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White-matter dendrites in the upper cervical spinal cord of the adult cat: a light and electron microscopic study.

The organization and structure of dendrites penetrating into the white matter of upper cervical spinal segments have been examined by means of Golgi staining techniques, intracellular horseradish peroxidase (HRP) injections, and ultrastructural studies. The Golgi studies established that several groups of neurons located in intermediate and ventral laminae of the upper cervical spinal cord have a substantial part of their dendritic tree extending into adjacent ventral and lateral funiculi. Most dendrites in white matter showed irregular varicosities along their length. They were devoid of spines and followed relatively direct paths. In contrast, grey matter dendrites were occasionally observed with spines and complex appendages frequently followed tortuous paths. The size and location of some Golgi stained neurons suggested that white matter dendrites might originate from neck muscle motoneurons. This possibility was confirmed using intracellular HRP injections. These studies also showed that the distribution of white matter dendrites of neck muscle motoneurons depended on the location of the motoneuron soma. White matter dendrites of neck muscle motoneurons located deep in the ventral horn projected into all regions of white matter surrounding the ventral horn. Other neck muscle motoneurons, located in the spinal accessory nucleus, had white matter dendrites largely confined to the lateral funiculus. White matter dendrites of motoneurons in the commissural nucleus were found to project across the ventral commissure into the contralateral spinal cord. Light microscopic studies of semi-thin sections stained with toluidine blue and electron microscopic studies of thin sections revealed that white matter dendrites were confined to special regions of the white matter. These regions resembled the grey matter neuropil and contained dendrites and unmyelinated and small diameter myelinated axons. Axon terminals were also found in white matter. These terminals contained either flattened or spherical vesicles and formed synaptic contacts on white matter dendrites. White matter dendrites, by virtue of their frequency of occurrence, distribution, and type of synaptic contacts may represent a means by which descending or ascending spinal systems can influence spinal neurons without recourse to axon collaterals which terminate in grey matter.

Animals↗

Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer's disease.

Cerebral white matter lesions in Alzheimer's disease (AD) consist of subcortical degeneration and ischaemic-hypoxic changes. Glial changes are intimately associated with the white matter lesions, and regressive changes in astrocytes and loss of oligodendroglial cells have been reported. We quantitatively compared glial changes including apoptosis and enhanced lysosomal activity in the frontal and temporal white matter by using terminal dUTP nick end labelling (TUNEL) and immunohistochemistry for glial markers, lysosomes and apoptosis-regulating proteins in non-familial AD brains. The degree of myelin pallor and axonal loss varied considerably in both the frontal and temporal white matter but fibrillary gliosis in demyelinated lesions tended to be less prominent in the temporal white matter in AD cases. A morphometric study with planimetric methods for cross-sectional areas of frontal and temporal white matter revealed that the white matter of AD cases manifested atrophy with significant reduction in frontal (11.9%) and temporal (29.4%) white matter compared to normal controls. Double immunolabelling for glial fibrillary acidic protein (GFAP) and KP1 (CD68) revealed KP1-positive fragmented structures within the weakly GFAP-labelled astrocytes. These KP1-positive structures correspond to process fragmentation and cytoplasmic vacuoles, which in turn indicate enhanced lysosomal activity during regressive changes in astrocytes. The KP1-modified astrocytes were not found in Pick's disease and corticobasal degeneration. The density of apoptotic glial cells, largely oligodendroglial, was significantly higher in the temporal than in the frontal white matter, and most GFAP-positive astrocytes with regressive changes were apoptotic. GFAP-positive astrocyte density was statistically the same in the frontal and temporal white matter, but the density of KP1-modified astrocytes was higher in the temporal than in the frontal white matter. The rate of white matter shrinkage was significantly correlated with the density of apoptotic glial cells and the density of KP1-modified astrocytes in the temporal lobe in AD cases. An increase in apoptotic glial cell density was found to contribute to GFAP-positive astrocytes with regressive changes in temporal white matter, while apoptosis of vascular smooth muscle cells did not show topographical accentuation. Astrocytes labelled with beta amyloid protein were not apoptotic, and the density of apoptotic cells labelled with CD95 and caspase-3 was too low in both types of white matter to be statistically evaluated. Our results imply that regressive changes in astrocytes and glial apoptosis are, to some extent, associated with white matter lesions, particularly of the temporal lobe in AD brains. The presence of apoptotic astrocytes with evidence of regressive change could therefore be a histological hallmark for white matter degeneration in AD.

Aged↗

Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study.

