Ethoxyquin, a Lipid Peroxidation Inhibitor, Has Protective Effects against White Matter Lesions in a Mouse Model of Chronic Cerebral Hypoperfusion.

White matter lesions induced by chronic cerebral hypoperfusion can cause vascular dementia; however, no appropriate treatments are currently available for these diseases. In this study, we investigated lipid peroxidation, which has recently been pointed out to be associated with cerebrovascular disease and vascular dementia, as a therapeutic target for chronic cerebral hypoperfusion. We used ethoxyquin, a lipid-soluble antioxidant, in a neuronal cell line and mouse model of the disease. The cytoprotective effect of ethoxyquin on glutamate-stimulated HT-22 cells, a mouse hippocampal cell line, was comparable to that of a ferroptosis inhibitor. In addition, the administration of ethoxyquin to bilateral common carotid artery stenosis model mice suppressed white matter lesions, blood-brain barrier disruption, and glial cell activation. Taken together, we propose that the inhibition of lipid peroxidation may be a useful therapeutic approach for chronic cerebrovascular disease and the resulting white matter lesions.

Changes in circMyt1l/rno-let-7d-5p/brain-derived neurotrophic factor. A damaged periventricular white matter damage model in neonatal rats.

OBJECTIVES: To investigate the function of circMyt1l/rno-let-7d-5p/BDNF in the white matter damage of premature rats. METHODS: Bioinformatic analysis was used to analyze the differential expression of circMyt1l and its interacting miRNAs and mRNAs in rats with periventricular white matter damage. Rats at postnatal day 3 had their right common carotid artery permanently ligated, and were then exposed for 2 h to 6 % O2, or sham surgery and exposure to normal O2 levels (sham). CircMyt1l and rno-let-7d-5p expression was detected and BDNF protein levels were analyzed at 24, 48, and 72 h post hypoxia-ischemia. RESULTS: Bioinformatic analysis suggested that circMyt1l, rno-let-7d-5p and BDNF interact. CircMyt1l expression decreased significantly relative to the sham-operated rats (p<0.01) in an exposure time-dependent manner. Contrastingly, rno-let-7d-5p increased significantly relative to the sham-operated rats (p<0.01) in an exposure time dependent manner. BDNF protein levels decreased significantly relative to the sham-operated rats (p<0.05) in an exposure time dependent manner. CONCLUSIONS: The expression levels of circMyt1l/rno-let-7d-5p/BDNF are interrelated in periventricular white matter damage. Decreased circMyt1l expression of promoted the effect of rno-let-7d-5p and decreased the level of its target, BDNF.

Hexahydrocurcumin attenuated demyelination and improved cognitive impairment in chronic cerebral hypoperfusion rats.

Age-related white matter lesions (WML) frequently present vascular problems by decreasing cerebral blood supply, resulting in the condition known as chronic cerebral hypoperfusion (CCH). This study aimed to investigate the effect of hexahydrocurcumin (HHC) on the processes of demyelination and remyelination induced by the model of the Bilateral Common Carotid Artery Occlusion (BCCAO) for 29 days to mimic the CCH condition. The pathological appearance of myelin integrity was significantly altered by CCH, as evidenced by Transmission Electron Microscopy (TEM) and Luxol Fast Blue (LFB) staining. In addition, CCH activated A1-astrocytes and reactive-microglia by increasing the expression of Glial fibrillary acidic protein (GFAP), complement 3 (C3d) and pro-inflammatory cytokines. However, S100a10 expression, a marker of neuroprotective astrocytes, was suppressed, as were regenerative factors including (IGF-1) and Transglutaminase 2 (TGM2). Therefore, the maturation step was obstructed as shown by decreases in the levels of myelin basic protein (MBP) and the proteins related with lipid synthesis. Cognitive function was therefore impaired in the CCH model, as evidenced by the Morris water maze test. By contrast, HHC treatment significantly improved myelin integrity, and inhibited A1-astrocytes and reactive-microglial activity. Consequently, pro-inflammatory cytokines and A1-astrocytes were attenuated, and regenerative factors increased assisting myelin maturation and hence improving cognitive performance. In conclusion, HHC improves cognitive function and also the integrity of white matter in CCH rats by reducing demyelination, and pro-inflammatory cytokine production and promoting the process of remyelination.

Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury.

Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.

White matter microglia heterogeneity in the CNS.

Microglia, the resident myeloid cells in the central nervous system (CNS) play critical roles in shaping the brain during development, responding to invading pathogens, and clearing tissue debris or aberrant protein aggregations during ageing and neurodegeneration. The original concept that like macrophages, microglia are either damaging (pro-inflammatory) or regenerative (anti-inflammatory) has been updated to a kaleidoscope view of microglia phenotypes reflecting their wide-ranging roles in maintaining homeostasis in the CNS and, their contribution to CNS diseases, as well as aiding repair. The use of new technologies including single cell/nucleus RNA sequencing has led to the identification of many novel microglia states, allowing for a better understanding of their complexity and distinguishing regional variations in the CNS. This has also revealed differences between species and diseases, and between microglia and other myeloid cells in the CNS. However, most of the data on microglia heterogeneity have been generated on cells isolated from the cortex or whole brain, whereas white matter changes and differences between white and grey matter have been relatively understudied. Considering the importance of microglia in regulating white matter health, we provide a brief update on the current knowledge of microglia heterogeneity in the white matter, how microglia are important for the development of the CNS, and how microglial ageing affects CNS white matter homeostasis. We discuss how microglia are intricately linked to the classical white matter diseases such as multiple sclerosis and genetic white matter diseases, and their putative roles in neurodegenerative diseases in which white matter is also affected. Understanding the wide variety of microglial functions in the white matter may provide the basis for microglial targeted therapies for CNS diseases.

Adverse neural effects of delayed, intermittent treatment with rEPO after asphyxia in preterm fetal sheep.

KEY POINTS: We have previously shown that high-dose constant infusion of recombinant human erythropoietin (rEPO) from 30 min to 72 h after asphyxia in preterm fetal sheep reduced histological injury and improved electrophysiological recovery. This study shows that a high-dose infusion of rEPO from 6 to 72 h after asphyxia did not improve EEG recovery, oligodendrocyte and neuronal survival at 1 week post-asphyxia. Of concern, intermittent rEPO boluses started 6 h after asphyxia were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter. Intermittent boluses of rEPO were associated with significantly increased cerebral vascular resistance and hypoperfusion, particularly after the first dose, but did not affect seizures, suggesting mismatch between perfusion and brain activity. ABSTRACT: Recombinant human erythropoietin (rEPO) is a promising treatment for hypoxic-ischaemic brain injury. Disappointingly, a large randomized controlled trial in preterm infants found that prophylactic, repeated high-dose rEPO boluses started within 24 h of birth did not improve neurodevelopmental outcomes. We examined whether initiation of a continuous infusion of rEPO at the end of the latent phase after hypoxic-ischaemia (HI) might improve outcomes compared with intermittent bolus injections. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham asphyxia or asphyxia induced by complete umbilical cord occlusion for 25 min. Six hours after asphyxia, fetuses received either a continuous infusion of rEPO (loading dose 2000 IU, infusion at 520 IU/h) from 6 to 72 h post-asphyxia or intravenous saline or 5000 IU rEPO, with repeated doses every 48 h for 5 days. Continuous infusion of rEPO did not improve EEG recovery, oligodendrocyte and neuronal survival at 1 week post-asphyxia. By contrast, intermittent rEPO boluses were associated with impaired EEG recovery and bilateral cystic injury of temporal lobe intragyral white matter in 6/8 fetuses. These studies demonstrate for the first time that initiation of intermittent rEPO boluses 6 h after HI, at a dose comparable with recent clinical trials, exacerbated neural injury. These data reinforce the importance of early initiation of many potential neuroprotective therapies.

Longitudinal analysis of T1w/T2w ratio in patients with multiple sclerosis from first clinical presentation.

