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

Gatto, Rodolfo G.; Li, Weiguo

doi:10.1016/j.brainres.2017.11.017

Cited by 31 publications

(45 citation statements)

References 76 publications

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“…In previous ex vivo ALS mouse studies (B6JL mice) from our group, we have shown that DTI is able to detect microstructural changes in the early stage of the disease . This study is a continuation of our previous work using a new line of mice (C57 mice) with a fluorescent reporter in vivo .…”

Section: Discussionsupporting

confidence: 57%

“…In this analysis, the largest eigenvalue determined the axial diffusivity (AD) (Equation ) and the radial diffusivity (RD) was calculated using the average of the second and third eigenvalues (Equation ). The sum of all three eigenvalues divided by 3 is the mean diffusivity (MD), which corresponds to an isotropic apparent diffusion coefficient (ADC) . Therefore, the fractional anisotropy (FA) was calculated using Equation :

MD = ((), λ_{1} + λ_{2} + λ_{3}) / 3

AD = ((), λ_{1})

RD = ((), λ_{2} + λ_{3}) / 2

FA = \sqrt{\frac{1}{2}} \frac{\sqrt{{((), λ_{1} - λ_{2})}^{2} + {((), λ_{2} - λ_{3})}^{2} + {((), λ_{1} - λ_{3})}^{2}}}{\sqrt{λ_{1}^{2} + λ_{2}^{2} + λ_{3}^{2}}}

…”

Section: Methodsmentioning

confidence: 99%

“…The sum of all three eigenvalues divided by 3 is the mean diffusivity (MD), which corresponds to an isotropic apparent diffusion coefficient (ADC). 28 Therefore, the fractional anisotropy (FA) was calculated using Equation (4):…”

Section: Mri and Calculation Of Diffusion Valuesmentioning

confidence: 99%

“…Although it is feasible to examine all segments of the SC (cervical, thoracic and lumbar), results from previous MRI diffusion ex vivo studies have shown predominant alterations in MRI diffusion specifically at the SC lumbar segments. 28 Thus, this study focuses on ALS WM anomalies in this particular SC region.…”

Section: Mri and Calculation Of Diffusion Valuesmentioning

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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Section: Discussionsupporting

confidence: 57%

MD = ((), λ_{1} + λ_{2} + λ_{3}) / 3

AD = ((), λ_{1})

RD = ((), λ_{2} + λ_{3}) / 2

FA = \sqrt{\frac{1}{2}} \frac{\sqrt{{((), λ_{1} - λ_{2})}^{2} + {((), λ_{2} - λ_{3})}^{2} + {((), λ_{1} - λ_{3})}^{2}}}{\sqrt{λ_{1}^{2} + λ_{2}^{2} + λ_{3}^{2}}}

…”

Section: Methodsmentioning

confidence: 99%

Section: Mri and Calculation Of Diffusion Valuesmentioning

confidence: 99%

Section: Mri and Calculation Of Diffusion Valuesmentioning

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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“…Advanced DTI methods are particularly challenging at the spinal level because of the small CSA of the human cord, physiological motions due to respiration, vascular pulsation effects, partial volume effects due to the surrounding cerebrospinal fluid, and magnetic field inhomogeneities around the intervertebral discs and the lungs. 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. 43 RD and AD are thought to be histologically more accurate, representing myelin and axonal changes with more specificity.…”

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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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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Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra‐high field MRI and diffusion tensor metrics

Gatto

Weissmann

Amin

et al. 2020

Anim Models and Exp Med

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ObjectiveCell structural changes are one of the main features observed during the development of amyotrophic lateral sclerosis (ALS). In this work, we propose the use of diffusion tensor imaging (DTI) metrics to assess specific ultrastructural changes in the central nervous system during the early neurodegenerative stages of ALS.MethodsUltra‐high field MRI and DTI data at 17.6T were obtained from fixed, excised mouse brains, and spinal cords from ALS (G93A‐SOD1) mice.ResultsChanges in fractional anisotropy (FA) and linear, planar, and spherical anisotropy ratios (CL, CP, and CS, respectively) of the diffusion eigenvalues were measured in white matter (WM) and gray matter (GM) areas associated with early axonal degenerative processes (in both the brain and the spinal cord). Specifically, in WM structures (corpus callosum, corticospinal tract, and spinal cord funiculi) as the disease progressed, FA, CL, and CP values decreased, whereas CS values increased. In GM structures (prefrontal cortex, hippocampus, and central spinal cord) FA and CP decreased, whereas the CL and CS values were unchanged or slightly smaller. Histological studies of a fluorescent mice model (YFP, G93A‐SOD1 mouse) corroborated the early alterations in neuronal morphology and axonal connectivity measured by DTI.ConclusionsChanges in diffusion tensor shape were observed in this animal model at the early, nonsymptomatic stages of ALS. Further studies of CL, CP, and CS as imaging biomarkers should be undertaken to refine this neuroimaging tool for future clinical use in the detection of the early stages of ALS.

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

Cited by 31 publications

References 76 publications

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

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

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

Assessing neuraxial microstructural changes in a transgenic mouse model of early stage Amyotrophic Lateral Sclerosis by ultra‐high field MRI and diffusion tensor metrics

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