Perinatal white matter injury: the changing spectrum of pathology and emerging insights into pathogenetic mechanisms

Perinatal brain injury in survivors of premature birth has a unique and unexplained predilection for periventricular cerebral white matter. Periventricular white-matter injury (PWMI) is now the most common cause of brain injury in preterm infants and the leading cause of chronic neurological morbidity. The spectrum of chronic PWMI includes focal cystic necrotic lesions (periventricular leukomalacia; PVL) and diffuses myelination disturbances. Recent neuroimaging studies support that the incidence of PVL is declining, whereas focal or diffuse noncystic injury is emerging as the predominant lesion. Factors that predispose to PVL during prematurity include hypoxia, ischemia, and maternal-fetal infection. In a significant number of infants, PWMI appears to be initiated by perturbations in cerebral blood flow that reflect anatomic and physiological immaturity of the vasculature. Ischemic cerebral white matter is susceptible to pronounced free radical-mediated injury that particularly targets immature stages of the oligodendrocyte lineage. Emerging experimental data supports that pronounced ischemia in the periventricular white matter is necessary, but not sufficient to generate PWMI. The developmental predilection for PWMI to occur during prematurity appears to be related to both the timing of appearance and regional distribution of susceptible oligodendrocyte progenitors. Injury to oligodendrocyte progenitors may contribute to the pathogenesis of PWMI by disrupting the maturation of myelin-forming oligodendrocytes. Chemical mediators that may contribute to white-matter injury include reactive oxygen species glutamate, cytokines, and adenosine. As our understanding of the pathogenesis of PWMI improves, it is anticipated that new strategies for directly preventing brain injury in premature infants will develop.     

The Yin and Yang of cell cycle progression and differentiation in the oligodendroglial lineage

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white matter, contact the axon, and differentiate into myelin-forming oligodendrocytes. Multiple mechanisms underlie the eventual progressive deterioration that typifies the natural history of developmental demyelination in LD and PVL and of adult-onset demyelination in MS. Over the past few years, pathophysiological studies have mostly focused on seeking abnormalities that impede oligodendroglial maturation at the level of migration, myelination, and survival. In contrast, there has been a strikingly lower interest for early proliferative and differentiation events that are likely to be equally critical for white matter development and myelin repair. This review highlights the Yin and Yang principles of interactions between intrinsic factors that coordinately regulate progenitor cell division and the onset of differentiation, i.e. the initial steps of oligodendrocyte lineage progression that are obviously crucial in health and diseases.     

Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults

White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1-7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored.     

Childhood multiple sclerosis: a review

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS) that is increasingly recognized as a disease that affects children. Similar to adult-onset MS, children present with visual and sensory complaints, as well as weakness, spasticity, and ataxia. A lumbar puncture can be helpful in diagnosing MS when CSF immunoglobulins and oligoclonal bands are present. White matter demyelinating lesions on MRI are required for the diagnosis; however, children typically have fewer lesions than adults. Many criteria have been proposed to diagnose MS that have been applied to children, mostly above 10 years of age. The recent revisions to the McDonald criteria allow for earlier diagnosis, such as after a clinically isolated event. However, children are more likely than adults to have monosymptomatic illnesses. None of the approved disease-modifying therapies used in adult-onset MS have been approved for pediatrics; however, a few studies have verified their safety and tolerability in children. Although children and adults with MS have similar neurological symptoms, laboratory (cerebrospinal fluid) data, and neuroimaging findings, the clinical course, pathogenesis, and treatment of childhood onset MS require further investigation.     

Psychological aspects of multiple sclerosis and its treatment: toward a biopsychosocial perspective

Multiple sclerosis (MS) is a chronic, progressive neurological disease that produces demyelination of the CNS nerve fibers. With onset most often in young adulthood, the disease produces a variety of neurological symptoms and follows an unpredictable course characterized by exacerbations and remissions. This article reviews the literature on psychological aspects of MS including early psychoanalytic studies and more current psychosocial research. Literature on the relationship between stress and symptoms, and the extent of cognitive impairment experienced is reviewed. A view of psychosocial adjustment to MS based upon an adaptive coping model, and a psychological treatment approach suited to the special needs of individuals with MS are discussed. Finally, a biopsychosocial research model is recommended due to the complex, interactive nature of MS and unique research difficulties it presents.     

