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J Fenstermacher

Publications and source records attributed to J Fenstermacher.

At least 19 recordsLinked to original sources

Single-coil arterial spin-tagging for estimating cerebral blood flow as viewed from the capillary: relative contributions of intra- and extravascular signal.

The single-capillary model was applied to the exchange microvessels for water in the cerebral parenchyma and used to calculate blood-to-brain flux of water; the theory of the steady-state arterial spin-tagging (AST) technique for estimating cerebral blood flow (CBF) was revised to incorporate the presence of both extravascular (tissue) and capillary signal. A crucial element of the single-coil AST experiment is that magnetization transfer (MT) shortens the effective T1 of the extravascular water, making it one-quarter that of the T1 of capillary blood. Furthermore, the mean capillary transit time is on the order of the T1 of the extravascular water. The single-coil AST experiment is distinguished from other methods which use water as an indicator for measurement of CBF in that the (flow-dependent) populations of inverted protons in the intra- and extravascular compartments can be nearly equal for normal physiological conditions. The following questions are considered: Is single-coil AST contrast linear in resting CBF? Is contrast in the single-coil AST technique likely to be linear under changes in CBF in normal tissue? Is the contrast likely to be linear in such common pathologies as stroke and cerebral tumor? We demonstrate that, if the population of inverted protons in the microvessels is included in the experiment, the voxel population of inverted protons will be approximately linear with flow across a broad range of flow values. We predict that the single-coil AST experiment will systematically overestimate resting CBF for flows in the normal range, that changes in CBF in normal tissue will produce an approximately linear response in AST measurement, and, finally, we predict the operating characteristics of the measurement in common cerebral pathologies.

Animals↗

In vitro evidence that beta-amyloid peptide 1-40 diffuses across the blood-brain barrier and affects its permeability.

Beta amyloid peptides are major insoluble constituents of amyloid fibrils in senile plaques and cerebrovascular deposits, both characteristic of Alzheimer disease (AD). Low concentrations of soluble forms of amyloid peptides are also present in normal CSF. We previously demonstrated that the 40 amino acid form of soluble beta-amyloid peptide (sAbeta) is rapidly cleared from rat CSF into blood. Herein we hypothesized that a saturable, outwardly directed flux of this peptide occurs at the blood-brain barrier (BBB) and tested whether supraphysiological (possibly pathological) concentrations of sAbeta could alter the permeability of this barrier to a paracellular tracer, polyethylene glycol (PEG). Using an in vitro model of BBB, we showed that influx and efflux of sAbeta were equal, modest (60%-160% greater than that of PEG), and not saturable. These observations suggest that sAbeta moved across the monolayer by a diffusional process, and not via a transporter. PEG flux was doubled immediately after the luminal concentration of cold sAbeta was raised to 5 microM, and was doubled 150 min after the abluminal concentration of sAbeta was increased to 5 microM. Pathological elevations of sAbeta concentration in plasma or brain interstitial fluid may, therefore, alter the permeability of brain capillaries in vivo.

Alzheimer Disease↗

High resolution quantitation of microvascular plasma perfusion in non-ischemic and ischemic rat brain by laser-scanning confocal microscopy.

Laser-scanning confocal microscopy (LSCM) was used to measure at high resolution cerebral plasma volumes (perfusion) using two fluorescent plasma markers in a rat model of embolic stroke. This application of LSCM to study the microvascular circulation in embolic stroke was developed as an alternative to autoradiography to measure cerebral perfusion. An additional benefit of LSCM is that it quantitates with great accuracy the structural relationships of the microcirculation to cells and the pathological alterations of the ischemic brain. Autoradiography allows only a quantitative analysis of cerebral perfusion. For example, in order to study the microcirculation and its relationship to blood brain barrier damage, the volume of perfused cerebral capillaries was measured by administering two fluorescent plasma markers (FITC-dextran and Evans blue) intravenously to a rat. Evans blue was administered before cerebral ischemia and FITC-dextran administered post-ischemia 1 min before sacrifice. Volumes of plasma perfusion were analyzed by means of a system developed for 3D analysis of fixed and stained serial brain histologies. Plasma volumes for the non-ischemic cerebral cortex were 1.00%+/-0.38% while plasma volumes in the caudate/putamen were 0.69%+/-0.17% in good agreement with the previously published values using the autoradiography method. The architecture of the capillaries in the ischemic core showed perfusion of Evans blue but there was no flow of FITC dextran. Our work represents a novel application of this technology to investigation of cerebral vascular disease and identifies its potential to become an important tool for investigation of cerebral pathology.