BACKGROUND: Cross-sectional studies suggest normal appearing white matter (NAWM) integrity loss may lead to cortical atrophy in late-stage relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To investigate the relationship between NAWM integrity and cortical thickness from first clinical presentation longitudinally. METHODS: NAWM integrity and cortical thickness were assessed with 3T magnetic resonance imaging (MRI) in 102 patients with clinically isolated syndrome or early MS (33.2 (20.1-60.1) years old, 68% female) from first clinical presentation over 2.8 ± 1.6 years. Fifty healthy controls (HCs) matched for age and sex were included. NAWM integrity was evaluated using the standardized T1w/T2w ratio (sT1w/T2w). The association between sT1w/T2w and cortical thickness was assessed using linear mixed models. The effect of disease activity was investigated using the No Evidence of Disease Activity (NEDA-3) criteria. RESULTS: At baseline, sT1w/T2w (p = 0.152) and cortical thickness (p = 0.489) did not differ from HCs. Longitudinally, decreasing sT1w/T2w was associated with cortical thickness and increasing lesion burden (marginal R2 = 0.061). The association was modulated by failing NEDA-3 (marginal R2 = 0.097). CONCLUSION: sT1w/T2w may be a useful MRI biomarker for early MS, detecting relevant NAWM damage over time using conventional MRI scans, although with less sensitivity compared to quantitative measures.

Circular RNA expression alteration in whole blood of premature infants with periventricular white matter damage.

Circular RNAs (circRNAs) are evolutionarily conserved and tissue-specific types of non-coding RNA and can serve as potential diagnostic biomarkers for disease. However, the clinical significance and levels of expression of circRNAs for whole blood samples of prematurely born infants afflicted by diseases such as periventricular white matter damage (PWMD) are largely unknown. Therefore, we sought to identify measures of expression of circRNAs in whole blood samples obtained from prematurely born infants afflicted by PWMD and comparatively in samples from prematurely born infants without PWMD. We found the expression levels of circRNAs which from premature with PWMD has changed. Further analysis suggests that these circRNAs have important roles in PWMD. This study can improve the understanding for the potential of the circRNAs to serve as biomarkers in PWMD. Moreover, these circRNAs may provide evidence for improving diagnosis and treatment for infants afflicted by PWMD, and merits continued research.

Bone Fracture Enhanced Blood-Brain Barrier Breakdown in the Hippocampus and White Matter Damage of Stroke Mice.

BACKGROUND: Tibia fracture (BF) before stroke shortly causes long-term post-stroke memory dysfunction in mice. The mechanism is unclear. We hypothesize that BF enhances neuroinflammation and blood brain barrier (BBB) breakdown in the hippocampus and white matter (WM) damage. METHODS: Mice were assigned to groups: BF, stroke, BF+stroke (BF 6 h before stroke) and sham. BBB integrity was analyzed 3 days after the surgeries and WM injury was analyzed 3 days and 8 weeks after the surgeries. RESULTS: Stroke and BF+stroke groups had more activated microglia/macrophages and lower levels of claudin-5 in the ipsilateral hippocampi than the BF group. BF+stroke group had the highest number microglia/macrophages and the lowest level of claudin-5 among all groups and had fewer pericytes than BF group. Stroke and BF+stroke groups had smaller WM areas in the ipsilateral basal ganglia than the sham group 8 weeks after the injuries. The BF+stroke group also had smaller WM areas in the ipsilateral than sham and BF groups 3 days after the injuries and in the contralateral basal ganglia than stroke and BF groups 8 weeks after the injuries. CONCLUSIONS: BF exacerbates neuroinflammation and BBB leakage in the hippocampus and WM damage in basal ganglia, which could contribute to the long-lasting memory dysfunction in BF+stroke mice.

Relevance of Porcine Stroke Models to Bridge the Gap from Pre-Clinical Findings to Clinical Implementation.

