Search

The excitatory amino acids as neurotransmitters in the neocortex, hippocampus, striatum, thalamus, amygdala, nucleus basalis of Meynert and cerebellum from rats aged 4 months, 12 months and 24 months have been examined by measuring sodium-dependent high affinity uptake of D-[3H]-aspartate into preparations containing synaptosomes. Calcium-dependent K(+)-stimulated release of endogenous glutamate from the nucleus basalis was also measured. The hippocampus and cerebellum failed to show significant age-related changes in uptake of D-[3H]-aspartate. D-[3H]-aspartate uptake decreased significantly in the neocortex (29%), striatum (29%), nucleus basalis (26%), amygdala (19%) and thalamus (16%) in the middle-aged rats as compared to the young rats, but the changes were not progressive with age. The release of glutamate from the nucleus basalis was unaltered during the aging process.

A quantitative study has been made of the number of neurofibrillary tangles and of the choline acetyltransferase activity in several sites in the cerebral hemispheres of eight patients who had had Alzheimer's disease. The neurofibrillary tangles were maximal in structures in the medial temporal lobe (uncus, amygdala, hippocampus and parahippocampal gyrus), severe in the neocortex on the lateral surface of the temporal lobe, moderate in the "association cortex" of the parietal and frontal lobes and minimal in primary somatic and visual sensory areas. There was a significant decrease in choline acetyltransferase activity in almost all areas, and the means of the percentage decreases for the different groups of areas correlate well with the counts of the neurofibrillary tangles. These results support the hypothesis that the pathological process in Alzheimer's disease may spread along a sequence of corticocortical connections between the main sensory areas and the hippocampal formation. The disease process may also spread along the reciprocal connections between the amygdala and the neocortex because the numbers of tangles in different areas of the neocortex closely parallel the density of their connections and the amygdala.

Alzheimer's disease may be associated with an early and clinically relevant degeneration of some cortical excitatory amino acid-releasing neurons. Tetrahydro-9-aminoacridine (tacrine) might be an effective drug for the treatment of the disease. Various pharmacological paradigms (in rats) related to amino acid release are shown here to be modified both in vivo and in vitro by the drug. These effects are only observed with high concentrations, so it is unlikely that tacrine acts through amino acid release in humans.

There is little information about major constituents of the brain in Alzheimer's disease. In the case of amino acids most of the previous data are contradictory. These have been interpreted in an anatomic and neurotransmitter as well as a metabolic context. To help clarify this, the contents of 14 amino acids and ethanolamine were determined in samples of neocortex from diagnostic craniotomies of 15 demented patients (10 with Alzheimer's disease) and other neurosurgical procedures (57 patients, 18 with intractable depression). A comprehensive survey of the effects of possible complicating factors on the concentrations of amino acids showed that artefacts were few; this was in contrast to a post mortem series of brains (16 with Alzheimer's disease and 16 controls; six regions assayed). We have used the ante mortem data to provide the basis for an accurate comparison of amino acid values between Alzheimer and control samples. In Alzheimer's disease, the mean contents of many amino acids were slightly higher (sum of the increases of those significantly affected was 15 nmol/mg protein) whereas glutamate content alone was significantly reduced (by 16 nmol/mg protein). This was not a feature of depression or a group of patients with other dementias. Glutamate content of Alzheimer samples was related to pyramidal neuron density in cortical layer III. These alterations were detected relatively early during the course of Alzheimer's disease and are considered to be due to loss of corticocortical glutamatergic association pathways.

Increasing age is associated with increased risk of developing both dementia and depression; both conditions appear to be associated with structural changes in the cerebral cortex. In depression, there was evidence for regional alterations in cortical neurons either as a result of the disease or its treatment. In Alzheimer's disease, a key change is likely to be either shrinkage or loss of corticocortical pyramidal neurones which probably use glutamate as their transmitter. The putative pathogenic role of glutamate and energy metabolism, as well as an approach to treatment of symptoms are outlined.

Neocortical tissue prisms prepared from rat and human brain were frozen to -196 degrees C by a two-step freezing procedure and 10% dimethyl sulphoxide as cryoprotectant. Frozen and thawed rat neocortical prisms incorporated glucose into acetylcholine and carbon dioxide at 89% and 86% of control values, respectively, and noradrenaline uptake into frozen and thawed rat prisms was 94% of the control value. Frozen and thawed prisms from three human neocortical specimens showed a similar degree of protection from freeze-thaw injury.

