Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimer's disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin‐releasing factor, serotonin, and 5‐hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin‐releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.

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Withdrawal of food or immobilization both led to changes in rat brain tryptophan metabolism. Brain tryptophan and 5-hydroxyindolylacetic acid concentrations both increased while changes in 5-hydroxytryptamine were much smaller. Changes were greater upon withdrawal of food. The brain tryptophan change did not appear merely to reflect an overall increase of brain amino acid concentrations, brain tyrosine concentration being only slightly increased by food withdrawal and significantly decreased upon immobilization. Plasma tryptophan did not increase. The changes in brain indole metabolism were not abolished by adrenalectomy. Results are discussed in relation to the regulation of brain serotonin metabolism. THE RATE limiting step in brain 5HT synthesis is the hydroxylation of tryptophan (MOIR and ECCLESTON, 1968). The enzyme tryptophan hydroxylase (tryptophan-5hydroxylase, EC 1.99.1.5) which is responsible for this reaction normally appears to be unsaturated as brain 5HT synthesis increases in rats given large amounts of tryptophan (ECCLESTON, ASHCROFT and CRAWFORD, 1965). Recently, injection of tryptophan in amounts such that plasma tryptophan altered only within the range of normal daily variation was also found to cause increased rat brain tryptophan and 5HT (FERNSTROM and WURTMAN, 1971~). Furthermore, various drugs known to stimulate brain 5HT synthesis are reported to cause increased brain tryptophan concentrations (TAGLIAMONTE, TAGLIAMONTE PEREZ-CRUET, STERN and GESSA, 1971). These findings indicate that the concentration of tryptophan is an important factor in determining the rate of 5HT synthesis in the brain.All the above work involved the administration of drugs or of large amounts of tryptophan or led to changes of plasma tryptophan which although within the range of normal daily variation occurred more rapidly than likely physiological changes. As certain stress situations are accompanied by increased brain 5HT turnover (BLISS, AILION and ZWANZIGER, 1968, CURZON and GREEN, 1969) it was of interest to study the relationships between the concentrations of tryptophan and of 5HT and its metabolite 5-hydroxyindolylacetic acid (5HIAA) in the brains of rats subjected to two procedures which involve stress-immobilization and food deprivation. These relationships were investigated using both intact and adrenalectomized animals. METHODSAdult male Sprague-Dawley rats 180-220 g (Carworth, Alconbury, Huntingdon, England) were kept under controlled conditions as previously described (CURZON and GREEN, 1969). Animals were killed by guillotine at the same time of day to minimize effects of diurnal variations. Food deprivation was imposed by withdrawing food but not water 24 h before killing except in experiments on adrenalectomized animals when 16 h deprivation was used. Control animals were given an ad libitum diet of Abbreviation used: 5HIAA, 5-hydroxyindolylacetic acid. NEURO 19/%11967

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1 The effects on tryptophan distribution and metabolism of drugs altering plasma unesterified fatty acid (UFA) concentration were investigated in the rat. 2 UFA and plasma free (i.e. ultrafilterable) tryptophan altered in the same direction. 3 Catecholamines and L-DOPA increased both plasma UFA and free tryptophan. L-DOPA also increased brain tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) but decreased brain 5-hydroxytryptamine (5-HT). 4 Aminophylline increased plasma UFA and free tryptophan and also brain tryptophan, 5-HT and 5-HIAA. Food deprivation had qualitatively similar effects. 5 Insulin decreased plasma UFA and free tryptophan in both fed and food-deprived rats. However, while in fed rats these changes were associated with small decreases of brain indoles, in food-deprived animals small increases occurred. 6 Nicotinic acid had only small effects in fed rats but it opposed both the UFA and indole changes in food-deprived animals. Total plasma tryptophan increased in nicotinic acid treated, food-deprived rats. 7 There was a tendency towards inverse relations between changes of plasma free and total tryptophan. 8 The results suggest that drugs which influence plasma UFA through actions on cyclic AMP thereby alter the binding of tryptophan to plasma protein and that this leads to altered distribution and metabolism of tryptophan.

Unilateral ligation of the left common carotid artery in anesthetized Mongolian gerbils resulted in a steep rise in extracellular dopamine in the ipsilateral striatum in 9 out of 19 animals. Extracellular dopamine was measured by cerebral dialysis in vivo and reached a peak of 0.19 mM at 40 min. At the same time, the level of homovanillic acid fell, whereas the levels of ascorbate and 3,4-dihydroxyphenylacetic acid remained relatively constant. In a separate group of animals studied with a combined dialysis/electrochemistry probe, a rise in the in vivo chronoamperometric signal in three out of six animals correlated with a rise in extracellular dopamine. The number of animals responding in these experiments (roughly 50%) corresponds to the frequency of incompetent Circle of Willis, as well as literature reports of the frequency of signs of stroke in unanesthetized gerbils. These results show a remarkable accumulation of dopamine in extracellular fluid in response to cerebral ischemia. Released dopamine appears to be responsible for the elevated in vivo electrochemical signal previously reported.

To investigate whether activation of afferent and central baroreceptor pathways could differentiate between pure autonomic failure (PAF) and multiple system atrophy with autonomic failure (MSA), we determined the effect of upright tilt on circulating levels of vasopressin in patients with PAF and patients with MSA. We also studied 14 normal subjects, nine of whom developed acute hypotension due to vasovagal syncope. In patients with PAF and in normal subjects with vasovagal syncope, upright tilt induced marked hypotension and a pronounced increase in the plasma concentration of vasopressin (1.1 +/- 0.3 to 38.0 +/- 8.0 pmol/l in PAF and 1.0 +/- 0.2 to 27.4 +/- 7.2 pmol/l in vasovagal syncope, p less than 0.005 for both). In patients with MSA, upright tilt also elicited profound hypotension but circulating levels of vasopressin increased little (0.5 +/- 0.1 to 1.5 +/- 0.3 pmol/l, p less than 0.05). During upright tilt, the plasma concentration of norepinephrine significantly increased in normal subjects but did not increase in patients with autonomic failure. Our results indicate that afferent and central baroreceptor pathways involved in vasopressin release are normal in patients with PAF but are impaired in patients with MSA. Thus, measurement of baroreceptor-mediated vasopressin release appears to provide a clear marker to differentiate between patients with PAF and patients with MSA.