimaging findings in motor neuron disease animal models
3.2.1. Atrophy of brain and spinal cord
Neuroimaging has consistently shown local central nervous system (CNS) tissue volume loss in MND animal models. Yet the affected anatomical CNS regions show a high degree of variability between reports. 1-year old mice overexpressing both APP and SOD1 mutations exhibited gray matter atrophy, most pronounced in the hippocampi as well as in entorhinal and cingulate cortices (36). In contrast, mice only overexpressing SOD1 exhibited atrophy specifically in cortical regions (cingulate, retrosplenial, and temporoparietal cortex) but not in the hippocampi (36). A loss in motor cortex volume has also been observed in the murine SOD1G93A model at postnatal day 100 (37). However, such motor cortex atrophy has not been consistent in other study using mice of similar age (38). Along these lines, a report using the TARDBPQ331K transgenic mouse strain, i.e., a model for ALS-FTD, found a more prominent atrophy in the entorhinal cortex compared to the motor cortex (39). Mice fed with cycad toxins (resulting in motor neuron loss) show lower volumes in the substantia nigra, striatum, basal nucleus/internal capsule, and olfactory bulb (40). A more recent study using a conditional TDP-43 mouse model found progressive volume loss of the gray matter in the olfactory bulb, frontal association cortices, lateral and dorsolateral orbital cortices, agranular insular cortices, globus pallidus, hippocampi, dorsal subiculum, secondary visual cortices, as well as in the cerebellum (41). Finally, several studies described atrophy of brain stem nuclei (42), particularly of motor nuclei, e.g., trigeminal, facial, and hypoglossal nuclei (34, 38).
Spinal cord volume loss has been observed in the murine SOD1G93A model (37, 43), but also in the cycad toxin animal model (40).
3.2.2. Signal changes of brain and spinal cord
T2w hyperintensities have been described in rodent ALS models in the brain stem (21–23, 44, 45). These hyperintensities seem to parallel or even precede first behavioral ALS symptoms (46, 47). Histopathological correlations found associated vacuolar degeneration (23, 45–49) as well as micro- and astroglial activation (42). Interestingly, magnetic resonance microscopy was able to also detect hyperintensities in the ventral motor tracts within the murine spinal cord (50). Higher T2 values, mainly in the ventral portions of the spinal cord, have also been observed using conventional sequences at 7T (51).
One study found iron accumulation in the cervical spinal cord (based on T2* contrast), that, however, disappeared with progressing disease (37). Iron changes have also been observed in the medulla oblongata and motor cortex (35).
3.2.3. Contrast enhancement patterns
Overt breakdown of the blood-brain barrier adjacent to lateral ventricles and in the hippocampal region was described in a rat ALS model (22). Such breakdown of the BBB was consistent in another study which also employed Ultrasmall superparamagnetic iron oxide (USPIO) enhanced MRI (52). Here, BBB breakdown was congruent with T cell infiltration. Finally, a study using dynamic contrast-enhanced MRI upon intracisternal injection of gadolinium found altered contrast medium clearance in ALS model mice compared to controls (41).
4. Discussion
4.1. Main findings
The main objective of this study was to systematically summarize the available evidence on structural CNS MRI features in ALS animal models. Frequent MRI features include brain and spinal cord atrophy, signal changes in brain stem motor nuclei and the motor cortex as well as breakdown of the blood-brain barrier (Table 1). In the following paragraphs, we will compare this phenotype with MRI features of human ALS.
Table 1. Synopsis of brain and spinal cord magnetic resonance imaging findings in amyotrophic lateral sclerosis (ALS) animal models.
4.2. Findings in the context of existing evidence
Based on the findings of our systematic review, ALS animal models seem to feature several imaging signs reminiscent of human ALS (Table 1). Among these features is the volume loss of CNS structures with progressive disease. Atrophy in both the motor cortex (37) and the spinal cord (37, 40, 43) has been reported in ALS animal models, similar to the human imaging phenotype (20, 53, 54), which could correspond to the underlying decline of the upper and lower motor neurons (14). These similarities between the human and animal imaging phenotype are particularly interesting since most eligible animal studies used the G93A-SOD1 model thus mimicking familial ALS, a rare clinical phenotype constituting around 10% of ALS patients. It is also noteworthy that, similar to the human population (20), a wide and not always consistent array of CNS structures have been reported to be affected by volume loss in animal models. For example, motor cortex atrophy has not been consistently shown in ALS animal models (38). It is likely that different methodological approaches for the quantification of atrophy patterns between animal studies is in part responsible for these inconsistencies: This has been emphasized by a human study in ALS-FTD patients which found variable atrophy patterns when comparing different software to assess cortical volumes (FSL, FreeSurfer, and SPM) (84). Further confounders could be technical parameters such as intra-/inter-scanner variability and physiological factors such as hydration state of animals during imaging [reviewed in (85)].
ALS rodent models can present with T2 signal changes in the CNS, potentially corresponding to axonal degeneration (23). In rodents, these signal alterations seem to commonly affect brain stem motor nuclei (21, 22). In ALS patients, T2 signal changes are also commonly observed (20, 77), albeit at different locations, i.e., mostly along the corticospinal tract (Figure 1).
