Delay In Myelination Research Articles

Relación entre los síntomas clínicos y los hallazgos en resonancia magnética en niños con leucomalacia periventricular

To assess whether there is a relationship between the various clinical symptoms and imaging findings on MR in children with periventricular leukomalacia (PVLM). We made a retrospective study of 41 consecutive paediatric patients, 19 boys and 22 girls, with an average age of 30.5+/-19 months (range 8 84 months) who had been diagnosed as having PVLM and studied using MR, recording imaging, clinical and epidemiological data. The MR images showed areas of gliosis in all the children (few foci in 68.3% and multiple foci in 31.7%), with cysts in 22%. The changes were seen mainly in the parietal and occipital regions, were bilateral and symmetrical in 80.5%, with ventricular dilatation in 75.6%, atrophy of the parenchyma in 48.8%, Wallerian degeneration in 7.3%, delay in myelination in 31.7%, lesions in the optic radiations in 9.8%, thalamus 12.2% and anomalous venous drainage in 2.4%. The overall degree of involvement on MR was severe in 43.9%, moderate in 31,7% and mild in 24.4%. There was a history of perinatal foetal distress in 56.8%, hyaline membrane disease in 40.5%, intracranial hemorrhage in 35.1%, psychomotor retardation in 58.5%, motor retardation in 29.3%, and squint in 22%. A significant relationship was found only between acute foetal distress and lateralization of the lesions (p= 0.038) and the presence of parenchymatous cysts (p= 0.024). The patients with a history of foetal distress had a greater tendency to symmetrical, bilateral involvement with cysts in the white matter of the brain. It was not possible to establish a model for classification of the overall involvement using MR and the data recorded. The imaging findings were not related overall to the patients symptoms.

Urologic Pathology, Abstract 211–219, Posters

The aim of this study was to define the risk ratios of the late-infancy magnetic resonance imaging pattern for long-term outcome in term infants with perinatal asphyxia. We evaluated 65 term infants with perinatal asphyxia and performed magnetic resonance imaging examinations between 4–12 months of age. Magnetic resonance imaging scans were classified as follows: (1) periventricular leukomalacia in 21 (32%) infants, (2) marked cortical atrophy in 17 (26%) infants, (3) multicystic encephalomalacia in 10 (15%) infants, (4) deep gray matter involvement in 8 (12%) infants, (5) focal cortical involvement in 6 (9%) infants, (6) myelination delay in 3 (5%) infants. The overall outcome was favorable in 19 (29%) of 65 infants. Infants with diffuse cortical involvement (multicystic encephalomalacia and marked cortical atrophy) are four times (odds ratio: 4.4 and 4.1 respectively) more likely to attain the unfavorable outcome than the infants with other patterns of magnetic resonance imaging. Infants with focal cortical involvement had relatively favorable outcome in 60% of the cases. In conclusion, it appears that the overall outcome of infants with perinatal asphyxia correlated well with the magnetic resonance imaging patterns obtained between 4 and 12 months of age.

Comparative Study of Brain Lesions Detected by Magnetic Resonance Imaging between Strabismus and Nonstrabismus in Infancy

Purpose: To elucidate the causative factors in infantile esotropia, we evaluated morphological abnormalities in brain structures of esotropia patients showing any abnormal neurological signs in comparison to those of normal controls. Methods: Sixty-five developmentally normal children participated in this study. Of these 65, 38 demonstrated infantile esotropia and 27 were normal controls. All underwent magnetic resonance imaging (MRI) of the brain between 2 and 30 months. Results: Abnormal brain findings were noted in 3 (7.9%) children in the strabismus group, whereas none of the children in the normal control group showed brain lesions. In these 3 cases, brain lesions involved periventricular leukomalacia, enlargement of the lateral ventricles with hypoplasia of the corpus callosum and myelination delay at the anterior horn adjacent to the lateral ventricles. Conclusions: Brain lesions that may disturb normal maturation of the visuomotor system and eventually lead to strabismus could be found in some patients without any episode that would cause birth injury.

Neurodevelopmental and neuroimaging correlates in nonsyndromal microcephalic children.

