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PubMed1993

Age-related change in the proportion of amyloid precursor protein mRNAs in the gray matter of cerebral cortex.

Alternative splicing of a transcript of amyloid precursor protein (APP) gene generates at least three types of mRNA coding for APP770, APP751, and APP695; the former two harbor, while the latter one lacks a Kunitz-type serine protease inhibitor (KPI). We compared, by using the RNase protection technique, APP mRNAs expression between gray and white matters in the frontal lobe, with special reference to Alzheimer's disease (AD) and aging. The proportions (y) of APP770 plus APP751 mRNAs in the white matter were nearly twice as much as those in the gray matter, both in control (non-AD) and AD brains; the difference between the two matters was statistically significant. Furthermore, in the gray matter of control, there was a positive correlation (y = 1.07 x-57.1, r = 0.899) between the age (x) and the proportion (y), but not in the white matter where the proportion varied markedly among individuals. In AD brains, no significant correlation was found in either of the two matters. These results indicated that the APP mRNAs proportion in the gray matter may serve as a molecular index of the brain aging in non-AD persons.

Aged↗
PubMed1994

Commissural connections of the cat periaqueductal gray matter studied with anterograde and retrograde tract-tracing techniques.

The commissural connections of the periaqueductal gray matter were investigated by light and electron microscopy by using the anterograde tracer Phaseolus vulgaris leucoagglutinin and the retrograde tracer horseradish peroxidase. In the first group of seven animals (1-7), single injections of Phaseolus vulgaris leucoagglutinin were performed iontophoretically (4.5 microA for 30 min) into various subdivisions of the periaqueductal gray matter. On light microscopic examination, injection sites were characterized by several immunolabeled neurons of different sizes and morphology, with the cytoplasm, nucleus and neuronal processes intensely stained. Many labeled fibers turned from injection sites toward all contralateral periaqueductal gray matter subdivisions, but anterograde labeling was densest in the regions homotopic to those injected. Commissural fibers bore along their course many en passant boutons of different sizes and morphology, and gave off spine-like processes, at the end of which one terminal bouton was observed. Labeled fibers branched into numerous collaterals which ended in a terminal array of 10-20 en passant and en grappe boutons. At the electron microscopic level, commissural axons were observed in close proximity to the cytoplasmic membranes of cells. Axon terminals formed symmetric or asymmetric synapses mainly on dendritic shafts of neurons and rarely on vesicle-containing profiles. Horseradish peroxidase experiments were carried out in four cats (1-4). The tracer was injected iontophoretically into different regions of the periaqueductal gray matter of three cats (1-3). Retrogradely labeled neurons giving rise to commissural connections had a morphology similar to that of polygonal, triangular and fusiform cells described in previous Golgi studies. The perikaryal cross-sectional area of commissural neurons was smaller than that of neurons projecting outside the periaqueductal gray matter (mean value of commissural neurons 149.77 microns 2 vs 261.19 microns 2 for projecting neurons), which were retrogradely labeled by pressure-injecting horseradish peroxidase into several targets of periaqueductal gray matter (4). Moreover, since the distribution of sizes of the two populations of the periaqueductal gray matter overlapped in the range of 90-300 microns 2, a considerable number of projecting neurons were as small as commissural neurons. The present results suggest that commissural fibers could reciprocally connect zones of the periaqueductal gray matter with similar functions, and originate from small and medium-sized neurons, some of which are also projecting neurons.

Animals↗
PubMed1996

Ventriculomegaly, delayed myelination, white matter hypoplasia, and "periventricular" leukomalacia: how are they related?

Preterm infants, including some who have sustained intracranial hemorrhage, appear to be at increased risk of lateral ventricular enlargement. Although some occurrences might be due to an impairment of cerebrospinal fluid flow or absorption, many instances of ventriculomegaly without accompanying macrocephaly reflect diffuse white matter damage resulting in diminished (i.e., hypoplastic) white matter or an inadequate density of axons. Perinatally acquired widespread white matter damage is sometimes associated with the focal white matter necrosis. We hypothesize that in some infants both ventriculomegaly and delayed myelination are consequences of disturbances to myelinogenesis that result from an impairment of cells destined to become oligodendroglia or of disturbances to rapidly growing axons. The vulnerability of developing white matter in preterm newborns might, in part, reflect the diminished availability of growth/ survival factors, or a vulnerability to toxins or physiologic perturbations. Awareness that some ventriculomegaly reflects widely distributed white matter damage should prevent overtreatment of what might appear to be hydrocephalus, but is not due to impaired cerebrospinal fluid dynamics. Increased understanding of the phenomena leading to ventriculomegaly related to paucity of white matter should lead to successful efforts to prevent white matter damage in preterm newborns.