Abnormal iron deposition in the motor cortex and spinal cord has been reported by some rodent ALS studies, measured by T2*-based MRI approaches (35, 37). Although respective publications did not include pictorial examples of iron deposition within the motor cortex, this feature could correspond to the “motor band sign” (linear motor cortex hypointensity) which is commonly observed in the motor cortex of ALS patients on T2*-based sequences (Figure 1). In ALS, these signal drops seem to correspond to astro- and microglia iron deposition within deep layers of the motor cortex (86).
One imaging feature which seems more specific to rodent ALS models is breakdown of the blood-brain barrier, as visualized by gadolinium enhancement in periventricular and hippocampal regions (22). However, although gadolinium enhancement is not observed in the clinical setting in ALS, several lines of evidence demonstrate damage to the blood–brain and blood-spinal cord barrier in ALS [reviewed in (87)]. Such vascular changes seem to include alterations of tight junction proteins (88) and can be observed already early in the disease process (89). Structural MRI features of preclinical ALS models are summarized in Table 1, alongside with MRI features of human ALS.
4.3. Limitations
To assess the external validity of ALS animal models, we focused our analysis on structural brain and spinal cord MRI features. However, other disease aspects such as patterns of physical disability or also more advanced MRI methods like diffusion-tensor imaging, which are able to more specifically reflect pathogenic disease processes, might enable a more comprehensive comparison between experimental and human phenotypes.
A genuine limitation of this systematic review is that only a limited number of studies employing MRI in ALS animal models was eligible. As a result, it is difficult to map imaging phenotypes of less commonly used ALS models such as cycad toxins or wobbler mice or even for different SOD1G93A mutants. It is possible that certain ALS rodent models might mimic specific human imaging phenotypes better than others (36), similarly to the situation in experimental autoimmune encephalomyelitis (EAE)—a commonly used animal model for multiple sclerosis (90).
Finally, although seven of the eligible publications tested a putative therapeutic intervention for ALS, no corresponding human MRI studies could be identified. Correlating the impact of therapeutic interventions on neuroimaging phenotypes between rodent models and humans would further enhance understanding of the translational value of experimental ALS models.
5. Conclusions
Our systematic review provides high-grade evidence that preclinical ALS models do show imaging features highly reminiscent of human ALS, including certain brain and spinal cord atrophy patterns and signal changes in motor systems (Table 1). Certain imaging features such as breakdown of the BBB are only partly reflected by these experimental models. Thus, ALS rodent models show a high external validity in the neuroimaging domain. This contrasts the high attrition of drugs in clinical ALS trials which have shown promising results in ALS animal models; and this raises concerns that a mere phenotypic comparability between experimental models and corresponding human diseases does not necessarily render an animal model appropriate for drug development. These findings emphasize a careful application of these model systems for ALS drug development thereby benefiting refinement of animal experiments.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.
Author contributions
CZ, TG, and BVI conceived the study. AC, WZ, CZ, and BVI performed the literature review and data extraction. BVI wrote the manuscript. All authors provided critical input on the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This study was supported by the Swiss National Science Foundation (Grant Nr. P400PM_183884, to BVI) as well as Region Stockholm and CIMED (to TG). None of the funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Acknowledgments
We cordially thank Emma-Lotta Säätelä and Carl Gornitzki for competent help with the comprehensive medical library database search. We thank Thijs van Leer (Focus) and Claude Debussy for help with data analysis.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fvets.2023.1135282/full#supplementary-material
Abbreviations
ALS, amyotrophic lateral sclerosis; BBB; blood-brain barrier; CNS, central nervous system; CST, corticospinal tract; FTD, frontotemporal dementia; MND, motor neuron disease; MRI, magnetic resonance imaging; SWI, susceptibility-weighted imaging.
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Keywords: motor neuron disease (MND), magnetic resonance imaging (MRI), systematic review, amyotrophic lateral sclerosis, neuroimaging, external validity, 3R, neuroscience
Citation: Cannon AE, Zürrer WE, Zejlon C, Kulcsar Z, Lewandowski S, Piehl F, Granberg T and Ineichen BV (2023) Neuroimaging findings in preclinical amyotrophic lateral sclerosis models—How well do they mimic the clinical phenotype? A systematic review. Front. Vet. Sci. 10:1135282. doi: 10.3389/fvets.2023.1135282
Received: 31 December 2022; Accepted: 10 April 2023;
Published: 02 May 2023.
Edited by:
Weiguo Li, Northwestern University, United StatesReviewed by:
Vito Antonio Baldassarro, University of Bologna, ItalyKejia Cai, University of Illinois at Chicago, United States
Copyright © 2023 Cannon, Zürrer, Zejlon, Kulcsar, Lewandowski, Piehl, Granberg and Ineichen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Benjamin Victor Ineichen, benjaminvictor.ineichen@uzh.ch
†These authors have contributed equally to this work and share first authorship
‡ORCID: Benjamin Victor Ineichen orcid.org/0000-0003-1362-4819