In the search of animal stroke models providing translational advantages for biomedical research, pigs are large mammals with interesting brain characteristics and wide social acceptance. Compared to rodents, pigs have human-like highly gyrencephalic brains. In addition, increasingly through phylogeny, animals have more sophisticated white matter connectivity; thus, ratios of white-to-gray matter in humans and pigs are higher than in rodents. Swine models provide the opportunity to study the effect of stroke with emphasis on white matter damage and neuroanatomical changes in connectivity, and their pathophysiological correlate. In addition, the subarachnoid space surrounding the swine brain resembles that of humans. This allows the accumulation of blood and clots in subarachnoid hemorrhage models mimicking the clinical condition. The clot accumulation has been reported to mediate pathological mechanisms known to contribute to infarct progression and final damage in stroke patients. Importantly, swine allows trustworthy tracking of brain damage evolution using the same non-invasive multimodal imaging sequences used in the clinical practice. Moreover, several models of comorbidities and pathologies usually found in stroke patients have recently been established in swine. We review here ischemic and hemorrhagic stroke models reported so far in pigs. The advantages and limitations of each model are also discussed.

Circular RNA Expression in the Brain of a Neonatal Rat Model of Periventricular White Matter Damage.

BACKGROUND/AIMS: Periventricular white matter damage (PWMD) is the predominant neurologic lesion in preterm infants who survive brain injury. In this study, we assessed the global changes in and characteristics of the transcriptome of circular RNAs (circRNAs) in the brain tissues of rats with PWMD. METHODS: We compared the expression profiles of circRNAs in brain samples from three rats with PWMD and three paired control tissues using deep RNA sequencing. Bioinformatics analysis was applied to investigate these differentially expressed circRNAs, and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis was performed to confirm the results. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict associated cell signaling pathways and functions. Network analysis was performed to predict circRNAs-microRNAs, and target genes related to PWMD. RESULTS: A total of 2151 more reliable circRNAs were dysregulated in the brain tissues of rats with PWMD, indicating a potential role in the condition. Of the 98 circRNAs significantly differentially expressed in rat brains with PWMD (P< 0.05), 52 were significantly over-expressed and 46 were significantly under-expressed. The expression profiles of seven of 10 randomly selected circRNAs were confirmed by qRT-PCR analysis. The glutamatergic synapse pathway and the VEGF signaling pathway, both associated with hypoxia/ischemia induced brain damage, were inriched. Relationship between miRNA (rno-miR-433-3p and rno-miR-206-3p) and HIF-1α were evident and potential associations between chr6: 48820833|48857932 and their target genes (rno-miR-433-3p and rno-miR-206-3p) were identified. CONCLUSION: The distinct expression patterns of circRNAs in the brain tissues of rats with PWMD suggest that circRNAs actively respond to hypoxia-ischemia. These findings could assist the development of novel diagnostic and therapeutic targets for PWMD therapy.

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study.

To understand the heterogeneity of functional connectivity results reported in the literature, we analyzed the separate effects of grey and white matter damage on functional connectivity and networks in multiple sclerosis. For this, we employed a biophysical thalamo-cortical model consisting of interconnected cortical and thalamic neuronal populations, informed and amended by empirical diffusion MRI tractography data, to simulate functional data that mimic neurophysiological signals. Grey matter degeneration was simulated by decreasing within population connections and white matter degeneration by lowering between population connections, based on lesion predilection sites in multiple sclerosis. For all simulations, functional connectivity and functional network organization are quantified by phase synchronization and network integration, respectively. Modeling results showed that both cortical and thalamic grey matter damage induced a global increase in functional connectivity, whereas white matter damage induced an initially increased connectivity followed by a global decrease. Both white and especially grey matter damage, however, induced a decrease in network integration. These empirically informed simulations show that specific topology and timing of structural damage are nontrivial aspects in explaining functional abnormalities in MS. Insufficient attention to these aspects likely explains contradictory findings in multiple sclerosis functional imaging studies so far.

Human Umbilical Cord Blood Therapy Protects Cerebral White Matter from Systemic LPS Exposure in Preterm Fetal Sheep.

