Insufficient remyelination due to impaired oligodendrocyte precursor cell (OPC) differentiation and maturation is strongly associated with irreversible white matter injury (WMI) and neurological deficits. We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2 (LCN2) in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1 (EGR1) as the key signals contributing to LCN2-mediated insufficient OPC remyelination. In LCN-knockdown and OPC EGR1 conditional-knockout mice, we discovered enhanced OPC differentiation in developing and injured white matter (WM); consistent with this, the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical, acute WMI due to subarachnoid hemorrhage and typical, chronic WMI due to multiple sclerosis. This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.
Mice ; Animals ; Remyelination/physiology* ; Oligodendrocyte Precursor Cells/metabolism* ; White Matter ; Subarachnoid Hemorrhage/metabolism* ; Lipocalin-2/metabolism* ; Early Growth Response Protein 1/metabolism* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Cell Differentiation/physiology* ; Brain Injuries/metabolism*

Monocarboxylic acid transporter 1 (MCT1) maintains axonal function by transferring lactic acid from oligodendrocytes to axons. Subarachnoid hemorrhage (SAH) induces white matter injury, but the involvement of MCT1 is unclear. In this study, the SAH model of adult male Sprague-Dawley rats was used to explore the role of MCT1 in white matter injury after SAH. At 48 h after SAH, oligodendrocyte MCT1 was significantly reduced, and the exogenous overexpression of MCT1 significantly improved white matter integrity and long-term cognitive function. Motor training after SAH significantly increased the number of ITPR2
Animals ; Male ; MicroRNAs/genetics* ; Monocarboxylic Acid Transporters/genetics* ; Rats ; Rats, Sprague-Dawley ; Subarachnoid Hemorrhage ; Symporters/genetics* ; White Matter/injuries*

BACKGROUND AND OBJECTIVES: Treatment with mesenchymal stem cells (MSC) in spinal cord injury (SCI) has been highlighted as therapeutic candidate for SCI. Although astrogliosis is a major phenomenon after SCI, the role of astrogliosis is still controversial. In this study, we determined whether acute transplantation of MSC improves the outcome of SCI through modulating astrogliosis. METHODS: Bone marrow derived rat MSCs were induced neural differentiation and transplanted after acute SCI rats. Matrix metalloproteinase (MMP) and neuro-inflammatory pathway were analyzed for acute astrogliosis at 1, 3 and 7 d after SCI in RT-PCR- and western blot analysis. Functional outcome was assessed serially at postoperative 1 d and weekly for 4 weeks. Histopathologic analysis was undertaken at 7 and 28 d following injury in immunohistochemistry. RESULTS: Transplantation of MSCs decreased IL-1α, CXCL-2, CXCL-10, TNF-α and TGF-β in a rat model of contusive SCI. Protein level of NF-κB p65 was slightly decreased while level of STAT-3 was increased. In immunohistochemistry, MSC transplantation increased acute astrogliosis whereas attenuated scar formation with increased sparing white matter of spinal cord lesions. In RT-PCR analysis, mRNA levels of MMP2 was significantly increased in MSC transplanted rats. In BBB locomotor scale, the rats of MSC treated group exhibited improvement of functional recovery. CONCLUSIONS: Transplantation of MSC reduces the inflammatory reaction and modulates astrogliosis via MMP2/STAT3 pathway leading to improve functional recovery after SCI in rats.
Animals ; Blotting, Western ; Bone Marrow ; Cicatrix ; Immunohistochemistry ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stromal Cells ; Models, Animal ; Rats ; RNA, Messenger ; Spinal Cord Injuries ; Spinal Cord ; White Matter

Diffusion-tensor imaging (DTI) is a noninvasive medical imaging tool used to investigate the structure of white matter. The signal contrast in DTI is generated by differences in the Brownian motion of the water molecules in brain tissue. Postprocessed DTI scalars can be used to evaluate changes in the brain tissue caused by disease, disease progression, and treatment responses, which has led to an enormous amount of interest in DTI in clinical research. This review article provides insights into DTI scalars and the biological background of DTI as a relatively new neuroimaging modality. Further, it summarizes the clinical role of DTI in various disease processes such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's dementia, epilepsy, ischemic stroke, stroke with motor or language impairment, traumatic brain injury, spinal cord injury, and depression. Valuable DTI postprocessing tools for clinical research are also introduced.
Amyotrophic Lateral Sclerosis ; Brain ; Brain Injuries ; Dementia ; Depression ; Diagnostic Imaging ; Disease Progression ; Epilepsy ; Multiple Sclerosis ; Nervous System Diseases* ; Neuroimaging ; Parkinson Disease ; Spinal Cord Injuries ; Stroke ; Water ; White Matter