Axons↗
PubMed2004

Silent cerebral white matter lesions and cognitive function in middle-aged essential hypertensive patients.

BACKGROUND: An association between midlife blood pressure levels and late-life cognitive impairment has been reported. Hypertension is one of the most important factors related to the presence of cerebral white matter lesions, which is a prognostic factor for the development of cognitive impairment. Studies have shown a relationship between white matter lesions and cognitive decline in elderly hypertensive patients. The aim of the present study was to evaluate cognitive function in asymptomatic middle-aged hypertensive patients according to the presence or absence of white matter lesions. METHODS: Sixty never-treated essential hypertensive patients (38 men, 22 women), aged 50 to 60 years (mean age, 54.4 +/- 3.8 years), without clinical evidence of target organ damage, were studied. All patients underwent brain magnetic resonance imaging to establish the presence or absence of white matter lesions, using the Rotterdam criteria. Cognitive function was evaluated by a neuropsychologic test battery measuring attention, memory, intelligence, anxiety, and depression. RESULTS: Twenty-three hypertensive patients (38%) were found to have white matter lesions on brain resonance. These patients exhibited a significantly worse performance on digit span forward, a standardized measure of attention than hypertensives without white matter lesions (4.86 +/- 1.14 v 5.51 +/- 0.97; P =.027). Hypertensive patients with white matter lesions showed no differences on both visual and logical memory tests when compared with patients without lesions. CONCLUSIONS: We conclude that the presence of silent cerebral white matter lesions in middle-aged hypertensive patients is associated with a mild decline in basic attention.

Blood Pressure↗
PubMed2005

White matter disease in magnetic resonance imaging predicts cerebral complications after coronary artery bypass grafting.

BACKGROUND: The aim of the present study was to assess neurologic and neuropsychologic complications in 104 patients randomized to coronary artery bypass grafting or spinal cord stimulation. An additional objective of the study was to assess whether preoperative white matter disease might predict cerebral complications, as previous studies have shown that there is a relationship between white matter disease and neuropsychologic decline after coronary artery bypass grafting. METHODS: The patients were subjected to neurologic examination before and six months after intervention. The patients underwent a cerebral magnetic resonance imaging before intervention and the presence of white matter disease was related to development of cerebral complications. RESULTS: More patients in the bypass group than in the spinal cord stimulation group developed focal cerebral ischemia (p < 0.05) and astheno-emotional disorder (p < 0.001). More patients with white matter disease undergoing bypass were affected by focal cerebral ischemia (p < 0.01) and astheno-emotional disorder (p < 0.001) after the intervention compared to patients with white matter disease undergoing spinal cord stimulation. In patients with no white matter disease there were no differences between the bypass group and spinal cord stimulation group with regard to cerebral complications. CONCLUSIONS: Patients undergoing bypass had more neurologic and neuropsychologic complications than patients undergoing spinal cord stimulation. Furthermore, patients with white matter disease were affected by cerebral complications in a higher extent after bypass than after spinal cord stimulation. Thus, preoperative assessment of white matter disease before undergoing coronary artery bypass grafting might predict the patient's risk of developing cerebral injury.

Adult↗
PubMed2005

Diagnosis-related regional gray matter loss over two years in first episode schizophrenia and bipolar disorder.

BACKGROUND: We examined gray- and white-matter brain volumes in first episode psychosis (FEP) at initial presentation and at two-year follow-up. We predicted that FEP subjects would show longitudinal reductions in fronto-temporal gray- and white-matter volumes compared with controls. Furthermore, we expected groups to be differentiated by diagnosis-related reductions. METHODS: Twenty-five schizophrenia and 8 bipolar disorder FEP patients underwent a structural MRI scan at first presentation and 2 years later. Matched healthy subjects (n = 22) underwent a single identical scan. RESULTS: At initial presentation FEP subjects had significantly less gray- and white-matter than healthy subjects. Diagnostic dissociations were revealed both at first presentation and at follow-up. In schizophrenia patients, gray-matter deficits were observed in lateral and medial frontal regions and in bilateral posterior temporal lobe regions, with additional extensive losses over time in lateral fronto-temporal regions and left anterior cingulate gyrus. By contrast, gray matter deficit in bipolar patients was localized to bilateral inferior temporal gyri with additional loss over time observed only in the anterior cingulate cortex. CONCLUSIONS: The results are consistent with a dual process model of psychosis, in which the diagnosis-related gray matter loss is determined by neurodevelopmental gray-matter volumetric differences which predate symptom onset, and diagnosis-related neurodegenerative gray-matter loss over time.