This descriptive study examined the relationship between head size, developmental functioning, and neuroimaging findings in children with absolute microcephaly. Subjects, aged 1 to 48 months, were assigned to one of two groups based on occipitofrontal head circumference (OFC). Group A included subjects with an OFC of 2 to 2.99 standard deviations below the mean, and Group B included subjects with an OFC of 3 or more standard deviations below the mean. Brain scan findings for 62% of the subjects were abnormal. Findings included cerebral atrophy, cortical dysplasia, myelination delay, and white matter hypoplasia. Mean scores for developmental measures in Groups A and B were less than 70. Mean developmental scores in the normal imaging group were 70 or greater, whereas developmental scores in the abnormal imaging group were 52 or less. Forty-three percent of the subjects in Group A and 80% of those in Group B had abnormal findings from imaging studies (p = .0394). Subjects with one or more brain abnormalities determined on the basis of magnetic resonance images or computed tomographic scans had significantly lower scores in all developmental areas (p < .05). The authors concluded that abnormal brain images seem to be a better reflection of developmental performance than the degree of microcephaly. J Dev Behav Pediatr 21:12-18, 2000. Index terms: microcephaly, neuroimaging, neurodevelopment.

Radiation-induced diffuse brain injury in the neonatal rat model--radiation-induced apoptosis of oligodendrocytes.

The mechanism of radiation-induced diffuse brain injury was investigated using a model of delayed myelination in the irradiated neonatal rat brain in which the number of oligodendrocytes decreases without associated necrosis of the cerebral white matter. Immunohistochemical analysis using antibody against the large myelin-associated glycoprotein, a specific marker of oligodendrocytes at an early stage of development, showed that the number of the oligodendrocytes associated with myelination decreased in the irradiated hemisphere 1 day after irradiation and remained low until 5 days after irradiation. In situ terminal deoxynucleotidyl transferase-mediated nick end-labeling assay revealed that apoptosis mainly occurred in the cerebral white matter of the irradiated hemisphere. Three hours after irradiation, apoptotic cells were found in the subcortical white matter and the periventricular white matter. Six hours after irradiation, apoptotic cells were found in the internal capsule, and the numbers of apoptotic cells in the periventricular white matter and subcortical white matter increased. One day after irradiation, the number of apoptotic cells in the periventricular white matter decreased. Three days after irradiation, apoptotic cells were not observed in the cerebral white matter. These results suggest that the oligodendrocytes associated with myelination may be damaged via radiation-induced apoptosis, and depletion of the oligodendrocytes may cause delay of myelination.

Bone marrow transplantation in aspartylglucosaminuria--histopathological and MRI study.

This study comprised two patients with aspartylglucosaminuria (AGU), who were followed up for 4 and 7 years. The patients underwent allogeneic bone marrow transplantation (BMT) at the ages of 2 and 2.6 years. Both patients had abnormal speech development and gross motor clumsiness. At the time of the BMT, they were mentally retarded. We report on follow-up data of these patients obtained by MRI, in addition to the histopathological, biochemical and clinical investigations. MR images of six non-transplanted patients and seven healthy children served as controls. In the non-transplanted patients, MRI revealed evident delay of myelination in contrast to the two transplanted patients showing fair or evident grey- vs. white matter differentiation on T2-weighted images. The aspartylglucosaminidase (AGA) activity in blood leukocytes reached a heterozygous level. Urinary excretion of aspartylglucosamine and glycoasparagines slowly decreased but remained about a third of the pre-BMT level 5 years after BMT. Storage lysosomes in electron microscopic investigations were not decreased 6 months after BMT, but after 1.5-2 years, rectal mucosa samples showed a decrease in the storage vacuoles of different cells. Three years after BMT, no cells with storage vacuoles were present. Allogeneic BMT slowly normalises the pathological, biochemical and MRI findings in patients with AGU.

Abnormalities of developing white matter in lysosomal storage diseases.

Inborn metabolic errors causing lysosomal storage have well-recognized effects on neuronal function and morphology. In some classically "neuronal" storage diseases, however, neuroradiologic observations of infants have suggested a delay in central nervous system myelination based on persistently "immature" signal intensities monitored over time. This review summarizes reported neuropathologic evaluations of central white matter in infantile and juvenile patients and in corresponding animal models with lysosomal storage disorders. The observed neuropathology is examined in light of published studies of the biochemistry and microscopic anatomy of normal myelinogenesis. Finally, arguments are advanced that at least part of the deficiency of white matter is attributable to direct effects of the metabolic state on oligodendrocyte maturation and function, in addition to secondary effects on neurons and their axons.