PURPOSE: To investigate the relationship between brain injury patterns on magnetic resonance imaging (MRI) and neurodevelopmental outcomes in neonates with postasphyxial hypoxic ischemic encephalopathy (HIE). METHODS: Clinical characteristics and brain MRI findings of 49 term neonates with postasphyxial HIE were retrospectively reviewed. Brain injury patterns in MRI were classified into five categories, along with evaluation of the posterior limb of internal capsule (PLIC). Neurodevelopmental outcomes were assessed by neurological examination combined with the Bayley Scales of Infant Development II between 1 and 2 years of age. RESULTS: Twenty-three neonates (46.9%) showed abnormal brain MRI finding associated with poor neurodevelopmental outcomes (odds ratio 9.7, 95% confidence interval 1.4, 67.4, P=0.022). The following injury patterns were seen in MRI: abnormality in the basal ganglia-thalamus (BGT) in 4 neonates (17.4%), watershed predominant (WP) pattern in 5 (21.7%), extensive global injury (EGI) in 3 (13.0%), lesions restricted to periventricular white matter (LPWM) in 4 (17.4%), and perinatal arterial ischemic stroke (PAIS) in 2 (8.7%). Additionally, 6 neonate (26.1%) showed lesion in the PLIC. Neonate with BGT and EGI injury patterns showed worse neurodevelopmental outcomes than those with WP and LPWM patterns (P<0.05). Neonate with PLIC lesion also showed poor outcomes (100%). CONCLUSION: Abnormal brain MRI findings in neonates with postasphyxial HIE were associated with the poor neurodevelopmental outcomes. BGT, EGI and PLIC patterns of injury are expected to have worse outcomes than white matter predominant injury patterns such as those in the WP and LPWM.
Brain Injuries* ; Brain* ; Child ; Child Development ; Extremities ; Humans ; Hypoxia-Ischemia, Brain* ; Infant, Newborn* ; Internal Capsule ; Magnetic Resonance Imaging ; Neurologic Examination ; Retrospective Studies ; Stroke ; Weights and Measures ; White Matter

OBJECTIVETo investigate the long-term effect of oligodendrocyte precursor cell (OPC) transplantation on a rat model of white matter injury (WMI) in the preterm infant.

METHODSA total of 80 Sprague-Dawley rats aged 3 days were randomly divided into sham-operation group, model control group, 5-day ventricular/white matter transplantation group, 9-day ventricular/white matter transplantation group, 14-day ventricular/white matter transplantation group (n=10 each). All groups except the sham-operation group were treated with right common carotid artery ligation and hypoxia for 80 minutes to establish a rat model of WMI in the preterm infant. OPCs were prepared from the human fetal brain tissue (10-12 gestational weeks). At 5, 9, and 14 days after modeling, 3×10OPCs were injected into the right lateral ventricle or white matter in each transplantation group, and myelin sheath and neurological function were evaluated under an electron microscope at ages of 60 and 90 days.

RESULTSElectron microscopy showed that at an age of 60 days, each transplantation group had a slight improvement in myelin sheath injury compared with the model control group; at an age of 90 days, each transplantation group had significantly thickened myelin sheath and reduced structural damage compared with the model control group, and the 14-day transplantation groups had the most significant changes. There were no significant differences in the degree of myelin sheath injury between the ventricular and white matter transplantation groups at different time points. At an age of 60 or 90 days, the transplantation groups had a significantly higher modified neurological severity score (mNSS) than the sham-operation group and a significantly lower mNSS than the model control group (P<0.05).

CONCLUSIONSOPC transplantation may have a long-term effect in the treatment of WMI in the preterm infant, and delayed transplantation may enhance its therapeutic effect.

Animals ; Animals, Newborn ; Disease Models, Animal ; Myelin Sheath ; pathology ; Oligodendrocyte Precursor Cells ; transplantation ; Rats ; Rats, Sprague-Dawley ; White Matter ; injuries ; pathology ; ultrastructure

