scholarly journals Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission

2021 ◽  
Author(s):  
Yafeng Wang ◽  
Yiran Xu ◽  
Kai Zhou ◽  
Shan Zhang ◽  
Yong Wang ◽  
...  
Keyword(s):  
White Matter ◽  
Late Onset ◽  
Mitochondrial Gene ◽  
Mitochondrial Fission ◽  
Cell Loss ◽  
Subcortical White Matter ◽  
Mitochondrial Fusion ◽  
White Matter Injury ◽  
Whole Brain Irradiation ◽  
Protein Levels

Abstract Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.

scholarly journals Autophagy inhibition reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission

2021 ◽  
Author(s):  
Yafeng Wang ◽  
Yiran Xu ◽  
Kai Zhou ◽  
Yong Wang ◽  
Tao Li ◽  
...  
Keyword(s):  
White Matter ◽  
Late Onset ◽  
Mitochondrial Gene ◽  
Mitochondrial Fission ◽  
Cell Loss ◽  
Subcortical White Matter ◽  
Mitochondrial Fusion ◽  
White Matter Injury ◽  
Whole Brain Irradiation ◽  
Protein Levels

Abstract Background Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has impact on subcortical white matter development in the juvenile mouse brain after irradiation. Methods Ten-day-old selective Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6 Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Results Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed there were numbers of differentially expressed genes (DEGs) in both Atg7 KO and WT group after irradiation, but GSEA analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the remaining DEGs between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 were dramatically decreased in KO mice under physiological conditions. The protein levels of phosphorylated DRP1 and OPA1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased level in the KO mice after irradiation. Conclusions These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.

scholarly journals Preliminary Evidence for a Relationship between Elevated Plasma TNFα and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity

2021 ◽  
Vol 22 (9) ◽  
pp. 4953
Author(s):  
Natalie M. Zahr ◽  
Kilian M. Pohl ◽  
Allison J. Kwong ◽  
Edith V. Sullivan ◽  
Adolf Pfefferbaum
Keyword(s):  
White Matter ◽  
Proinflammatory Cytokines ◽  
Soluble Protein ◽  
Subcortical White Matter ◽  
Control Group ◽  
White Matter Volume ◽  
Brain Volumes ◽  
Protein Levels ◽  
Matter Volume ◽  
Patient Groups

Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1β in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.

scholarly journals Combining Hypothermia and Oleuropein Subacutely Protects Subcortical White Matter in a Swine Model of Neonatal Hypoxic-Ischemic Encephalopathy

2020 ◽  
Author(s):  
Jennifer K Lee ◽  
Polan T Santos ◽  
May W Chen ◽  
Caitlin E O’Brien ◽  
Ewa Kulikowicz ◽  
...  
Keyword(s):  
White Matter ◽  
Motor Cortex ◽  
Corpus Callosum ◽  
Internal Capsule ◽  
Subcortical White Matter ◽  
White Matter Injury ◽  
Swine Model ◽  
Cortex Neuron ◽  
Motor Cortex Neuron ◽  
Ischemic Encephalopathy

Abstract Neonatal hypoxia-ischemia (HI) causes white matter injury that is not fully prevented by therapeutic hypothermia. Adjuvant treatments are needed. We compared myelination in different piglet white matter regions. We then tested whether oleuropein (OLE) improves neuroprotection in 2- to 4-day-old piglets randomized to undergo HI or sham procedure and OLE or vehicle administration beginning at 15 minutes. All groups received overnight hypothermia and rewarming. Injury in the subcortical white matter, corpus callosum, internal capsule, putamen, and motor cortex gray matter was assessed 1 day later. At baseline, piglets had greater subcortical myelination than in corpus callosum. Hypothermic HI piglets had scant injury in putamen and cerebral cortex. However, hypothermia alone did not prevent the loss of subcortical myelinating oligodendrocytes or the reduction in subcortical myelin density after HI. Combining OLE with hypothermia improved post-HI subcortical white matter protection by preserving myelinating oligodendrocytes, myelin density, and oligodendrocyte markers. Corpus callosum and internal capsule showed little HI injury after hypothermia, and OLE accordingly had minimal effect. OLE did not affect putamen or motor cortex neuron counts. Thus, OLE combined with hypothermia protected subcortical white matter after HI. As an adjuvant to hypothermia, OLE may subacutely improve regional white matter protection after HI.