BACKGROUND: Infants born preterm following exposure to in utero inflammation/chorioamnionitis are at high risk of brain injury and life-long neurological deficits. In this study, we assessed the efficacy of early intervention umbilical cord blood (UCB) cell therapy in a large animal model of preterm brain inflammation and injury. We hypothesised that UCB treatment would be neuroprotective for the preterm brain following subclinical fetal inflammation. METHODS: Chronically instrumented fetal sheep at 0.65 gestation were administered lipopolysaccharide (LPS, 150 ng, 055:B5) intravenously over 3 consecutive days, followed by 100 million human UCB mononuclear cells 6 h after the final LPS dose. Controls were administered saline instead of LPS and cells. Ten days after the first LPS dose, the fetal brain and cerebrospinal fluid were collected for analysis of subcortical and periventricular white matter injury and inflammation. RESULTS: LPS administration increased microglial aggregate size, neutrophil recruitment, astrogliosis and cell death compared with controls. LPS also reduced total oligodendrocyte count and decreased mature myelinating oligodendrocytes. UCB cell therapy attenuated cell death and inflammation, and recovered total and mature oligodendrocytes, compared with LPS. CONCLUSIONS: UCB cell treatment following inflammation reduces preterm white matter brain injury, likely mediated via anti-inflammatory actions.

Pretreatment with magnesium sulfate attenuates white matter damage by preventing cell death of developing oligodendrocytes.

AIM: Antenatal maternal administration of magnesium sulfate (MgSO4 ) reduces cerebral palsy in preterm infants. However, it remains controversial as to whether it also reduces occurrence of white matter damage, or periventricular leukomalacia. We assessed the effect of MgSO4 against white matter damage induced by hypoxic-ischemic insult using a neonatal rat model and culture of premyelinating oligodendrocytes (pre-OL). METHODS: Rat pups at postnatal day (P) 6 were administered either MgSO4 or vehicle intraperitoneally before hypoxic-ischemic insult (unilateral ligation of the carotid artery followed by 6% oxygen for 1 h). The population of oligodendrocyte (OL) markers and CD-68-positive microglia at P11, and TdT-mediated biotin-16-dUTP nick-end labeling (TUNEL)-positive cells at P8 were evaluated in pericallosal white matter. Primary cultures of mouse pre-OL were subjected to oxygen glucose deprivation condition, and the lactate dehydrogenase release from culture cells was evaluated to assess cell viability. RESULTS: Pretreatment with MgSO4 attenuated the loss of OL markers, such as myelin basic protein and Olig2, in ipsilateral pericallosal white matter and decreased the number of CD-68-positive microglia and TUNEL-positive cells in vivo. Pretreatment with MgSO4 also inhibited lactate dehydrogenase release from pre-OL induced by oxygen glucose deprivation in vitro. CONCLUSION: Pretreatment with MgSO4 attenuates white matter damage by preventing cell death of pre-OL.

White matter damage and systemic inflammation in Parkinson's disease.

BACKGROUND: Systemic inflammation and white matter (WM) alterations have been noted as effects of Parkinson's disease (PD). This study sought to evaluate WM integrity in PD patients using diffusion tensor imaging (DTI) and to assess its relationship with systemic inflammation. METHODS: Sixty-six patients with PD (23 men and 43 women) and 67 healthy volunteers (29 men and 38 women) underwent blood sampling to quantify inflammatory markers and DTI scans to determine fiber integrity. The inflammatory markers included leukocyte apoptosis, as well as cellular and serum adhesion molecules, in each peripheral blood sample. DTI-related indices [including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD)] were derived from DTI scans. The resulting FA maps were compared using voxel-based statistics to determine differences between the PD and control groups. The differences in the DTI indices, clinical severity, and inflammatory markers were correlated. RESULTS: Exploratory group-wise comparison between the two groups revealed that the PD patients exhibited extensive DTI index differences. Low FA accompanied by high RD and MD, without significant differences in AD, suggesting a demyelination process, were found in the parietal, occipital, cerebellar, and insular WM of the PD patients. The declined DTI indices were significantly correlated with increased clinical disease severity, adhesion molecules, and leukocyte apoptosis. CONCLUSIONS: Patients with PD experience WM integrity damage in vulnerable regions, and these impairments are associated with increased disease severity and systemic inflammation. The possible interactions among them may represent variant neuronal injuries and their consequent processes in PD.

