METABOLISM OF THE CENTRAL NERVOUS SYSTEM IN VIVO 



'857 



hyperglycemia (38, 39). Unfortunately, the cerebral 

 R.Q., which might indicate the nature of the sub- 

 strate being consumed by the brain, has not been 

 reported in such cases. The finding by Geiger & 

 Yamasaki (54) of the requirement of liver factors, 

 subsequently shown to be replaceable by the pyrroli- 

 dine nucleosides, cytidine and uridine, for the con- 

 tinued normal utilization of glucose by the perfused 

 cat brain may be of relevance here. In their absence, 

 the levels of galactosides and phospholipids in the 

 brain decrease and the ability to utilize glucose 

 progressively fails, both changes reversible by the 

 replacement of the nucleosides. The failure to utilize 

 administered glucose is one of the defects which de- 

 velops in irreversible posthypoglycemic coma. 



The change which occurs in the intermediary 

 metabolites within the brain during insulin hypo- 

 glycemia or coma reflects only the expected effects of 

 glucose lack and the reduction in energy availability. 

 Thus, glycogen, glucose and lactic acid levels in the 

 cat brain have been found (o l»- decreased, and there 

 is a degradation of high-energy phosphate compounds, 

 such as creatine phosphate and ATP, to inorganic 

 phosphate (135). 



Intracellular Defects 



A number of disturbances of cerebral function and 

 metabolism must by exclusion be attributed to 

 intracellular defects (table 3). Those which result 

 from an excessively prolonged deficiency of either or 

 both of the essential nutrients, oxygen and glucose, 

 have already been discussed. There are others, how- 

 ever, which cannot be related to the nutrient supply 

 to the brain 



systemic metabolic disease. Several metabolic 

 diseases with broad systemic manifestations, including 

 impairment of cerebral functions, have been studied 

 in man. Diabetes mellitus, when permitted to progress 

 to the stage of acidosis and ketosis, leads to mental 

 confusion and ultimately to deep coma with parallel 

 proportionate reductions in cerebral oxygen con- 

 sumption (99) (table 3). In diabetic acidosis in which 

 both mental function and cerebral metabolic rate 

 were only moderately depressed, Kety and his as- 

 sociates (99) found the mean cerebral R.Q. to be 

 0.92 or within normal limits. In deep coma the 

 cerebral R.Q. was 0.88, a value significantly reduced 

 from the normal level. This change in R.Q. may be 

 meaningful, but the low blood carbon dioxide levels 

 found in this condition make accurate analysis of 



this metabolic function difficult. Both the functional 

 and metabolic disturbances of the brain in diabetic 

 acidosis unassociated with coma were completely 

 reversible by adequate insulin therapy; of the six 

 patients in deep coma, only one survived despite 

 rigorous therapeutic measures (99). Kety (95) has 

 found in diabetic acidosis evidence for a slight but 

 significant production, o.gi mg per 100 gm per min., 

 of lactic acid by the brain. There was no evidence 

 of cerebral utilization or production of a-ketoglutarate 

 and pyruvate, nor of total ketones which are elevated 

 in the blood in this disease. Neither the nature of 

 the metabolic defect nor the cause of the depressed 

 cerebral metabolic rate are known. Deficiency of 

 nutrient material cannot be implicated as a cause 

 of the cerebral disturbances since blood glucose is 

 elevated, and cerebral blood flow and oxygen supply 

 are more than adequate (99). Neither is the insulin 

 lack, which is presumably the basis of the systemic 

 manifestations of the disease, a likely cause of the 

 cerebral abnormalities since no direct role of this 

 hormone in the cerebral metabolism lias been demon- 

 strated and, indeed, there is evidence to the contrarj 

 (180). Ketosis may be severe in this disease, and there 

 is conflicting evidence that a rise in the blood level 

 of one of the ketones, acetoacrtatc, can cause coma 

 in animals (30, 47, 86, 163). Kety and his associates 

 (99) in their studies of diabetic acidosis and coma 

 did observe a significant correlation between the 

 depression of cerebral metabolic rate and the degree 

 of ketosis. However, they also obtained an almost 

 rqualh good correlation with the degree of acidosis. 

 It is possible that either the ketosis or the acidosis 

 may be responsible for the defect in the cerebral 

 functions, but it is more likely that the\ are both 

 reflections of some other more directly responsible 

 metabolic disturbance (47). 



Coma is occasionally associated with severe im- 

 pairment of liver function, as, lor example, in cirrhosis 

 of the liver. In patients in hepatic coma, Fazekas and 

 co-workers (44), and Wcchsler and his associates (192) 

 have found the cerebral oxygen consumption to be 

 profoundly depressed. Cerebral blood flow is also 

 moderately depressed; but since there is no evidence 

 of any significant impairment of the nutrient supply, 

 the low cerebral oxygen consumption reflects only a 

 reduced metabolic demand in the brain. Bessman & 

 Bessman (14) have found in such cases a significant 

 positive arterial-cerebral venous ammonia difference, 

 evidence for the cerebral uptake of ammonia by r the 

 brain, and the degree of coma and the arteriovenous 

 difference were both roughly proportional to the 