Measuringin VivoMyelination of Human White Matter Fiber Tracts with Magnetization Transfer MR

Precise characterization of white matter pathways is important for the understanding of structural–functional relationships in the human brain. While it is known from postmortem studies that the connectivity of cortical areas is conveyed by projection, commissural, and association fibers, most clinical studies disregard useful information about specific fiber tracts. Magnetization transfer (MT) MR detects the relative proportion of free mobile protons and immobile protons bound to macromolecules. MT values correlate with histopathology and it has been proposed that in the white matter, the amount of magnetization transfer correlates with the degree of myelination. Thus, MT-MR provides measures that may reflect more accurately the physiology and natural course of diseases involving the white matter. We applied this quantitativein vivomethod to five children at different ages to determine whether the maturational changes of distinct fiber tracts could be measured. All regions of interest were localized by means of Brodmann's original descriptions and the additional use of reconstructed 3D-matched data from 10 myelin-stained human brain specimens. With this atlas-guided approach we localized and measured 26 supratentorial white matter fiber tracts in each hemisphere, connecting to primary as well as association cortices. All fiber tracts showed consistent age-related MT changes and the strongest effects were found in those tracts projecting to the primary cortical areas. These results suggest that our method is suitable forin vivoMT measurements in specific fiber tracts. It can provide data that relate to myelination during ontogenesis or myelination delays in myelin disorders. In the clinical domain, the focus on specific fiber tracts appears to be advantageous over standard approaches, because such system of parcellation is based on the functional anatomy of the white matter. Consequently, it may be especially useful for topical analysis in neurology allowing the assessment of the functional consequences of white matter damage as well as the effectiveness of treatments in patients with any lesion that can be visualized by MRI.

The neurobiology of Schwann cells.

This selective review of Schwann cell biology focuses on questions relating to the origins, development and differentiation of Schwann cells and the signals that control these processes. The importance of neuregulins and their receptors in controlling Schwann cell precursor survival and generation of Schwann cells, and the role of these molecules in Schwann cell biology is addressed. The reciprocal signalling between peripheral glial cells and neurons in development and adult life revealed in recent years is highlighted, and the profound change in survival regulation from neuron-dependent Schwann cell precursors to adult Schwann cells that depend on autocrine survival signals is discussed. Besides providing neuronal and autocrine signals, Schwann cells signal to mesenchymal cells and influence the development of the connective tissue sheaths of peripheral nerves. The importance of Desert Hedgehog in this process is described. The control of gene expression during Schwann cell development and differentiation by transcription factors is reviewed. Knockout of Oct-6 and Krox-20 leads to delay or absence of myelination, and these results are related to morphological or physiological observations on knockout or mutation of myelin-related genes. Finally, the relationship between selected extracellular matrix components, integrins and the cytoskeleton is explored and related to disease.

Monitoring the CNS pathology in aspartylglucosaminuria mice.

Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal storage disorder caused by the deficiency of the aspartylglucosaminidase (AGA) enzyme. The hallmark of AGU is slowly progressing mental retardation but the progression of brain pathology has remained uncharacterized in humans. Here we describe the long-term follow-up of mice carrying a targeted AGU-mutation in both alleles. Immunohistochemistry, histology, electron microscopy, quantitative magnetic resonance imaging (MRI) and behavioral studies were carried out to evaluate the CNS affection of the disease during development. The lysosomal storage vacuoles of the AGA -/- mice were most evident in central brain regions where MRI also revealed signs of brain atrophy similar to that seen in the older human patients. By immunohistochemistry and MRI examinations, a subtle delay of myelination was observed in AGA -/- mice. The life span of the AGA -/- mice was not shortened. Similar to the slow clinical course observed in human patients, the AGA -/- mice have behavioral symptoms that emerge at older age. Thus, the AGU knock-out mice represent an accurate model for AGU, both histopathologically and phenotypically.

