Abnormalities of Glucose Metabolism in Alzheimer's Disease SIEGFRIED HOYER Department of Pathochemistry and General Neurochemistry University of Heidelberg Heidelberg, Germany
Normal brain function is closely correlated with unimpaired cerebral circulation and an adequate supply of the substrates oxygen and glucose as well as with unimpaired neuronal utilization of these two substrates. The mature, healthy, nonstarved mammalian brain uses glucose only to obtain energy in the form of ATP to meet its functional and structural requirements (Hoyer 1970; Siesjo 1978). The breakdown of 1 mol of glucose provides a total of 38 mol of ATP. Glycolysis yields a total of 8 mol of ATP, 6 mol of which is derived from oxidation ofNADH 2 generated in the glycerine aldehyde phosphate dehydrogenase reaction. Equivalents for the formation of another 30 mol of ATP are provided by mitochondrial oxidation via pyruvate dehydrogenase (PDHC), isocitrate dehydrogenase (ICDHC), alpha-ketoglutarate dehydrogenase (KGDHG), succinate dehydrogenase, and malate dehydrogenase. Thus, nearly one-half (47%) the oxidation equivalents for ATP production are formed in the calcium-dependent multienzyme complexes pyruvate dehydrogenase, isocitrate dehydrogenase, and alphaketoglutarate dehydrogenase, whereas only 2 mol of ATP (-5%) is formed by processes other than oxidation (Erecinska and Silver 1989).Disturbances in cerebral energy formation may therefore be assumed to cause brain dysfunction. Recently, the principle of differentiating between dementia of the Alzheimer type (DA T) of early and late onset has been reinstated (Bowen and Davison 1986; Farrer et al. 1990;Roth 1986). In this contribution, the results of the measurements of cerebral blood flow (CBF) and of the cerebral metabolic rates (CMRs) of oxygen, glucose, CO2 , and lactate in incipient early-onset dementia of the Alzheimer type (EODA T), and late-onset dementia of the Alzheimer type (LODAT; incipient and advanced) are dealt with, and the changes in oxidative metabolism are discussed with respect to the implications for cerebral energy metabolism.
MATERIAL AND METHODS Investigations were performed in 20 patients with EODA T and 11 patients with LODAT during incipient dementia. Seven patients had advanced states of LODAT. The inclusion criteria and diagnostic procedures have been discussed elsewhere (Hoyer, Oesterreich, and Wagner 1988;Hoyer, Nitsch, and Oesterreich 1991). Global CBF was determined by a modified Kety-Schmidt technique (1948). Volumes of oxygen and CO2 and concentrations of glucose and lactate were measured in one femoral artery and in the superior bulb of the internal jugular vein, which contains mixed cerebral venous blood only. The respective CMRs were calculated from CBF and the cerebral arteriovenous substrate differences. (For further methodologic details, see Hoyer, Nitsch, and Oesterreich 1991). 53
54
ANNALS NEW YORK ACADEMY OF SCIENCES
RESULTS Mean values and standard deviations for CBF and the CMRs of oxygen, COz, glucose, and lactate and the calculated lactate-to-glucose ratio in each group of patients studied are presented in TABLE l. The data for each patient group were compared among the patient groups and with those obtained for middle-aged healthy controls. In incipient EODAT, significant changes became obvious in the CMR of glucose (decreased), the CMR of lactate, and the lactate-to-glucose ratio (both increased). In incipient LODAT, CBF and the CMRs of oxygen and CO 2 were lower than those in middle-aged healthy controls and in patients with incipient EODAT. Whereas the reduced CMR of glucose did not show any difference from that in incipient EODAT, the CMR of lactate returned to normal. In advanced LODAT, CBF had dropped further than in incipient LODAT, but no other differences of significance compared with incipient LODAT were observed. On the basis of the biochemical equation for ATP production from glucose and oxygen (I mol of glucose is oxidized by 6 mol of oxygen to form 6 mol of COz and 36 mol of ATP), the rate of ATP formation was calculated from the CMRs measured for oxygen, glucose, and lactate (TABLE 2). The rate of ATP formation in middle-aged healthy controls is in good agreement with ATP production rates in experimental animals under resting conditions (Erecinska and Silver 1989). ATP formation was reduced by 54% in incipient EODAT, by 46% in incipient LODAT, and by 58% in advanced LODAT compared with that in middle-aged healthy controls. The positive balance between the measured and the calculated CMR of oxygen in patients with dementia indicates that oxygen is not exclusively used for the oxidation of glucose as it is in middle-aged healthy controls. The positive balance between measured and calculated CMR of oxygen as well as the positive balance between measured and calculated CMR of CO 2 may indicate the oxidation of substrates other than glucose in the multienzyme complexes forming COz'