Animals↗

Quantitation of microvascular plasma perfusion and neuronal microtubule-associated protein in ischemic mouse brain by laser-scanning confocal microscopy.

In an exposition of the technique of calculating distribution volumes from laser-scanning confocal microscopic (LSCM) data, three-dimensional images of the distribution of one or two fluorescent markers in mouse brain specimens were generated by LSCM and processed by a system developed for morphometric analysis of fixed and stained serial brain histologic samples. To determine the volume of perfused cerebral capillaries, one of two fluorescent plasma markers, either fluorescein isothiocyanate (FITC)-dextran or Evans blue, was intravenously administered to mice subjected to 1 hour of embolic middle cerebral artery (MCA) occlusion (n = 9) and to mice that were not operated on (n = 3); after 1 minute of circulation, brains were removed, immersion-fixed, and processed for LSCM. In some of these animals (n = 5), the volume of endogenous microtubule-associated protein-2 (MAP2) fluorescence was also determined using immunohistochemical staining. For mice that were not operated on, this methodology yielded highly localized volumes of (1) microvascular plasma, which agree with those determined for rodents by other techniques, and (2) MAP2 expression, which appears physiologically and morphologically reasonable. After 1 hour of MCA occlusion, the MAP2 volumes of distribution were less than 10% of normal in the ipsilateral hemisphere in which plasma perfusion essentially ceased. In conclusion, precise colocalization and quantitation of early ischemic neuronal damage and cerebral plasma perfusion deficit can be done with this three-dimensional, microphysiologic and microanatomic methodology.

Animals↗

Slightly altered permeability-surface area products imply some cerebral capillary recruitment during hypercapnia.

To test the capillary recruitment hypothesis in brain, cerebral blood flow was raised markedly in rats by exposure to 8% CO2 (hypercapnia), and capillary permeability-surface area (PS) products were measured. Local cerebral blood flow (LCBF), volume of radiolabeled blood in parenchymal microvessels (also referred to as the blood space or Vb), plus the local capillary influx rate constants (K1) and PS products of [14C]antipyrine and 3-O-[14C]methyl-D-glucose (3OMG) were estimated in 44 brain areas. Hypercapnia raised PaO2 to 140 mm Hg, elevated LCBF by two- to threefold through out the brain, and increased Vb from 5 to 33% (mean = 22%) in 42 of 44 brain areas; hypercapnia did not, however, alter microvessel hematocrit. With hypercapnia, the influx of antipyrine was increased by 40-65% in all brain areas, and the PS products of antipyrine were elevated from 0-35% (mean = 17%). The PS products of antipyrine plus the parenchymal blood spaces suggest modest (< 30%) capillary recruitment in most brain areas as well as some microvessel dilation, mainly in forebrain gray matter and white matter areas. In contrast, hypercapnia did not appreciably alter K1 nor PS of 3OMG; it slightly but not significantly raised the blood levels of glucose. In view of the blood space and antipyrine evidence for modest capillary recruitment and vasodilation, the lack of change in PS of 3OMG implies that glucose transporter activity was lowered by hypercapnia, an effect similar to that reported for high-dose pentobarbital. Finally, the microvessel hematocrit and 3OMG data suggest that cerebral capillary permeability (P) was not increased by hypercapnia. Overall, hypercapnia seems to increase LCBF mainly by raising the velocity of blood flow; capillary recruitment and dilation appear to play relatively minor roles in this flow increase.