OBJECTIVE: White matter lesions are often seen on MR scans of elderly non-demented and demented people. They are attributed to degenerative changes of small vessels and are implicated in the pathogenesis of cognitive decline and dementia. There is evidence that especially periventricular white matter lesions are related to cognitive decline, whereas subcortical white matter lesions may be related to late onset depression. The frequency distribution of subcortical and periventricular white matter lesions according to age and sex reported. METHODS: A total of 1077 subjects aged between 60-90 years were randomly sampled from the general population. All subjects underwent 1.5T MR scanning; white matter lesions were rated separately for the subcortical region and the periventricular region. RESULTS: Of all subjects 8% were completely free of subcortical white matter lesions, 20% had no periventricular white matter lesions, and 5% had no white matter lesions in either of these locations. The proportion with white matter lesions increased with age, similarly for men and women. Women tended to have more subcortical white matter lesions than men (total volume 1.45 ml v 1. 29 ml; p=0.33), mainly caused by marked differences in the frontal white matter lesion volume (0.89 ml v 0.70 ml; p=0.08). Periventricular white matter lesions were also more frequent among women than men (mean grade 2.5 v 2.3; p=0.07). Also severe degrees of subcortical white matter lesions were more common in women than in men (OR 1.1; 95% confidence interval (95% CI) 0.8-1.5) and periventricular white matter lesions (OR 1.2; 95% CI 0.9-1.7), albeit that none of these findings were statistically significant. CONCLUSIONS: The prevalence and the degree of cerebral white matter lesions increased with age. Women tended to have a higher degree of white matter lesions than men. This may underlie the finding of a higher incidence of dementia in women than in men, particularly at later age.

Aged↗

Reduced cerebral blood flow in white matter in ischaemic leukoaraiosis demonstrated using quantitative exogenous contrast based perfusion MRI.

OBJECTIVE: White matter hypoperfusion may play a part in the pathogenesis of ischaemic leukoaraiosis, but demonstration of this requires a high resolution quantitative method of cerebral blood flow (CBF) measurement. Initial exogenous contrast based MRI methods only allowed measurement of relative cerebral blood volume (CBV) values, but more recently a mathematical approach has been developed which enables absolute regional CBF and CBV to be determined. This technique was applied to patients with ischaemic leukoaraiosis to determine whether reduced white matter CBF in this patient group could be demonstrated. METHODS: Eight patients with ischaemic leukoaraiosis (radiological leukoaraiosis and clinical lacunar stroke), and nine age matched controls were studied. A spin echo echoplanar image sequence was used on a 1.5 Tesla MR system. An arterial input function was obtained from voxels placed over the middle cerebral arteries. Cerebral blood flow, CBV, and mean transit (MTT) maps were derived. Regions of interest were placed at standard positions in the white and grey matter and mean values of CBF, CBV, and MTT were compared between the two groups. RESULTS: Mean (SD) white matter CBF was significantly reduced in patients by 38% (13.40 (4.87) v 21.74 (3.53) ml/min/ 100 g, p=0.002). Significant reductions in CBF were seen in all white matter regions. By contrast there was no reduction in CBF in any grey matter region. There was no significant difference in white matter CBV between cases and controls; mean values were lower in all white matter regions for patients but this did not reach significance for any region. By contrast mean grey matter CBV was significantly higher in patients than in controls. Mean MTT values were higher in all regions of grey and white matter in the patient group, but this only achieved significance for the superior white matter. CONCLUSION: A quantitative MR perfusion method showed reduced white matter CBF in patients with ischaemic leukoaraiosis, but normal grey matter CBF. This is consistent with hypoperfusion playing a part in the pathogenesis of ischaemic leukoaraiosis. The absolute values of white matter and grey matter CBF obtained in the patient groups were very similar to those in previous PET studies, providing further evidence for the validity of the regional CBF measurements obtained using this quantitative MR perfusion technique. The high spatial resolution and lack of radioactive administration makes such techniques ideal for longitudinal studies in this condition.

Aged↗

Clinical correlates of white-matter abnormalities on head magnetic resonance imaging.

We undertook this study to investigate the relationship between white-matter abnormalities (seen on brain magnetic resonance imaging [MRI]) and muscle tone and muscle stretch reflexes on clinical examination. We identified all patients less than 5 years of age who had undergone cranial MRI studies at Riley Hospital for Children between June 30, 1999, and July 1, 2000, whose scans were read as showing white-matter abnormalities. We measured two ratios and the thickness of the corpus callosum as indicators of the quantity of cerebral white matter. The ratios were R1, the ratio of the thickness of the white matter at the level just above the body of the lateral ventricle compared with the width of the hemisphere, and R2, the ratio of the thickness of the white matter to the width of the hemisphere at the level of the trigone of the lateral ventricle. The thickness of the corpus callosum was measured at the junction of the anterior two thirds and the posterior third. We also evaluated the signal intensity of the cerebral white matter by reviewing the fluid-attenuated inversion-recovery images and grading the signal as normal to severely abnormal depending on the degree and extent of high signal intensity seen (0 = normal to 4+). Thirty-eight children less than 5 years of age who underwent MRI scans between June and August 2000 and who were found to have normal tone prospectively and normal MRI scan on review served as a control group. We identified 215 patients who had white-matter abnormalities; of these, only 142 (66%) had documented tone assessments in their medical record. Our study group was divided into three groups: increased (n = 35), decreased (n = 53), and normal tone (n = 54). All three measurements of white matter in each of the three study groups were significantly below values for control children. The children with white-matter abnormalities and decreased tone had significantly less signal intensity abnormality than the other study groups. Children with white-matter abnormalities and increased tone had a greater frequency of increased reflexes and tended to have more signal abnormalities than the other groups. The group of children with white-matter abnormalities and normal tone had the least amount of cerebral white-matter deficiency of the three study groups. In patients with strikingly decreased quantities of cerebral white matter, those with normal signal-intensity white matter are likely to be hypotonic with normal reflexes and those with increased signal intensity in the white matter are likely to be spastic.

