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Biomedical subjects

Dixon M Moody

Publications and source records attributed to Dixon M Moody.

At least 19 recordsLinked to original sources
PubMed2006

Immunolocalization of tight junction proteins in blood vessels in human germinal matrix and cortex.

Brain development occurs in a specialized environment maintained by a blood-brain barrier (BBB). An important structural element of the BBB is the endothelial tight junction (TJ). TJs are present during the embryonic period, but BBB impermeability accrues over an extended gestational interval. In studies of human premature infants, we used immunomicroscopy to determine if amounts of the TJ proteins ZO-1, claudin and occludin increase with gestational age in vessels of germinal matrix (GM) and cortex. By 24 weeks postconception (PC), TJ proteins were present in both GM and cortical vessels, but immunoreactivity in the GM of the youngest subjects was less than in older subjects. At 24 weeks PC, TJ protein immunoreactivity in GM vessels was less than in cortical vessels suggesting that TJ maturation progresses along a superficial to deep brain axis. This concept correlates with conclusions from previous analyses of the expression of brain endothelial cell alkaline phosphatase (AP) activity. AP appears in cortical vessels before appearing in deep white matter and GM vessels. Together, these data indicate that differentiation of some functional specializations is still in progress in GM vessels during the third trimester. This maturation could relate to the pathogenesis of germinal matrix hemorrhage-intraventricular hemorrhage.

Blood Vessels↗
PubMed2006

The blood-brain barrier and blood-cerebral spinal fluid barrier.

An intact blood-brain barrier and normal production, circulation, and absorption of cerebrospinal fluid are critical for normal brain function. Minor disruptions of barrier function are without clinical consequences. Major disruptions accompany most significant acute brain injuries. The anatomic location of the blood-brain barrier is the endothelial cells of arterioles, capillaries, veins, and the epithelial cell surface of the choroid plexus. However, endothelial cells require the presence of glial cells to maintain barrier function. During cardiopulmonary bypass, several factors may result in a temporary disruption of the barrier; the most important are systemic inflammatory response and focal ischemia due to emboli. Lacking a lymphatic system, the brain depends on the circulation of cerebrospinal fluid to remove the products of metabolism, and the circulation of cerebrospinal fluid depends on a vascular systolic pulse wave to drive this fluid antegrade along the brain paravascular spaces. Although it is not possible to identify this paravascular space histologically, its presence is confirmed by tracer methods.

Animals↗
PubMed2005

Single crossclamp improves 6-month cognitive outcome in high-risk coronary bypass patients: the effect of reduced aortic manipulation.

OBJECTIVE: We hypothesized that a strategy that reduced aortic manipulation would reduce the incidence of cognitive deficits in patients undergoing coronary artery bypass grafting compared with the "traditional" approach and that neurobehavioral outcomes with the reduced aortic manipulation strategy would approach those obtained with off-pump coronary artery bypass surgery. METHODS: Consenting high-risk patients (those with older age, diabetes, or hypertension) scheduled for coronary artery bypass grafting and cardiopulmonary bypass were randomly assigned to 1 of 2 aortic management protocols: (1) a traditional approach in which distal anastomoses were accomplished while the aorta was crossclamped but in which proximal anastomoses were sewn while a partial occlusion clamp was applied to the aorta (multiple aortic clamping group) or (2) a reduced aortic manipulation approach in which the aorta was clamped a single time with a reduced-pressure clamp (single aortic clamping group) and the partial occlusion clamp was not used. A contemporaneous group of patients undergoing off-pump coronary artery bypass surgery without cardiopulmonary bypass was also enrolled. Subjects in all 3 groups underwent neurologic and neuropsychological testing before and after surgery. After randomization, patients assigned to either approach could be changed to another strategy if the attending surgeon determined that patient safety demanded this change. The study design anticipated that surgical techniques would evolve over the course of patient enrollment and anticipated that some patients would have intraoperative echocardiographic findings that would demand that the traditional approach (eg, severe aortic atherosclerosis) or the reduced manipulation protocol (eg, severe ischemia or poor left ventricular function) be abandoned. Thus, an unequal distribution of patients was expected. By surgeon decision, 20 of 84 multiple aortic clamping patients crossed over to single aortic clamping, and 3 of 85 single aortic clamping patients switched to multiple aortic clamping. Eligible patients had a battery of neuropsychological tests before surgery and at 6 months after surgery. A 20% decrement in 2 or more tests was defined as a neuropsychological deficit. RESULTS: [table: see text]. CONCLUSIONS: A surgical strategy designed to minimize aortic manipulation can significantly reduce the incidence of cognitive deficits in coronary artery bypass grafting patients compared with traditional techniques. In this series, the results of the reduced aortic manipulation strategy were not significantly different from those in patients having off-pump coronary artery bypass surgery, thus emphasizing surgical technique as the primary cause of brain damage in coronary artery bypass grafting patients.

