Oxidative energy metabolism in Alzheimer brain

Reduction of the cerebral metabolic rate of glucose is one of the most predominant abnormalities generally found in the Alzheimer brain, whereas the cerebral metabolic rate of oxygen is only slightly diminished or not at all the beginning of this dementive disorder. This metabolic abnormality may induce severe functional disturbances, obviously preceding morphobiological changes. From the cerebral metabolic rates of oxidized glucose and oxygen, the cerebral ATP formation rate was calculated in incipient early-onset, incipient late-onset and stable advanced dementia of Alzheimer type. A reduction of ATP formation was found from at least 7% in incipient early-onset, to around 20% in incipient late-onset DAT, and from 35% to more than 50% in stable advanced dementia. This approximation was adjusted to findings demonstrating diminished activities of enzymes active in glucose metabolism and formation of oxidation equivalents for ATP production from substrates other than glucose. A reduction for energy formation to the same rrange was found, as was also recently reported, in vivo in Alzheimer patients. From this rather theoretical point of view, a permanent loss of energy by at least 7–20% in incipient and progressively advancing dementia of the Alzheimer type may by assumed, with an increasing tendency in stable advanced dementia to around 50% energy loss. This energy deficit may have drastic impacts on brain function.     

Glucose metabolism as the site of the primary abnormality in early-onset dementia of Alzheimer type?

Summary Global cerebral blood flow, oxidative brain metabolism, and the cerebral arteriovenous differences of amino acids and ammonia were studied in 20 clinically diagnosed patients with early-onset dementia of Alzheimer type (DAT). Eleven healthy age-matched subjects and 15 healthy young volunteers served as controls. The most prominent abnormality in patients with early-onset DAT was a 44% reduction in the cerebral metabolic rate of glucose and a fourfold increase of lactate production, whereas cerebral blood flow and the cerebral metabolic rate of oxygen were found not to be altered. The cerebral amino-N balance substantially changed in patients with early-onset DAT, showing a massive loss of amino acids and ammonia from the brain, which was indicative of excess protein catabolism due to cell degeneration in the acutely diseased brain. The abnormality found in glucose metabolism may suggest a perturbed control of glycolytic breakdown of glucose and its first oxidation step at the pyruvate dehydrogenase complex level, this thus being of pivotal significance in early-onset DAT.     

Multiinfarct and Alzheimer-type dementia investigated by transcranial Doppler sonography

Primary degenerative dementia of the Alzheimer type and multiinfarct dementia exhibit differences in cerebrovascular blood flow velocity profiles, which were investigated by transcranial Doppler sonography. The pulsatility indices, as angle-independent parameters of peripheral vascular resistence, measured in middle cerebral and basilar arteries of patients with multiinfarct dementia were significantly increased (p less than 0.005) compared with cases of primary degenerative dementia of the Alzheimer type and with healthy age-matched controls.     

Pathogenesis and pathophysiology of ischemic leukoencephalopathy

The cerebral white matter is highly susceptible to ischemic damage because of its location in the end-fields of penetrating arteries. Our studies have shown that hypertension, short-term variability of blood pressure, decreased oxygen dissociation of hemoglobin, and increased resistance of cerebral arterioles play important roles in the pathogenesis of Binswanger type dementia. While hypoperfusion was most remarkable in the frontal area and dopamine metabolism in the cerebrospinal fluid was impaired in Binswanger type dementia, cerebral blood flow decreased most conspicuously in the parietal area and there was an impairment of noradrenaline metabolism in the cerebrospinal fluid in senile dementia of Alzheimer type. Previous anatomical studies have indicated that the ascending dopaminergic system predominantly innervates the frontal cortex, while the noradrenergic system projects all cortical areas, including the parietal cortex. Our findings suggest frontally-dominant dysfunctions in Binswanger type dementia.     