Dietary Docosahexanoic Acid (DHA) Effects upon the Rat Pup Auditory System• 1526

Rats fed diets high in n3 fatty acids have lower whole brain levels of myelin basic protein, lower activities of 2′-3′cyclic nucleotide 3′-phosphodiesterase(an indicator of myelination) (DiBiase & Salvati, 1997), and longer auditory brainstem conduction times (ABCTs) (Saste et al., in press). We investigated the effects of varying levels of the n3 fatty acid DHA upon development of the rat pup auditory system.Methods: Dams were fed, from day 2 of gestation and throughout lactation, a purified diet whose fat source (22% of cals) was a vegetable oil blend supplemented with an algae oil containing 0% or 3% DHA. On postnatal day(pnd) 3, pups were culled to 10 per dam and were randomly cross fostered among dams of the same diet group to minimize litter effects (n=6 dams per diet group, 60 pups per diet group). Milk from culled pup stomachs was used for fatty acid analysis. On pnd 15, auditory electromyelographic reflexes (AEMR) to 130 db peak sound pressure level clicks were recorded from needle electrodes placed in the muscle of the thigh of 20 pups per diet group; pups were then sacrificed and brainstems removed for fatty acid analysis. For the remaining 40 pups per diet group, ABCTs were measured on pnd 24 and 31, and the postnatal day of appearance of the auditory startle reflex was determined. An additional group of dams fed 1% DHA diet had pups whose weight gains were 2/3 that of dams fed the 0% or 3% DHA diets; data from these pups are not presented. Results: Length of gestation, maternal weight gains and pup weights on pnd 3 did not differ between diet groups. Weight gains to pnd 12 were slightly lower among pups of dams fed the 3% DHA diet. The fatty acid composition of dam milk and pup brainstems reflected maternal diet. AEMRs were not different, however, ABCTs on pnd 24 were longer and the time of appearance of the auditory startle reflex was later in pups of dams fed 3% DHA.Conclusion: High levels of dietary DHA during development may be associated with delays in myelination of the central nervous system as suggested by longer ABCTs and a delay in appearance of the auditory startle reflex. Similar AEMRs between diet groups suggest minimal effects upon the peripheral nervous system. Table

Myelination delay in the cerebral white matter of immature rats with kaolin-induced hydrocephalus is reversible.

We hypothesized that hydrocephalus in young animals could cause a delay in myelination. Hydrocephalus was induced in 3-week-old rats by injecting kaolin into the cisterna magna. Ventricular size was assessed by magnetic resonance imaging. After 1 to 4 weeks, rats were either sacrificed, or treated by diversionary shunting of cerebrospinal fluid and then sacrificed 3 to 4 weeks later. Samples of corpus callosum/supraventricular white matter, fimbria, medulla, and spinal cord were assayed for myelin-related enzyme activities including p-nitrophenylphosphorylcholine phosphocholine phosphodiesterase (PNPCP), glycerophosphocholine phosphocholine phosphodiesterase (GPCP), and 2',3'-cyclic neucleotide 3'-phosphodiesterase (CNPase), and the oligodendrocyte enzyme UDP-galactose, ceramide galactosyltransferase (CGa1T). Myelin basic protein (MBP) and proteolipid protein (PLP) were assayed in cerebrum by immunoblots and Northern blot. The corpus callosum was processed for electron microscopy and myelin thickness to axon diameter ratios were quantified. One week after induction of hydrocephalus, CGa1T and GPCP activity were reduced in the corpus callosum there was less MBP and PLP in the cerebrum, and myelin sheaths around axons greater than 0.4 micron in diameter were abnormally thin. With persistent hydrocephalus, the corpus callosum became thinned, axons were lost, and myelin-related enzyme activities and proteins were decreased. Treatment of hydrocephalus at 1 week largely prevented the damage while shunting at 4 weeks failed to restore the injured white matter. Early reduction in CGa1T activity in the medulla and spinal cord suggest that oligodendrocyte production of myelin was reduced, even before irreversible damage occurred in the corticospinal tracts. We conclude that hydrocephalus in the immature rat brain delays myelination, but compensatory myelination is possible if treatment is instituted prior to the development of axonal injury. Possible mechanisms of oligodendrocyte impairment are discussed.