The concentration of somatostatin-like immunoreactivity (SLI) in lumbar cerebrospinal fluid was measured in clinically suspected examples of either Alzheimer's disease (AD) or Pick's disease and controls. No significant correlation was found between the concentration of SLI and the age (22-73 years) of controls. Histological examination of brain material from the demented patients enabled the samples to be divided into AD and examples of clinically suspected AD or Pick's disease without specific histological change. The mean concentration of SLI was only slightly reduced in patients with AD in the presenium compared to control, and was unaltered from control in the examples of AD of senile age. The group of demented patients without specific histological change had a reduced concentration of SLI in lumbar CSF compared to control patients.

Production of [14C]acetylcholine and 14CO2 was examined by using tissue prisms from neocortex, hippocampus, and striatum from rats aged approximately 5 months, 13 months, and 27 months. [14C]Acetylcholine synthesis in the striatum showed highly significant decreases with age for measurements in the presence of both 5 mM- and 31 mM-K+, contrasting with the lack of significant change in 14CO2 production in this region. The neocortex and hippocampus showed only small changes, especially when comparison was made between 13-month and senescent animals. Measurements of the release of [14C]acetylcholine and influence of atropine on this release confirmed the relative stability with age of the cholinergic system in the neocortex.

The binding of [3H]kainic acid to caudate nucleus membranes prepared from brains of examples of Alzheimer's dementia and controls has been determined. No changes were detected in either the affinity or the number of kainate binding sites in the Alzheimer samples compared to control, although there was a large decrease in choline acetyltransferase activity.

The extent and distribution of biochemical abnormalities thought to reflect disorders of subpopulations of neurons have been determined in the cerebral cortex from brains of patients with Alzheimer-type dementia and depressive illness who died of natural causes. In dementia, loss of gray matter from areas of the parietal and temporal lobes is most obvious. In depression, these areas are not affected, but the pars opercularis and temporal pole are smaller than in controls. Results expressed per unit mass of total protein indicate selective reductions in both disorders of serotonin 2 recognition sites in all areas examined and of somatostatin content in only the temporal pole of the six areas examined. In dementia alone a selective loss was found of somatostatin content of the superior parietal lobule and of serotonin 1A sites and choline acetyltransferase activity in all areas examined. Results for depression expressed per entire area indicate additionally reduced somatostatin content and serotonin 1A sites in the pars opercularis and serotonin 1A sites in the temporal pole. These multiple analyses performed on each sample provide further support for a prominent disorder of pyramidal neurons in dementia as well as more evidence for alterations in cortical neurons in depression, either as a result of the disease itself or its treatment.

Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) from control subjects and patients of both presenile and senile age with histologically verified Alzheimer's dementia. CSF HVA increased with age in control but not in Alzheimer patients. HVA and 5-HIAA in the CSF of presenile Alzheimer patients was lower than that of age matched control subjects.

Investigation by cerebral biopsy of patients with dementia associated with cerebral atrophy permits the examination of clinico-pathochemical relationships, and provides a means of distinguishing and classifying forms of cerebral atrophy. Benefits of the procedure must however be weighed against possible adverse effects of surgical intervention. The study examines the outcome following biopsy of 24 patients with presenile dementia. No major operative complications were encountered, and recovery was uneventful in all but a single patient. The relevance of the findings to the study of dementia by cerebral biopsy is discussed.

Reaggregate cultures of foetal rat brain grown in a serum-free medium were used to determine the presence or absence of cholinergic neurotrophic factors in Alzheimer's disease brain tissue. These preliminary data show that both normal and Alzheimer's disease brain contain factors which elevate choline acetyltransferase activity in the reaggregate cultures.

Extracellular concentrations of excitatory amino acids in the neostriatum of anaesthetized rats were studied by in vivo microdialysis and the influence of chemical stimulation of the neocortex assessed. Administration of gamma-aminobutyric acid (GABA) antagonists to the neocortex evoked an increase in the extracellular concentration of aspartate (to 315 and 210% of basal values for microinfusion and topical application, respectively), but not of extracellular glutamate. Such selectivity was also found in response to N-methyl-D-aspartate (NMDA, 348% increase in extracellular aspartate concentration). Yet co-administration of NMDA with GABA antagonists increased the extracellular concentration of glutamate (to 278% of basal values) as well as aspartate (to 611% of basal values). The results suggest that either the activated neurons are hypoglycemic or hypoxic, or that aspartate is the major neurotransmitter of corticostriatal neurons.