3-O-Methylglucose↗

Virtually unaltered permeability-surface area products imply little capillary recruitment in brain with hypoxia.

OBJECTIVE: To test the capillary recruitment hypothesis for the brain with control and hypoxic rats. METHODS: Local cerebral blood flow (LCBF) was sharply raised by respiring 10% O2 (hypoxia). LCBF as well as local influx rate constants (K1) and permeability-surface area (PS) products of 14C-antipyrine and 14C-3-O-methyl-D-glucose (30MG) were estimated for capillary systems in 44 brain areas. RESULTS: With this testing, an increase in PS product would be suggestive of capillary recruitment. In all brain areas, LCBF was increased by 30-90% by hypoxia. Hypoxia modestly raised the influx of antipyrine in brain but did not appreciably alter its PS products. With hypoxia, K1's and PS products of 30MG were significantly lowered (5-25%) throughout the brain, and the blood levels of glucose were sizeably raised. The latter increase would diminish the transfer of 30MG across the blood-brain barrier by the hexose transporter because of increased glucose competition. By applying a glucose-concentration correction to the data, the apparent PS product of 30MC for the hypoxic group became equal to that for the controls, which agrees with the antipyrine PS product results. CONCLUSIONS: Hypoxia, thus, leads to virtually no increase in PS products and no capillary recruitment in brain, and elevates LCBF mainly, perhaps exclusively, by raising the velocity of flow through already perfused capillaries.

3-O-Methylglucose↗

Parenchymal microvascular systems and cerebral atrophy in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) are hypertensive, hyperactive, and hydrocephalic; furthermore SHR have smaller brain volume and weight than age-matched, normotensive Wistar-Kyoto rats (WKY). At 6-7 months of age, local cerebral glucose is sizably lower in SHR than WKY. The hypothesis that these several abnormalities of SHR lead to variations in cerebral microvascular bed morphology was tested in 6-7-month-old SHR and WKY by quantitating various parameters of small, intermediate, and large parenchymal microvessels (grouped by luminal diameter) in 21 brain areas. Within each rat strain, the microvascular bed properties such as vessel profile frequency (density) varied considerably among the 21 brain areas. In opposition to the hypothesis, mean luminal diameter as well as profile frequency, surface area, and luminal volume of the microvascular beds per unit tissue mass were virtually identical in each brain area of SHR and WKY for the three groups of microvessels. These findings coupled with the reports of less tissue per structure but similar density of neurons throughout the brain of SHR and WKY indicate that there are fewer neurons and less vascular tissue per brain structure in 6-7-month-old SHR than WKY; in addition, they suggest a linkage between the size of parenchymal microvascular beds and the surrounding nervous tissue.

Animals↗

Hypoxia increases velocity of blood flow through parenchymal microvascular systems in rat brain.

The postulation that hypoxia increases local cerebral blood flow (lCBF) mainly by perfusing more capillaries (the capillary recruitment hypothesis) was tested in awake adult male Sprague-Dawley rats exposed to 10% O2 and control rats. The [14C]iodoantipyrine technique was used to measure lCBF. Local cerebral blood volume was determined by measuring plasma and red cell distribution spaces within the brain parenchyma with 125I-labeled serum albumin (RISA) and 55Fe-labeled red cells (RBC), respectively. Tissue radioactivity in 44 brain areas was estimated by quantitative autoradiography. Hypoxia raised lCBF by 25-90% in all brain areas. In about one-quarter of the brain areas, the rise in blood flow was associated with a small increase in microvascular plasma and blood volumes. This change in blood volume, which could be the result of perfusing more parenchymal microvessels and/or increasing parenchymal microvessel diameter, is not sufficient to account for the observed rise in lCBF. In the remaining areas the RISA, RBC, and blood spaces were either unchanged or only marginally increased by hypoxia. For this hypoxic perturbation, the major mechanism of raising blood flow appears to be increased velocity of microvessel perfusion and not perfusion of more capillaries. These findings provide only limited support for the capillary recruitment hypothesis.