The effect of intracranial pressure on myelination and the relationship with neurodevelopment in infantile hydrocephalus.

The effect of raised intracranial pressure (ICP), due to infantile hydrocephalus, on the process of myelination has been suggested in the literature. In this study 19 hydrocephalic infants were followed-up with anterior fontanelle pressure (AFP) measurement (assessment of ICP), MRI (assessment of the myelination process and the CSF volume), and neurodevelopmental testing (NDT). There was a high correlation (r = 0.80) between the myelination and NDT scores. The size of the CSF volume showed a poor correlation with the mean AFP, the degree of myelination and the NDT scores. There was, however, a significant correlation between the mean AFP and the degree of myelination (r = 0.67) and also between the mean AFP and the NDT scores (r = 0.70). Longer-term follow-up (mean = 27 months) showed a significant correlation between the early progress of myelination and later developmental level (r = 0.78). Most of the children with a severely delayed myelination, preoperatively, showed a recovery of myelination following CSF drainage. It was concluded that: (1) raised ICP is related to developmental outcome, through the process of myelination; (2) the delay in myelination can be (partially) reversible; and (3) CSF volume is of minor importance regarding neurodevelopment.

An MRI study of the myelination pattern in West syndrome

Using magnetic resonance imaging (MRI), we studied the myelination of the brains of 8 patients with West syndrome. All cases were symptomatic, 2 having severe asphyxia, 1 lissencephaly, 1 Leigh encephalopathy, 2 tuberous sclerosis, 1 multiple anomalies and 1 microcephaly. Myelination of the pons, cerebellum, thalamus, internal capsules, optic radiation, centrum semiovale and cerebral white matter was separately assessed. The 2 cases with tuberous sclerosis exhibited normal myelination patterns, although asymmetry of the cerebral white matter was noted. These cases had a moderate degree of mental retardation and persistent seizures. The other 6 cases exhibited a marked delay of myelination throughout the central nervous system except for the midbrain. These cases had severe psychomotor retardation and persistent seizures. Although the difference in the outcome may simply reflect the different etiological disorders, these results suggest that the myelination pattern is related to the psychomotor retardation but not to the severity of the seizures in West syndrome. Atrophy of the corpus callosum developed during ACTH therapy and disappeared after the therapy. It was thus suggested that the callosal atrophy caused by the ACTH therapy was reversible.

Myelination and axonal regeneration in the central nervous system of mice deficient in the myelin-associated glycoprotein.

The myelin-associated glycoprotein, a member of the immunoglobulin superfamily, has been implicated in the formation and maintenance of myelin sheaths. In addition, recent studies have demonstrated that myelin-associated glycoprotein is inhibitory for neurite elongation in vitro and it has therefore been suggested that myelin-associated glycoprotein prevents axonal regeneration in lesioned nervous tissue. The generation of mice deficient in the expression of myelin-associated glycoprotein by targeted disruption of the mag gene via homologous recombination in embryonic stem cells has allowed the study of the functional role of this molecule in vivo. This review summarizes experiments aimed at answering the following questions: (i) is myelin-associated glycoprotein involved in the formation and maintenance of myelin in the CNS? and (ii) does myelin-associated glycoprotein restrict axonal regeneration in the adult mammalian CNS? Analysis of optic nerves from mutant mice revealed a delay in myelination when compared to optic nerves of wild-type animals, a lack of a periaxonal cytoplasmic collar from most myelin sheaths, and the presence of some doubly and multiply myelinated axons. Axonal regeneration in the CNS of adult myelin-associated glycoprotein deficient mice was not improved when compared to wild-type animals. These observations indicate that myelin-associated glycoprotein is functionally involved in the recognition of axons by oligodendrocytes and in the morphological maturation of myelin sheaths. However, results do not support a role of myelin-associated glycoprotein as a potent inhibitor of axonal regeneration in the adult mammalian CNS.

Early MR detection of cortical and subcortical hypoxic-ischemic encephalopathy in full-term-infants.