DISCUSSION In a series of postmortem studies in DAT brain, involvement of enzymes active in glucose metabolism was demonstrated. The enzyme phosphofructokinase, which controls flux in glycolytic glucose breakdown, was decreased to 10% of control values (Bowen et al. 1979; Iwangoff et al. 1980). PDHC was diminished in different cortical areas by 30 to 40%, whereas neither citrate synthase nor fumarase activity changed (Perry et al: 1980; Sorbi, Bird, and Blass 1983). KGDHC activity was most markedly reduced, by around 90% in the frontal and occipital cortices and by 100% in the midtemporal cortex (Gibson et al. 1988). Although these metabolic abnormalities derive from patients with obviously late-onset DAT, in obviously early-onset DAT the activity of the glycolytic enzyme hexokinase was decreased by nearly 40% and that of lactate dehydrogenase was increased by 13% in the nucleus basalis of Meynert. The concentration of the energy-utilizing enzyme (Na +, K +)-ATPase dropped to 54% in this brain region, whereas Ca?+-ATPase did not vary (Liguri et al. 1990). In neocortical tissue samples removed at diagnostic craniotomy from patients with apparently earlyonset DAT, no clear changes were found in the activity of phosphofructokinase. In two of a total of four samples, values greater than 2 standard deviations below the control mean were reported, corresponding to a 20% reduction (Sims et al. 1987). Despite this inconsistent result in a small number of samples, the foregoing findings
44 ± II
46 ± 9 66 ± 5 75 ± 5
II
20 11 7
55.7 54.4 46.5 32.0
± ± ± ± 3.0 2.5 6.2"'· 5.0"'
!
=
~>
::
ANNALS NEW YORK ACADEMY OF SCIENCES
56
TABLE 2. Cerebral Metabolic Rates (CMRs, measured and calculated") of Oxygen (02)' Carbon Dioxide (C0 2), Oxidizable Glucose (Glucg.), and ATP Formation in Middle-Aged Healthy Controls (MAHC) and in Patients with Incipient (inc.) EODAT, Incipient LODAT, and Advanced (adv.) LODAT CMRS (umol/g X min) O2 MAHC Measured Calculated Balance inc. EODAT Measured Calculated Balance inc. LODAT Measured Calculated Balance adv. LODAT Measured Calculated Balance
1.54 1.56 - 0.02
CO 2
Gluc o , 0.26
+
1.67 1.56 0.11
+
1.50 0.72 0.78
0.12
+
1.45 0.72 0.73
1.24 0.84 + 0.60
0.14
+
1.27 0.84 0.43
1.13 0.66 0.47
0.11
+
1.03 0.66 0.37
+
ATP
9.36
4.32-46% of MAHC
5.04-54% of MAHC
3.96-42% of MAHC
a Basis of calculation of ATP production from the above CMRs: I. Measured CMR Glue is diminished by measured CMR of lactate: Calculated CMR of Gluc"" 2. Calculated CMR of Gluc.; X 6: Calculated CMR of oxygen (which is used for oxidative phosphorylation of glucose). 3. ATP production from oxidative phosphorylation of glucose: Calculated CMR of oxygen X 6. 4. Calculated balance of oxygen and CO2 is assumed to be used for and formed from oxidation of substrates other than glucose.
suggest overall that a functional insufficiency of enzymes is involved in glycolytic and oxidative glucose breakdown and energy metabolism in DAT brain. As is obvious from the data in TABLE 2, the reduction of ATP formation in incipient DAT of both early and late onset was approximately twice that demonstrated by Sims et al. (1983) in tissue samples taken at diagnostic craniotomy. When the positive balance ofoxygen and CO 2is taken into account, however, the oxidation of substrates other than glucose for energy production may be assumed. Evidence indicates that endogenous glutamate may be one candidate for glucose substitution (Hoyer and Nitsch 1989) and that this glutamate may be provided from glutamine catabolism (Hoyer, Nitsch, and Oesterreich 1990). Furthermore, cerebral free fatty acids may be metabolized when glucose is lacking from the brain, as in DAT (Farooqui, Liss, and Horrocks 1988; Westerberg, Deshpande, and Wieloch 1987). In oxidation of amino acids, free fatty acids, or both, CO 2 is formed (TABLE 2), and certain amounts of ATP may be produced to minimize the loss of ATP from glucose oxidation. In contrast to other interpretations of the abnormalities in oxidative metabolism in DAT brain (Sims et al. 1983; 1987), the present data along with the reduced enzyme activities just discussed are not more suggestive of an uncoupling of oxidative phosphorylation in DAT brain than of a disturbance in glycolytic glucose breakdown and oxidation of pyruvate at its control level (Hoyer et al. 1988; 1991).
