Sami I. Harik

Reduced glucose transporter at the blood-brain barrier and in cerebral cortex in Alzheimer disease.

Abstract: We studied the hexose transporter prtotein of the frontal and temporal neocortex, hippocampui, putamen, cerebellum, and cerebral microvessels (which constitute the blood‐brain barrier) in Alzheimer disease and control subjects by reversible and covalent binding with [3H]cytochalasin B and by immunological reactivity. In Alzheimer disease subjects, we found a marked decrease in the hexose transporter in brain microvessels and in the cerebral neocortex and hippocampus, regions that are most affected in Alzheimer disease, but there were no abnormalities in the putajnen or cerebellum. Hexose transporter reduction in cerebrajl microves‐sels of Alzheimer subjects is relatively specific because other enzyme markers of brain endothelium were not significantly altered. The low density of the hexose transporter at the blood‐brain barrier and in the cerebral cortex in Alzheimer disease may be related to decreased in vivo measurements of cerebral oxidative metabolism.

Neurologic complications of gastric bypass surgery for morbid obesity.

Background: The number of bariatric procedures is rapidly growing as the prevalence of obesity in the USA is increasing. Such procedures are not without complications, and those affecting the nervous system are often disabling and irreversible. We now describe our experience with these complications and review the pertinent literature. Methods: We describe 26 patients with major neurologic conditions that seemed causally related to bariatric surgery encountered in the neurology service of a tertiary referral university medical center over a decade. Results: The neurologic complications affected most regions of the nervous system: encephalopathy, optic neuropathy, myelopathy, polyradiculoneuropathy, and polyneuropathy. Myelopathy was the most frequent and disabling problem; symptoms began about a decade after surgery. Encephalopathy and polyradiculoneuropathy were acute and early complications. Except for vitamin B12 and copper deficiencies in patients with myelopathy, we could not correlate specific nutritional deficiencies to the neurologic complications. All patients had multiple nutritional deficiencies, but their correction did not often yield dramatic results. The best result was achieved in one patient after surgical revision to reduce the bypassed jejunum. Conclusions: A wide spectrum of serious neurologic conditions may follow bariatric surgery. These complications may occur acutely or decades later.

Adrenergic Receptors in Aging and Alzheimer's Disease: Increased β2-Receptors in Prefrontal Cortex and Hippocampus

Abstract: Loss of pigmented noradrenergic locus ceruleus neurons occurs in Alzheimers disease (AD) and, to a lesser extent, in aging. We studied β‐adrenergic receptors and their subtypes, β1 and β2, by the specific binding of 125I‐pindolol to particulate membrane preparations from prefrontal cortex, hippocampus, putamen, and cerebellum and to sections from frontal cortex by in vitro autoradiography. In prefrontal cortex from controls, numbers of total β‐ and β‐adrenoceptors did not significantly correlate with age, but number of β1‐adrenoceptors showed a weak but significant negative correlation. Binding in tissue particulate preparations to total β‐receptors did not reveal significant differences in samples from prefrontal cortex between AD subjects and age‐matched controls. However, β1‐adrenoceptors were decreased and β2‐adrenoceptors were increased in number by ∼30‐50% in AD subjects. Thus, the relative ratio of β/β2‐receptors was decreased in AD. Binding by in vitro receptor autoradiography performed in a subset of samples of frontal cortex also showed β2‐adrenoceptors, and less consistently total β‐and β1recep‐tors, to be increased significantly in number in cortical laminae II, III, IV, and V of tissue sections from AD subjects. In these subjects, number of locus ceruleus cells and norepinephrine concentrations in putamen and frontal cortex were markedly reduced compared with values in controls. In the hippocampus, total β‐ and both β2‐ and β1‐adrenoceptors were increased in number in AD. In contrast, in the putamen. where β‐receptors predominate, total β‐ and β1‐receptors were significantly decreased in number with no consistent change in content of β2‐receptors in AD. There were no significant changes in the cerebellum. Specific pindolol binding was not affected by interval between death and sampling of tissue at autopsy. Our results indicate selective changes in number of β‐receptors in AD. These changes in the cortex and hippocampus suggest receptor upregulation in response to noradrenergic deafferentation from the locus ceruleus or may simply reflect glial proliferation in AD.