scholarly journals Subcortical ischemic vascular disease: Roles of oligodendrocyte function in experimental models of subcortical white-matter injury

2015 ◽  
Vol 36 (1) ◽  
pp. 187-198 ◽  
Author(s):  
Akihiro Shindo ◽  
Anna C Liang ◽  
Takakuni Maki ◽  
Nobukazu Miyamoto ◽  
Hidekazu Tomimoto ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Nerve Conduction ◽  
Neurovascular Unit ◽  
Cell Types ◽  
Subcortical White Matter ◽  
Experimental Models ◽  
White Matter Injury ◽  
Cerebral White Matter ◽  
Myelin Sheaths

Oligodendrocytes are one of the major cell types in cerebral white matter. Under normal conditions, they form myelin sheaths that encircle axons to support fast nerve conduction. Under conditions of cerebral ischemia, oligodendrocytes tend to die, resulting in white-matter dysfunction. Repair of white matter involves the ability of oligodendrocyte precursors to proliferate and mature. However, replacement of lost oligodendrocytes may not be the only mechanism for white-matter recovery. Emerging data now suggest that coordinated signaling between neural, glial, and vascular cells in the entire neurovascular unit may be required. In this mini-review, we discuss how oligodendrocyte lineage cells participate in signaling and crosstalk with other cell types to underlie function and recovery in various experimental models of subcortical white-matter injury.

White Matter but not Gray Matter Volumes are Associated with Cognition in Community-Dwelling Chinese Populations

2021 ◽  
pp. 1-9
Author(s):  
Quan Wang ◽  
Ning Su ◽  
Jin Huang ◽  
Xinyu Liang ◽  
Jing Yuan ◽  
...  
Keyword(s):  
White Matter ◽  
Gray Matter ◽  
Completion Time ◽  
Brain Volume ◽  
Small Vessel Disease ◽  
Digit Span ◽  
Subcortical White Matter ◽  
Community Dwelling ◽  
White Matter Injury ◽  
Imaging Markers

Background: Few studies have investigated the association between cognition and brain volume associated with cerebral small vessel disease (CSVD). Objective: We investigated the association between cognition and brain volume and neuroimaging markers of CSVD in a community-dwelling population. Methods: Participants (n = 993, age≥35 years) from the community-based Shunyi Study were included to investigate the association between neuroimaging markers and cognition cross-sectionally. Magnetic resonance imaging markers included brain volume measurements of the total cerebrum, white matter, gray matter, and CSVD imaging markers. Cognitive performance was assessed using neuropsychological tests of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Fuld Object Memory, digit span, Trail Making Test (TMT)-A, and TMT-B. Results: For brain volume measurement, subcortical white matter fraction was positively associated with MMSE score (β= 0.034, p = 0.0062) and MoCA score (β= 0.034, p = 0.0174), and negatively associated with TMT-A and TMT-B completion time (β= –2.319, p = 0.0002; β= –2.827, p = 0.0073, respectively). For evaluation of CSVD imaging markers, the presence of lacunes was positively associated with TMT-B completion time (β= 17.241, p = 0.0028). Conclusion: In community-dwelling populations, reduced white matter volumes, as a consequence of aging and vascular damage, are associated with worse global cognition and executive function. Our findings provide potential insights into the correlation between cognition and CSVD-associated subcortical white matter injury.

Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

2017 ◽  
Vol 39 (1-4) ◽  
pp. 141-155 ◽  
Author(s):  
Anna Karynna Alves de Alencar Rocha ◽  
Beth J. Allison ◽  
Tamara Yawno ◽  
Graeme R. Polglase ◽  
Amy E. Sutherland ◽  
...  
Keyword(s):  
White Matter ◽  
Brain Development ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Early Onset ◽  
Late Onset ◽  
Placental Insufficiency ◽  
White Matter Injury ◽  
Fetal Sheep ◽  
Cell Counts