HOYER: ABNORMALITIES OF GLUCOSE METABOLISM IN AD
57
SUMMARY In normoglycemic patients with either incipient early-onset or incipient late-onset dementia of the Alzheimer type, the predominant disturbance consisted of a significant reduction in cerebral glucose utilization. Alterations in cerebral blood flow and oxygen consumption first occurred in late-onset dementia types. In advanced late-onset dementia, these parameters had decreased most severely. The calculated ATP production rate from glucose indicated a drastic loss of energy in all patients studied. As not all oxygen consumed by the brain was used for glucose oxidation, oxidation of substrates other than glucose (endogenous amino acids and free fatty acids) is assumed to minimize the energy loss from glucose. The possibility that the abnormalities in oxidative and energy metabolism in dementias of the Alzheimer type are due to metabolic abnormalities in glycolytic glucose breakdown and pyruvate oxidation, rather than to an uncoupling of oxidative phosphorylation, is discussed.
REFERENCES BOWEN, D. M. & A. N. DAVISON. 1986. Biochemical studies of nerve cells and energy metabolism in Alzheimer's disease. Br. Med. Bull. 42: 75-80. BOWEN, D. M., P. WHITE, J. A. SPILLANE, M. J. GOODHARDT, G. CURZON, P. IWANGOFF, W. MEIER-RUGE & A. N. DAVISON. 1979. Accelerated ageing or selective neuronal loss as an important cause of dementia? Lancet I: 11-14. ERECINSKA, M. & I. A. SILVER. 1989. ATP and brain function. J. Cereb. Blood Flow Metab. 9: 2-19. FAROOQUI, A. A., L. LISS & L. A. HORROCKS. 1988. Neurochemical aspects of Alzheimer's disease: Involvement of membrane phospholipids. Metab, Brain Dis. 3: 19-35. FARRER, L. A., L. H. MYERS, L. A. CUPPLES, P. H. ST. GEORGE-HYSLOP, T. D. BIRD, M. N. ROSSOR, M. J. MULLAN, R. POLINSKY, L. HESTON, C. VAN BROEKHOVEN, J. J. MARTIN, D. CRAPPER-McLACHLAN & J. H. GROWDON. 1990. Transmission and age-at-onset patterns in familial Alzheimer's disease: Evidence for heterogeneity. Neurology 40: 395-403. GIBSON, G. E., K. F. R. SHEU, J. P. BLASS, A. BAKER, K. C. CARLSON, B. HARDING & P. PERRINO. 1988. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Arch. Neurol. 45: 836-840. HOYER, S. 1970. Der Aminosaurenstoffwechsel des normalen menschlichen Gehirns. Klin. Wochenschr. 48: 1239-1243. HOYER, S. & R. NITSCH. 1989. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J. Neural Transm. 75: 227-232. HOYER, S., R. NITSCH & K. OESTERREICH. 1990. Ammonia is endogenously generated in the brain in the presence of presumed and verified dementia of Alzheimer type. Neurosci. Lett. 117: 358-362. HOYER, S., R. NITSCH & K. OESTERREICH. 1991. Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type. A cross-sectional comparison against advanced late-onset and incipient early-onset cases. J. Neural Transm. (Parkinson's diseaseDementia section). 3: 1-14. HOYER, S., K. OESTERREICH & O. WAGNER. 1988. Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J. Neurol. 235: 143-148. IWANGOFF, P., R. ARMBRUSTER, A. ENZ, W. MEIER-RUGE & P. SANDOZ. 1980. Glycolytic enzymes from human autoptic brain cortex: Normally aged and demented cases. In Biochemistry of Dementia. P. J. Roberts, Ed.: 258-262. Wiley. Chichester. KETY, S. S. & C. F. SCHMIDT. 1948. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: Theory, procedure and normal values. J. Clin. Invest. 27: 476-483.