Advanced Neuroimaging Techniques in Pediatric Hydrocephalus.

From the early days of pneumoencephalography and ventriculography to the emerging technology of magnetic resonance diffusion tensor imaging (DTI) of the present day, neuroimaging has always been a critical tool in the diagnosis and treatment of pediatric hydrocephalus. There is accumulating evidence from both human and animal research suggesting that one of the major pathophysiological mechanisms underlying poor outcomes in these children is damage to vulnerable white matter (WM) structures in the brain as a result of ventricular enlargement and increased intracranial pressure. However, a clear understanding of these WM abnormalities and their implications on neurobehavioral outcomes in these patients is not well understood. To this end, DTI has recently been studied to allow noninvasive quantification of these abnormalities. Our review discusses the evolution of neuroimaging in pediatric hydrocephalus and focuses on the use of advanced imaging techniques, such as DTI, which is supported by a growing body of literature as a promising noninvasive imaging tool in the diagnosis and long-term management of this patient population. We conclude with a brief discussion on emerging techniques and experimental imaging.

Effects of Aerobic Capacity on Thrombin-Induced Hydrocephalus and White Matter Injury.

We have previously shown that intracerebral hemorrhage-induced brain injury is less in rats bred for high aerobic capacity (high capacity runners; HCR) compared with those bred for low aerobic capacity (low capacity runners; LCRs). Thrombin, an essential component in the coagulation cascade, is produced after cerebral hemorrhage. Intraventricular injection of thrombin causes significant hydrocephalus and white matter damage. In the present study, we examined the effect of exercise capacity on thrombin-induced hydrocephalus and white matter damage. Mid-aged (13-month-old) female LCRs (n = 13) and HCRs (n = 12) rats were used in this study. Rats received an intraventricular injection of thrombin (3 U, 50 µl). All rats underwent magnetic resonance imaging (MRI) at 24 h and were then euthanized for brain histology and Western blot. The mortalities were 20 % in LCRs and 33 % in HCRs after thrombin injection (p > 0.05). No rats died after saline injection. Intraventricular thrombin injection resulted in hydrocephalus and periventricular white matter damage as determined on MRI. In LCR rats, thrombin induced significant ventricle enlargement (23.0 ± 2.3 vs12.8 ± 1.9 mm(3) in LCR saline group; p < 0.01) and white matter lesion (9.3 ± 7.6 vs 0.6 ± 0.5 mm(3) in LCR saline group, p < 0.05). In comparison, in HCR rats thrombin induced less ventricular enlargement (17.3 ± 3.9 vs 23.0 ± 2.3 mm(3) in LCRs, p < 0.01) and smaller white matter lesions (2.6 ± 1.2 mm(3) vs 9.3 ± 7.6 mm(3) in LCRs, p < 0.05). In LCR rats, there was also upregulation of heat shock protein-32, a stress marker, and microglial activation in the periventricular white matter. These changes were significantly reduced in HCR rats. Intraventricular injection of thrombin caused more white matter damage and hydrocephalus in rats with low aerobic capacity. A differential effect of thrombin may contribute to differences in the effects of cerebral hemorrhage with aerobic capacity.

Oligodendroglial maldevelopment in the cerebellum after postnatal hyperoxia and its prevention by minocycline.

