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In vivo magnetization transfer MRI shows dysmyelination in an ischemic mouse model of periventricular leukomalacia.

ABSTRACT: Periventricular leukomalacia, PVL, is the leading cause of cerebral palsy in prematurely born infants, and therefore more effective interventions are required. The objective of this study was to develop an ischemic injury model of PVL in mice and to determine the feasibility of in vivo magnetization transfer (MT) magnetic resonance imaging (MRI) as a potential monitoring tool for the evaluation of disease severity and experimental therapeutics. Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal day 5 (P5); at P60, in vivo T2-weighted (T2w) and MT-MRI were performed and correlated with postmortem histopathology. In vivo T2w MRI showed thinning of the right corpus callosum, but no significant changes in hippocampal and hemispheric volumes. Magnetization transfer MRI revealed significant white matter abnormalities in the bilateral corpus callosum and internal capsule. These quantitative MT-MRI changes correlated highly with postmortem findings of reduced myelin basic protein in bilateral white matter tracts. Ventriculomegaly and persistent astrogliosis were observed on the ligated side, along with evidence of axonopathy and fewer oligodendrocytes in the corpus callosum. We present an ischemia-induced mouse model of PVL, which has pathologic abnormalities resembling autopsy reports in infants with PVL. We further validate in vivo MRI techniques as quantitative monitoring tools that highly correlate with postmortem histopathology.

SUBMITTER: Fatemi A

PROVIDER: S-EPMC3208153 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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In vivo magnetization transfer MRI shows dysmyelination in an ischemic mouse model of periventricular leukomalacia.

Fatemi Ali A Wilson Mary Ann MA Phillips Andre W AW McMahon Michael T MT Zhang Jiangyang J Zhang Jiangyang J Smith Seth A SA Arauz Edwin J EJ Falahati Sina S Gummadavelli Abhijeet A Bodagala Hima H Mori Susumu S Johnston Michael V MV

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20110504 10

Periventricular leukomalacia, PVL, is the leading cause of cerebral palsy in prematurely born infants, and therefore more effective interventions are required. The objective of this study was to develop an ischemic injury model of PVL in mice and to determine the feasibility of in vivo magnetization transfer (MT) magnetic resonance imaging (MRI) as a potential monitoring tool for the evaluation of disease severity and experimental therapeutics. Neonatal CD-1 mice underwent unilateral carotid art ...[more]

PMID: 21540870

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Project description:In established multiple sclerosis, tissue abnormality-as assessed using magnetization transfer ratio-increases close to the lateral ventricles. We aimed to determine whether or not (i) these changes are present from the earliest clinical stages of multiple sclerosis; (ii) they occur independent of white matter lesions; and (iii) they are associated with subsequent conversion to clinically definite multiple sclerosis and disability. Seventy-one subjects had MRI scanning a median of 4.6 months after a clinically isolated optic neuritis (49 females, mean age 33.5 years) and were followed up clinically 2 and 5 years later. Thirty-seven healthy controls (25 females, mean age 34.4 years) were also scanned. In normal-appearing white matter, magnetization transfer ratio gradients were measured 1-5 mm and 6-10 mm from the lateral ventricles. In control subjects, magnetization transfer ratio was highest adjacent to the ventricles and decreased with distance from them; in optic neuritis, normal-appearing white matter magnetization transfer ratio was lowest adjacent to the ventricles, increased over the first 5 mm, and then paralleled control values. The magnetization transfer ratio gradient over 1-5 mm differed significantly between the optic neuritis and control groups [+0.059 percentage units/mm (pu/mm) versus -0.033 pu/mm, P = 0.010], and was significantly steeper in those developing clinically definite multiple sclerosis within 2 years compared to those who did not (0.132 pu/mm versus 0.016 pu/mm, P = 0.020). In multivariate binary logistic regression the magnetization transfer ratio gradient was independently associated with the development of clinically definite multiple sclerosis within 2 years (magnetization transfer ratio gradient odds ratio 61.708, P = 0.023; presence of T2 lesions odds ratio 8.500, P = 0.071). At 5 years, lesional measures overtook magnetization transfer ratio gradients as significant predictors of conversion to multiple sclerosis. The magnetization transfer ratio gradient was not significantly affected by the presence of brain lesions [T2 lesions (P = 0.918), periventricular T2 lesions (P = 0.580) or gadolinium-enhancing T1 lesions (P = 0.724)]. The magnetization transfer ratio gradient also correlated with Expanded Disability Status Scale score 5 years later (Spearman r = 0.313, P = 0.027). An abnormal periventricular magnetization transfer ratio gradient occurs early in multiple sclerosis, is clinically relevant, and may arise from one or more mechanisms that are at least partly independent of lesion formation.