Choline acetyltransferase activity (presynaptic cholinergic system) and high affinity binding of cholinergic antagonists (postsynaptic cholinergic system) were measured in brain tissue removed after death from both mentally normal and demented old people. Muscarinic receptor binding sites in frontal cortex decreased with advancing years only in old people without appreciable morphological evidence of senile degeration. Preliminary data for temporal lobe suggested that also in Pick's disease the density of receptor binding sites is reduced. The markers are not significantly reduced in cases of mixed senile and vascular dementia. However, in non-vascular senile dementia of the Alzheimer type, there were indications that the presynaptic marker is selectively depleted. Therefore, centrally acting anticholinesterases might be beneficial, particularly in the early stages of the disease.

Twenty antagonist substances with varying potencies for central and peripheral postsynaptic muscarinic receptors have been examined for effects on the central presynaptic muscarinic autoreceptor. This has been monitored by measuring the stimulating effects of the substances on acetylcholine synthesis by rat neocortical tissue prisms. Dose-response curves for selected agents showed that maximal stimulation of synthesis was to 136-140% of the value without an antagonist. At a concentration of 1 microM, 17 of the substances caused a significant increase in synthesis, whilst at 0.01 microM significant stimulation occurred with only atropine, dexetimide, N-methyl-piperdin-4-yl (R)-2-cyclohexyl-2-hydroxyl-2-phenylacetate, quinuclidinyl benzilate (QNB) and scopolamine. Linear regression analysis between synthesis values obtained with the substances and published data for the effects on either cholinoceptor-agonist induced contraction of guinea-pig ileum or the binding of [3H]-QNB to rat forebrain membranes gave correlation coefficients of r = 0.84 (P less than 0.01), and r = 0.75 (P less than 0.02) respectively. The results provide no indication of a pharmacological difference between the central presynaptic muscarinic autoreceptor and central and peripheral postsynaptic muscarinic receptors.

Biochemical indices of cortical nerve cells affected in Alzheimer's disease have been proposed (excitatory dicarboxylic amino acid, EDAA, sodium-dependent carrier; phosphate-activated glutaminase activity; serotonin type 2 recognition site; somatostatin-like immunoreactivity). These and the content of EDAAs and two related amino acids, and choline acetyltransferase (ChAT) activity have been measured in up to 13 areas of cerebral cortex and the cerebellar cortex from 16 patients with Alzheimer's disease and 17 controls. Reduction of the index of the serotonin recognition site, somatostatin content and another biochemical index of interneurones coincide and indicate a rather unexpected focal loss of such neurones from the parietal lobe. No unequivocal measure of the integrity of pyramidal neurones could be established as the content of no amino acid was reduced, the index of the EDAA carrier showed evidence of change in few brain regions and glutaminase activity was subject to unexplained variability. ChAT activity alone closely paralleled a previous report of the distribution of morphological degeneration. The results are discussed in relation to therapy and positron emission tomography.

The concentration of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), was measured in the cerebral cortex obtained at diagnostic craniotomy from 10 patients with Alzheimer's disease of 3 yrs mean duration and 6 patients with other causes of dementia, and from 31 subjects undergoing other neurosurgical procedures (for which removal of apparently normal tissue was necessary). GABA content of 5 areas of the cerebral cortex and the cerebellar cortex was measured postmortem in the brains of 23 Alzheimer and 19 control subjects and 5 patients with other causes of dementia. Fourteen of these specimens, including 7 from patients with Alzheimer's disease of 8 yrs mean duration, were obtained within 3 h of death. These were processed in a similar manner to the neurosurgical specimens and are regarded also as fresh tissue samples. The remaining 33 specimens are regarded as conventional postmortem samples as the mean interval of death to autopsy was 21 h. GABA concentration in conventional autopsy specimens from Alzheimer subjects was not reduced as compared with controls in either cingulate or cerebellar cortex. In the inferior parietal cortex, agonal status confounded this comparison. The concentration was reduced in superior parietal, frontal and temporal cortex but there is a possibility that agonal state also confounded these comparisons. There was no deficit in GABA concentration in fresh cortical tissue from Alzheimer patients except for the temporal lobe from autopsy specimens. The content of somatostatin-like immunoreactivity was, like GABA, found to be comparable to control in some groups of Alzheimer specimens. It is argued that the deficits in autopsy samples and lack of change in surgical specimens is likely to be due to the duration of illness at the time of sampling. Losses of choline acetyltransferase activity were observed in all groups of Alzheimer specimens in all areas of brain studied. The data are consistent with other results which suggest that cholinergic under-activity is most closely related to the clinical course of Alzheimer's disease.