58
ANNALS NEW YORK ACADEMY OF SCIENCES
LIGURI, G., N. TADDEI, P. NASSI, S. LATORRACA, C. NEDIANI & S. SORBI. 1990. Changes in Na ", K+ -ATP-ase, Ca2+-ATP-ase and some soluble enzymes related to energy metabolism in brains of patients with Alzheimer's disease. Neurosci. Lett. 112: 338-342. PERRY, E. K., R. H. PERRY, B. E. TOMLINSON, G. BLESSED & P. H. GIBSON. 1980. Coenzyme A-acetylating enzymes in Alzheimer's disease: Possible cholinergic "compartment" of pyruvate dehydrogenase. Neurosci. Lett. 18: 105-110. ROTH, M. 1986. The association of clinical and neurological findings and its bearing on the classification and aetiology of Alzheimer's disease. Br, Med. Bull. 42: 42-50. SIESJO, B. K. 1978. Brain Energy Metabolism. Chapt. 1 and 6. Wiley. Chichester. SIMS, N. R., J. P. BLASS, C. MURPHY, D. M. BOWEN & D. NEARY. 1987. Phosphofructokinase activity in the brain in Alzheimer's disease. Ann. Neurol. 21: 509-510. SORBI, S., E. D. BIRD & J. P. BLASS. 1983.Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann. Neurol. 13: 72-78. SIMS, N. R., D. M. BOWEN, D. NEARY & A. N. DAVISON. 1983. Metabolic processes in Alzheimer's disease: Adenine nucleotide content and production of I'C02 from (V_I'C) glucose in vitro in human neocortex. J. Neurochem. 41: 1329-1334. SIMS, N. R., J. M. FINEGAN, J. P. BLASS, D. M. BoWEN & D. NEARY. 1987. Mitochondrial function in brain tissue in primary degenerative dementia. Brain Res. 436: 30-38. WESTERBERG, E., J. K. DESHPANDE & T. WIELOCH. 1987. Regional differences in arachidonic acid release in rat hippocampal CAl and CA3 regions during cerebral ischemia. 1. Cereb. Blood Flow Metab. 7: 189-192.
Normal brain function is closely correlated with unimpaired cerebral circulation and an adequate supply of the substrates oxygen and glucose as well as with unimpaired neuronal utilization of these two substrates. The mature, healthy, nonstarved mammalian brain uses glucose only to obtain energy in the form of ATP to meet its functional and structural requirements (Hoyer 1970; Siesjo 1978). The breakdown of 1 mol of glucose provides a total of 38 mol of ATP. Glycolysis yields a total of 8 mol of ATP, 6 mol of which is derived from oxidation ofNADH 2 generated in the glycerine aldehyde phosphate dehydrogenase reaction. Equivalents for the formation of another 30 mol of ATP are provided by mitochondrial oxidation via pyruvate dehydrogenase (PDHC), isocitrate dehydrogenase (ICDHC), alpha-ketoglutarate dehydrogenase (KGDHG), succinate dehydrogenase, and malate dehydrogenase. Thus, nearly one-half (47%) the oxidation equivalents for ATP production are formed in the calcium-dependent multienzyme complexes pyruvate dehydrogenase, isocitrate dehydrogenase, and alphaketoglutarate dehydrogenase, whereas only 2 mol of ATP (-5%) is formed by processes other than oxidation (Erecinska and Silver 1989).Disturbances in cerebral energy formation may therefore be assumed to cause brain dysfunction. Recently, the principle of differentiating between dementia of the Alzheimer type (DA T) of early and late onset has been reinstated (Bowen and Davison 1986; Farrer et al. 1990;Roth 1986). In this contribution, the results of the measurements of cerebral blood flow (CBF) and of the cerebral metabolic rates (CMRs) of oxygen, glucose, CO2 , and lactate in incipient early-onset dementia of the Alzheimer type (EODA T), and late-onset dementia of the Alzheimer type (LODAT; incipient and advanced) are dealt with, and the changes in oxidative metabolism are discussed with respect to the implications for cerebral energy metabolism.
