A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Marcuzzo, Stefania; Bonanno, Silvia; Scotti, Alessandro; Zucca, Ileana; Minati, Ludovico; Riva, Nilo; Domi, Teuta; Fossaghi, Andrea; Quattrini, Angelo; Galbardi, Barbara; D’Alessandro, Sara; Bruzzone, Maria Grazia; García‐Verdugo, José Manuel; Moreno‐Manzano, Victoria; Mantegazza, Renato; Bernasconi, Pia

doi:10.1016/j.expneurol.2017.03.018

Cited by 19 publications

(24 citation statements)

References 70 publications

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“…43 RD and AD are thought to be histologically more accurate, representing myelin and axonal changes with more specificity. 47 Our current understanding of the microstructural correlates of MRI metrics in neurologic conditions is largely putative, further animal studies are needed, and robust human combined postmortem MRI and histology studies are required. 44,45 NODDI is an advanced diffusion imaging technique that has already been applied to highlight widespread presymptomatic changes in asymptomatic C9 + subjects from the same cohort.…”

Section: Discussionmentioning

confidence: 99%

“…A few SC imaging studies have validated the histological and microstructural correlates of diffusivity metrics, but the pathological underpinnings of WM volumes are especially poorly characterized. 47 Our current understanding of the microstructural correlates of MRI metrics in neurologic conditions is largely putative, further animal studies are needed, and robust human combined postmortem MRI and histology studies are required. 48,49 Our study is not without limitations.…”

Section: Discussionmentioning

confidence: 99%

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Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study

Querin

Bede

Mendili

et al. 2019

Annals of Neurology

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Objective: C9orf72 hexanucleotide repeats expansions account for almost half of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases. Recent imaging studies in asymptomatic C9orf72 carriers have demonstrated cerebral white (WM) and gray matter (GM) degeneration before the age of 40 years. The objective of this study was to characterize cervical spinal cord (SC) changes in asymptomatic C9orf72 hexanucleotide carriers. Methods: Seventy-two asymptomatic individuals were enrolled in a prospective study of first-degree relatives of ALS and FTD patients carrying the c9orf72 hexanucleotide expansion. Forty of them carried the pathogenic mutation (C9 + ). Each subject underwent quantitative cervical cord imaging. Structural GM and WM metrics and diffusivity parameters were evaluated at baseline and 18 months later. Data were analyzed in C9 + and C9 − subgroups, and C9 + subjects were further stratified by age. Results: At baseline, significant WM atrophy was detected at each cervical vertebral level in C9 + subjects older than 40 years without associated changes in GM and diffusion tensor imaging parameters. At 18-month follow-up, WM atrophy was accompanied by significant corticospinal tract (CST) fractional anisotropy (FA) reductions. Intriguingly, asymptomatic C9 + subjects older than 40 years with family history of ALS (as opposed to FTD) also exhibited significant CST FA reduction at baseline. View this article online at wileyonlinelibrary.com.Additional supporting information can be found in the online version of this article.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study

Querin

Bede

Mendili

et al. 2019

Annals of Neurology

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“…The similar distal to proximal alteration in AD and RD may indicate a multicellular degeneration produced by an early disruption of a trophic relationship between glial and neuronal cells. 75,76 The study of AD to measure axonal damage in ALS has been elusive because of the numerous different and contradictory results reported between animal models (decreased AD) 21,22,77 and human studies (no significant changes in AD). 19,36,49,78,79 In that context, our data suggested that AD showed a decrease in values in the mutant group compared with controls, particularly at the presymptomatic stage ( Figure 4c).…”

Section: Discussionmentioning

confidence: 57%

“…The study of AD to measure axonal damage in ALS has been elusive because of the numerous different and contradictory results reported between animal models (decreased AD) and human studies (no significant changes in AD) . In that context, our data suggested that AD showed a decrease in values in the mutant group compared with controls, particularly at the presymptomatic stage (Figure c).…”

Section: Discussionmentioning

confidence: 62%

“…High spatial resolution is beneficial and theoretically easier to achieve at high magnetic fields (e.g. at 7‐ and 9.4‐T MRI), where it has been able to identify axonal degeneration in SCs from animals with ALS following the onset of symptoms . However, the underlying connections between diffusivity parameters and biological structural changes at the early stages of the disease remain to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

Gatto

Gao

2018

NMR in Biomedicine

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Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro- and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High-field MRI data were acquired using a 9.4-T animal scanner to examine the spinal cord of an ALS mouse model at pre- and post-symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A-SOD1 mouse strain. DTI maps of diffusion-weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p < 0.01), AD (19.5% decrease, p < 0.01) and RD (16.1% increase, p < 0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.

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Diffusion tensor imaging identifies presymptomatic axonal degeneration in the spinal cord of ALS mice

Gatto

2018

Brain Research

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A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Cited by 19 publications

References 70 publications

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study

Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

Diffusion tensor imaging identifies presymptomatic axonal degeneration in the spinal cord of ALS mice

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