Diffusion basis spectrum imaging measures anti-inflammatory and neuroprotective effects of fingolimod on murine optic neuritis

Neuroinflammation is both a consequence and driver of overfeeding and weight gain in rodent obesity models. Advances in magnetic resonance imaging (MRI) enable investigations of brain microstructure that suggests neuroinflammation in human obesity. To assess the convergent validity across MRI techniques and extend previous findings, we used diffusion basis spectrum imaging (DBSI) to characterize obesity-associated alterations in brain microstructure in 601 children (age 9–11 years) from the Adolescent Brain Cognitive DevelopmentSM Study. Compared to children with normal-weight, greater DBSI restricted fraction (RF), reflecting neuroinflammation-related cellularity, was seen in widespread white matter in children with overweight and obesity. Greater DBSI-RF in hypothalamus, caudate nucleus, putamen, and, in particular, nucleus accumbens, correlated with higher baseline body mass index (BMI) and related anthropometrics. Comparable findings were seen in the striatum with a previously reported restriction spectrum imaging (RSI) model. Gain in waist circumference over one and two years related, at nominal significance, to greater baseline RSI-assessed restricted diffusion in nucleus accumbens and caudate nucleus, and DBSI-RF in hypothalamus, respectively. Here we demonstrate that childhood obesity is associated with microstructural alterations in white matter, hypothalamus, and striatum. Our results also support the reproducibility, across MRI methods, of findings of obesity-related putative neuroinflammation in children.

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“…2014 ), and rodent optic neuritis ( Lin et al. 2017 ; Yang et al. 2021 ), validation remains ongoing for obesity.…”

Section: Discussionmentioning

confidence: 99%

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

Samara

Ray

et al. 2023

Cerebral Cortex Communications

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“…Finally, the largest limitation of the current study is the limited interpretation of diffusion-weighted MRI neuroinflammation metrics. While DBSI-assessed neuroinflammation metrics have been histopathologically validated in some inflammatory neurological diseases including human multiple sclerosis (Wang et al, 2015), rodent models of multiple sclerosis (Chiang et al, 2014; Wang et al, 2011), and rodent optic neuritis (Lin et al, 2017; Yang et al, 2021), this is not the case for obesity. The validity of DBSI and RSI neuroinflammation metrics as true reflections of obesity-related cellularity and/or gliosis remains to be proven using histopathology in post-mortem brains of individuals that, ideally, were recently neuroimaged, or in animal models of obesity.…”

Section: Discussionmentioning

confidence: 99%

“…Investigating obesity-related neuroinflammation in living humans, however, requires non-invasive methods, such as brain magnetic resonance imaging (MRI)-based assessments. Diffusion basis spectrum imaging (DBSI) (Cross & Song, 2017), a diffusion MRI-based technique applied to diffusion-weighted images to model anisotropic and isotropic water diffusivities separately within tissue microstructure (Wang et al, 2011; White et al, 2013), has been histopathologically validated as neuroinflammation-sensitive using rodent and human neural tissue in multiple sclerosis (Chiang et al, 2014; Wang et al, 2014; Wang et al, 2011, 2015), epilepsy (Zhan et al, 2018), and optic neuritis (Lin et al, 2017; Yang et al, 2021). DBSI-assessed putative neuroinflammation in white matter (WM) correlates with cerebrospinal fluid biomarkers in Alzheimer’s disease (Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