We present the case of a 33-year-old man who experienced a 10,000-V electrical shock when working with electrical wiring. He suffered third-degree burns on his scalp at the right occiput (entry wound) and on his left arm (exit would), and a second-degree burn on his left foot (exit wound). He presented with severe spasticity of both lower extremities, motor weakness with a Medical Research Council grade of 3, and sensory impairments below thoracic level 11 that included an inability to sense light touch and defects in proprioception. Initial magnetic resonance imaging (MRI) scans of his spine and brain showed no definite abnormalities. However, tractography obtained by diffusion tensor imaging of the brain showed absence of the right medial lemniscus tract. A cervical MRI scan 1 month later showed spinal cord swelling from cervical 1-5 levels, and signal changes in the lateral and posterior white matter in the axial view. After 6 months of rehabilitation, he recovered almost normal degree of motor function in his lower extremities and disappearance of spasticity. However, since the sensory impairments persisted, especially defects in proprioception, he was unable to walk independently.
Adult ; Arm ; Brain ; Burns ; Diffusion Tensor Imaging ; Electric Injuries ; Electric Wiring ; Foot ; Humans ; Lower Extremity ; Magnetic Resonance Imaging ; Muscle Spasticity ; Proprioception ; Rehabilitation ; Scalp ; Shock ; Spinal Cord ; Spine ; White Matter

A developing central nervous system is vulnerable to various insults such as infection and ischemia. While increased understanding of the dynamic nature of brain development allows a deeper insight into the pathophysiology of perinatal brain injury, the precise nature of specific fetal and neonatal brain injuries and their short- and long-term clinical consequences need special attention and further elucidation. The current review will describe the pathophysiological aspects and clinical significance of white matter injury of prematurity, a main form of perinatal brain injury in premature newborns, with a particular emphasis on its potential antenatal components.
Brain ; Brain Injuries ; Central Nervous System ; Humans ; Infant, Newborn ; Ischemia ; Leukomalacia, Periventricular ; White Matter*

Spinal cord injury (SCI) is a catastrophic condition associated with significant neurological deficit, social, and financial burdens. Over the past decades, various treatments including medication, surgery, and rehabilitation therapy for SCI have been performed, but there were no definite treatment option to improve neurological function of patients with chronic SCI. Therefore, new treatment trials with stem cells have been studied to regenerate injured spinal cord. Among various types of stem cells, bone marrow derived mesenchymal stem cells is highly expected as candidates for the stem cell therapy. The result of the current research showed that direct intramedullary injection to the injured spinal cord site in subacute phase is most effective. Neurological examination, electrophysiologic studies, and magnetic resonance imaging are commonly used to assess the effectiveness of treatment. Diffusion tensor imaging visualizing white matter tract can be also alternative option to identify neuronal regeneration. Despite various challenging issues, stem cell therapy will open new perspectives for SCI treatment.
Bone Marrow ; Cell- and Tissue-Based Therapy ; Diffusion Tensor Imaging ; Humans ; Magnetic Resonance Imaging ; Mesenchymal Stromal Cells ; Neurologic Examination ; Neurons ; Regeneration ; Rehabilitation ; Spinal Cord Injuries* ; Spinal Cord* ; Stem Cells* ; White Matter

BACKGROUNDThe ability to predict posttraumatic stress disorder (PTSD) is a critical issue in the management of patients with mild traumatic brain injury (mTBI), as early medical and rehabilitative interventions may reduce the risks of long-term cognitive changes. The aim of the present study was to investigate how diffusion tensor imaging (DTI) metrics changed in the transition from acute to chronic phases in patients with mTBI and whether the alteration relates to the development of PTSD.

METHODSForty-three patients with mTBI and 22 healthy volunteers were investigated. The patients were divided into two groups: successful recovery (SR, n = 22) and poor recovery (PR, n = 21), based on neurocognitive evaluation at 1 or 6 months after injury. All patients underwent magnetic resonance imaging investigation at acute (within 3 days), subacute (10-20 days), and chronic (1-6 months) phases after injury. Group differences of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed using tract-based spatial statistics (TBSS). The accuracy of DTI metrics for classifying PTSD was estimated using Bayesian discrimination analysis.

RESULTSTBSS showed white matter (WM) abnormalities in various brain regions. In the acute phase, FA values were higher for PR and SR patients than controls (all P < 0.05). In subacute phase, PR patients have higher mean MD than SR and controls (all P < 0.05). In the chronic phase, lower FA and higher MD were observed in PR compared with both SR and control groups (all P < 0.05). PR and SR groups could be discriminated with a sensitivity of 73%, specificity of 78%, and accuracy of 75.56%, in terms of MD value in subacute phase.

CONCLUSIONSPatients with mTBI have multiple abnormalities in various WM regions. DTI metrics change over time and provide a potential indicator at subacute stage for PTSD following mTBI.

Adult ; Brain Injuries, Traumatic ; pathology ; Diffusion Tensor Imaging ; methods ; Female ; Humans ; Male ; Prospective Studies ; Stress Disorders, Post-Traumatic ; pathology ; White Matter ; pathology