Role of dopamine in ischemic striatal injury: Metabolic evidence

We studied the effect of a prior unilateral substantia nigra lesion on the recovery of local cerebral glucose utilization (ICMRgl) and blood flow (ICBF), measured autoradiographically, following 30 minutes of forebrain ischemia in rats. On the lesioned side, striatal dopamine (DA) and its metabolites were depleted by more than 95% and did not change after ischemia. In contrast, significant increases in striatal DA metabolites occurred on the nonlesioned side following ischemia. Despite unilateral DA depletion, no side-to-side ICBF differences were observed. However, the normally occurring postischemic restoration of ICMRgl in the dorsolateral striatum at 2 and 4 hours of recirculation was suppressed on the DA-depleted side, and the degree of ICMRgl/ICBF uncoupling diminished. These results suggest that integrity of the DA system accentuates postischemic metabolism/flow uncoupling in the striatum and may therefore contribute to selective ischemic injury of this structure.

Spontaneously Remitting Spinal Epidural Hematoma in a Patient on Anticoagulants

ACUTE spinal epidural hemorrhage (SEH) is a potentially curable cause of spinal-cord and root compression if recognized and treated promptly. The treatment of choice is immediate surgical decompres...

Blood-brain barrier monoamine oxidase: enzyme characterization in cerebral microvessels and other tissues from six mammalian species, including human.

Abstract: We studied the enzyme monoamine oxidase (MAO) in isolated cerebral microvessels, and in mitochondria‐enriched brain and liver preparations from six mammalian species, including human. We also studied MAO distribution in various tissues and in discrete brain regions of the rat. MAO was assessed by measuring the specific binding of [3H]pargyline, an irreversible MAO inhibitor, and the rates of oxidation of known MAO substrates: benzylamine, tyramine, tryptamine, and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetra‐hydropyridine (MPTP). Molecular forms of MAO were examined by using specific MAO inhibitors, and by polyacrylamide gel electrophoresis after [3H]pargylihe binding. In general, the liver from all species had higher MAO levels than the brain, with minor variation among species in their brain and liver MAO content. However, there were remarkable species differences in brain microvessel MAO, with rat microvessels having one of the highest MAO activity among all tissues, whereas MAO activities in brain microvessels from humans, mice, and guinea pigs were very low. In most rat tissues, including the brain, there was a preponderance of MAO‐B over MAO‐A. The only exceptions were the heart and skeletal muscle. Estimates of MAO half‐life in rat brain microvessels, rat brain, and rat liver indicated that microvessel MAO had a higher turnover rate. The reasons underlying the remarkable enrichment of rat cerebral microvessels with MAO‐B are unknown, but it is evident that there are marked species differences in brain capillary endothelium MAO activity. The biological significance of these findings vis a vis the role of MAO as a “biochemical blood‐brain barrier” that protects the brain from circulating neurotoxins and biogenic amines should be investigated.

Hypoxia‐induced brain angiogenesis in the adult rat.

1. Prolonged hypoxia increases the brain vascularity. Here we studied the protein and deoxyribonucleic acid (DNA) content of isolated cerebral microvessels in hypoxic and control rats. 2. Adult male Wistar rats that were subjected to hypobaric hypoxia at 50.5 kPa (0.5 atm) for periods of 1, 2, or 3 weeks and normoxic littermate controls were used. Cerebral microvessels were harvested by bulk isolation from the pooled cortical mantles of three to six rats in each group. The isolated microvessels were assayed for their protein and DNA content. 3. Microvessel protein yield increased from 0.31 to 0.45 mg of microvessel protein (g wet wt)‐1 of cerebral cortex after 1 week of hypoxia, but did not increase further during up to 3 weeks of hypoxia. In contrast, microvessel DNA yield did not increase during the first week of hypoxia, but increased significantly after 2 weeks of hypoxia and continued to increase up to 56 micrograms of microvessel DNA (g cerebral cortex)‐1 at 3 weeks of hypoxia (normoxic mean was 32 micrograms DNA g‐1). 4. The cell size index (mg protein:mg DNA) of isolated cerebral microvessels increased after 1 week of hypoxia, suggesting microvascular hypertrophy, but returned to control by the second week of hypoxia and decreased to below control levels by the third week of hypoxia, suggesting microvascular hyperplasia. These results indicate that the increased vascularity of the brain in hypobaric hypoxia progresses from an early phase of microvascular hypertrophy to later microvascular hyperplasia.