Aged↗
PubMed2005

Germinal matrix cells associate with veins and a glial scaffold in the human fetal brain.

Germinal matrix (GM) in the subventricular zone (SVZ) includes progenitor cells of neurons and glia, which migrate from the SVZ to regions where they become integrated into the developing brain. In the human fetal brain, GM cells pack into high density clusters that encircle GM veins producing a profile we describe as a venous cuff. Venous cuffs are, in turn, encircled by GFAP-positive astrocytes that project processes through the cuff to the venous wall. The high cell density exhibited by cuffs, as well as their association with astrocytes, are reminiscent of features associated with chain migration. However, chain migration has not been associated previously with veins. We suggest that the GM cuff cells may represent a distinct subset of GM cells that migrate away from the GM on a pathway consisting of a vein and its associated astrocytic scaffold.

Astrocytes↗
PubMed2005

Morphometric assessment of collagen accumulation in germinal matrix vessels of premature human neonates.

Germinal matrix haemorrhage in premature neonates is commonly attributed to vascular immaturity, possibly related to an abbreviated process of angiogenesis. Terminal steps in the progression of angiogenesis are the formation of a subendothelial basal lamina containing collagen IV and an extracellular matrix containing collagens I and III. Immature vessels would predictably be deficient in these collagen subtypes. We analysed germinal matrix (GM), cortical, and white matter (WM) vessels with antibodies specific for collagens I, III and IV to test the hypothesis that GM vessels are immature. Brains were collected during post-mortem from prematurely born human neonates ranging in age from 17 weeks to 36 weeks postconception. All GM vessels were immunoreactive for collagen subtypes I, III and IV. Using digital image analysis, collagen IV immunoperoxidase-labelling was measured in vessels in GM, cortex and WM. Intensity values in GM and WM were normalized relative to cortical intensity within the same subject. At week 17 of gestation, GM vessels exhibited a higher concentration of collagen IV than did WM or cortical vessels. Regression analysis demonstrated that collagen intensity in GM was greater than that in cortex and WM at all stages. We conclude that GM vessels in even the youngest, prematurely born, viable neonates do not exhibit evidence of structural immaturity. The high incidence of GM haemorrhage in premature neonates may be related to factors other than a deficiency in accumulated collagen.

Brain↗
PubMed2005

Vascular damage after fractionated whole-brain irradiation in rats.

Whole-brain irradiation of animals and humans has been reported to lead to late delayed structural (vascular damage, demyelination, white matter necrosis) and functional (cognitive impairment) alterations. However, most of the experimental data on late delayed radiation-induced brain injury have been generated with large single doses or short fractionation schemes that may provide a less accurate indication of the events that occur after clinical whole-brain radiotherapy. The pilot study reported here investigates cerebral vascular pathology in male Fischer 344 rats after whole-brain irradiation with a fractionated total dose of 137Cs gamma rays that is expected to be biologically similar to that given to brain tumor patients. The brains of young adult rats (4 months old) were irradiated with a total dose of 40 Gy, given as eight 5-Gy fractions twice per week for 4 weeks. Brain capillary and arteriole pathology was studied using an alkaline phosphatase enzyme histochemistry method; vessel density and length were quantified using a stereology method with computerized image processing and analysis. Vessel density and length were unchanged 24 h after the last dose, but at 10 weeks postirradiation, both were substantially decreased. After 20 weeks, the rate of decline in the vessel density and length in irradiated rats was similar to that in unirradiated age-matched controls. No gross gliosis or demyelination was observed 12 months postirradiation using conventional histopathology techniques. We suggest that the early (10-week) and persistent vascular damage that occurs after a prolonged whole-brain irradiation fractionation scheme may play an important role in the development of late delayed radiation-induced brain injury.

