Patterns of cerebral white matter damage and cognitive impairment in adolescents born very preterm

There is increasing evidence about the presence of white matter damage in subjects with a history of premature birth, even in those classified as good outcome because of an apparently normal development. Although intellectual performance is within normal limits in premature children it is significantly decreased compared to paired controls. The purpose of this study was to investigate the relationship between a lower performance intelligence quotient and white matter damage in preterm adolescents. The sample comprised 44 adolescents (mean age ± S.D.: 14.4 ± 1.6 years) born before 32 weeks of gestational age and 43 term-born adolescents (14.5 ± 2.1 years). Individual voxel-based morphometry analyses demonstrated that 35/44 (80%) preterm subjects had white matter abnormalities. The centrum semiovale and the posterior periventricular regions were the most frequently affected areas. Correlation analysis showed that in preterms the performance intelligence quotient correlated with the whole-brain white matter volume (r = 0.32; P = 0.036) but not with grey matter volume. Complementary analysis showed that low scores in the Digit Symbol subtest, a measure of processing speed, in the preterm group correlated with reductions in white matter concentration. These results suggest that white matter damage is highly common and that it persists until adolescence. Hence, diffuse white matter loss may be responsible for performance intelligence quotient and processing speed decrements in subjects with very preterm birth.     

Interleukin-2 in the pathogenesis of perinatal white matter damage

Proinflammatory cytokines were reported to be implicated in the pathogenesis of perinatal white matter lesions. The authors document for the first time the in situ detection of interleukin-2 and interleukin-2 receptor (IL-2R) in these human white matter lesions. These results suggest that interleukin-2, reported to be toxic to oligodendrocytes and myelin, could play a role in the molecular cascade leading to white matter damage in periventricular leukomalacia.     

Differential vulnerability of white matter structures to experimental infantile hydrocephalus detected by diffusion tensor imaging

Purpose

The differential vulnerability of white matter (WM) to acute and chronic infantile hydrocephalus and the related effects of early and late reservoir treatment are unknown, but diffusion tensor imaging (DTI) could provide this information. Thus, we characterized WM integrity using DTI in a clinically relevant model.

Methods

Obstructive hydrocephalus was induced in 2-week-old felines by intracisternal kaolin injection. Ventricular reservoirs were placed 1 (early) or 2 (late) weeks post-kaolin and tapped frequently based solely on neurological deficit. Hydrocephalic and age-matched control animals were sacrificed 12 weeks postreservoir. WM integrity was evaluated in the optic system, corpus callosum, and internal capsule prereservoir and every 3 weeks using DTI. Analyses were grouped as acute (<6 weeks) or chronic (≥6 weeks).

Results

In the corpus callosum during acute stages, fractional anisotropy (FA) decreased significantly with early and late reservoir placement (p?=?0.0008 and 0.0008, respectively), and diffusivity increased significantly in early (axial, radial, and mean diffusivity, p?=?0.0026, 0.0012, and 0.0002, respectively) and late (radial and mean diffusivity, p?=?0.01 and 0.0038, respectively) groups. Chronically, the corpus callosum was thinned and not detectable by DTI. FA was significantly lower in the optic chiasm and tracts (p?=?0.0496 and 0.0052, respectively) with late but not early reservoir placement. In the internal capsule, FA in both reservoir groups increased significantly with age (p?Conclusions All hydrocephalic animals treated with intermittent ventricular reservoir tapping demonstrated progressive ventriculomegaly. Both reservoir groups demonstrated WM integrity loss, with the CC the most vulnerable and the optic system the most resilient.     

氧化应激在慢性缺血性脑白质损伤中的作用

目的 阐明氧化应激是否参与大鼠慢性脑缺血所致的脑白质损伤.方法 健康雄性Wistar大鼠按照完全随机数字表法分为假手术组,持久性双侧颈总动脉结扎3 d组、7 d组、3周组及6周组,每组6只.应用大鼠双侧颈总动脉结扎制备慢性脑缺血模型,检测大鼠脑白质内超氧化物歧化酶(SOD)活性、过氧化氢酶(CAT)活性、谷胱甘肽(GSH)含量以及脂质过氧化产物丙二醛(MDA)和4-羟基壬烯醛(4-HNE)加合物的变化.结果 与假手术组比较,慢性脑缺血大鼠脑白质内MDA含量在手术后3周明显增加,手术后6周进一步增高,差异有统计学意义(P<0.05).手术后3d至6周,慢性脑缺血大鼠脑白质内4-HNE蛋白加合物逐渐增高,与假手术组比较有差异有统计学意K(P<0.05).SOD活性在手术后3周和6周才明显降低,与假手术组比较差异有统计学意义(P<0.05).此外,慢性脑缺血大鼠脑白质内GSH含量在手术后7d即开始降低,而在手术后3周及6周则进一步下降,与假手术组比较差异有统计学意义(P<0.05).结论 慢性脑缺血导致大鼠脑白质氧化性损伤增加,抗氧化防御能力降低:氧化性损伤的增加和抗氧化防御能力的降低与慢性脑缺血所致的脑白质损伤密切相关.     