Growth of white matter in the adolescent brain: Myelin or axon?

White matter occupies almost half of the human brain. It contains axons connecting spatially segregated modules and, as such, it is essential for the smooth flow of information in functional networks. Structural maturation of white matter continues during adolescence, as reflected in age-related changes in its volume, as well as in its microstructure. Here I review recent observations obtained with magnetic resonance imaging in typically developing adolescents and point out some of the known variations in structural properties of white matter vis-à-vis brain function in health and disease. I conclude by re-focusing the interpretations of MR-based studies of white matter from myelin to axon.     

中枢肥大细胞在脑功能和行为调节中的作用

已知肥大细胞作为免疫细胞在过敏反应和炎性疾病中发挥重要作用。肥大细胞在中枢亦有表达, 但对其作用了解不足。新近的研究发现中枢肥大细胞在脑功能和行为调节中发挥重要的内源性平衡作用。一方面, 中枢肥大细胞在维持相关脑区发育, 正常神经活动, 以及动机, 情绪和认知等多种行为中发挥保护性作用, 各种应激条件诱导的中枢肥大细胞表达和活动改变参与脑和行为的适应性反应过程。另一方面, 中枢肥大细胞过度激活或者过度抑制都可导致脑功能和行为异常, 并参与某些免疫相关心身疾病的病理过程。体外神经解剖学和功能学研究证据提示中枢肥大细胞与神经系统间存在结构性和功能性相互作用网络。肥大细胞和神经组织间通过形成类似突触的结构性联系直接影响相邻细胞的活动。肥大细胞还可以通过脱颗粒释放多种生物活性介质调节神经活动, 同时表达多种受体接受脑内免疫性和神经性分子调节。但是目前对于中枢肥大细胞-神经系统相互作用的认识主要基于体外研究, 其在脑内相互作用方式及其与特定脑区功能和行为表型的关系所知甚少, 开展相关研究可以为认识脑与行为的神经免疫调节机制提供新的视角。     

孤独症生命早期脑过度生长现象及启示

孤独症神经结构研究中近来一个重要的发现是,孤独症生命早期存在脑过度生长的现象。进一步的探查表明,孤独症个体脑的过度生长主要由脑白质的过度生长造成,并且脑的过度生长又主要体现于那些较晚成熟的高级脑区。这一研究成果有助于孤独症儿童的早期发现和诊断,也提示孤独症并不是由单一的局部神经缺陷造成,其存在着广泛分布式的神经发展障碍     

Inflammation Causes a Long-Term Hyperexcitability in the Nociceptive Sensory Neurons of Aplysia

Nerve injury, tissue damage, and inflammation all cause hyperalgesia. A factor contributing to this increased sensitivity is a long-term (>24 hr) hyperexcitability (LTH) in the sensory neurons that mediate the responses. Using the cluster of nociceptive sensory neurons in Aplysia californica as a model, we are examining how inflammation induces LTH. A general inflammatory response was induced by inserting a gauze pad into the animal. Within 4 days, the gauze is enmeshed in an amorphous material that contains hemocytes, which comprise a cellular immune system. Concurrently, LTH appears in both ipsilateral and contralateral sensory neurons. The LTH is manifest as increased action potential discharge to a normalized stimulus. Immunocytochemistry revealed that hemocytes have antigens recognized by antibodies to TGFβ1, IL-6, and 5HT. When a localized inflammation was elicited on a nerve, hemocytes containing the TGFβ1 antigen were present near axons within the nerve and those containing the IL-6 were on the surface. Western blots of hemocytes, or of gauze that had induced a foreign body response, contained a 28-kD polypeptide recognized by the anti-TGFβ1 antibody. Exposure of the nervous system to recombinant human TGFβ1 elicited increased firing of the nociceptive neurons and a decrease in threshold. The TGFβ1 also caused an activation of protein kinase C (PKC) in axons but did not affect a kinase that is activated in axons after injury. Our findings, in conjunction with previous results, indicate that a TGFβ1-homolog can modulate the activity of neurons that respond to noxious stimuli. This system could also contribute to interactions between the immune and nervous systems via regulation of PKC.     