A series of Alzheimer's disease and control brains were dissected to determine the extent of atrophy (based on total protein content) and loss of choline acetyltransferase activity in the cerebral cortex from the entire surface of the diseased brains. The distribution of intensity of pathology so determined is strikingly similar to the degree of hypometabolism as shown by positron emission tomography. It is argued that the hypometabolism can be explained (at least in part) by focal areas of atrophy.

Indices of dopaminergic and noradrenergic varicosities were assayed in neocortical tissue obtained at diagnostic craniotomy from patients with Alzheimer's disease in the presenium. Dopaminergic markers (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not significantly different from controls in either frontal or temporal cortex. In the frontal cortex, the release of endogenous dopamine and noradrenaline (in the presence of both resting and stimulating concentrations of potassium) was also unaffected whereas release of endogenous serotonin was significantly reduced. In the temporal cortex, noradrenergic markers (concentration of noradrenaline and uptake of radiolabelled noradrenaline) were significantly reduced, to at least 47% of mean control values. These deficits are interpreted as reflecting denervation and were present in patients examined only some two years after developing symptoms of dementia. The ratio of 3-methoxy-4-hydroxyphenylglycol to noradrenaline (a putative index of noradrenaline turnover) was elevated in the temporal cortex, suggesting increased activity of the remaining noradrenergic varicosities. Noradrenergic markers did not correlate with either clinical or histological indices of the severity of the disease which contrasts with presynaptic cholinergic and serotonergic markers.

All the cerebral cortex and some subcortical nuclei from six examples of senile dementia of the Alzheimer type (SDAT) and six age- and sex-matched controls have been dissected and weighed. The weight of the parietal and temporal cortex are significantly reduced. The parietal lobe shows the largest weight loss and this is most obvious in the precuneus and the superior lobule. The posterior cingulate, the middle and superior temporal, the supramarginal and the superior frontal gyri also show significant weight reduction. Weight loss of the amygdala is more than that of the hippocampus, the caudate nucleus and the putamen, but the weights of all are reduced significantly. These results are rather unexpected but are consistent with other data (e.g. the clinical parietal lobe syndrome and focus of glucose hypometabolism in Alzheimer's disease). They indicate that prominent changes occur in SDAT in the association areas of the parietal lobe as well as in the amygdala.

In the elderly, loss of brain wet weight and reduction in neuronal populations may be related to declining cognitive function. In some brain areas there appear to be reduced dendritic arborization. In the aging brain, neurotransmitter metabolism is affected. Catecholamine concentration appears to be especially reduced. More marked loss of cells and synapses is seen in senile dementia of the Alzheimer's type, and there is a significant reduction in choline acetyltransferase activity and in the ability of isolated biopsy tissue to synthesise acetylcholine. The significance of these findings and the possibility of drug intervention is discussed.

In a prospective study of 24 patients with presenile dementia associated with cerebral atrophy, clinical and psychological characteristics of patients' disorder were examined in relation to pathological and chemical findings obtained from tissue analysis following cerebral biopsy. The histological features of Alzheimer's disease were found in 75% of cases, but not in 25%. Distinctive patterns of neuropsychological breakdown emerged allowing clinical grouping of patients. While clinical patterns were helpful in differentiating Alzheimer's disease from non-Alzheimer's disease, there was not an absolute concordance between clinical and patho-chemical groupings. The findings, which support the notion that the "cerebral atrophies" represent a heterogeneous group of conditions, have relevance for the clinical diagnosis of presenile dementia.

Markers of serotonin synapses in entire temporal lobe and frontal and temporal neocortex were examined for changes in Alzheimer's disease by use of both neurosurgical and autopsy samples. Uptake of [3H]serotonin, binding of [3H]imipramine, and content of indolamines were all significantly reduced, indicating that serotonin nerve terminals are affected. Binding of [3H]serotonin was also reduced, whereas that of [3H]quinuclidinyl benzilate, [3H]muscimol, and [3H]dihydroalprenolol were unaltered. When the Alzheimer's samples were subdivided according to age, the reduction in [3H]serotonin binding was a feature of only autopsy samples from younger patients. In contrast, presynaptic cholinergic activity was reduced in all groups of Alzheimer's samples, including neurosurgical specimens. Five markers, thought to reflect cerebral atrophy, cytoplasm, nerve cell membrane, and neuronal perikarya were measured in the entire temporal lobe. In Alzheimer's disease the reductions (mean 25%, range 20-35%) were thought to be too large to be due only to loss of structures associated with the presumed cholinergic perikarya in the basal forebrain and monoamine neurones in the brain stem.