The value of transcranial Doppler sonography in the differential diagnosis of Alzheimer disease vs multi-infarct dementia

Primary degenerative dementia of the Alzheimer type and multi-infarct dementia exhibit differences in cerebrovascular blood flow velocity profiles, which were investigated by means of transcranial Doppler sonography. The pulsatility indices, as angle-independent parameters of peripheral vascular resistance, measured in middle cerebral and basilar arteries of patients with multi-infarct dementia (MID), were significantly increased (p<0.005) with respect to cases of primary degenerative dementia of the Alzheimer type and to healthy age-matched controls. Approximately 75% of all MID patients exhibited small vessel disease rather than thromboembolism from the extracranial arteries and the heart, as judged by extracranial and transcranial Doppler sonographies, computerized cerebral tomographies, EEGs, and, if necessary, 2-D echocardiographies.     

Positron emission tomography in neuropsychology

By positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) local cerebral metabolic rate for glucose (LCMRGl) can be measured in man. Normal values in cerebral cortex and basal ganglia range from 35 to 50 mumol/100 g/min, the values in gray matter structures of the posterior fossa were 25-30 mumol/100 g/min, the lowest LCMRGl was found in the white matter (15-20 mumol/100 g/min). During sensory stimulation by various modalities functional activation increases LCMRGl in the respective special areas, while sleep decreases metabolic rate in all cortical and basal gray matter structures. In many neurological disorders CMRGl is altered in a disease-specific pattern. In dementia of the Alzheimer type CMRGl is impaired even in early stages with accentuation in the parieto-temporal cortex, while in multi-infarct dementia glucose uptake is mainly reduced in the multifocal small infarcts. In Huntington's chorea the most conspicuous changes are found in the caudate nucleus and putamen. In cases of focal lesions (e.g. ischemic infarcts) metabolic disturbances extend far beyond the site of the primary lesion and inactivation of metabolism is found in intact brain structures far away from the anatomical lesion. Additional applications of PET include determination of the metabolism of various substrates, of protein synthesis, of function and distribution of receptors, of tumor growth and of the distribution of drugs as well as the measurement of oxygen consumption, blood flow and blood volume.     

Cerebral metabolism of oxygen and glucose in a patient with MELAS syndrome

We studied cerebral oxygen and glucose metabolism as well as cerebral blood flow using positron emission tomography (PET) in a case with MELAS showing dementia, diabetes mellitus, ataxia and lactic acidosis without any signs of stroke. This case, confirmed to have a point mutation at position 3243 in the transfer RNA gene of mitochondrial DNA, developed a stroke-like episode 8 months after the PET study. Uncoupling was observed between cerebral oxygen metabolism and cerebral blood flow with reduced fractional oxygen extraction ratio, indicating "hyperemia", not ischemia. The "hyperemia" may be closely related to the malfunction of mitochondria in aerobic energy production. A drastic decrease in cerebral oxygen metabolism (CMR₂) was found globally in contrast to preserved cerebral glucose metabolism (CMR_glu), resulting in a remarkable decrease in the metabolic ratio (CMRO₂/CMR_glu). The dissociation between cerebral glucose and oxygen metabolism may be characteristic of MELAS.     

Positron emission tomography study of the human hypothalamus during normal ageing and in ischemic and degenerative disorders.

Regional blood flow and oxygen metabolism were determined by positron emission tomography, using the steady state technique with 15O, in the hypothalamus and in the whole brain of fifty two normal persons and patients suffering from cerebral ischemia and degenerative dementia. During normal ageing regional blood flow and oxygen consumption appeared to increase slightly in the hypothalamus and to decrease in the whole brain in 24 persons. In the young age group the hypothalamus was more protected against ischemia than in the elderly group. In the aged group with cerebral ischemia and degenerative dementia regional blood flow and oxygen consumption were decreased in the hypothalamus to the same extent as in the whole brain.     