Brain↗

Relative phosphocreatine and nucleoside triphosphate concentrations in cerebral gray and white matter measured in vivo by 31P nuclear magnetic resonance.

Rates of ATP metabolism generally are higher in cerebral gray matter compared to white matter. In order to study the physiology of this regional difference in vivo, the 1-dimensional chemical shift imaging technique (1D-CSI) was used to acquire 31P nuclear magnetic resonance spectra from 2.5 mm slices of 4-week old piglet brains. Spectra from predominantly gray matter slices (estimated 76% gray matter, 7 mm below the scalp) were compared to predominantly white matter slices (56% estimated white matter, 13 mm below the scalp) as assessed by magnetic resonance images. The 1D-CSI technique introduced no systematic changes in the ratio of signals from a single chamber phantom containing a phosphocreatine (PCr) and ATP solution. Gray matter slices showed a PCr/NTP ratio of 0.93 +/- 0.11 (mean +/- S.D.) using a 2 s interpulse interval, a value very close to the ratio in surface coil localized spectra. The predominantly white matter slices showed a PCr/NTP ratio of 1.32 +/- 0.18 (P < 0.02 for gray versus white matter). Using the estimated percentages of gray and white matter in the two slices and calculated concentrations from fully relaxed spectra, the gray matter PCr/NTP ratio is approximately 0.77, while the ratio in white matter is approximately 2.18. The difference in PCr/NTP measured in vivo suggests that either the total NTP concentration is higher or the steady state PCr concentration is lower in gray matter than in white matter in the piglet brain.

Adenosine Triphosphate↗

Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy.

OBJECTIVE: Ultrasonographically detectable neonatal brain white matter lesions are the most important identifiable risk factor for cerebral palsy. Inflammatory cytokines released during the course of intrauterine infections have been implicated in the genesis of brain white matter lesions and subsequent cerebral palsy. This study was undertaken to determine whether fetuses who subsequently were diagnosed to have periventricular brain white matter lesions could be identified by determining the concentrations of inflammatory cytokines in the amniotic fluid. STUDY DESIGN: Women with complicated preterm gestations underwent amniocentesis for clinical indications. Amniotic fluid concentrations of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and the natural interleukin-1 receptor antagonist were determined by immunoassay. Periventricular white matter lesions of the neonate were diagnosed by neurosonography. Univariate and multivariate analyses were conducted. RESULTS: Ninety-four women and their neonates were included in the study; white matter lesions were diagnosed in 24% (23/94) of the newborns. The mothers of newborns with brain white matter lesions had higher median concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (but not interleukin-1 receptor antagonist) in amniotic fluid than did those who were delivered of newborns without white matter lesions (p < 0.01 for each). Acute histologic chorioaminionitis was more common in the placentas of neonate with white matter lesions than in those without these lesions (82% [18/22] vs 42% [30/71], p < 0.005). Neonates with white matter lesions were delivered at a lower mean gestational age and birth weight and had a higher rate of significant complications (including respiratory distress syndrome, intraventricular hemorrhage, and infection-related complications) than did those without white matter lesions. The differences in median interleukin-1beta and interleukin-6 levels between these two groups remained significant after adjustment for gestational age and birth weight (interleukin-6: odds ratio 5.7, 95% confidence interval 1.3 to 24.4; interleukin-1beta: odds ratio 4.4, 95% confidence interval 1.1 to 17.0). Of the 94 newborns included in this study, 11 died before age 6 months and eight had cerebral palsy; all eight had white matter lesions and elevated cytokine levels in amniotic fluid. Histologic chorioamnionitis was more common in the placentas of neonates with cerebral palsy than in those without cerebral palsy (86% [6/7] vs 44% [33/75], p < 0.05). CONCLUSIONS: Infants at risk for development of brain white matter lesions can be identified by the concentrations of interleukin-6 and interleukin-1beta in amniotic fluid. Our findings support the hypothesis that inflammatory cytokines released during the course of intrauterine infection play a role in the genesis of brain white matter lesions.

Amniocentesis↗