Selective vulnerability of cerebral white matter in a murine model of multiple sclerosis detected using diffusion tensor imaging

In this study, axial (lambda(parallel)) and radial (lambda(perpendicular)) diffusivities derived from diffusion tensor imaging (DTI) were used to evaluate white matter injury in brains of mice affected by experimental autoimmune encephalomyelitis (EAE). Sixteen female C57BL/6 mice were immunized with amino acids 35-55 of myelin oligodendrocyte glycoprotein (MOG(35-55)). Three months after immunization, optic nerve and tract were severely affected with 19% and 18% decrease in lambda(parallel) respectively, suggesting the presence of axonal injury. In addition, a 156% and 86% increase in lambda( perpendicular) was observed in optic nerve and tract respectively, suggestive of myelin injury. After in vivo DTI, mice were perfusion fixed and immunohistochemistry for the identification of myelin basic protein (MBP) and phosphorylated neurofilament (pNF) was performed to verify the presence of axonal and myelin injury. The present study demonstrated that the visual pathway is selectively affected in MOG(35-55) induced murine EAE and these injuries are non-invasively detectable using lambda(parallel) and lambda( perpendicular).     

Pathogenesis of periventricular white matter hemorrhages in preterm infants

Periventricular white matter hemorrhage (PWMH) was frequently found in very low-birth weight infants with perinatal asphyxia or respiratory distress. Primary PWMH with or without intraventricular rupture was found at the deep arterial borderzones of the frontal or occipital lobes. The ischemic tissue damage induced by hypoperfusion may be a predisposing factor for PWMH. However, the high incidence of visceral intravascular thrombi and the fan-shaped appearance of hemorrhage suggested venous hemorrhagic infarction. Venous thrombosis with coagulopathy may be an important factor for the pathogenesis of PWMH.     

绞股蓝总皂甙对慢性脑缺血性白质氧化性损伤的保护作用

目的 探讨绞股蓝总皂甙对慢性脑缺血大鼠脑白质氧化性损伤的保护作用以及对脑缺血大鼠认知功能的影响.方法 将57只成年雄性SD大鼠按随机数字表法分成假手术组(n=12)、模型组(n=15)、绞股蓝总皂甙200 mg组(n=15)、绞股蓝总皂甙400 mg组(n=15),后3组采用双侧颈总动脉结扎法制备慢性脑缺血模型,且在造模后3h分别将等量生理盐水,200 mg/kg、400mg/kg绞股蓝总皂甙溶液灌胃,1次/d,持续33 d.应用Morris水迷宫实验测试各组大鼠空间学习与记忆能力的改变,酶联免疫吸附法(ELISA)测定大鼠胼胝体、视束内超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量,免疫组化染色用8-羟基脱氧鸟苷(8-OHdG)抗体测定中枢神经细胞的氧化损伤水平.结果 与模型组相比,绞股蓝总皂甙400 mg组大鼠的逃避潜伏期明显缩短及在原平台象限的游泳时间明显延长,差异有统计学意义(P＜0.05).与假手术组比较,模型组大鼠胼胝体及视束内MDA含量明显增加,SOD活性明显降低,差异有统计学意义(P＜0.05).与模型组相比,绞股蓝总皂甙400 mg组MDA含量明显降低,SOD活性明显升高,8-OHdG阳性细胞数明显减少,差异有统计学意义(P＜0.05).与模型组相比,绞股蓝总皂甙200 mg组SOD活性、MDA含量及8-OHdG阳性细胞数差异无统计学意义(P＞0.05).结论 绞股蓝总皂甙能有效改善慢性脑缺血大鼠脑白质氧化性损伤,提示其可能是一种有效的抗痴呆药物,但其作用的确切机制还有待进一步研究.     

Characterization of cerebral white matter damage in preterm infants using 1H and 31P magnetic resonance spectroscopy.