Cerebral metabolic effects of glycerol infusion in diabetics with stroke

Measurement of cerebral blood flow and metabolism before and after intravenous infusion of 10% glycerol was investigated in 22 patients with acute cerebral ischemia, 10 of whom had diabetes mellitus and 12 of whom did not. In diabetic patients, resulting increases of hemispheric blood flow and reduction of oxygen consumption and CO₂ production were not significant whereas these changes in the non-diabetic group were significant. In diabetics cerebral glucose consumption and glucose:oxygen utilization ratio increased significantly but remained unchanged in non-diabetics. Following glycerol infusion, release of free fatty acids and inorganic phosphate from the infarcted hemisphere was diminished or reversed in both groups. It is postulated that the differences in cerebral metabolic responses to glycerol among an acute stroke population with diabetes compared to a similar group with acute stroke but without diabetes may be accounted for by the depressed cerebral glucose consumption in diabetics resulting from elevated blood levels of β-hydroxybutyrate, which tends to be reversed by the antiketogenic effect of glycerol and/or by the greater rise in blood glucose in diabetics following glycerol administration. Hence glycerol would not reduce cerebral oxygen consumption and CO₂ production in the diabetics as much as in the non-diabetics although the release of cerebral free fatty acids and inorganic phosphate from the infarcted brain would be reduced or reversed in both groups. It is concluded that intravenous glycerol infusion may improve uncoupled cerebral oxidative phosphorylation or provide the brain with an additional source of high energy phosphate bonds (ATP production) such as glycerol phosphate.     

Regional cerebral blood flow in Down's syndrome

Regional cerebral blood flow was measured in 14 patients with Down's syndrome, in 46 patients with Alzheimer's disease and senile dementia of the Alzheimer type, and in 114 age-matched controls, using the xenon 133 inhalation technique. Cerebral blood flow was reduced in 13 of 14 Down's patients by a mean of 16.8 +/- 2.5% from expected age-matched normal values. Degrees of regional cerebral blood flow reduction did not differ among the frontal, temporal, parietal, and occipital regions in both cerebral hemispheres. The regional cerebral blood flow decreases were similar in magnitude and pattern to those in Alzheimer patients. These findings constitute an additional similarity between the two disorders.     

In vivo disturbance of the oxidative metabolism of glucose in human cerebral gliomas

Abnormalities in the oxidative metabolism of glucose in human cerebral gliomas have been studied in seven patients using positron emission tomography. Measurements of regional cerebral blood flow and oxygen consumption were obtained using the oxygen-15 steady-state inhalation technique. Values of regional cerebral glucose consumption were obtained using fluorine 18-labeled 2-fluoro-2-deoxy-D-glucose and a simplification of the method of Sokoloff. Functional values were obtained for regions of tumor and brain tissue in the middle cerebral artery territory of the contralateral cortex. Values of regional glucose consumption were calculated for both regions using a value of the lumped constant quoted for normal brain tissue (0.42). Tumor regional cerebral blood flow was comparable to that in the contralateral cortex, whereas regional cerebral oxygen consumption was depressed. This depression resulted in low tumor values of the fractional oxygen extraction ratio (0.21 +/- 0.07), indicating that oxygen supply exceeded the metabolic demand. In contrast, tumor regional cerebral glucose consumption was not depressed and regional glucose extraction ratios were similar for tumor and brain tissue. The metabolic uncoupling between regional oxygen consumption and regional glucose consumption (CMRO2/CMRGlu = 0.24 +/- 0.07 ml of oxygen per milligram of glucose) is indicative of increased aerobic glycolysis.     

Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type

Summary A massive cerebral release of amino acids and ammonia was found in early-onset dementia of Alzheimer type. Aspartate and glycine were liberated in high concentrations, whereas glutamate remained rather unchanged. This excess cerebral protein catabolism is due to a 44% reduction in cerebral glucose metabolism. Whereas glutamate and other glucoplastic amino acids may substitute glucose, elevated aspartate may contribute to neuronal damage. The results are discussed with respect to a possible neuronal insulin/insulin receptor deficiency.     

脑血管病性痴呆与Alzheimer病患者脑局部区域的血流量

目的 测定多灶脑梗塞痴呆及Ａｌｚｈｅｉｍｉｅｒ病患者的脑局部区域的血流量（ｒＣＢＦ），方法 用＾１３３氙（＾１３３Ｘｅ）吸入法测定１０例多灶脑梗塞痴呆患者。１０例Ａｌｚｈｅｉｍｅｒ病及２０名正常人的ｒＣＢＦ。结果 两个病例组双半球，脑干－小脑ｒＣＢＦ均明显低于正常健康组，脑梗塞痴呆组多数病例双侧半球灰质ｒＣＢＦ降低呈斑块状，Ａｌｚｈｅｉｍｅｒ病例组均为双侧大脑半球弥散性对称性的ｒＣＢＦ降低，前乾脑     

Effect of 33% xenon inhalation on whole-brain blood flow and metabolism in awake and fentanyl-anesthetized monkeys.