Animals↗

The velocities of red cell and plasma flows through parenchymal microvessels of rat brain are decreased by pentobarbital.

Local cerebral blood flow is lowered in many brain areas of the rat by high-dose pentobarbital (50 mg/kg). In the present study, the mechanism of this flow change was examined by measuring the distribution of radiolabeled red blood cells (RBCs) and albumin (RISA) in small parenchymal microvessels and calculating the microvascular distribution spaces and mean transit times of RBCs, RISA, and blood. In most brain areas, pentobarbital slightly decreased the RISA space, modestly increased the RBC space, and did not alter the blood space. The mean transit times of RBCs, RISA, and blood through the perfused microvessels were considerably greater in treated rats than in controls. These findings indicate that the mechanism by which high-dose pentobarbital diminishes local cerebral blood flow in rat brain is, in the main, a lowered linear velocity of plasma and RBC flow through small parenchymal microvessels and not decreased percentage of perfused capillaries (capillary retirement). This response is probably driven mainly by lowered local metabolism and may well entail a slight increase in the number of small microvessels that are perfused by RBCs.

Animals↗

Hypercapnia slightly raises blood volume and sizably elevates flow velocity in brain microvessels.

The increase in local cerebral blood flow (LCBF) caused by hypercapnia may be mainly accomplished by raising the velocity of plasma and/or red blood cell (RBC) flow through the microvessels and not by perfusing more capillaries. This suggestion was tested in awake rats exposed to 8% CO2 and in control rats. LCBF was measured by the 14C-labeled iodoantipyrine method. The volume of blood in small parenchymal microvessels was estimated from the distribution spaces of 125I-labeled serum albumin (RISA) and 55Fe-labeled RBCs. Hypercapnia elevated LCBF 2.0- to 3.5-fold in the 40 brain areas studied, marginally raised the RBC spaces, and significantly increased the RISA and whole blood distribution spaces (approximately 25 and 19%, respectively). These changes in microvessel distribution volumes could be the result of perfusing a slightly larger fraction of capillaries (recruitment), increasing microvessel diameter somewhat, or both. With hypercapnia, the mean transit times fell to approximately 45% of control, which indicated that LCBF was mainly increased by raising the velocity of RBC and plasma flow through already perfused microvessels. Overall, few, if any, capillaries or other microvessels were recruited by hypercapnia.

Animals↗

Nicotine increases microvascular blood flow and flow velocity in three groups of brain areas.

To examine the mechanism of local cerebral blood flow (LCBF) elevation, nicotine (1.75 mg/kg sc) was administered to rats, and LCBF plus the distribution spaces of radiolabeled albumin (RISA) and red blood cells (RBC) in parenchymal microvessels were measured throughout the brain. Microvascular blood spaces and transit times were calculated from the data. From 1.5 to 3 min after nicotine administration, LCBF was raised by 40-150% in 16 of the brain areas and unaltered in the remaining 28 areas. The affected structures included parts of the visual-auditory, sensorimotor-cortical, and interpeduncular systems. RBC spaces were not changed by nicotine treatment. RISA and blood spaces were increased slightly but not significantly in some of the LCBF-affected areas but nowhere else. Nicotine seemingly elevates LCBF in the affected areas mainly by increasing linear velocity of flow through the microvascular beds. In agreement with this, mean transit time, which is inversely related to velocity, was decreased from 0.3-0.5 to approximately 0.2 s in the microvascular systems of the nicotine-affected areas.