Fetal growth restriction (FGR) is a common complication of pregnancy, principally caused by suboptimal placental function, and is associated with high rates of perinatal mortality and morbidity. Clinical studies suggest that the time of onset of placental insufficiency is an important contributor towards the neurodevelopmental impairments that are evident in children who had FGR. It is however currently unknown how early-onset and late-onset FGR differentially affect brain development. The aim of this study was to examine neuropathology in early-onset and late-onset FGR fetal sheep and to determine whether they differentially alter brain development. We induced placental insufficiency and FGR via single umbilical artery ligation at either 88 days (early-onset) or 105 days (late-onset) of fetal sheep gestation (term is approx. 147 days), reflecting a period of rapid white matter brain development. Fetal blood samples were collected for the first 10 days after surgery, and all fetuses were sacrificed at 125 days' gestation for brain collection and subsequent histopathology. Our results show that early-onset FGR fetuses became progressively hypoxic over the first 10 days after onset of placental insufficiency, whereas late-onset FGR fetuses were significantly hypoxic compared to controls from day 1 after onset of placental insufficiency (SaO2 46.7 ± 7.4 vs. 65.7 ± 3.9%, respectively, p = 0.03). Compared to control brains, early-onset FGR brains showed widespread white matter injury, with a reduction in both CNPase-positive and MBP-positive density of staining in the periventricular white matter (PVWM), subcortical white matter, intragyral white matter (IGWM), subventricular zone (SVZ), and external capsule (p < 0.05 for all). Total oligodendrocyte lineage cell counts (Olig-2-positive) did not differ across groups, but mature oligodendrocytes (MBP-positive) were reduced, and neuroinflammation was evident in early-onset FGR brains with reactive astrogliosis (GFAP-positive) in the IGWM and cortex (p < 0.05), together with an increased number of Iba-1-positive activated microglia in the PVWM, SVZ, and cortex (p < 0.05). Late-onset FGR was associated with a widespread reduction of CNPase-positive myelin expression (p < 0.05) and a reduced number of mature oligodendrocytes in all white matter regions examined (p < 0.05). NeuN-positive neuronal cell counts in the cortex were not different across groups; however, the morphology of neuronal cells was different in response to placental insufficiency, most notable in the early-onset FGR fetuses, but it was late-onset FGR that induced caspase-3-positive apoptosis within the cortex. This study demonstrates that early-onset FGR is associated with more widespread white matter injury and neuroinflammation; however, both early- and late-onset FGR are associated with complex patterns of white and grey matter injury. These results indicate that it is the timing of the onset of fetal compromise relative to brain development that principally mediates altered brain development associated with FGR.

scholarly journals Insulin-Like Growth Factor-1 Reduces Postischemic White Matter Injury in Fetal Sheep

2001 ◽  
Vol 21 (5) ◽  
pp. 493-502 ◽  
Author(s):  
Jian Guan ◽  
Laura Bennet ◽  
Shirley George ◽  
David Wu ◽  
Harry J. Waldvogel ◽  
...  
Keyword(s):  
White Matter ◽  
Growth Factor ◽  
Close Association ◽  
Proteolipid Protein ◽  
Cell Loss ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
White Matter Injury ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep

Insulin-like growth factor-1 (IGF-1) is known to be important for oligodendrocyte survival and myelination. In the current study, the authors examined the hypothesis that exogenous IGF-1 could reduce postischemic white matter injury. Bilateral brain injury was induced in near-term fetal sheep by 30 minutes of reversible carotid artery occlusion. Ninety minutes after ischemia, either vehicle (n = 8) or a single dose of 3 μg IGF-1 (n = 9) was infused intracerebroventricularly over 1 hour. White matter changes were assessed after 4 days recovery in the parasagittal intragyral white matter and underlying corona radiata. Proteolipid protein (PLP) mRNA staining was used to identify bioactive oligodendrocytes. Glial fibrillary acidic protein (GFAP) and isolectin B-4 immunoreactivity were used to label astrocytes and microglia, respectively. Myelin basic protein (MBP) density and the area of the intragyral white matter tracts were determined by image analysis. Insulin-like growth factor-1 treatment was associated with significantly reduced loss of oligodendrocytes in the intragyral white matter ( P < 0.05), with improved MBP density ( P < 0.05), reduced tissue swelling, and increased numbers of GFAP and isolectin B-4 positive cells compared with vehicle treatment. After ischemia there was a close association of PLP mRNA labeled cells with reactive astrocytes and macrophages/microglia. In conclusion, IGF-1 can prevent delayed, postischemic oligodendrocyte cell loss and associated demyelination.