BACKGROUND AND PURPOSE: Despite the documented diagnostic value of local cerebral blood flow maps by xenon-enhanced computed tomography, reports of cerebral blood flow activation by inhaled 33% Xe raised concerns about the method's safety and accuracy. We evaluated the effect of 33% Xe inhalation on cerebral blood flow and cerebral metabolic rates for oxygen and glucose in four awake and six fentanyl-anesthetized rhesus monkeys. METHODS: Platinum microelectrodes and catheters in the torcular Herophili were used to measure cerebral blood flow by hydrogen clearance, and oxygen and glucose concentrations. Cerebral variables were measured after 5 and 35 minutes of exposure to room air followed randomly by 67% O2 in 33% N2 or Xe. Five- and 35-minute measurements were combined because the duration of exposure had no effect. RESULTS: In awake monkeys, 33% Xe compared with 33% N2 reduced (p less than 0.05) cerebral blood flow from 75 +/- 12 to 66 +/- 9 (mean +/- SD) ml.100 g-1.min-1 and oxygen consumption from 6.1 +/- 0.7 to 5.1 +/- 0.6 ml.100 g-1.min-1. In fentanyl-anesthetized monkeys, cerebral variables during 33% N2 versus 33% Xe were cerebral blood flow, 84 +/- 26 versus 79 +/- 23 ml.100 g-1.min-1; oxygen consumption, 5.0 +/- 0.7 versus 4.9 +/- 0.5 ml.100 g-1.min-1; and glucose consumption, 8.4 +/- 1.9 versus 7.9 +/- 2.0 mg.100 g-1.min-1. CONCLUSIONS: In awake monkeys, 33% Xe reduced rather than activated cerebral blood flow and oxygen consumption by 12% and 16%, respectively; it had no effect in fentanyl-anesthetized monkeys.     

Effect of withdrawal from chronic naltrexone on regional cerebral oxygen consumption in the cat

This investigation determined the effects of withdrawal from chronic naltrexone administration on average and regional cerebral blood flow, oxygen extraction and oxygen consumption. The relationship between the effects of withdrawal from chronic administration of this opiate receptor antagonist, which may increase the numbers of postsynaptic opiate receptors, and these parameters was investigated. Fourteen adult mongrel cats were administered subcutaneous injections of 1 mg/kg naltrexone HCl or 1 ml 0.9% saline twice daily for 21 days. Two days later, regional cerebral blood flow was monitored using radioactively tagged microspheres. The animals were sacrificed and prepared for microspectrophotometric analysis of regional cerebral venous and arterial oxygen saturation. Regional cerebral oxygen consumption was calculated as the product of cerebral blood flow and oxygen extraction for each area examined. After 2 days of withdrawal from chronic naltrexone treatment, the blood pressure, heart rate and blood gas parameters did not change significantly when compared to saline-treated animals. Average cerebral blood flow was significantly increased from 47.9 +/- 3.4 ml/min/100 g (mean +/- S.E.M.) in the control group to 80.3 +/- 6.5 (ml/min/100 g) in the chronic naltrexone-treated group. Flow was significantly increased in the cortex, lenticulate nuclei, thalamus and pons. Neither average cerebral oxygen consumption, which increased slightly, nor cerebral oxygen extraction, which decreased slightly, were significantly altered by treatment. The distribution of flow among the examined regions was, however, significantly altered in the animals 2 days after receiving chronic naltrexone injections. These changes were not restricted to brain regions dense in neuronal opiate receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Does the severity of leukoaraiosis contribute to senile dementia? A comparative computerized and positron emission tomographic study.