Animals↗

Smaller local brain volumes and cerebral atrophy in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) have enlarged cerebral ventricles from 8 weeks of age onward and smaller brains than age-matched, normotensive Wistar-Kyoto (WKY) rats (controls). At 6-7 months of age local cerebral glucose utilization is apparently lower in many brain areas of SHR relative to WKY rats. These observations led to the hypothesis that there are morphological differences between these two strains of rats in many, if not all, brain areas. This hypothesis was tested in 6-7-month-old SHR and WKY rats by quantitating 1) the volumes of the ventricular system, whole brain, six gray matter structures, and two white matter areas; 2) the thickness of two regions of the cerebral cortex; and 3) the frequency of neuronal nuclei (neuronal frequency) in nine brain areas. Ventricular volume was twofold greater in SHR than in control rats. The volumes of the entire brain and all six gray matter structures plus the thickness of the two cortical regions were 11-25% less in SHR. Neuronal frequency was, however, similar in the two rat strains. The latter finding coupled with the smaller regional tissue volumes indicates appreciably fewer neurons per brain structure in young adult SHR than in controls. These results indicate significant cerebral structural differences between young adult SHR and WKY rats and suggest that structure as well as metabolism are abnormal in the SHR brain.

Animals↗

Differences and similarities in albumin and red blood cell flows through cerebral microvessels.

The hypothesis that microvessels in brain parenchyma are continuously perfused by plasma but intermittently perfused by red blood cells (RBCs) was tested in awake Sprague-Dawley rats. The microvascular distribution volumes of radioiodinated serum albumin (RISA) and 51Cr- and 55Fe-labeled RBCs were measured for periods from 15 s to 30 min. Local cerebral blood flow (LCBF) was assessed by the iodoantipyrine technique. The RISA and RBC distribution volumes were constant in the 12 areas studied from 15 s onward. These data fit a model of continuous plasma flow with intermittent RBC flow (and thus support the hypothesis), but they are also consistent with other models, e.g., continuous flow of both plasma and RBCs through all perfused microvessels. In parallel with LCBF, microvascular blood volume varied greater than 10-fold among brain areas. Relative to arterial hematocrit, microvascular hematocrits were low, which indicates that the passage of RBCs through parenchymal microvessels is more rapid than that of RISA. This could be the result of both the Fahraeus effect and intermittent RBC flow.

Animals↗

Technique-dependent variations in cerebral microvessel blood volumes and hematocrits in the rat.

To quantitate small parenchymal microvessel blood volumes in the brain, the distribution spaces of radiolabeled red blood cells (RBC) and serum albumin (RISA) were assessed in rats by different methods of tissue sampling and radioassay. Three minutes after intravenous administration of 55Fe-RBCs and/or 125I-RISA, the rats were decapitated. The brain was either immediately frozen within the skull and later removed (head-frozen group) or rapidly removed from the skull and then frozen (brain-frozen group). Radioactivity was measured either by liquid scintillation counting of tissue pieces, which contained pial plus large and small parenchymal microvessels, or by quantitative autoradiography (QAR) of tissue sections, which indicated small parenchymal microvessel blood only. In 12 of 15 areas, the RISA, RBC, and blood volumes determined by liquid scintillation counting of head-frozen tissue pieces were equal to or greater than those of brain-frozen tissue; this indicated less than or equal to 25% greater blood retention in pial and parenchymal microvessels with head freezing. At the parenchymal microvessel level (QAR assay), the distribution volumes of RBCs, RISA, and blood were similar with the two freezing techniques; hence with QAR either freezing procedure can be used to assess small parenchymal microvessel blood volumes.

Animals↗

Cerebral glucose utilization and blood flow in adult spontaneously hypertensive rats.

Not only blood pressure but also behavioral activity, brain morphology, and cerebral ventricular size differ between young spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. This suggests that cerebral blood flow and cerebral metabolism may vary between these two rat strains. To test this hypothesis, we measured local cerebral glucose utilization in 31 brain areas of 26-30-week-old rats. Local cerebral blood flow was also assessed in these same areas. Cerebral glucose utilization was measured by the 2-deoxyglucose method; cerebral blood flow was determined by the iodoantipyrene method. In virtually all gray matter structures, the apparent rate of glucose utilization was lower in SHR than in normotensive WKY rats; the interstrain differences varied significantly among structures and were statistically significant (uncorrected t tests) in 14 of 28 gray matter areas. Local cerebral blood flow was fairly similar in the two rat strains. The coupling of blood flow to glucose utilization varied significantly among brain areas in normotensive WKY rats as well as in SHR. In a number of gray matter structures, the coupling of flow to metabolism differed between hypertensive and normotensive animals. These data suggest that for many brain areas, either glucose utilization or glucose partitioning differs between WKY rats and SHR.