Adolescent↗
PubMed2006

Relationship between N-acetyl-aspartate in gray and white matter of abstinent methamphetamine abusers and their history of drug abuse: a proton magnetic resonance spectroscopy study.

OBJECTIVE: Altered concentrations of the brain metabolites, including N-acetyl-aspartate (NAA) and myo-inositol (MI), may indicate neurotoxicity associated with drug abuse. In this study, the authors explored differences in brain metabolites between abstinent methamphetamine (MA) abusers and healthy comparison subjects and the associations between metabolite concentrations and clinical characteristics. METHOD: Proton magnetic resonance spectroscopy (MRS) was performed on 30 abstinent MA abusers and 20 healthy comparison subjects. Two sets of MA user subgroups were defined depending on abstinence duration (greater or less than 6 months) or the total cumulative MA dose (greater or less than 100 g lifetime). NAA and other metabolites were measured in the frontal gray and white matter and compared between MA abuser groups and healthy comparison subjects. RESULTS: MI concentrations were higher for the MA abusers relative to healthy comparison subjects. NAA concentration was lower in frontal white matter of MA abusers with a 'large' cumulative dose relative to those with a 'small' cumulative dose and to healthy comparison subjects. Additionally, in MA abusers NAA concentrations in frontal white matter correlated inversely with the cumulative MA dose. In contrast, there was no significant difference in frontal gray matter NAA concentration among the three groups. However, frontal gray matter NAA concentrations for MA abusers correlated negatively with the total cumulative MA dose and positively with the duration of abstinence. There were no differences between the different MA user groups for MI. CONCLUSIONS: The current findings suggest that MA-induced metabolic alterations of frontal gray and white matter are dose-dependent, for primarily male subjects. Additionally, these findings potentially suggest that the MA-related abnormalities may, in part, recover with abstinence in gray matter, but not in the white matter regions.

Adult↗
PubMed2006

Dissociation of grey and white matter reduction in spinocerebellar ataxia type 3 and 6: a voxel-based morphometry study.

The aim of this study was to examine the different patterns of cerebellar and/or brainstem atrophy in spinocerebellar ataxia (SCA) type 3 and 6. Eighteen patients (SCA3 n=9, SCA6 n=9) and 15 healthy volunteers were studied. Voxel-based morphometry (VBM) was applied to segmented grey matter (GM) and white matter (WM) of high-resolution T1-weighted brain volumes of each group. We found reduction of grey matter in the pons as well as in the vermis in SCA3 as compared to control subjects. In SCA6 significant grey matter loss was found in hemispheric lobules bilaterally as well as in the vermis. White matter analysis revealed significant changes in SCA3, especially in the pons, in the white matter surrounding the dentate nucleus (DN) and in the cerebellar peduncles, whereas no significant white matter reduction was found in SCA6 patients. Our results demonstrate different patterns of grey and white matter affection detected by magnetic resonance imaging (MRI) in SCA3 and SCA6 patients, confirming the pathological concept of cortical cerebellar atrophy in SCA6. In contrast, SCA3 represents a form of ponto-cerebellar atrophy with predominant affection of pontine nuclei and fibre tracts.

Aged↗
PubMed2006

Effects of cerebrovascular risk factors on gray matter volume in adults aged 60-64 years: a voxel-based morphometric study.

The effect of putative cerebrovascular risk factors on gray matter volume in a community-dwelling, non-demented 60- to 64-year-old cohort was investigated. Cranial T1-weighted MRI scans were obtained in 337 adults and voxel-based morphometric analyses were applied to detect regional gray matter volume differences related to hypertension, diabetes, smoking, and hyperlipidemia in men and women, respectively. Hypertension-related gray matter volume reduction was found in right superior, bilateral medial frontal, left superior temporal and left precentral gyri in men. No regional differences in gray matter related to hypertension were seen in women. Conversely, female but not male smokers had more gray matter volume in right fusiform gyrus and right temporal subgyral gray matter. No differences were observed in gray matter volume in association with diabetes or hyperlipidemia for men or women. Our results suggest that there are different patterns of regional effects in gray matter volume in relation to different cerebrovascular risk factors, and sex differences for the same risk factors.