The present study evaluates the origin, severity and location of leukoaraiosis in senile dementia and in normal ageing. The regional white-matter lucency scores, determined on computed-tomographic scan of the brain, are compared to the regional blood flow, oxygen extraction rate and oxygen consumption, determined by the [15O] steady-state technique with positron emission tomography. Thirty patients, classified according to the presence or absence of leukoaraiosis and their mental status, are examined. The occurrence and severity of dementia appear to be mainly correlated to decreased blood flow and oxygen metabolism in the frontal, temporal and parietal cerebral cortex. Leukoaraiosis in demented and nondemented patients is associated with lowered blood flow in the frontal and parietal white matter. The regional lucency score is increased, and blood flow and oxygen consumption decreased in the frontal white matter of severely demented patients. Frontal leukoaraiosis contributes to dementia and is probably of ischemic origin, while parietal and occipital leukoaraiosis is due to wallerian degeneration.     

Uncoupling of oxygen and glucose metabolism in persistent crossed cerebellar diaschisis.

BACKGROUND AND PURPOSE: The pathophysiology of deafferentation-induced changes after stroke remains unclear. Some supratentorial strokes cause persistent decreases in blood flow and metabolism in the contralateral cerebellum (persistent crossed cerebellar diaschisis[CCD]). Our previous study showed uncoupling of oxygen consumption and blood flow in this condition, which may reflect a characteristic change in brain metabolism caused by deafferentation. This uncoupling might be related to oxidation of some substrates other than blood-borne glucose, which could also lead to the uncoupling of oxygen consumption and glucose utilization. The purpose of this study was to investigate whether oxygen consumption is uncoupled from glucose utilization in persistent CCD. METHODS: Using positron emission tomography in 10 unilateral supratentorial stroke patients, we evaluated regional blood flow, oxygen consumption, and glucose utilization in the cerebellar cortex in the chronic stage. Eight patients with a significant cerebellar blood flow asymmetry, defined as outside the 95% confidence limits predefined in 9 normal subjects, were selected as patients with persistent CCD. RESULTS: In patients with CCD, the cerebellar cortex contralateral to the stroke showed significant decreases in both oxygen consumption and glucose utilization compared with the ipsilateral cerebellar cortex. The decrease in oxygen consumption was less than the decrease in glucose utilization, resulting in a significant increase in the oxygen consumption/glucose utilization ratio. CONCLUSIONS: Persistent CCD caused by stroke may induce uncoupling of oxygen consumption and glucose utilization, which may reflect a characteristic change in brain metabolism caused by deafferentation.     

Disturbance of oxidative metabolism of glucose in recent human cerebral infarcts

Eight patients with recent cerebral hemispheric infarction were studied with positron emission tomography and the oxygen-15 steady-state inhalation and [¹⁸F]deoxyglucose techniques to obtain values of regional cerebral blood flow, oxygen consumption, and glucose metabolism. The Sokoloff equation, used to calculate glucose metabolism, was simplified to exclude the exponential terms containing the rate constants. A value of the lumped constant quoted for normal brain (0.42) was used for infarcted regions and contralateral hemisphere. Mean regional cerebral blood flow, oxygen consumption, and glucose metabolism were all significantly depressed within the infarcts compared with the mirror regions in the contralateral cerebral hemisphere. The mean fractional extraction of oxygen was low, indicating an adequate supply of oxygen for residual oxidative metabolism. Regional oxygen consumption and glucose metabolism were significantly correlated within the infarcts, but with a relationship of 2 moles of oxygen per mole of glucose—one-third that in the contralateral hemisphere and in normal brain. Although these results suggest that the metabolizing tissue of a recent cerebral infarct utilizes aerobic glycolysis, caution about the validity of this pathophysiological observation is dictated by limitations in current positron emission tomographic tracer methodology.     

Diagnostic value of regional cerebral blood flow in SPECT pattern in Alzheimer's disease]

Regional cerebral blood flow in SPECT pattern was estimated in 20 cases of Alzheimer disease. In all patients diffuse hypoperfusion was found evidencing a great diagnostic value of SPECT. A special significance has the study of regional cerebral blood flow in the differential diagnosis of Alzheimer disease, frontal lobe dementia and pseudodementia in major depression.