Effectiveness of minocycline in acute white matter injury after intracerebral hemorrhage

2016 ◽  
Vol 126 (6) ◽  
pp. 1855-1862 ◽  
Author(s):  
Xiang Zou ◽  
Zehan Wu ◽  
Wei Zhu ◽  
Liang Chen ◽  
Ying Mao ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Critical Role ◽  
White Matter Injury ◽  
High Morbidity ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Injection Group ◽  
Jnk Activation

OBJECTIVEIntracerebral hemorrhage (ICH) is a fatal disease with high morbidity and mortality, which may be followed by white matter injury (WMI) due to the local oxidizing reaction induced by iron (Fe). In this study, the authors examined the effect of the tetracycline antibiotic minocycline on Fe-induced WMI and c-Jun N-terminal kinase (JNK) activation in rats.METHODSThirty-six male Sprague-Dawley rats underwent an intracaudate injection of saline, Fe, or Fe + minocycline. Another 36 rats had an intracaudate injection of autologous blood and were treated with minocycline or vehicle (saline). Biomarkers of both WMI and JNK activation were examined.RESULTSIn the Fe-injection group, minocycline suppressed WMI labeled by β-amyloid precursor protein (β-APP) and degraded myelin basic protein (dMBP)/MBP ratio. Protein levels of phosphorylated-JNK were increased after Fe injection, and could be suppressed by minocycline treatment. In the autologous blood–injection group, β-APP and dMBP/MBP levels increased in the ipsilateral site compared with the contralateral site, which could be suppressed by 7 days of minocycline intervention.CONCLUSIONSIron plays a critical role in WMI after ICH, which can be suppressed by minocycline through reducing the damage induced by Fe.

scholarly journals White Matter Injury Is Associated with Reduced Manual Dexterity and Elevated Serum Ceramides in Subjects with Cerebral Small Vessel Disease

2020 ◽  
pp. 1-8
Author(s):  
Yousef Hannawi ◽  
Lisa R. Yanek ◽  
Brian G. Kral ◽  
Lewis C. Becker ◽  
Dhananjay Vaidya ◽  
...  
Keyword(s):  
White Matter ◽  
Small Vessel Disease ◽  
Elevated Serum ◽  
Subcortical White Matter ◽  
Cerebral Small Vessel Disease ◽  
Manual Dexterity ◽  
White Matter Injury ◽  
Small Vessel ◽  
Bonferroni Correction ◽  
Vessel Disease

<b><i>Introduction:</i></b> We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. <b><i>Methods:</i></b> rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. <b><i>Results:</i></b> 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (β = −0.497, <i>p</i> = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: β = −0.03, <i>p</i> = 0.003, C20: β = −0.0002, <i>p</i> = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (β = −0.0103, <i>p</i> = 0.027). <b><i>Conclusions:</i></b> These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.

scholarly journals Striatal Hypodensities, Not White Matter Hypodensities on CT, Are Associated with Late-Onset Depression in Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Jessica A. Brommelhoff ◽  
Bryan M. Spann ◽  
John L. Go ◽  
Wendy J. Mack ◽  
Margaret Gatz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Frontal Lobe ◽  
Gray Matter ◽  
Late Onset ◽  
Subcortical White Matter ◽  
Ct Scans ◽  
Deep White Matter ◽  
Depression History

This study examined whether there were neuroanatomical differences evident on CT scans of individuals with dementia who differed on depression history. Neuroanatomical variables consisted of visual ratings of frontal lobe deep white matter, subcortical white matter, and subcortical gray matter hypodensities in the CT scans of 182 individuals from the Study of Dementia in Swedish Twins who were diagnosed with dementia and had information on depression history. Compared to individuals with Alzheimer's disease and no depression, individuals with Alzheimer's disease and late-onset depression (first depressive episode at age 60 or over) had a greater number of striatal hypodensities (gray matter hypodensities in the caudate nucleus and lentiform nucleus). There were no significant differences in frontal lobe deep white matter or subcortical white matter. These findings suggest that late-onset depression may be a process that is distinct from the neurodegenerative changes caused by Alzheimer's disease.

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