[Blood flow and oxidative metabolism of the brain in patients with dementia (author's transl)]. / Veränderungen von Durchblutung und oxydativem Stoffwechsel des Gehirns bei Patienten mit einer Demenz

The purpose of this retrospective study was to investigate how the blood flow and oxidative metabolism of the brain was changed in dementia and the influence of the age factor. Cerebral blood flow (CBF) was measured in 115 patients aged from 40 to 83 years by means of the Kety-Schmidt technique with the modification of Bernsmeier and Siemons. The cerebral metabolic rates of oxygen and CO2 were determined by the van Slyke method and by gaschromatography respectively and of glucose and lactate by standard enzymatic methods. All cases of dementia due to head injuries, cerebral infections, cerebral infarctions, exogenous or endogenous intoxications or circulatory diseases were excluded from this study, but no classification of the dementias was made. Statistical calculations were carried out by means of the analysis of variance for a two-way design. Cerebral blood flow did not show a normal distribution curve but was at least triphasic; CBF in demented patients was either lower than normal, normal or higher than normal. The distribution curves showed further that a low cerebral blood flow of mean 32.5 ml/100 g min coincided with a low CMR oxygen of 2.50 ml/100 g min; however, CMR glucose was either low (2.50 mg/100 g min), or nearly normal (4.50 mg/100 g min) or elevated (7.50 mg/100 g min). A normal (45.0 ml/100 g min) or enhanced (62.5 ml/100 g min) CBF correlated with a CMR oxygen which was either decreased to 2.75 ml/100 g min or increased to 4.75 ml/100 g min; CMR glucose was either decreased to 1.50 mg/100 g min, or nearly normal (4.50 mg/100 g min), or was elevated to 6.50 and 10.50 mg/100 g min with respect to the peaks of the distribution curves. It is assumed that the variability of the findings with respect to the blood flow and oxidative metabolism of the brain in dementia is due to different pathophysiological and pathobiochemical disturbances in the brain. A significant influence of age on CBF and metabolism in patients with dementia was not found.

Divalent metals of myelin and their differential binding by myelin basic protein of bovine central nervous system.

Divalent metal ions are being implicated in the compaction of myelin. Levels of Cd, Co, Cu, Hg, Mn, Pb, Zn, Ca and Mg of isolated myelin of bovine central nervous system (CNS) were measured by flame atomic absorption spectrophotometry. Binding of these metal ions by isolated myelin basic protein (MBP, M(r) 18,500) of bovine CNS was concurrently assessed by centrifugal equilibrium dialysis. Metals were bound in the order of Hg > Cu > Zn > Mg > Cd > Co, exempting Mn, Pb and Ca. The results are indicative of differential metal affinity of MBP which may account for the immobilization or anchoring of MBP in myelin by zinc and other divalent metal cations.

Hepatic failure with neonatal tissue siderosis of hemochromatotic type in an infant presenting with meconium ileus. Case report and differential diagnosis of the perinatal iron storage disorders.

We report on a female preterm infant with hepatic failure and neonatal tissue siderosis of hemochromatotic type diagnosed by using both histochemistry and atomic absorption spectroscopy. The infant presented with meconium ileus, signs of rapidly progressive hepatic failure, and hyperferritinemia (7132 ng/ml). Despite surgery and intensive care the infant died 32 days after birth. Postmortem examination showed a wrinkled liver with extensive collapse of the hepatic architecture and regenerating nodules as well as hepatic and extrahepatic iron accumulation of hemochromatotic type, sparing the reticuloendothelial system. Atomic absorption spectroscopy confirmed an increase in the iron content of various organs: liver, heart, pancreas, oral salivary gland, kidney, and adrenal gland. The increase in the iron content of various organs was determined by comparing the analysis of the propositus with those of 5 gestationally age-related preterm infants who had died in the intensive care unit: 2 died of meconium aspiration syndrome, the other 3 of hyaline membrane disease, bronchopulmonary dysplasia, and immaturity, respectively. We also compared the analysis of 15 fetuses having a a condition predisposing to iron accumulation (trisomy 21, trisomy 18, cytomegalovirus, amnion infection syndrome, Rhesus- and ABO-incompatibility, congenital hemolysis, anti-phospholipid syndrome, congenital heart disease). Delta F508, the most frequent mutation seen in cystic fibrosis patients, was excluded by gene sequencing. Different noxae causing iron accumulation in the neonatal period have led to the statement that neonatal hemochromatosis may collect different etiologies, such as metabolic disorders, infections, chromosomal aberrations, and immunological disorders. In this study, we report the singular evidence of neonatal iron accumulation of hemochromatotic type in an infant presenting with meconium ileus and propose a classification of the neonatal disorders associated with iron accumulation.