Brain↗
PubMed2004

Search for EPR markers of the history and origin of the insoluble organic matter in extraterrestrial and terrestrial rocks.

The insoluble organic matter (IOM) of three carbonaceous meteorites (Orgueil, Murchison and Tagish Lake meteorites) and three samples of cherts (microcrystalline SiO2 rock) containing microfossils with age ranging between 45 million years and 3.5 billion years is studied by electron paramagnetic resonance (EPR). The age of the meteorites is that of the solar system (4.6 billion years). The purpose of this work was to determine the EPR parameters, which allow us to discriminate between biogenic and extra terrestrial origin for the organic matter. Such indicators should be relevant for the controversy regarding the biogenicity of the organic matter in the oldest cheroot (3.5 billion years) and in Martian meteorites containing microbe-like microstructures. The organic matter of meteorites contains a high concentration of diradicaloid moieties characterised by a diamagnetic ground state S = 0 and a thermally accessible triplet state S = 1. The three meteorites exhibit the same singlet-triplet gap (ST gap) DeltaE approximately 0.1 eV. To the best of our knowledge, such diradicaloids are unknown in insoluble organic matter of terrestrial origin. We have also shown that the EPR linewidth of insoluble organic matter in cherts and coals decrease logarithmically with the age of the organic matter. We conclude from this result that the organic matter in the oldest cherts (3.5 billion years) has the same age as their SiO2 matrix, and is not due to a latter contamination by bacteria, as was recently found in meteoritic samples.

Carbon↗
PubMed2005

Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia.

Alterations in the density or distribution of interstitial white matter neurons are taken as evidence in support of an early developmental component to schizophrenia. However, the existence and nature of interstitial white matter neuron changes in schizophrenia remain inconclusive. Recently, we reported that interstitial white matter neuron density is increased in the superficial white matter of the superior temporal gyrus in schizophrenia, but unchanged in deep white matter. This study extends our investigations to the dorsolateral prefrontal cortex and parahippocampal gyrus. Using the specific neuronal antibody NeuN, interstitial white matter neuron density was found to be increased in schizophrenia in the superficial white matter of the dorsolateral prefrontal cortex, with no significant changes elsewhere. As interstitial white matter neurons are presumed to be remnants of the embryonic cortical subplate, these findings provide additional evidence supportive of an early developmental abnormality in schizophrenia.

Adult↗
PubMed2004

Characterizing algogenic organic matter (AOM) and evaluating associated NF membrane fouling.

Occasional algal blooms, comprised of blue-green algae and/or green algae, cause significant challenges in drinking water treatment due to the release of algogenic organic matter (AOM) into water extracellularly and, upon cell lysis, intracellularly. AOM has been extracted from blue-green algae (cyanobacteria) by various means and analyzed by UV absorbance scanning, HPSEC-UV-fluorescence-DOC, UV absorbance ratio index (URI), FTIR, and fluorescence excitation emission matrix (EEM). AOM extracted in water as a solvent exhibited a high hydrophilic fraction (57.3%) with a low SUVA (1.0 L/m-mg). The molecular weight (MW) distribution showed a significant heterogeneity (high value of polydispersivity) and high protein content (as indicated by specific fluorescence). Significant amounts of proteinaceous components such as mycosporine-like amino acids (MAAs, UV-screening components) and phycobilins (light-harvesting pigment) were detected by UV/visible absorption. The presence of proteins was confirmed by FTIR (at 1661 and 1552 cm(-1)), EEM spectra (EX:278-282 nm and EM:304-353 nm), and high URI values (3.1-6.0). A bench-scale cross-flow unit, employing a flat-sheet membrane specimen, was used to examine nanofiltration (NF) membrane fouling and removal of natural organic matter (NOM) derived from different blends of Suwannee River humic acid (SRHA) and AOM: SRHA 10 mgC/L, AOM 3mg C/L + SRHA 7 mgC/L, AOM 7 mgC/L + SRHA 3 mgC/L, and AOM 10 mgC/L. The study focused mainly on the effects of two different sources of organic matter on NF (NF 200) membrane fouling under otherwise similar conditions. Flux decline and organic matter rejection as a function of delivered DOC (cumulative mass of feed DOC per unit area) showed significantly different results depending on the organic matter composition of samples even though the test conditions were the same (organic matter concentration, pH, temperature, inorganic salt composition and concentration, and recovery). A higher flux decline was observed with increasing proportions of AOM. Organic matter rejections also decreased with higher AOM contributions to the samples, indicating that lower molecular weight (MW) AOM components were not well rejected by the NF 200 membrane having a 360 Da MWCO. However, SRHA that exhibited a relatively high MW (1000-5000 Da range) and high SUVA (7.4 L/m-mg) was preferentially rejected through electrostatic repulsion/size exclusion by the NF 200 membrane, having a high negative charge, low MWCO, and relatively low hydrophobicity. Even though the DOC concentration of feed water is a decisive factor for membrane fouling along with membrane properties and operating conditions, the characteristics of organic matter are more influential in fouling potential. Protein-like and polysaccharide-like substances were found as major foulants by FTIR.