Age Factors↗
PubMed2004

Subependymal veins in premature neonates: implications for hemorrhage.

The germinal matrix contains a concentrated network of blood vessels. The unusual structural qualities of these vessels are implicated as a factor underlying the high incidence of hemorrhage that occurs in the germinal matrix of prematurely born neonates. The present study is a histologic analysis of an postmortem examination series of brains collected from neonates born between 23 weeks gestation and term and is designed to determine if subependymal veins can be recognized in neonates born at the limits of viability, approximately 23 weeks gestation. Alkaline phosphatase histochemistry is used to differentiate cerebral afferent from efferent vessels. The results demonstrate that precursors of the subependymal veins can be recognized as early as the twenty-third gestational week. These veins increase progressively in diameter from 23 weeks to term, but the wall of the veins, which at early stages consists of endothelial cells only, does not thicken until after postconception week 36. Thus in all premature neonates, including the youngest capable of independent existence, the subependymal veins are present and appear vulnerable to rupture. These data support our suggestion that the structural immaturity of these veins in premature neonates is causally related to the high incidence of germinal matrix hemorrhage in these patients.

Cerebral Hemorrhage↗
PubMed2004

Quantification of afferent vessels shows reduced brain vascular density in subjects with leukoaraiosis.

PURPOSE: To investigate vessel density changes with increasing age in three areas of the brain and to correlate these changes with leukoaraiosis (LA) on the basis of magnetic resonance (MR) images and location in deep white matter (WM). MATERIALS AND METHODS: Internal review board approval or informed consent from next of kin was not required. Brains of 21 subjects (mean age, 72.5 years; 12 men, nine women) were evaluated at autopsy with MR imaging. The presence of LA was indicated by confluent or patchy areas of hyperintensity in deep WM. Microvascular density (percentage of vessel area divided by total area) in subjects with LA was measured with computerized morphometric analysis in LA lesions, healthy-appearing WM at MR imaging, and the cortex. These measurements were compared with each other and with measurements from corresponding areas in healthy subjects. Afferent vasculature was stained with alkaline phosphatase in celloidin sections. Hypotheses were tested with computation of a series of repeated-measures linear mixed models. RESULTS: Autopsy brains from 12 subjects with LA (mean age, 72 years; six men, six women) and nine subjects without LA (mean age, 73 years; six men, three women) were studied. Afferent microvascular density +/- standard deviation in LA lesions in deep WM (2.56% +/- 1.56) was significantly lower than that in corresponding deep WM of healthy subjects (3.20% +/- 1.82) (P = .018). Subjects with LA demonstrated decreased afferent vascular density at early ages in all three areas of the brain when compared with healthy subjects of the same age. CONCLUSION: Findings of decreased afferent vascular density in the area of LA and outside the lesion indicate that LA is a generalized cerebrovascular disease process rather than one confined to deep WM.

Aged↗
PubMed2004

Increase of white matter string vessels in Alzheimer's disease.