According to recent research, brain injury after premature birth often includes impaired growth of the cerebellum. However, causes of cerebellar injury in this population are poorly understood. In this study, we analyzed whether postnatal hyperoxia perturbs white matter development of the cerebellum, and whether cerebellar glial damage can be prevented by minocycline. We used a hyperoxia model in neonatal rats providing 24 h exposure to fourfold increased oxygen concentration (80% O2) from P6 to P7, followed by recovery in room air until P9, P11, P15, P30. Injections with minocycline were performed at the beginning and 12 h into hyperoxia exposure. Hyperoxia induced oxidative stress in the cerebellum at P7 as evidenced by increased nitrotyrosine concentrations. Numbers of proliferating, NG2+Ki67+ oligodendroglial precursor cells were decreased at P7 after hyperoxia and at P11 following recovery in room air. Numbers of mature, CC1+ oligodendrocytes were diminished in recovering hyperoxia rats, and myelin basic protein expression was still decreased at P30. Electron microscopy analysis of myelinated fibers at P30 revealed thinner myelin sheath after hyperoxia. Long-term injury of the cerebellum by neonatal hyperoxia was confirmed by reduced volumes in MRI measurements at P30. In response to 80% O2, expression of platelet-derived growth factor (PDGF)-A was largely reduced in cerebellar tissue and also in cultured cerebellar astrocytes. Treatment with minocycline during hyperoxia prevented oxidative stress, attenuated oligodendroglial injury, and improved astroglial PDGF-A levels. In conclusion, early hyperoxia causes white matter damage in the cerebellum with astroglial dysfunction being involved, and both can be prevented by treatment with minocycline. Neonatal exposure to hyperoxia causes hypomyelination of the cerebellum. Reduced astroglial growth factor production but not microglial inflammation seems to contribute to oligodendroglial damage, and minocycline rescues oligodendroglia development in the cerebellum after hyperoxia.

White matter microstructure abnormalities in pediatric migraine patients.

BACKGROUND: Diffusion tensor (DT) magnetic resonance imaging (MRI) provides several quantities with the potential to disclose white matter (WM) microstructural abnormalities. We explored alterations of WM architecture in pediatric migraine patients using DT MRI and two different methods of analysis. METHODS: Dual-echo and DT MRI scans were acquired from 15 pediatric migraine patients and 15 age-matched controls. Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). A DT probabilistic tractography analysis was also run. RESULTS: Both TBSS and DT tractography analysis showed that, compared to controls, pediatric migraine patients had significant lower mean (MD), axial (AD) and radial (RD) diffusivity of WM tracts located in the brainstem, thalamus and fronto-temporo-occipital lobes, bilaterally. Patients also experienced increased fractional anisotropy (FA) of the optic radiations. No correlation was found between WM tract abnormalities and disease duration and attack frequency. CONCLUSIONS: Pediatric migraine patients harbor diffuse brain WM microstructural abnormalities. High FA and low MD, AD and RD in these patients might be explained by repeated neuronal activation, which may lead to cell swelling and stimulate activity-dependent myelin-modulation, or by increased fiber and dendritic densities. Both these mechanisms might reflect a hyperexcitability of the brain in migraineurs.

Mild cognitive impairment in Parkinson's disease is associated with a distributed pattern of brain white matter damage.

This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinson's disease and mild cognitive impairment (PD-MCI) compared with healthy controls and cognitively unimpaired PD patients (PD-Cu). Three-dimensional T1-weighted and diffusion tensor (DT) magnetic resonance imaging (MRI) scans were obtained from 43 PD patients and 33 healthy controls. Cognition was assessed using a neuropsychological battery. Tract-based spatial statistics was applied to compare DT MRI indices between groups on a voxel-by-voxel basis. Voxel-based morphometry was performed to assess GM atrophy. Thirty PD patients were classified as MCI. Compared with healthy controls, PD-Cu and PD-MCI patients did not have GM atrophy. No region of WM damage was found in PD-Cu patients when compared with healthy controls. Relative to healthy controls and PD-Cu patients, PD-MCI patients showed a distributed pattern of WM abnormalities in the anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto-occipital, uncinate, and superior longitudinal fasciculi, bilaterally. Subtle cognitive decline in PD is associated with abnormalities of frontal and interhemispheric WM connections, and not with GM atrophy. DT MRI might contribute to the identification of structural changes in PD-MCI patients prior to the development of dementia.