Samara

Ray

et al. 2022

Preprint

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Introduction Childhood obesity is increasingly prevalent and confers elevated risk of developing medical complications across the lifespan. Given the brain's prominent involvement in homeostatic and hedonic eating, it is crucial to understand brain health in obesity. Recent studies using quantitative T2-weighted MRI and diffusion-weighted MRI showed obesity-related putative neuroinflammation in human brain. To assess convergent validity across diffusion-based MRI techniques and extend these findings, this study characterized tissue microstructure of white matter (WM) tracts and energy regulation and reward processing brain regions in children across levels of obesity-related measures, using diffusion basis spectrum imaging (DBSI). Methods Using data from the Adolescent Brain Cognitive Development Study (ABCD Study®), DBSI metrics indicative of putative neuroinflammation were computed for WM tracts, hypothalamus, nucleus accumbens, caudate nucleus, and putamen. DBSI metrics were compared between children with normal-weight vs. obesity. DBSI metrics were also correlated to baseline and one- and two-year change in continuous obesity-related measures (waist circumference, BMI, and BMI z-scores). Striatal DBSI findings were compared to those of restriction spectrum imaging (RSI). Results A total of 263 nine- and ten-year old children from the ABCD Study® 2.0.1 data release (5 underweight; 126 with normal-weight; 64 with over-weight; 68 with obesity) who met inclusion and exclusion criteria were randomly selected. Relative to children with normal-weight, children with obesity had lower DBSI fiber fraction (FF; reflects apparent axonal/dendritic density) and higher DBSI restricted fraction (RF; reflects cellularity) in WM tracts throughout the brain (voxel-wise FWE-corrected p < 0.05), as well as higher DBSI-RF in the hypothalamus, nucleus accumbens, and caudate nucleus (Cohen's d's ≥ 0.28, p's ≤ 0.05). Across all children, greater baseline waist circumference was related to higher DBSI-RF in the hypothalamus (standardized β = 0.17, p = 0.0033), nucleus accumbens (standardized β = 0.21, p = 0.0001), and caudate nucleus (standardized β = 0.14, p = 0.013). Gain in waist circumference over one and two years related to higher baseline DBSI-RF in nucleus accumbens (standardized β = 0.12, p = 0.08) and in hypothalamus (standardized β = 0.15, p = 0.03), respectively. Overall, results were consistent for BMI and BMI z-scores. Similar results were observed using RSI metrics. Conclusion Novel findings include demonstration that, as in adults, childhood obesity is associated with DBSI-assessed putative neuroinflammation in WM tracts and hypothalamus. In addition, our results support the reproducibility of previous findings that MRI-assessed putative neuroinflammation in striatum and hypothalamus is related to obesity in children, contributing to a growing understanding of the role of adiposity in brain health across the lifespan.

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“…Axonal damage Sun et al, 2007;Chaudhary et al, 2011; Lin et al, 2014a,b;Manogaran et al, 2019;Nishioka et al, 2019;Tassoni et al, 2019;Marenna et al, 2020;Yang et al, 2021 Demyelination Sun et al, 2007Chaudhary et al, 2011;Horstmann et al, 2013Horstmann et al, , 2016 Lin et al, 2014a,b;Larabee et al, 2016;Manogaran et al, 2019;Nishioka et al, 2019;Tassoni et al, 2019;Marenna et al, 2020;Wu et al, 2021;Yang et al, 2021;Guo et al, 2022 Immune infiltration Chaudhary et al, 2011;Horstmann et al, 2013Horstmann et al, , 2016 Lin et al, 2014a,b;Larabee et al, 2016;Jin et al, 2019;Manogaran et al, 2019;Wu et al, 2021 Microglia activation Sun et al, 2007;Horstmann et al, 2013;Horstmann et al, 2016;Larabee et al, 2016;Jin et al, 2019;Manogaran et al, 2019;Marenna et al, 2020;Wu et al, 2021;Guo et al, 2022 Neuronal loss Horstmann et al, 2013Horstmann et al, , 2016Larabee et al, 2016;Jin et al, 2019;Manogaran et al, 2019;Nishioka et al, 2019;…”

Section: Atrophymentioning

confidence: 99%

Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis

Voskuhl

MacKenzie-Graham²

2022

Front. Mol. Neurosci.

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Animal models of multiple sclerosis (MS), specifically experimental autoimmune encephalomyelitis (EAE), have been used extensively to develop anti-inflammatory treatments. However, the similarity between MS and one particular EAE model does not end at inflammation. MS and chronic EAE induced in C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 share many neuropathologies. Beyond both having white matter lesions in spinal cord, both also have widespread neuropathology in the cerebral cortex, hippocampus, thalamus, striatum, cerebellum, and retina/optic nerve. In this review, we compare neuropathologies in each of these structures in MS with chronic EAE in C57BL/6 mice, and find evidence that this EAE model is well suited to study neuroaxonal degeneration in MS.

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Diffusion basis spectrum imaging measures anti-inflammatory and neuroprotective effects of fingolimod on murine optic neuritis

Abstract: Highlights DBSI quantified optic nerve axon loss in EAE mice. DBSI detected axonal preservation with ten-week fingolimod treatment. DBSI could serve as an outcome measure to profile disease progression.

Cited by 5 publications

References 38 publications

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

Childhood obesity is linked to putative neuroinflammation in brain white matter, hypothalamus, and striatum

Chronic experimental autoimmune encephalomyelitis is an excellent model to study neuroaxonal degeneration in multiple sclerosis

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