The biochemical characteristics of white matter damage (WMD) in preterm infants were assessed using magnetic resonance spectroscopy (MRS). The authors hypothesized that preterm infants with WMD at term had a persisting cerebral lactic alkalosis and reduced N-acetyl aspartate (NAA)/ creatine plus phosphocreatine (Cr), similar to that previously documented in term infants weeks after perinatal hypoxiaischemia (HI). Thirty infants (gestational age 27.9 +/- 3.1 weeks, birth weight 1,122 +/- 445 g) were studied at postnatal age of 9.8 +/- 4.1 weeks (corrected age 40.3 +/- 3.9 weeks). Infants were grouped according to the presence or absence of WMD on magnetic resonance (MR) images. The peak area ratios of lactate/Cr, NAA/Cr, myo-inositol/Cr, and choline (Cho)/Cr were measured from an 8-cm3 voxel in the posterior periventricular white matter (WM) using proton MRS. Intracellular pH (pHi) was calculated using phosphorus MRS. Eighteen infants had normal WM on MR imaging; 12 had WMD. For infants with WMD, lactate/Cr and myo-inositol/Cr were related (P < 0.01); lactate/Cr and pHi were not (P = 0.8). In the WMD group, mean lactate/Cr and myo-inositol/Cr were higher (P < 0.001, P < 0.05, respectively) than the normal WM group. There was no difference in the NAA/Cr, Cho/Cr, or pHi between the two groups, although pHi was not measured in all infants. These findings suggest that WMD in the preterm infant at term has a different biochemical profile compared with the term infant after perinatal HI.     

A cyclooxygenase-2 inhibitor attenuates white matter damage in chronic cerebral ischemia.

The effects of nimesulide, a cyclooxygenase-2 inhibitor, were examined during chronic cerebral hypoperfusion. After bilateral ligation of the common carotid arteries in 30 rats, 21 received dosages of 2 or 5 mg/kg nimesulide daily and nine received vehicle daily for 14 days. The serum was then analyzed biochemically, and pathological changes were estimated in the white matter by the emergence of major histocompatibility complex (MHC) antigen-immunoreactive activated microglia and white matter lesions. In the vehicle-treated animals, activated microglia and white matter lesions were observed. Following treatment with either 2 or 5mg/kg nimesulide, the magnitude of these changes was reduced (p < 0.001) without significant side effects. These results indicate a potential use for cyclooxygenase-2 inhibitors in cerebrovascular disease.     

Juvenile striatal white matter is resistant to ischemia‐induced damage

White matter injury following ischemic stroke is a major cause of functional disability. Injury to both myelinated axons and oligodendrocytes, the myelin producing cells in the central nervous system, occurs in experimental models of ischemic stroke. Age‐related changes in white matter vulnerability to ischemia have been extensively studied and suggest that both the perinatal and the aged periods are times of increased white matter vulnerability. However, sensitivity of white matter following stroke in the juvenile brain has not been evaluated. Interestingly, the late pediatric period is an important developmental stage, as it is the time of maximal myelination. The current study demonstrates that neurons in late pediatric/juvenile striatum are vulnerable to ischemic damage, with neuronal injury being comparable in juvenile and adult mice following ischemia. By contrast, actively myelinating striatal oligodendrocytes in the juvenile brain are resistant to ischemia, whereas adult oligodendrocytes are quite sensitive. As a result, myelin sheaths are remarkably intact and axons survive well in the injured striatum of juvenile mice. In addition to relative resistance of juvenile white matter, other glial responses were very different in juvenile and adult mice following cerebral ischemia, including differences in astrogliosis, fibrosis, NG2‐cell reactivity, and vascular integrity. Together, these responses lead to long‐term preservation of brain parenchyma in juvenile mice, compared to severe tissue loss and scarring in adult mice. Overall, the current study suggests that equivalent ischemic insults may result in less functional deficit in children compared to adults and an environment more conducive to long‐term recovery. GLIA 2016;64:1972–1986     

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI‐based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel‐wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue‐states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2‐weighted hyperintense lesional tissue without T1‐weighted hypointensity (T2L), and T1‐weighted hypointense lesional tissue with corresponding T2‐weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue‐states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions.     

Contributors to white matter damage in the frontal lobe in Alzheimer's disease

Abnormalities of cerebral white matter are present in a majority of patients with Alzheimer's disease (AD) and probably contribute to motor dysfunction and cognitive impairment. The white matter abnormalities are usually attributed to degenerative vascular disease and cerebral amyloid angiopathy (CAA) but the evidence is scanty or inconclusive. In the present study we examined sections of frontal lobe from 125 autopsy-confirmed cases of AD and assessed the relationship of degenerative large and small vessel disease, CAA, parenchymal Abeta load and APOE genotype, to several objective measures of white matter damage: extent of immunolabelling for glial fibrillary acidic protein (GFAP), axonal accumulation of amyloid precursor protein (APP), axon density in superficial and deep white matter, and intensity of staining for myelin. We found no association between atherosclerosis, arteriolosclerosis, CAA or APOE genotype and white matter damage. However, labelling of white matter for GFAP correlated strongly with the parenchymal Abeta load (P = 0.0003) and with APP accumulation (P = 0.008). Our findings suggest that severity of frontal white matter damage in AD is closely related to parenchymal Abeta load and that in most cases the contribution of degenerative vascular disease, CAA and APOE is relatively minor.     