String vessels are collagenous structures connected to capillaries. They have no endothelial cells or lumen. We assessed collagen IV-labeled string vessels in the white matter (WM) of subjects with Alzheimer's disease (AD) (n = 12) and non-AD controls (n = 11) using 100 microm celloidin sections. Ten standard fields were digitally captured and the number and length of normal vessels and string vessels were quantified by computerized image analysis. The WM of the AD-diagnosed individuals contained more strings per mm2 (3.95 +/- 0.49) than comparable WM from controls (1.36 +/- 0.39) (p = 0.0005) and had increased total string vessel length in mm/mm2 (AD = 0.29 +/- 0.04; control = 0.10 +/- 0.03; p = 0.0015). There was a 25% increase (not statistically significant) in vessel density in mm/mm2 in AD subjects (AD = 11.88 +/- 0.87; control = 9.53 +/- 0.78; p = 0.06), presumably due to brain atrophy in the white matter. Although vessel length was slightly increased in AD subjects, they still had more than double the string length per total vessel length (AD = 2.88 +/- 0.38) compared to controls (1.36 +/- 0.27) (p = 0.0057). This increase in string vessels in the white matter of AD subjects suggests a decrease in vascular supply in this disease.

Aged↗
PubMed2003

Dietary caffeine consumption and withdrawal: confounding variables in quantitative cerebral perfusion studies?

PURPOSE: To evaluate the effects of dietary caffeine intake and withdrawal on cerebral blood flow (CBF), as determined from a randomized, blinded, placebo-controlled study. MATERIALS AND METHODS: Twenty adults (16 men, four women; age range, 24-64 years) categorized as low (mean, 41 mg/d) or high (mean, 648 mg/d) caffeine users underwent quantitative flow-sensitive alternating inversion-recovery perfusion magnetic resonance (MR) imaging twice: 90 minutes after a dose of caffeine (250 mg) on one day and after a dose of placebo on another day (randomized counterbalanced design). Doses were preceded by 30 hours of caffeine abstinence to induce withdrawal in high caffeine users. Quantitative CBF maps were gray matter (GM)-white matter (WM) segmented and subjected to region-of-interest analysis to obtain mean CBF in WM, anterior circulation GM (AGM), and posterior circulation GM (PGM). By using two-way repeated-measures analysis of variance, regional CBF data were tested for within-subject differences between caffeine and placebo and for between-subject differences related to dietary caffeine habits. Linear regression was used to determine whether dietary caffeine use predicts CBF or CBF response to caffeine. RESULTS: Caffeine reduced CBF (P < or =.05) by 23% (AGM, PGM) and 18% (WM) in all subjects. Postplacebo (withdrawal) CBF in high caffeine users exceeded that in low users (P < or =.05) by 31% (AGM) and 32% (WM) (PGM, not significant). Mean postcaffeine CBF reduction in AGM was 26% in high users versus 19% in low users (P < or =.05; PGM and WM, not significant). Increasing caffeine consumption predicted higher CBF (P < or =.05) in all regions: r = 0.79 (AGM), 0.57 (PGM), and 0.76 (WM). Dietary caffeine use did not predict CBF response to caffeine. CONCLUSION: Dietary caffeine consumption and withdrawal are potential confounding variables in cerebral perfusion and functional MR imaging.

Caffeine↗
PubMed2003

Relationship between caffeine-induced changes in resting cerebral perfusion and blood oxygenation level-dependent signal.

BACKGROUND AND PURPOSE: Recent interest has emerged in the use of pharmacologic methods to maximize blood oxygenation level-dependent (BOLD) signal intensity changes in functional MR imaging (fMRI). Adenosine antagonists, such as caffeine and theophylline, have been identified as potential agents for this purpose. The present study was designed to determine whether caffeine-induced decreases in cerebral perfusion result in enhanced BOLD responses to visual and auditory stimuli. METHODS: MR imaging was used to measure resting cerebral perfusion and stimulus-induced BOLD signal intensity changes in 19 patients. We evaluated the relationship between resting cerebral perfusion and the magnitude of BOLD signal intensity induced by visual and auditory stimulation under caffeine and placebo conditions. RESULTS: The data showed that changes in resting cerebral perfusion produced by caffeine are not a consistent predictor of BOLD signal intensity magnitude. Although all cerebral perfusion was reduced in all study participants in response to caffeine, only 47% of the participants experienced BOLD signal intensity increase. This finding was independent of the participants' usual caffeine consumption. CONCLUSION: The data presented herein show that the relationship between resting cerebral perfusion and the magnitude of BOLD signal intensity is complex. It is not possible to consistently enhance BOLD signal intensity magnitude by decreasing resting perfusion with caffeine. Future studies aimed at evaluating the relationship between perfusion and BOLD signal intensity changes should seek a means to selectively modulate known components of the neural and vascular responses independently.