Extensive biochemical analysis of whole temporal lobe from cases of dementia and controls suggests that Alzheimer's disease is a primary degenerative nerve-cell disorder and not the result of accelerated ageing. There is selective loss of neocortical cholinergic neurones. Transmitter systems apart from the cholinergic system appears to be affected, but to a lesser extent, and there are no significant changes in the caudate nucleus. The change in cholinergic neurones has been confirmed in biopsy samples.

Loss of neurons from the ageing human brain is accompanied by reduction in biochemical markers. Compared with age-matched controls about one third of nerve cell components are lost from the temporal lobe of patients with senile dementia of Alzheimer's type. There is marked loss of choline acetyltransferase activity, especially in the hippocampus. This alteration parallels the intensity of neuropathological damage and relates to prior mental impairment. Smaller changes in other neurotransmitter synthesizing enzymes are generally found.

The concentration of vitamin E (alpha-tocopherol) was measured in samples of cortex from patients with Alzheimer's disease (AD), fetuses with Down's syndrome (DS), and also in a group of centenarians. The mean tocopherol concentrations in the two patient groups did not differ significantly from appropriate controls. When expressed per lipid the mean tocopherol concentration of the centenarians was greater than that of the controls but this reflected a significant decrease in the lipid concentration of the former group. These results indicate that neither the normal aging processes, Alzheimer's disease, nor the increased in vitro lipid peroxidation reported in fetuses with Down's syndrome result from a gross lack of alpha-tocopherol, or cause a significant depletion of the vitamin.

The binding of [3H]MK-801 to the N-methyl-D-aspartate receptor complex of well-washed cortical membranes from brains of examples of Alzheimer's disease and controls has been determined in incubations containing either glutamate or glycine plus glutamate. No changes were detected in the IC50 values for inhibition by zinc in the Alzheimer's samples compared to control although 'glycine-dependent' binding of the [3H]-ligand was significantly reduced in Alzheimer's disease.

Well washed membranes have been prepared from samples of cerebral cortex of control subjects and patients with Alzheimer's disease, obtained both at post mortem and by neurosurgical procedures earlier in the course of the disease. Binding to these membranes of two radioligands for the N-methyl-D-aspartate-phencyclidine receptor complex has been determined in the presence and absence of glycine. Glycine increased the binding in both control and Alzheimer tissue samples. At one concentration of radioligand, in the presence of glycine there was less binding to post-mortem samples, which Scatchard analysis showed was associated with a 36% loss of sites. In rare neurosurgical samples, there was also a loss of binding of radioligand which suggests that the effect is not due to post-mortem artefacts or epiphenomena. These new results may have implications for the symptomatic and preventative treatment of Alzheimer's disease.

The K+-evoked release of 13 amino acids has been determined from tissue prisms of neocortex from patients of various ages, and from rats. Prisms were prepared from various regions of human neocortex obtained at neurosurgery. Upon depolarization aspartate, glutamate and gamma-aminobutyrate (GABA) were shown to be preferentially released. The efflux of glutamate was calcium-dependent. Prisms prepared from human neocortex obtained shortly after death also exhibited preferential K+-induced release of putative amino acid transmitters. Absolute concentrations released into the media were similar to those found for neurosurgical samples. Comparison of the release data for rat and human samples revealed that the efflux of aspartate, glutamate and GABA occurred to a greater extent from rat brain preparations. The K+-evoked release of glutamate from human samples showed a significant linear increase from 12 to 68 years of age.

Cell counts have been performed on cholinergic subcortical nuclei, dorsal raphe nucleus, and locus caeruleus from up to 18 cases of Alzheimer's disease and 10 age-matched control subjects. In general, the extent of cell loss in these structures was similar. In the basal nucleus the anteromedial subdivision was the least, and the posterior subdivision the most affected. A subgroup of demented subjects with Alzheimer's disease had a relatively preserved basal nucleus, and frontal lobe (CAT) choline acetyltransferase activities similar to those in control subjects, but significantly more neuronal loss in the locus caeruleus.