MATERIAL AND METHODS Investigations were performed in 20 patients with EODA T and 11 patients with LODAT during incipient dementia. Seven patients had advanced states of LODAT. The inclusion criteria and diagnostic procedures have been discussed elsewhere (Hoyer, Oesterreich, and Wagner 1988;Hoyer, Nitsch, and Oesterreich 1991). Global CBF was determined by a modified Kety-Schmidt technique (1948). Volumes of oxygen and CO2 and concentrations of glucose and lactate were measured in one femoral artery and in the superior bulb of the internal jugular vein, which contains mixed cerebral venous blood only. The respective CMRs were calculated from CBF and the cerebral arteriovenous substrate differences. (For further methodologic details, see Hoyer, Nitsch, and Oesterreich 1991). 53
54
ANNALS NEW YORK ACADEMY OF SCIENCES
RESULTS Mean values and standard deviations for CBF and the CMRs of oxygen, COz, glucose, and lactate and the calculated lactate-to-glucose ratio in each group of patients studied are presented in TABLE l. The data for each patient group were compared among the patient groups and with those obtained for middle-aged healthy controls. In incipient EODAT, significant changes became obvious in the CMR of glucose (decreased), the CMR of lactate, and the lactate-to-glucose ratio (both increased). In incipient LODAT, CBF and the CMRs of oxygen and CO 2 were lower than those in middle-aged healthy controls and in patients with incipient EODAT. Whereas the reduced CMR of glucose did not show any difference from that in incipient EODAT, the CMR of lactate returned to normal. In advanced LODAT, CBF had dropped further than in incipient LODAT, but no other differences of significance compared with incipient LODAT were observed. On the basis of the biochemical equation for ATP production from glucose and oxygen (I mol of glucose is oxidized by 6 mol of oxygen to form 6 mol of COz and 36 mol of ATP), the rate of ATP formation was calculated from the CMRs measured for oxygen, glucose, and lactate (TABLE 2). The rate of ATP formation in middle-aged healthy controls is in good agreement with ATP production rates in experimental animals under resting conditions (Erecinska and Silver 1989). ATP formation was reduced by 54% in incipient EODAT, by 46% in incipient LODAT, and by 58% in advanced LODAT compared with that in middle-aged healthy controls. The positive balance between the measured and the calculated CMR of oxygen in patients with dementia indicates that oxygen is not exclusively used for the oxidation of glucose as it is in middle-aged healthy controls. The positive balance between measured and calculated CMR of oxygen as well as the positive balance between measured and calculated CMR of CO 2 may indicate the oxidation of substrates other than glucose in the multienzyme complexes forming COz'
DISCUSSION In a series of postmortem studies in DAT brain, involvement of enzymes active in glucose metabolism was demonstrated. The enzyme phosphofructokinase, which controls flux in glycolytic glucose breakdown, was decreased to 10% of control values (Bowen et al. 1979; Iwangoff et al. 1980). PDHC was diminished in different cortical areas by 30 to 40%, whereas neither citrate synthase nor fumarase activity changed (Perry et al: 1980; Sorbi, Bird, and Blass 1983). KGDHC activity was most markedly reduced, by around 90% in the frontal and occipital cortices and by 100% in the midtemporal cortex (Gibson et al. 1988). Although these metabolic abnormalities derive from patients with obviously late-onset DAT, in obviously early-onset DAT the activity of the glycolytic enzyme hexokinase was decreased by nearly 40% and that of lactate dehydrogenase was increased by 13% in the nucleus basalis of Meynert. The concentration of the energy-utilizing enzyme (Na +, K +)-ATPase dropped to 54% in this brain region, whereas Ca?+-ATPase did not vary (Liguri et al. 1990). In neocortical tissue samples removed at diagnostic craniotomy from patients with apparently earlyonset DAT, no clear changes were found in the activity of phosphofructokinase. In two of a total of four samples, values greater than 2 standard deviations below the control mean were reported, corresponding to a 20% reduction (Sims et al. 1987). Despite this inconsistent result in a small number of samples, the foregoing findings
44 ± II
46 ± 9 66 ± 5 75 ± 5
II
20 11 7
55.7 54.4 46.5 32.0
± ± ± ± 3.0 2.5 6.2"'· 5.0"'
!