Project description:BackgroundPeriventricular leukomalacia (PVL) is a frequent consequence of hypoxic-ischemic injury. Functional cytokine gene variants that result in altered production of inflammatory (tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1β]) or anti-inflammatory (interleukin-10 [IL-10]) cytokines may modify disease processes, including PVL.ObjectiveThe aim of this study was to evaluate if there is a relationship between the two proinflammatory polymorphisms (TNF-α-1031T/C and IL-1β-511C/T) and the anti-inflammatory polymorphism IL-10-1082G/A and PVL risk in Brazilian newborns with and without this injury.Materials and methodsA cross-sectional case-control study performed at the Neonatal Intensive Care Unit of the Children's Hospital and Maternity of the São José do Rio Preto Medical School (FAMERP). Fifty preterm and term newborns were examined as index cases and 50 term newborns as controls, of both sexes for both groups. DNA was extracted from peripheral blood leukocytes, and the sites that encompassed the three polymorphisms were amplified by polymerase chain reaction-restriction fragment length polymorphism.ResultsGestational age ranged from 25 to 39 weeks, in the case group, and in the control group it ranged from 38 to 42.5 weeks (P<0.0001). Statistically significant association was found between TNF-α-1031T/C high expression genotype TC (odds ratio [OR], 2.495; 95% confidence interval [CI], 1.10-5.63; P=0.043) as well as between genotypes (TC + CC) (OR, 2.471; 95% CI, 1.10-5.55; P=0.044) and risk of PVL. Statistically significant association was found between IL-1β-511C/T high expression genotypes (CT + TT) (OR, 23.120; 95% CI, 1.31-409.4; P=0.003) and risk of PVL. Statistically significant association between IL-10-1082G/A high expression genotype GG (OR, 0.07407; 95% CI, 0.02-0.34; P<0.0001) as well as between IL-10-1082G high expression allele (OR, 0.5098; 95% CI, 0.29-0.91; P=0,030) and PVL reduced risk was observed. There was a statistically significant association between TC/CT/GA genotype combination and the risk of PVL (OR, 6.469; 95% CI, 2.00-20.92; P=0.001).ConclusionThere is evidence of an association between the polymorphisms TNF-α-1031T/C, IL-1β-511C/T, and IL-10-1082G/A and PVL risk in this Brazilian newborn population studied.

Project description:Background: Periventricular leukomalacia (PVL) is the major form of brain injury in premature infants. Currently, there are no therapies to treat PVL. Several studies suggested that polarization of microglia, a resident macrophage-like immune cell in the central nervous system, plays a vital role in brain injury and recovery. As an important mediator of immunity, interleukin-4 (IL-4) has critical effects on many immune cells, such as astrocytes and microglia. Increasing evidence shows that IL-4 plays a well-established role in attenuating inflammation in neurological disorders. Additionally, as a noninvasive and highly effective method, intranasal drug administration is gaining increasing attention. Therefore, in our study, we hypothesized that intranasal IL-4 administration is a promising strategy for PVL treatment. Methods: The therapeutic effects of IL-4 on neuroprotection were evaluated using a Control group, Hypoxia group, and Hypoxia + IL-4 treatment group. The PVL mouse model was established by a severe acute hypoxia (SAH) protocol. Exogenous IL-4 was intranasally administered to investigate its neuroprotective effects. A functional study was used to investigate neurological deficits, immunohistochemical technology and Western blotting were used to detect protein levels, and electron microscopy was used to evaluate myelination. Results: The results suggested that hypoxia stimulated Iba1+ microglial activation, downregulated myelin-related gene (NG2, MAG, and MBP) expression, reduced MBP protein levels, and caused neurological deficits. However, the intranasal administration of exogenous IL-4 partially inhibited Iba1+ microglial activation, improved myelination, and alleviated neurological deficits. The mechanistic study showed that IL-4 improved myelination possibly through the IL-4Ra-mediated polarization of microglia from the M1 phenotype to the M2 phenotype. Conclusion: In summary, our findings demonstrated that the intranasal administration of exogenous IL-4 improves myelination and attenuates functional deficits in a hypoxia-induced PVL model. Intranasal IL-4 administration may be a promising strategy for PVL treatment, for which further mechanistic studies are urgent.

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In vivo magnetization transfer MRI shows dysmyelination in an ischemic mouse model of periventricular leukomalacia.

Publications

In vivo magnetization transfer MRI shows dysmyelination in an ischemic mouse model of periventricular leukomalacia.

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