The cell density in the Nucleus Basalis in six patients with clinical and histological evidence of Alzheimer's disease and reduced choline acetyltransferase activity in frontal and temporal cortex was found to be in approximately 50% of the cell count in five control subjects.

The novel N-methyl-D-aspartate receptor channel ligand (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5, 10-imine maleate ([3H]MK-801) has been utilized to label this receptor in human brain tissue. Characteristics of [3H]MK-801 binding to well-washed membranes from 17 control subjects and 16 patients with Alzheimer's disease were determined in frontal, parietal, and temporal cerebral cortex and cerebellar cortex. In control tissue the pharmacological specificity of the binding of this substance is entirely consistent with the profile previously reported for rat brain. Binding could be stimulated by the addition of glutamic acid to the incubation medium; addition of glycine produced further enhancement which was not prevented by strychnine. The specificity of the effects of these and other amino acids on the binding was the same as in the rat. In Alzheimer's disease significantly less binding was observed in the frontal cortex under glutamate- and glycine-stimulated conditions. This appears to be associated with a reduced affinity of the site whereas the pharmacological specificity of the site remained unchanged. The effect did not appear to be due to differences in mode of death between Alzheimer's disease and control subjects and is unlikely to be related to factors for which the groups were matched. In contrast, binding was not altered in the absence of added amino acids and presence of glutamate alone. These results imply that in the cerebral cortex the agonist site and a site in the cation channel of the receptor are not selectively altered, but that their coupling to a strychnine-insensitive glycine recognition site is impaired.

Somatostatin-like immunoreactivity (SLIR) has been assayed in frontal and temporal cortex obtained at diagnostic craniotomy and post-mortem from patients with histologically verified Alzheimer's disease. SLIR content was not significantly different from controls in the frontal and temporal lobes, except in the temporal cortex post-mortem. The K+-stimulated release of endogenous SLIR from tissue prisms ('mini-slices') prepared from neocortex obtained at diagnostic craniotomy from Alzheimer patients was not below the control values. Indices of cholinergic varicosities in similar samples from the frontal and temporal lobes are reduced; accordingly, somatostatin does not seem to be as prominently involved in these regions. Patients with Alzheimer's disease underwent neuropsychological assessment shortly before sampling the temporal lobe. Scores for WAIS full scale and the verbal subscale and the Token Test (measure of language comprehension) significantly correlated with the SLIR content; mean values (fmole/mg protein) were 817, 1468 and 1363 for aphasic and non-aphasic Alzheimer patients and controls, respectively. Ventricular fluid obtained from Alzheimer patients during surgery, did not have a significantly different SLIR content compared to controls. SLIR contents of ventricular fluid and neocortex from demented patients, without any specific histological changes in the sample obtained at diagnostic craniotomy, were also not significantly different from controls. Previously, we have shown that these demented patients, as well as those with histologically verified Alzheimer's disease, have a reduced SLIR content of lumbar fluid so it seems that somatostatin neurones located outside the frontal and temporal lobes are affected relatively early in the disease process.

Samples of neocortex removed at diagnostic craniotomy from patients with Alzheimer's disease and incubated in vitro showed an increased production of 14CO2 from [U-14C]glucose compared with neurosurgical controls. This was a feature of incubations in the presence of both 5 mM K+ (142% control) and 31 mM K+ (126%). Specific labelling of the amino acid pool was unaltered, suggesting that the apparent increase of CO2 production was not merely a reflection of changes in dilution of the radiolabel from glucose. The content of adenine nucleotides was significantly less than control values in the tissue from patients with Alzheimer's disease after in vitro incubations but the adenylate energy charge was unchanged, indicating that normal energy metabolism was not grossly impaired in these preparations.

Binding of [3H]8-hydroxy-2-(di-n-propylamino) tetralin, a putative ligand for the 5-hydroxytryptamine (5-HT, serotonin) 1A recognition site, was measured in neocortex from postmortem human brain. The substance was found to bind to a saturable site with a KD value and pharmacological profile similar to that of rat. Binding to membranes from normal human temporal cortex was found to significantly correlate (inversely) with age. A significant reduction in binding, reflecting decreased density of recognition sites, was observed in the frontal cortex of patients with Alzheimer's disease (48% loss). This region in the dement brains showed unaltered presynaptic 5-HT function (5-HT and 5-hydroxyindoleacetic acid content) whereas 5-HT concentration was reduced in the temporal cortex.