=
~>
::
ANNALS NEW YORK ACADEMY OF SCIENCES
56
TABLE 2. Cerebral Metabolic Rates (CMRs, measured and calculated") of Oxygen (02)' Carbon Dioxide (C0 2), Oxidizable Glucose (Glucg.), and ATP Formation in Middle-Aged Healthy Controls (MAHC) and in Patients with Incipient (inc.) EODAT, Incipient LODAT, and Advanced (adv.) LODAT CMRS (umol/g X min) O2 MAHC Measured Calculated Balance inc. EODAT Measured Calculated Balance inc. LODAT Measured Calculated Balance adv. LODAT Measured Calculated Balance
1.54 1.56 - 0.02
CO 2
Gluc o , 0.26
+
1.67 1.56 0.11
+
1.50 0.72 0.78
0.12
+
1.45 0.72 0.73
1.24 0.84 + 0.60
0.14
+
1.27 0.84 0.43
1.13 0.66 0.47
0.11
+
1.03 0.66 0.37
+
ATP
9.36
4.32-46% of MAHC
5.04-54% of MAHC
3.96-42% of MAHC
a Basis of calculation of ATP production from the above CMRs: I. Measured CMR Glue is diminished by measured CMR of lactate: Calculated CMR of Gluc"" 2. Calculated CMR of Gluc.; X 6: Calculated CMR of oxygen (which is used for oxidative phosphorylation of glucose). 3. ATP production from oxidative phosphorylation of glucose: Calculated CMR of oxygen X 6. 4. Calculated balance of oxygen and CO2 is assumed to be used for and formed from oxidation of substrates other than glucose.
suggest overall that a functional insufficiency of enzymes is involved in glycolytic and oxidative glucose breakdown and energy metabolism in DAT brain. As is obvious from the data in TABLE 2, the reduction of ATP formation in incipient DAT of both early and late onset was approximately twice that demonstrated by Sims et al. (1983) in tissue samples taken at diagnostic craniotomy. When the positive balance ofoxygen and CO 2is taken into account, however, the oxidation of substrates other than glucose for energy production may be assumed. Evidence indicates that endogenous glutamate may be one candidate for glucose substitution (Hoyer and Nitsch 1989) and that this glutamate may be provided from glutamine catabolism (Hoyer, Nitsch, and Oesterreich 1990). Furthermore, cerebral free fatty acids may be metabolized when glucose is lacking from the brain, as in DAT (Farooqui, Liss, and Horrocks 1988; Westerberg, Deshpande, and Wieloch 1987). In oxidation of amino acids, free fatty acids, or both, CO 2 is formed (TABLE 2), and certain amounts of ATP may be produced to minimize the loss of ATP from glucose oxidation. In contrast to other interpretations of the abnormalities in oxidative metabolism in DAT brain (Sims et al. 1983; 1987), the present data along with the reduced enzyme activities just discussed are not more suggestive of an uncoupling of oxidative phosphorylation in DAT brain than of a disturbance in glycolytic glucose breakdown and oxidation of pyruvate at its control level (Hoyer et al. 1988; 1991).
HOYER: ABNORMALITIES OF GLUCOSE METABOLISM IN AD
57
SUMMARY In normoglycemic patients with either incipient early-onset or incipient late-onset dementia of the Alzheimer type, the predominant disturbance consisted of a significant reduction in cerebral glucose utilization. Alterations in cerebral blood flow and oxygen consumption first occurred in late-onset dementia types. In advanced late-onset dementia, these parameters had decreased most severely. The calculated ATP production rate from glucose indicated a drastic loss of energy in all patients studied. As not all oxygen consumed by the brain was used for glucose oxidation, oxidation of substrates other than glucose (endogenous amino acids and free fatty acids) is assumed to minimize the energy loss from glucose. The possibility that the abnormalities in oxidative and energy metabolism in dementias of the Alzheimer type are due to metabolic abnormalities in glycolytic glucose breakdown and pyruvate oxidation, rather than to an uncoupling of oxidative phosphorylation, is discussed.