早产儿脑白质损伤早期相关高危因素

目的 分析早产儿脑白质损伤(WMD)早期相关高危因素.方法 选取郑州大学第二附属医院2018-10—2019-05住院的210例早产儿,根据出生后2周内头颅磁共振结果有无异常分为WMD组及对照组.对比2组患儿在围生期的情况及检查结果,进行单因素分析,对单因素分析中的显著因素进行多因素Logistic回归分析.结果 21...     

Protective effects of carnosine on white matter damage induced by chronic cerebral hypoperfusion

Carnosine is a dipeptide that scavenges free radicals,inhibits inflammation in the central nervous system,and protects against ischemic and hypoxic brain damage through its anti-oxidative and anti-apoptotic actions.Therefore,we hypothesized that carnosine would also protect against white matter damage caused by subcortical ischemic injury.White matter damage was induced by right unilateral common carotid artery occlusion in mice.The animals were treated with 200,500 or 750 mg/kg carnosine by intraperitoneal injection 30 minutes before injury and every other day after injury.Then,37 days later,Klüver-Barrera staining,toluidine blue staining and immunofluorescence staining were performed.Carnosine(200,500 mg/kg) substantially reduced damage to the white matter in the corpus callosum,internal capsule and optic tract,and it rescued expression of myelin basic protein,and alleviated the loss of oligodendrocytes.However,carnosine at the higher dose of 750 mg/kg did not have the same effects as the 200 and 500 mg/kg doses.These findings show that carnosine,at a particular dose range,protects against white matter damage caused by chronic cerebral ischemia in mice,likely by reducing oligodendroglial cell loss.     

Assessing white matter ischemic damage in dementia patients by measurement of myelin proteins

White matter ischemia is difficult to quantify histologically. Myelin-associated glycoprotein (MAG) is highly susceptible to ischemia, being expressed only adaxonally, far from the oligodendrocyte cell body. Myelin-basic protein (MBP) and proteolipid protein (PLP) are expressed throughout the myelin sheath. We compared MAG, MBP, and PLP levels in parietal white matter homogenates from 17 vascular dementia (VaD), 49 Alzheimer''s disease (AD), and 33 control brains, after assessing the post-mortem stability of these proteins. Small vessel disease (SVD) and cerebral amyloid angiopathy (CAA) severity had been assessed in paraffin sections. The concentration of MAG remained stable post-mortem, declined with increasing SVD, and was significantly lower in VaD than controls. The concentration of MBP fell progressively post-mortem, limiting its diagnostic utility in this context. Proteolipid protein was stable post-mortem and increased significantly with SVD severity. The MAG/PLP ratio declined significantly with SVD and CAA severity. The MAG and PLP levels and MAG/PLP did not differ significantly between AD and control brains. We validated the utility of MAG and MAG/PLP measurements on analysis of 74 frontal white matter samples from an Oxford cohort in which SVD had previously been scored. MAG concentration and the MAG/PLP ratio are useful post-mortem measures of ante-mortem white matter ischemia.     

MPP(+) increases the vulnerability to oxidative stress rather than directly mediating oxidative damage in human neuroblastoma cells

MPP(+), an active metabolite of MPTP, causes a dopaminergic neuronal degeneration similar to that observed in Parkinson's disease. Current data suggest that MPP(+)-induced cytotoxicity may be mediated by oxygen free radicals. To evaluate this hypothesis, we first investigated whether MPP(+) could cause oxidative stress by producing oxygen free radicals in the SH-SY5Y, human neuroblastoma cell line. MPP(+) was toxic to the cells dose-dependently but did not increase the level of lipid peroxidation at toxic concentrations. Second, we examined the effects of various antioxidants and an inhibitor of nitric oxide synthase (NOS) on the development of MPP(+) cytotoxicity. Pretreatment with antioxidants such as ascorbic acid, Trolox, phenyl-tertiary-butyl-nitrone (PBN), which show protective effects on tert-butyl hydroperoxide (tBOOH) toxicity did not attenuate MPP(+) cytotoxicity. Similarly, the combination of antioxidant enzymes, SOD and catalase (50 U/ml, respectively), did not protect the cells from the toxic action of MPP(+). Also N-nitro-l-arginine methyl ester (NAME), a competitive inhibitor of NOS, and combined incubation with NAME and antioxidant enzymes failed to attenuate MPP(+) cytotoxicity. On the other hand, a sublethal dose of MPP(+) potentiated iron and H(2)O(2)-induced cytotoxicity. These results suggest that oxygen free radicals may not be a primary cause of MPP(+)-induced cell death but that MPP(+) increases the vulnerability of cells to oxidative stress.