Environmental Monitoring↗
PubMed1997

Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits.

OBJECTIVE: Periventricular leukomalacia, a common brain white matter lesion in preterm neonates, is a major risk factor for cerebral palsy. Epidemiologic studies have demonstrated an association between infection and periventricular leukomalacia. The purpose of this study was to determine whether ascending intrauterine infection could cause brain white matter lesions in the fetal rabbit. STUDY DESIGN: Rabbits with timed pregnancies underwent hysteroscopy at 20 to 21 days of gestation (70%). Animals were allocated in a ratio of 2:1 for inoculation with either Escherichia coli (0.2 ml containing 10(3) to 10(4) colony-forming units) or sterile saline solution. Both groups were treated with ampicillin-sulbactam (Unasyn, 100 mg/kg per day; Pfizer, Seoul) every 8 hours until they were killed 5 to 6 days after hysteroscopy. Histologic examination of the placentas and fetal brains was conducted. RESULTS: Forty-five animals underwent hysteroscopy; 31 were inoculated with E. coli and 14 with sterile saline solution. At the time the animals were killed, the rate of intrauterine infection was higher and there were fewer live fetuses in the E. coli-inoculated animals than in the saline solution group. Histologic evidence of brain white matter damage was identified in 12 fetuses born to 10 E. coli-inoculated rabbits but none in the saline solution group (p < 0.05). All rabbits with brain white matter lesions had evidence of intrauterine infection. Evidence of white matter damage included increased karyorrhexis, rarefaction, and disorganization of white matter. Apoptosis was demonstrated in areas of white matter damage by immunohistochemical studies. CONCLUSION: Experimental ascending intrauterine infection can cause fetal brain white matter lesions.

Animals↗
PubMedDate not supplied

Increased microglial activation and protein nitration in white matter of the aging monkey.

Activated microglia are important pathological features of a variety of neurological diseases, including the normal aging process of the brain. Here, we quantified the level of microglial activation in the aging rhesus monkey using antibodies to HLA-DR and inducible nitric oxide synthase (iNOS). We observed that 3 out of 5 white matter areas but only 1 of 4 cortical gray matter regions examined showed significant increases in two measures of activated microglia with age, indicating that diffuse white matter microglial activation without significant gray matter involvement occurs with age. Substantial levels of iNOS and 3-nitrotyrosine, a marker for peroxynitrite, increased diffusely throughout subcortical white matter with age, suggesting a potential role of nitric oxide in age-related white matter injury. In addition, we found that the density of activated microglia in the subcortical white matter of the cingulate gyrus and the corpus callosum was significantly elevated with cognitive impairment in elderly monkeys. This study suggests that microglial activation increases in white matter with age and that these increases may reflect the role of activated microglia in the general pathogenesis of normal brain aging.

Aging↗
PubMed1999

Diffuse T1 reduction in gray matter of sickle cell disease patients: evidence of selective vulnerability to damage?

The objective of our study was to test the hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients normal by conventional MR imaging (cMRI). We examined 50 SCD patients to identify those patients who were normal by cMRI. Quantitative MR imaging (qMRI) was then used to map spin-lattice relaxation time (T1) in a single slice in brain tissue of all 50 patients and in 52 healthy age-similar controls. We also used a radiofrequency (RF) pulse to saturate blood spins flowing into the T1 map slice, to characterize the effect of blood flow on brain T1. Abnormalities were noted by cMRI in 42% (21/50) of patients, with lacunae in 32%, and encephalo malacia in 20%. Brain T1 in patients normal by cMRI was significantly lower than controls, in caudate, thalamus, and cortex (p < or =0.007), and regression showed that gray matter T1 abnormality was present in caudate and cortex by age 4 (p < or =0.002). In patients abnormal by cMRI, T1 reductions in gray matter were larger and more significant. White matter T1 was not significantly increased except in patients abnormal by cMRI. RF saturation in a slab below the T1 map produced no significant change in T1, compared to RF saturation in a slab above the T1 map, suggesting that inflow of untipped spins in blood does not cause an artifactual shortening of T1. Gray matter T1 abnormality was present in patients normal by cMRI, while white matter T1 abnormality was present only in patients also abnormal by cMRI. These findings suggest that gray matter is selectively vulnerable to damage in pediatric SCD patients and that white matter damage occurs later in the disease process. Our inability to find an effect from saturation of inflowing blood implies that rapid perfusion cannot account for T1 reduction in gray matter.