Four observations illustrate the potential of MR imaging in the early depiction of multiple types of neuropathologic lesions which may coexist in the full-term newborn, upon severe hypoxic-ischemic encephalopathy (HIE). In particular, diffuse, postnatal involvement of cerebral cortex and subcortical white matter (WM) is demonstrated. Cortical hyperintensity on both proton-density- and T1-weighted images is probably related to cellular necrosis which is distributed diffusely or parasagittally. Hyperintense, frontal, subcortical WM edging on proton-density-weighted images results from the increase of water concentration, induced either by infarct or by edema. Diffuse WM areas of low intensity on T1-weighted images and of high intensity on T2-weighted images are presumably related to cytotoxic and/or vasogenic edema, proportional to the underlying damaged tissues. On follow-up MR examinations, several months later, the importance of cortical atrophy and of the myelination delay appeared related to the importance of the lesions detected during the postnatal period.

Normal High-Resolution Cerebral 99mTc-HMPAO SPECT Scans in Symptomatic Neonates Exposed to Cocaine

Vascular constriction is said to account for a variety of clinical effects of cocaine. High-resolution 99mTc-hexamethylpropylene amine oxime single photon emission computed tomographic (SPECT) scans, which measure cerebral blood flow, were used to determine whether neonatal brain perfusion deficits are present in newborns with confirmed cocaine exposure. Normal, age-appropriate SPECT scans were found in 21 babies. Conventional neuroimaging was also performed when possible. All but one of the 14 magnetic resonance imaging (MRI) scans and one computed tomographic scan were normal. One MRI showed a mild delay in myelination. All but four neonates had behavioral or electroencephalographic abnormalities, and microcephaly was found in five of 21. The normal neonatal SPECT scans contrast with findings in adult cocaine users, which typically report abnormal findings of cerebral hypoperfusion. This study identifies a unique lack of corresponding cerebral vascular pathology in symptomatic neonates. It raises the possibility that many of these children can escape significant ischemic injury.

Delayed Myelination in Children with West Syndrome: An MRI-Study

Eighteen children with West syndrome underwent MRI-examination of the brain. Five children were examined twice. Myelination of ten regions of the brain was retrospectively assessed on the MRI-examinations. The children could be divided in three groups of main diagnosis (cryptogenic West syndrome, tuberous sclerosis, pre-/perinatally acquired brain lesions). Delays in myelination were found in 17 out of a total of 23 examinations. In children with cryptogenic West syndrome and with tuberous sclerosis myelination was normal or only mildly delayed in the first month after onset of the spasms, but delays seemed to increase in the course of the West syndrome in these groups. In children with pre- or perinatally acquired brain lesions severe delays of myelination could be found already in the first weeks after the onset of the West syndrome. The assessment of myelination can therefore contribute to the diagnosis and understanding of the underlying disease in children with West syndrome.

MRI assessment of myelination: an age standardization.

777 cerebral MRI examinations of children aged 3 days to 14 years were staged for myelination to establish an age standardization. Staging was performed using a system proposed in a previous paper, separately ranking 10 different regions of the brain. Interpretation of the results led to the identification of four clinical diagnoses that are frequently associated with delays in myelination: West syndrome, cerebral palsy, developmental retardation, and congenital anomalies. In addition, it was found that assessment of myelination in children with head injuries was not practical as alterations in MRI signal can simulate earlier stages of myelination. Age limits were therefore calculated from the case material after excluding all children with these conditions. When simplifications of the definition of the stages are applied, these age limits for the various stages of myelination of each of the 10 regions of the brain make the staging system applicable for routine assessment of myelination.

MRI in motor delay: Important adjunct to classification of cerebral palsy

Cranial magnetic resonance imaging (MRI) was performed prospectively in 45 children (ages 3–27 months) with clinically documented motor delay to evaluate the ability of MRI to determine etiologic factors, to determine whether myelination correlated with motor delay, and whether the clinical category corresponded with the imaging findings. Of the 22 children diagnosed clinically as having major motor delay (i.e., cerebral palsy), 77% had magnetic resonance imaging abnormalities. In 23%, etiologic associations were established from MRI alone and in 32% a clinically suspected etiology was supported. No children had myelination delay as the sole abnormality. In 23 children with minor motor delay, only 17% had abnormal scans. Clearly, MRI provided useful information in the majority of children with cerebral palsy; therefore, a classification system is proposed in which MRI can be used in conjunction with clinical assessment to specify more precisely the etiologic factors in cerebral palsy.