LETTERS

Altered Glucose Metabolism in Microvessels from Patients with Alzheimer’s Disease Sami I. Harik, MD, and Joseph C . LaManna, PhD The article by Marcus and collaborators { 1) may have implications but has left us confused. The authors investigated, on one hand, the in vivo kinetic phosphorylation constant for hexokinase (K3),and calculated the cerebral 2-deoxyglucose uptake rate in human subjects by positron emission tomography. They reported decreased cerebral metabolic rate for glucose in Alzheimer disease (AD) subjects, which is consistent with the results of others (see [2) for review). The novel aspect of their study, on the other hand, was their in vitro investigation of 2-deoxyglucose uptake in isolated brain microvessel preparations obtained at autopsy from AD and control subjects. They reported an increased apparent Km (i.e., decreased affinity) for 2-deoxyglucose uptake by brain microvessels from AD subjects, which they interpreted as indicating decreased hexokinase activity. However, their results are incomplete and not fully interpretable in the absence of the Vmax data, which they surely must have obtained as prerequisite for Km estimations. In any case, we do not believe they should have linked their in vitro results with the decreased brain glucose metabolism in AD subjects in vivo in a cause and effect relationship. The brain is effectively isolated from the systemic circulation by specialized capillaries with tight interendothelial junctions that form the blood-brain barrier (BBB).The BBB limits the simple diffusion of water-soluble glucose from blood to brain. A carrier-mediated glucose transport system in brain capillaries enables glucose entry into the brain [3, 4). The brain capillary endothelial cells, which constitute much less than 1% of the brain weight, have to transport glucose for the whole brain. We estimate that these cells transport 10 times their weight of glucose per minute [ 3 , 51. Glucose transport across the BBB does not involve glucose phosphorylation by hexokinase. In fact, phosphorylation would impede transport. Only a negligible fraction of the glucose that is transported across the BBB is phosphorylated in brain endothelial cells, presumably to support their metabolic requirements. Furthermore, brain endothelial cells can use other metabolic substrates for their metabolism {b]. Thus, brain endothelial cells are, in this respect, perfect servants that transport enormous amounts of glucose without using much of it. Our confusion with the paper by Marcus and colleagues [11 relates to their rationale for investigating hexokinase activity of brain microvessels, since it has little to do with their primary function: transport. We previously reported that cerebral microvessels isolated from AD subjects have a marked decrease in their glucose transporter density [7), and suggested that this may be related to the decreased brain glucose metabolism, probably as a result rather than the cause. Even if we accept the conclusion of Marcus and associates 111 that hexokinase is decreased in brain capillaries of AD

subjects, it is not clear why this should be related to the decreased metabolic rate for glucose in AD, as they claim. To the contrary, decreased hexokinase activity in brain capillaries of AD subjects might be considered an advantage, or a compensatory response for the decreased density of the glucose transporter in these microvessels [7). Decreased hexokinase activity in brain microvessels probably means that the microvessels are using even less of the glucose that they transport than they would othcrwise, and suggests that they now may be using other sources of metabolic fuel.

Department of Neurology University Hospitals of Clwelund Case WJesternReserve University School of Medicine Cleveland, OH

References 1. Marcus RDL, deLeon MJ, Goldman J, et al. Altered glucose metabolism in microvessels from patients with Alzheimer’s disease. Ann Neurol 1989;26:91-94 2. Riege WH, Metter EJ. Cognitive and brain imaging measures of Alzheimer’s disease. Neurobiol Aging 1988;9:69-86 3. Dick APK, Harik SI, Klip A, Walker DM. Identification and characterizationof the glucose transporter of the blood-brain barrier by cytochalasin B binding and immunological reactivity. Proc Natl Acad Sci USA 1984;81:7233-7237 4. Kalaria RN, Gravina SA, SchmidleyJW, et al. The glucose transporter of the human brain and blood-brain barrier. Ann Neurol

1988;24:757-764 5. LaManna JC, Harik SI. Regional comparisons of brain glucose influx. Brain Res 1985;326:299-305 6. Goldstein GW. Relation of potassium transport co oxidative metabolism in isolated brain capillaries.J Physioi 1979;286:185-1’95 7. Kalaria RN, Harik SI. Reduced glucose transporter at the bloodbrain barrier and in cerebral cortex in Alzheimer disease. J Neurochem 198933: 1083-1 088

Intellectual Functioning in Treated Wilson’s Disease Alice Medalia, W D , and I. Herbert Scheinberg, M D Wilson’s disease (WD) is associated with hepatic, neurological, and psychiatric symptoms. Patients with W D and neurological symptomatology generally manifest cognitive deficits whereas those with only hepatic involvement do not El, 2). Since little is known about the effect, if any, of penicillamine treatment on cognitive deficits [3, 41, we have analyzed the results of intelligence testing in 7 patients with WD who were examined shortly afrer penicillamine treatment was started and again from 21 to 34 years later. All but one patient-who was neurologically asymptomatic-had mild or moderate neurological disease at the time of the first intellectual assessment. The Wechsler Adult Intelligence Scale (WAIS) or the Wechsler Intelligence Scale for Children (WISC) was administered initially. Patients were retested with the Wechsler Adult Intelligence Scale-Revised (WAIS-R), which yields IQ scores that are 7 to 8 points lower than those of the WAIS and WISC [ 5 ) . Therefore, 7

Copyright 0 1991 by the American Neurological Association

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Intellectual functioning in treated Wilson's disease.

LETTERS Altered Glucose Metabolism in Microvessels from Patients with Alzheimer’s Disease Sami I. Harik, MD, and Joseph C . LaManna, PhD The article...
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