Brain oxidative metabolism and blood flow in alcoholic syndromes.

42 alcoholic patients were grouped together according to the symptom-sign clusters derived from original classification variables of AMDP-rating scale system: (1) mild withdrawal, (2) severe withdrawal, (3) Korsakoff's syndrome, and (4) the clinical syndrome of dementia. Groups determined by clusteranalysis were subjected to a discriminant function analysis. Total cerebral blood flow (CBF) and the cerebral metabolic rates of oxygen, carbon dioxide, glucose and lactate were investigated. Patients with mild withdrawal tended to display increased oxygen uptakes reflecting 'pseudonormal' mean values with a wide range of the single data but predominantly elevated over the normal range. In mild withdrawal lactate production showed a tendency to increasing derangement of metabolism. There was much evidence of disturbance of brain oxidative metabolism with progressively decreasing cerebral metabolic rates of glucose, lactate, oxygen, and CBF from mild to severe withdrawal, Korsakoff's syndrome and dementia. Progression of both clinical phenomenology and cerebral dysfunction and/or damage culminates in simplified (reduced, "burnt-out") neuronal functional levels in advanced cases.

[Barbiturate infusion in severe brain trauma (preliminary report) (author's transl)]. / Barbituratinfusion bei schwerem Schädelhirntrauma (vorläufiger Bericht).

The pathophysiology of brain trauma regarding disturbances of energy and transmitter metabolism, development of intra- and extracellular cerebral oedema are briefly outlined. Possible mechanisms of action of barbiturates in amelioration of cerebral ischaemia, decrease of cerebral metabolism, preservation of membrane stability, reduction of cerebral oedema and intracranial pressure are reviewed. We report on 6 patients with severe brain trauma due to head injury whose intracranial pressure despite conventional treatment with hyperventilation, steroids and osmotic diuresis remained above 25 mm Hg. They were infused with thiopentone 6--12 mg/kg x h for 6 to 15 days, to reduce cerebral electrical activity to the point of "burst suppression" in the electroencephalogram. Three patients survived, two of them regaining their previous good health. The results in these patients are discussed as regards thiopentone dosage and severity of trauma. Marked cardiovascular instability in one case and cholostatic jaundice due to barbiturate administration in two cases were the most important side effects. Barbiturate infusion seems to be indicated in brain trauma with sustained elevation of intracranial pressure above 25 mm Hg despite vigorous conventional therapy. Monitoring most essential to this aggressive treatment scheme comprises measurement of intracranial pressure and continuous observation of the EEG.

[Comparison of the psychopathology with cerebral blood flow and brain metabolism in cerebrovascular insufficiencies]. / Vergleich von Psychopathologie mit Hirndurchblutung und Hirnstoffwechsel im Verlauf zerebrovaskulärer Insuffizienzen.