REFERENCES BOWEN, D. M. & A. N. DAVISON. 1986. Biochemical studies of nerve cells and energy metabolism in Alzheimer's disease. Br. Med. Bull. 42: 75-80. BOWEN, D. M., P. WHITE, J. A. SPILLANE, M. J. GOODHARDT, G. CURZON, P. IWANGOFF, W. MEIER-RUGE & A. N. DAVISON. 1979. Accelerated ageing or selective neuronal loss as an important cause of dementia? Lancet I: 11-14. ERECINSKA, M. & I. A. SILVER. 1989. ATP and brain function. J. Cereb. Blood Flow Metab. 9: 2-19. FAROOQUI, A. A., L. LISS & L. A. HORROCKS. 1988. Neurochemical aspects of Alzheimer's disease: Involvement of membrane phospholipids. Metab, Brain Dis. 3: 19-35. FARRER, L. A., L. H. MYERS, L. A. CUPPLES, P. H. ST. GEORGE-HYSLOP, T. D. BIRD, M. N. ROSSOR, M. J. MULLAN, R. POLINSKY, L. HESTON, C. VAN BROEKHOVEN, J. J. MARTIN, D. CRAPPER-McLACHLAN & J. H. GROWDON. 1990. Transmission and age-at-onset patterns in familial Alzheimer's disease: Evidence for heterogeneity. Neurology 40: 395-403. GIBSON, G. E., K. F. R. SHEU, J. P. BLASS, A. BAKER, K. C. CARLSON, B. HARDING & P. PERRINO. 1988. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Arch. Neurol. 45: 836-840. HOYER, S. 1970. Der Aminosaurenstoffwechsel des normalen menschlichen Gehirns. Klin. Wochenschr. 48: 1239-1243. HOYER, S. & R. NITSCH. 1989. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type. J. Neural Transm. 75: 227-232. HOYER, S., R. NITSCH & K. OESTERREICH. 1990. Ammonia is endogenously generated in the brain in the presence of presumed and verified dementia of Alzheimer type. Neurosci. Lett. 117: 358-362. HOYER, S., R. NITSCH & K. OESTERREICH. 1991. Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type. A cross-sectional comparison against advanced late-onset and incipient early-onset cases. J. Neural Transm. (Parkinson's diseaseDementia section). 3: 1-14. HOYER, S., K. OESTERREICH & O. WAGNER. 1988. Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type? J. Neurol. 235: 143-148. IWANGOFF, P., R. ARMBRUSTER, A. ENZ, W. MEIER-RUGE & P. SANDOZ. 1980. Glycolytic enzymes from human autoptic brain cortex: Normally aged and demented cases. In Biochemistry of Dementia. P. J. Roberts, Ed.: 258-262. Wiley. Chichester. KETY, S. S. & C. F. SCHMIDT. 1948. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: Theory, procedure and normal values. J. Clin. Invest. 27: 476-483.
58
ANNALS NEW YORK ACADEMY OF SCIENCES
LIGURI, G., N. TADDEI, P. NASSI, S. LATORRACA, C. NEDIANI & S. SORBI. 1990. Changes in Na ", K+ -ATP-ase, Ca2+-ATP-ase and some soluble enzymes related to energy metabolism in brains of patients with Alzheimer's disease. Neurosci. Lett. 112: 338-342. PERRY, E. K., R. H. PERRY, B. E. TOMLINSON, G. BLESSED & P. H. GIBSON. 1980. Coenzyme A-acetylating enzymes in Alzheimer's disease: Possible cholinergic "compartment" of pyruvate dehydrogenase. Neurosci. Lett. 18: 105-110. ROTH, M. 1986. The association of clinical and neurological findings and its bearing on the classification and aetiology of Alzheimer's disease. Br, Med. Bull. 42: 42-50. SIESJO, B. K. 1978. Brain Energy Metabolism. Chapt. 1 and 6. Wiley. Chichester. SIMS, N. R., J. P. BLASS, C. MURPHY, D. M. BOWEN & D. NEARY. 1987. Phosphofructokinase activity in the brain in Alzheimer's disease. Ann. Neurol. 21: 509-510. SORBI, S., E. D. BIRD & J. P. BLASS. 1983.Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann. Neurol. 13: 72-78. SIMS, N. R., D. M. BOWEN, D. NEARY & A. N. DAVISON. 1983. Metabolic processes in Alzheimer's disease: Adenine nucleotide content and production of I'C02 from (V_I'C) glucose in vitro in human neocortex. J. Neurochem. 41: 1329-1334. SIMS, N. R., J. M. FINEGAN, J. P. BLASS, D. M. BoWEN & D. NEARY. 1987. Mitochondrial function in brain tissue in primary degenerative dementia. Brain Res. 436: 30-38. WESTERBERG, E., J. K. DESHPANDE & T. WIELOCH. 1987. Regional differences in arachidonic acid release in rat hippocampal CAl and CA3 regions during cerebral ischemia. 1. Cereb. Blood Flow Metab. 7: 189-192.