Specific Ouabain Binding to Brain Microvessels and Choroid Plexus

The energy-dependent transport of ions across the blood-brain barrier and the blood-cerebrospinal fluid barrier by Na+, K+-ATPase is credited with an important role in brain homeostasis. In this study, we have assessed the relative enrichment of Na+, K+-ATPase in regional brain capillary preparations and in the choroid plexus by the quantitative determination of the cardiac glycoside binding sites in these preparations using [3H]ouabain as a ligand. We find that ouabain binds specifically to brain microvessels of the rat and the pig and to the choroid plexus of the pig in a saturable manner. The maximum density of ouabain binding sites in brain microvessels of both species is about one-fourth that of the crude membranes of the cerebrum and cerebellum. The density of ouabain binding sites in the pig choroid plexus is intermediate between that of the brain and brain microvessels. We do not find regional differences in ouabain binding to membrane fractions of the cerebrum and cerebellum, nor any significant differences in ouabain binding to cerebral and cerebellar microvessels. These findings provide quantitative estimates of Na+, K+-ATPase in brain capillaries and choroid plexus.

Time-course and reversibility of the hypoxia-induced alterations in cerebral vascularity and cerebral capillary glucose transporter density

The adult rat adapts to prolonged moderate hypobaric hypoxia by polycythemia, increased brain vascularity, and increased density of the brain capillary glucose transporter (GLUT-1). We now report on the time-course and reversibility of these adaptive alterations. Adult male Wistar rats were subjected to hypobaric hypoxia at 0.5 atmosphere for periods of 4 days or 1, 2 or 3 weeks, and compared to normoxic littermate controls. Reversibility of the effects of hypoxia was studied in rats subjected to hypobaric hypoxia for 3 weeks and then allowed to recover at normobaric conditions for 3 additional weeks. Cerebral vascularity was studied in cross-sections of the cerebral cortex that were immunocytochemically stained with a GLUT-1 antibody. The density of GLUT-1 was determined in isolated cerebral microvessels by quantitative autoradiography of immunoblots. Blood hematocrit and cerebral microvascularity did not significantly increase after 4 days of hypoxia, but were significantly increased at 1, 2 and 3 weeks of hypoxia. Three weeks of normoxic recovery after 3 weeks of hypoxia reversed the polycythemia and cerebral hypervascularity. However, the density of GLUT-1 in isolated cerebral microvessels, which was significantly increased after 1 and 3 weeks of hypoxia, remained elevated after 3 weeks of normoxia.

Vascular Perfusion and Blood‐Brain Glucose Transport in Acute and Chronic Hyperglycemia

Abstract: We studied the effects of acute and streptozotocin‐induced chronic hyperglycemia on regional brain blood flow and perfusion characteristics, and on the regional transport of glucose across the blood‐brain barrier in awake rats. We found (1) a generalized decrease in regional brain blood flow in both acute and chronic hyperglycemia; (2) that chronic, but not acute, hyperglycemia is associated with a marked and diffuse decrease in brain l‐glucose space; and (3) that chronic hyperglycemia does not alter blood‐to‐brain glucose transport. Taken together, these results suggest that in streptozotocin‐induced chronic hyperglycemia, there is a reduction in the proportion of perfused brain capillaries and/or an alteration in brain endothelial membrane properties resulting in decreased noncarrier diffusion of glucose.