Acoustic Stimulation↗
PubMed2002

Venous collagenosis and arteriolar tortuosity in leukoaraiosis.

Leukoaraiosis (LA), an age-related white matter degeneration, is thought to be caused by chronic ischemia. To understand the pathogenesis of LA, we studied the pathology, particularly of the blood vessels, in 186 brains [84 of them with magnetic resonance imaging (MRI)] over the past 10 years. With normal aging, there is gradual thickening of the walls of periventricular veins and venules with collagen subtypes I and III. This venous collagenosis (VC) was increased in brains with LA. Occasionally, LA lesions are not periventricular, but nearer the cortex. In such cases, the most severe VC occurs in the LA lesion rather than near the ventricle. Therefore, LA and VC are not independent degenerative processes coincidentally found near the ventricles, and although damage to the ependyma could be a cause of VC, it cannot be the only cause. Whether VC precedes LA is unknown, but our experience suggests that severe VC is usually accompanied by LA. Arteriolar tortuosity, another age-related vascular pathology, is common in LA. Our thick celloidin sections show three-dimensional views of tortuous arterioles. The tortuosity is much more severe in the white matter and there is considerable loss of parenchyma around them. Staining for collagen IV in the basal lamina reveals tortuous vessels in an "empty bag" that represents the limits of the surrounding parenchyma. These enlarged perivascular spaces correspond to état criblé. The demyelination in LA lesions is accompanied by loss of cells, mostly oligodendrocytes. In studies of apoptosis in LA, we found increased apoptosis within the lesion compared to the surrounding white matter. In conclusion, our studies support the concept that LA results from chronic ischemia due to age-related vascular pathology.

Aged↗
PubMed2002

Apoptosis in leukoaraiosis lesions.

Leukoaraiosis (LA), an age-related degenerative condition, appears as an area of hyperintense signal in the deep white matter on MRI. It may be caused by chronic ischemia. LA lesions are characterized by demyelination, loss of glial cells, spongy appearance, and occlusion of veins and venules by collagenous thickening of the vessel walls. Since necrosis is not obvious in LA lesions, we investigated the occurrence of apoptosis. We obtained 1.5-cm-thick coronal brain slices at autopsy from two patients with LA. MRI was performed on the brain slices. Blocks were fixed in formalin, embedded in paraffin, and sectioned. Sections were stained by several methods including the TUNEL method for DNA fragmentation. Some TUNEL-positive cells showed nuclear morphology indicative of apoptosis. In case 1, TUNEL-positive cells were more numerous in an LA lesion than in nearby unaffected white matter (P=0.008). In case 2, LA lesions were examined in six areas; left and right frontal, middle, and occipital slices. TUNEL-positive cells were more numerous in the LA lesions than in nearby white matter (P=0.002). We also found TUNEL-positive cells in the cortex and in the walls of blood vessels. In case 1, more severe venous collagenosis was found in the LA lesion, which was near the cortex, than in the periventricular area, where venous collagenosis and LA are more commonly found. The presence of numerous scattered cells in the LA lesions showing DNA fragmentation suggests that those cells are damaged and dying, at least some by apoptosis. The apoptosis in the white matter adjacent to the LA lesions suggests progressive cell loss and expansion of the LA lesions.

Aged↗
PubMed2002

Test-retest reproducibility of quantitative CBF measurements using FAIR perfusion MRI and acetazolamide challenge.