Analysis of Variance↗

Functional variations in parenchymal microvascular systems within the brain.

Variations in microvascular system functions were observed among a number of brain areas. The rates of local blood flow varied 18-fold among areas and were extremely high in neuroendocrine structures. Marked differences in blood flow were also found within some brain structures. The volume of radiolabeled blood in perfused parenchymal microvessels ranged from 5 to 70 microliters/g and correlated closely with local cerebral blood flow. The hematocrits within parenchymal microvessels were 45-75% of the arterial hematocrit, which indicates that red cells more rapidly traverse brain microvessels than do plasma proteins. The mean transit times of blood through parenchymal microvessels were extremely short and ranged from 0.3 to 0.6 s.

Animals↗

The effects of chronic serum sickness on albumin distribution and glucose utilization in rat brain.

The level of cerebrospinal fluid (CSF) protein is elevated in diseases and disease models that are associated with circulating immune complexes such as serum sickness. Circulatory immune complexes are known to deposit in the basal lamina of fenestrated capillaries and may, as a result, affect both capillary bed and parenchymal function. Since the brain has both fenestrated and unfenestrated capillaries and immune complexes deposit to a varying extent in the fenestrated capillaries in chronic serum sickness, cerebral capillary permeability to protein may be altered in some brain areas and lead to the elevation of CSF proteins. In addition various other cerebrovascular and metabolic functions may also be affected by this condition. In this study either radio-iodinated serum albumin (RISA) or 2-[14C]deoxyglucose (14C-2DG) was intravenously injected into control Wistar rats and Wistar rats with chronic serum sickness; subsequently the tissue levels of radioactivity were measured by quantitative autoradiography in 4 brain areas with fenestrated capillaries and 11 brain areas with unfenestrated capillaries. The 2-min distribution of RISA, which demarcates the volume of circulating plasma in perfused microvessels and is generally proportional to local plasma flow, was the same in control and experimental rats. The passage of RISA from blood into brain over 30 min was negligible in both groups; thus cerebral capillary permeability to albumin was not detectably increased in any of these 15 brain areas by chronic serum sickness. The rate of local cerebral glucose utilization, an indicator of local metabolic and neural activity, was calculated from the 14C-2DG data and was virtually identical in control and experimental rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗

Pentobarbital produces dissimilar changes in glucose influx and utilization in brain.

The effects of pentobarbital sodium on local cerebral glucose utilization (LCGU) and 3-O-methylglucose (3-MG) influx were measured by quantitative autoradiography in 52 brain areas of control and treated rats. Pentobarbital (50 mg/kg ip) lowered LCGU to a relatively uniform rate (approximately 35 mumol.100 g-1.min-1) in 24 of 25 forebrain areas. Among the 18 hindbrain areas, LCGU was decreased by pentobarbital by 15-55% (range 50-157 and 28-110 mumol.100 g-1.min-1 in control and treated rats, respectively). In contrast, pentobarbital lowered the 3-MG influx rate constant and permeability-surface area product by 20-30% in nearly all brain structures. The 3-MG results fit a model in which both the half-saturation constant and the maximal velocity of the glucose carrier are decreased by pentobarbital. After pentobarbital treatment, the ratio of local cerebral plasma flow (LCPF) to LCGU was the same as in controls for brain areas in which LCGU was less than 35 mumol.100 g-1.min-1 but was higher in brain areas where LCGU exceeded 35 mumol.100 g-1.min-1. Pentobarbital produced dissimilar changes in LCGU, 3-MG influx, and LCPF; these processes may thus not be closely linked during pentobarbital anesthesia.

3-O-Methylglucose↗