Transverse diffusivity of cerebral parenchyma predicts visual tracking performance in relapsing–remitting multiple sclerosis

This study investigated the relation between cerebral damage related to multiple sclerosis (MS) and cognitive decline as determined by two classical mental tracking tests. Cerebral damage in 15 relapsing–remitting MS patients was measured by diffusion tensor imaging (DTI). Fractional anisotropy, longitudinal and transverse diffusivity were defined in the cerebral parenchyma. Cognitive performance of the MS patients was assessed with the oral response format of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). A significant correlation was found between performance on the SDMT and the fractional anisotropy in the brain. This correlation was predominantly induced by transverse diffusivity. Transverse diffusivity refers to the diffusion across fibers rather than along the fibers and is believed to be a specific marker for axonal loss and demyelination associated with MS. No significant association between DTI-measures and PASAT performance was found and this negative finding was mainly attributed to psychometric qualities. These results indicate that diffusivity along the non-principal diffusion direction, a possible signature of MS-related white matter pathology, contributes to information processing speed as measured with the SDMT, a task that requires close visual tracking and a widely used clinical marker for cognitive decline in MS.     

MRA和无创FAIR灌注成像在早期脑缺血中的诊断价值

为了探讨3D—TOFMRA脑血管成像及流动敏感交互式反转恢复（FAIR）MR灌注成像在早期（发病2h-7d）脑缺血中的诊断价值,对27例早期脑缺血患者行3D—TOFMRA和FAIR检查。结果显示,MRA异常27例,表现为血管闭塞、狭窄、硬化;FAIR异常27例,表现为缺血区血流灌注的减低,患侧和对侧灰、白质信号强度的差异均有统计学意义（P〈0．005）,患者患侧与志愿者灰、白质信号强度的差异亦均有统计学意义（P〈0．005）。FAIR灌注技术无需注射造影剂,能够提供早期脑缺血患者血流动力学受损情况,FAIR与3D—TOF法MRA联合运用,对早期脑缺血的诊断、血流灌注评价会更全面、更准确。     

Perceived behavioral changes in early multiple sclerosis

Acquired behavioral changes have essentially been described in advanced multiple sclerosis (MS). The present study was designed to determine whether behavioral modifications specifically related to the MS pathological process could be identified in the initial phase of the disease, as compared to control patients with chronic, relapsing and progressive inflammatory disorders not involving the central nervous system (CNS). Eighty-eight early MS patients (Expanded Disability Status Scale score 相似文献   

Altered bodily self‐consciousness in multiple sclerosis

In this study, we assessed the impact of multiple sclerosis (MS) on bodily self‐consciousness (BSC) using the Rubber Hand Illusion. Patients with MS showed a dissociation between body ownership and self‐location: they did report an explicit ownership of the rubber hand, but they did not point towards it, showing a defective ability of localizing body parts in space. This evidence indicates that MS may affect selective components of BSC, whose impairment may contribute to, and even worsen, the functional disability of MS.     