The reproducibility of quantitative cerebral blood flow (CBF) measurements using MRI with arterial spin labeling and acetazolamide challenge was assessed in 12 normal subjects, each undergoing the identical experimental procedure on two separate days. CBF was measured on a 1.5T scanner using a flow-sensitive alternating inversion recovery (FAIR) pulse sequence, performed both at baseline and 12 min after intravenous administration of acetazolamide. T(1) was measured in conjunction with the FAIR scan in order to calculate quantitative CBF. The CBF maps were segmented to separate gray matter (GM) from white matter (WM) for region-of-interest (ROI) analyses. Post- acetazolamide CBF values (ml/100 g/min, mean +/- SD) of 87.5 +/- 12.5 (GM) and 46.1 +/- 10.8 (WM) represented percent increases of 37.7% +/- 24.4% (GM) and 40.1% +/- 24.4% (WM). Day-to-day differences in baseline CBF were -1.7 +/- 6.9 (GM) and -1.4 +/- 4.7 (WM) or, relative to the mean CBF over both days for each subject, -2.5% +/- 11.7% (GM) and -3.8% +/- 13.6% (WM) Day- to-day differences in absolute post-ACZ CBF increase were -2.5 +/- 6.8 (GM) and 2.7 +/- 9.4 (WM) or, relative to the mean CBF increase over both days for each subject, -4.7% +/- 13.3% (GM) and 9.1% +/- 26.2% (WM). Thus, FAIR- based CBF measurements show satisfactory reproducibility from day to day, but with sufficient variation to warrant caution in interpreting longitudinal data. The hemispheric asymmetry of baseline CBF and post-acetazolamide CBF increases varied within a narrower range and should be sensitive to small changes related to disease or treatment.

Acetazolamide↗
PubMed2002

Temporal expression pattern of cerebrovascular endothelial cell alkaline phosphatase during human gestation.

In premature human neonates, immaturity of cerebral vessels can contribute to clinical problems such as germinal matrix hemorrhage and white matter damage. Afferent cerebral vessels in the brain of term babies express alkaline phosphatase (AP), an ectoenzyme located on the surface of endothelial cells. Using AP enzyme histochemistry we have examined the cerebrovasculature of premature live-born human neonates to determine when cerebral afferent vessels begin to express AP. Brains were collected at autopsy and processed for histological examination. AP-stained vessel density in the periventricular white matter was quantified using digital imaging and automated morphometry. Babies born prior to 28 wk gestation display few AP-positive vessels in the periventricular white matter, whereas, babies born after 28 wk gestation exhibit an AP-positive vascular pattern that resembles the adult pattern. In contrast, immunostaining for collagen revealed an extensive vascular network in both early and late gestation infants. Our measurements indicate that neonates born prior to 28 wk gestation are characterized by immature cerebral white matter afferent vessels and raise the possibility that the immaturity compromises vascular function.

Alkaline Phosphatase↗
PubMed2002

Anatomical analysis of the developing cerebral vasculature in premature neonates: absence of precapillary arteriole-to-venous shunts.

Germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) commonly affects premature neonates. The gravity of the consequences associated with GMH-IVH makes it a major concern in their care. GMH-IVH begins in the germinal matrix tissue and is, most commonly, the result of venous rupture. Arteriole-to-venous precapillary shunts in the cerebrum of premature neonates could, if present, lead to elevated venous pressure in the germinal matrix and, thus, would be an important etiological factor. We report an autopsy study, involving 33 cases of premature neonates, designed to determine whether precapillary arteriole-to-venous shunts are present in the cerebral vasculature. Brain tissue was embedded in celloidin, sectioned into 100- micro m-thick slices and stained using alkaline phosphatase enzyme histochemistry, a method that distinguishes afferent from efferent vessels. Our sections, which are ideal for tracing vessels over long distances and for displaying patterns of branching and connections with other vessels, indicate that precapillary arteriole-to-venous shunts are not a major influence on cerebral blood flow in babies born at 23 wk gestation or later. The cerebral vasculature in one baby, who died at 24 wk postconception, included shunt-like connections, whereas in 34 babies shunts were not identified. We conclude that precapillary arteriole-to-venous shunts are not a significant factor leading to GMH.

Arterioles↗