40 patients (13 males, 27 females) with a mean age of 68 years presented organic brain syndromes of cerebrovascular etiology. They were studied to make an attempt upon the relationship between descriptive symptomatology on one hand and brain-blood-flow and oxidative metabolism on the other. The assessment of psychopathology and additional neurological and physical symptoms and signs was documented by the AMDP-rating scale system, then further computed by cluster analytic procedures. Cerebral blood flow (CBF) was measured by the Bernsmeier and Siemons (1955) modification of the Kety and Schmidt method. The cerebral metabolic rates of oxygen (CMR O2) and carbondioxide (CMR CO2) were determined by gaschromatography, the cerebral metabolic rates of glucose (CMR gluc) and lactate (CMR lac) by standard enzymatic methods. Five symptom-sign clusters were markedly differentiated by size and shape of their profiles. The mean values of the biological data within the clusters found did show different patterns of brain metabolism derangement with increasing tendency to reduced levels and functional decompensation. The latter reflected clinical deterioration in terms of psychopathology: disorders of cognitive functioning as well as psychomotor activity, social and illness behavior, i.e. need for special care. The cerebral metabolism balance worsened resulting in a widespread, gross disturbance of oxidative metabolism with a likely shift to anaerobic glycolysis. The lactate production was extremely heightened. CMR lac may be regarded as a causal quantitative factor significantly linked with pathogenesis, manifestation, and severity of organic brain syndromes.

Disturbed oxidative metabolism in organic brain syndrome caused by bismuth in skin creams.

Two patients are described with an organic brain syndrome thought to be due to bismuth (Bi) absorbed from a skin cream. Both patients had intellectual impairment and memory loss punctuated by periods of confusion, tremulousness, clumsiness, difficulty in walking, and myoclonic jerks. A similar clinical picture has been reported from Australia and France in patients taking insoluble bismuth salts by mouth. Bi was found in cerebral venous blood in both patients and in the cerebrospinal fluid in one. It is suggested that bismuth can cross the blood/brain barrier and disturb oxidative cerebral metabolism, because increased lactate production was found with decreased consumption of oxygen and glucose and lowered cerebral blood-flow.

Cerebral blood flow and oxidative brain metabolism during and after moderate and profound arterial hypoxaemia.

In anaesthetized artificially ventilated dogs, the effect of graded arterial hypoxaemia on cerebral blood flow (CBF) and on the oxidative carbohydrate metabolism of the brain was tested. It is shown that the hypoxic vasodilatory influence on cerebral vessels is present even at moderate systemic hypoxaemia, provide that PaCO2 is kept within normal limits. At PaO2 of about 50 Torr, CBF increased from 56.6 to 89.7 ml/100g/min. With increasing cerebral hyperamia (CBF increased to 110.9 ml/100g/min, at PaO2 of 30 Torr), CMRO2 (4.2 ml/100g/min) was not significantly raised above its normal level (4.7 ml/100g/min) even with profound arterial hypoxaemia. This shows that CMRO2 levels are poor indices of hypoxic hypoxia. A disproportionately high increase in cerebral glucose uptake (CMR glucose levels rose from 4.4 to 10.4 mg/100g/min) and enhanced cerebral glycolysis (CMR lactate changed from 0.2 to 1.6 mg/100g/min) at moderately reduced PaO2 (50 Torr) indicated early metabolic changes which became more marked with further falls in arterial oxygen tension. However, 60 minutes after restoration of a normal PaO2 level, CBF and brain metabolism were found to have completely recovered. It is concluded that a short period of profound systemic hypoxaemia does not produce long lasting metabolic and circulatory disorders of the brain provided the cerebral perfusion pressure does not vary, and is kept at normal levels.

[Influence of combined moderate arterial hypoxaemia and moderate hypovolaemic hypotension on cerebral blood flow and cerebral oxidative and energy metabolism in the dog (author's transl)]. / Einfluss von gleichzeitiger mässiger arterieller Hypoxämie und mässiger hypovolämischer Hypotension auf Gehirndurchblutung, Oxidativen und Energiestoffwechsel des Gehirns beim Hund.