Neurological and developmental effects of HIV and AIDS in children and adolescents

HIV-related encephalopathy is an important problem in vertically infected children with HIV. Infected infants may manifest early, catastrophic encephalopathy, with loss of brain growth, motor abnormalities, and cognitive dysfunction. Even without evidence of AIDS, infected infants score lower than serorevertors on developmental measures, particularly language acquisition. Children with perinatal or later transfusion-related infection generally are roughly comparable developmentally to their peers until late in their course. Symptoms similar to adult AIDS dementia complex are occasionally seen in adolescents with advanced AIDS, including dementia, bradykinesia, and spasticity. Opportunistic CNS infections such as toxoplasmosis and progressive multifocal leukoencephalopathy are less common in children and adolescents than in adults. Increasing evidence suggests that aggressive antiretroviral treatment may halt or even reverse encephalopathy. Neuroimaging changes may precede or follow clinical manifestations, and include early lenticulostriate vessel echogenicity on cranial ultrasound, calcifying microangiopathy on CT scan, and/or white matter lesions and central atrophy on MRI. Differential diagnosis of neurological dysfunction in an HIV-infected infant includes the effects of maternal substance abuse, other CNS congenital infections, and other causes of early static encephalopathy. Initial entry of HIV into the nervous system occurs very early in infection. The risk of clinical HIV encephalopathy increases with very early age of infection and with high viral loads. Virus is found in microglia and brain derived macrophages, not neurons. The neuronal effect of HIV is probably indirect, with various cytokines implicated. Apoptosis is the presumed mechanism of damage to neurons by HIV.     

Central Nervous System Complications of Sickle Cell Disease in Children: An Overview

Complications involving the central nervous system are among the most devastating manifestations of sickle cell disease. Although overt stroke occurs in 1 in 10 children with Hemoglobin SS, “silent cerebral infarcts” are even more frequent. Both are associated with significant neuropsychological deficits. The end result of these effects on the CNS often is diminished school performance. The use of transcranial Doppler ultrasonography screening allows the identification of patients at high risk for clinical stroke as well as stroke prevention by chronic transfusion. However, definitive prophylaxis and treatment for most CNS complications of sickle cell disease have yet to be determined.     

Central nervous system complications of sickle cell disease in children: an overview.

Complications involving the central nervous system are among the most devastating manifestations of sickle cell disease. Although overt stroke occurs in 1 in 10 children with Hemoglobin SS, "silent cerebral infarcts" are even more frequent. Both are associated with significant neuropsychological deficits. The end result of these effects on the CNS often is diminished school performance. The use of transcranial Doppler ultrasonography screening allows the identification of patients at high risk for clinical stroke as well as stroke prevention by chronic transfusion. However, definitive prophylaxis and treatment for most CNS complications of sickle cell disease have yet to be determined.     

Sickle cell disease as a neurodevelopmental disorder

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which typically manifest as deficits in specific cognitive domains and academic difficulties. We discuss SCD as a neurodevelopmental disorder by reviewing the mechanisms of neurological morbidity in SCD, the timing of these mechanisms, the types of cognitive and behavioral morbidity that is typical, and the interaction of social-environmental context with disease processes. The impact of the disease on families shares many features similar to other neurodevelopmental disorders; however, social-environmental factors related to low socioeconomic status, worry and concerns about social stigma, and recurrent, unpredictable medical complications can be sources of relatively higher stress in SCD. Greater public awareness of the neurocognitive effects of SCD and their impact on child outcomes is a critical step toward improved treatment, adaptation to illness, and quality of life.     

Vanishing white matter disease: a review with focus on its genetics

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive brain disorder, most often with a childhood onset. Magnetic resonance imaging and spectroscopy indicate that, with time, increasing amounts of cerebral white matter vanish and are replaced by fluid. Autopsy confirms white matter rarefaction and cystic degeneration. The process of localization and identification of the first two genes related to VWM, EIF2B5 and EIF2B2, was facilitated by two founder effects in the Dutch population. EIF2B5 and EIF2B2 encode the epsilon and beta subunits of translation initiation factor eIF2B. Soon it was shown that mutations in all five eIF2B subunit genes can cause VWM. EIF2B is essential for the initiation of translation of RNA into protein and is involved in regulation of the process, especially under stress conditions, which may explain the sensitivity to stress conditions observed in VWM patients. The pathophysiology of the disease is still poorly understood.