Anemia, Sickle Cell↗
PubMed1999

Mapping of grey matter changes in schizophrenia.

Studies of brain changes in schizophrenia have suggested that the disorder is associated with reductions in both global and regional grey matter. In this study, we used structural neuroimaging to differentiate between these two types of change and to examine regional grey matter throughout the whole brain. Grey matter from magnetic resonance images was segmented and transformed into stereotactic space, and patients with schizophrenia and controls were compared with respect to regional grey matter (after compensating for global grey matter differences). In two preliminary analyses to test our methodology, we demonstrated that: (1) in the transformed grey matter maps, voxel values at the location of the caudate nuclei were correlated with region-of-interest measurements of caudate area in native image space, and (2) the technique detected regional grey matter changes resulting from artificial lesions created in the native images. We then used a factorial design to examine data from two studies, comprising a total of 42 schizophrenics and 52 controls. Analysis of the main effect of schizophrenia on regional grey matter revealed significant reductions in (a) the right temporal pole, insula and amygdala, (b) the left temporal pole, insula and dorsolateral prefrontal cortex.

Adult↗
PubMed2002

Increased A beta peptides and reduced cholesterol and myelin proteins characterize white matter degeneration in Alzheimer's disease.

Relative to the gray matter, there is a paucity of information regarding white matter biochemical alterations and their contribution to Alzheimer's disease (AD). Biochemical analyses of AD white matter combining size-exclusion, normal phase, and gas chromatography, immunoassays, and Western blotting revealed increased quantities of Abeta40 and Abeta42 in AD white matter accompanied by significant decreases in the amounts of myelin basic protein, myelin proteolipid protein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase. In addition, the AD white matter cholesterol levels were significantly decreased while total fatty acid content was increased. In some instances, these white matter biochemical alterations were correlated with patient apolipoprotein E genotype, Braak stage, and gender. Our observations suggest that extensive white matter axonal demyelination underlies Alzheimer's pathology, resulting in loss of capacitance and serious disturbances in nerve conduction, severely damaging brain function. These white matter alterations undoubtedly contribute to AD pathogenesis and may represent the combined effects of neuronal degeneration, microgliosis, oligodendrocyte injury, microcirculatory disease, and interstitial fluid stasis. To accurately assess the success of future therapeutic interventions, it is necessary to have a complete appreciation of the full scope and extent of AD pathology.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed2003

White matter injury following systemic endotoxemia or asphyxia in the fetal sheep.

White matter injury is the most frequently observed brain lesion in preterm infants. The etiology remains unclear, however, both cerebral hypoperfusion and intrauterine infections have been suggested as risk factors. We compared the neuropathological outcome, including the effect on oligodendrocytes, astrocytes, and microglia, following either systemic asphyxia or endotoxemia in fetal sheep at midgestation. Fetal sheep were subjected to either 25 minutes of umbilical cord occlusion or systemic endotoxemia by administration of Escherichia coli lipopolysaccharide (LPS O111:B4, 100 ng/kg, IV). Periventricular white matter lesions were observed in 2 of 6 asphyxiated fetuses, whereas the remaining animals showed diffuse injury throughout the subcortical white matter and neuronal necrosis in subcortical regions, including the striatum and hippocampus. LPS-treatment resulted in focal inflammatory infiltrates and cystic lesions in periventricular white matter in 2 of 5 animals, but with no neuron specific injury. Both experimental paradigms resulted in microglia activation in the white matter, damaged astrocytes, and loss of oligodendrocytes. These results show that the white matter at midgestation is sensitive to injury following both systemic asphyxia and endotoxemia. Asphyxia induced lesions in both white and subcortical grey matter in association with microglia activation, and endotoxemia resulted in selective white matter damage and inflammation.

Animals↗