The influence on total cerebral blood flow, cerebral metabolic rates for oxygen, carbon dioxide, glucose, lactate and pyruvate and on cerebral grey matter content of glucose, lactate and pyruvate and high energy phosphate compounds of combined moderate reduction in cerebral perfusion pressure (CPP) and moderate arterial hypoxaemia was studied. Individually arterial hypoxaemia and arterial hypotension of the same degree would neither impair autoregulation of cerebral blood flow nor cerebral oxygen availability. Four groups of 10 dogs each were studied under control conditions (group I), with reduction of CPP to 70 mm Hg (group II), with reduction of paO2 to 45 mm Hg (group III) or with a combination of these degrees of hypotension and hypoxaemia (group IV) after steady states of 30 min duration. Cbf was elevated by 40% in group III (p less than or equal to 0.01), CMRO2 was reduced significantly in group IV (p less than or equal to 0.01, CMR lactate was raised significantly in all three experimental groups (p less than or equal to 0.01). All other data were not significantly different from values in control animals. Cerebral tissue lactate content was elevated significantly in groups II to IV as compared to controls (less than or equal to 0.05); changes in cerebral tissue content of glucose and energy rich phosphate compounds were not statistically significant. From the seemingly normal cerebral blood flow in hypotensive-hypoxaemic dogs it is concluded that autoregulation of cerebral blood flow has become ineffective because of vasodilatation consequent upon arterial hypoxaemia. Reduction of CMRO2 in this group points to metabolic insufficiency and to relative cerebral hypoperfusion, but since changes in cerebral content of high energy phosphate compounds were not significant, severe tissue hypoxia may be excluded. The increase in cerebral tissue lactate content is attributable to increased glycolytic activity known from hypotensive and hypoxaemic states. The present investigation suggests that in patients with hypoxaemia and hypotension, brain function may be endangered by a similarly marked change of circulatory and metabolic parameters.

Cerebral glucose and energy metabolism, cerebral oxygen consumption, and blood flow in arterial hypoxaemia.

The influence of moderately reduced arterial oxygen tension (aPO2 of about 45 Torr) on the metabolism and the blood flow of the brain was tested in 20 anaesthetized, artificially ventilated normotensive, normocapnic beagle dogs. It is demonstrated that the decrease in systemic oxygen delivery to the brain is countered by an appropriate increase in flow (CBF being 60.3 ml/100 g min at normoxia and 84.5 mg/100 g min in hypoxaemia) which maintained the cerebral oxygen consumption unchanged (CMRO2 3.80 versus 3.32 ml/100 g min). The cortical tissue content of energy-rich phosphates such as ATP, ADP, AMP, and phosphocreatine was also found to be unaltered. Neuropathological examinations excluded any hypoxic cell damage. This reactive vasodilatory reaction of the cerebral vessels is apparently a sensitive regulatory process which protects the brain against marked oxygen lack. However, a normal carbohydrate metabolism is not restored by this cerebrovascular mechanism. For, significantly increased CMRlactate (0.32 versus 1.46 ml/100 g min) indicated raised cerebral glycolysis, and the tissue metabolites of glucose suggested an increased glycolytic flux in the brain. It is concluded that in moderate arterial hypoxaemia, which is not uncommon in clinical practice, cerebral blood flow plays an effective homeostatic role in preventing a disturbance of the energy metabolism of the brain.

The effect of carbon dioxide on cerebral blood flow and cerebral metabolism in dogs.

In 11 normally oxygenated, normotensive mongrel dogs, blood flow and oxidative metabolism of the brain was studied during normocapnia and during respiratory alkalosis and respiratory acidosis. During respiratory alkalosis (mean PaCO2 17.8 mm Hg) CBF decreased significantly from 61.0 to 33.9 ml/100 g/min (44%) while arteriovenous-substrate differences increased and the rates of oxygen and glucose metabolism remained constant. Cerebral venous-arterial difference of lactate was increased significantly as compared with the resting state. During hypercapnia CBF increased significantly from 61.0 (resting state) to 115.7 ml/100 g/min (89%) (mean PaCO2 64.7 mm Hg). The arteriovenous-substrate differences decreased while the cerebral metabolic rates remained constant. The data show that the relationship between PaCO2 and CBF in the range 20-65 mm Hg PaCO2 is expressed by a linear relationship: y = 2.88 + 1.69x; in this range, the oxidative metabolism of the brain is unchanged and the increased cerebral lactate production in respiratory alkalosis is not necessarily linked to tissue hypoxia.