Brain neurotransmitter changes in three patients who had a fatal hyperthermia syndrome.

The authors examined the autopsied brains from three patients who had a fatal hyperthermia syndrome. There was marked hypothalamic noradrenaline depletion in all three patients, severe brain choline acetyltransferase deficiency with nucleus basalis cell loss in two patients, and mild to moderate brain choline acetyltransferase loss in one patient. Striatal dopamine metabolite/dopamine ratio was below normal in two patients and not elevated, as would be expected after short-term neuroleptic administration, in the third. This suggests that reduced capability (aggravated by the cholinergic deficit) of the nigrostriatal dopamine system to respond adequately to stress and/or neuroleptic-induced receptor blockade may be important in the development and course of fatal hyperthermia syndrome.

Nerve growth factor receptor and choline acetyltransferase remain colocalized in the nucleus basalis (Ch4) of Alzheimer's patients.

Previous investigations have demonstrated an almost exclusive "coupling" between the receptor for nerve growth factor and cholinergic neurons within the basal forebrain. The present series of experiments were carried out to address two questions. First, what is the status of nerve growth factor receptor-containing neurons within the basal forebrain of patients with histopathologically confirmed diagnoses of Alzheimer's disease (AD)? More importantly, the second experiment assesses the degree to which the receptor for nerve growth factor and choline acetyltransferase remain colocalized within AD basal forebrain. A "decoupling" of this relationship, in which nerve growth factor receptors are no longer present upon magnocellular cholinergic neurons, would suggest that a loss of trophic support is functionally antecedent to the neuronal shrinkage and neuronal death seen in the basal forebrain in AD. Data obtained from six AD cases and four normal controls demonstrated an extensive reduction in number and shrinkage in size of nerve growth factor receptor containing neurons within the Ch4 region of the basal forebrain. Double label studies using either immunofluorescence or immunoperoxidase techniques demonstrated that the receptor for nerve growth factor and choline acetyltransferase remain colocalized in AD patients. This was true for neurons exhibiting either healthy or dystrophic morphological profiles. These data confirm previous studies, demonstrating that both a loss and shrinkage of cholinergic neurons occurs within the AD basal forebrain. The results of the present immunohistochemical investigation suggest that the degenerative changes associated with these neurons do not result from impaired trophic support related to a loss of NGF receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes within the basal nucleus in Parkinson's disease.

The magnocellular nuclei in the basal forebrain--the medial septal nucleus, the nucleus of the diagonal band, and the basal nucleus within the substantia innominata--are tightly connected with each other. Large multipolar neurons clearly predominating in number can be differentiated from a spindle-shaped and a small globular type of neuron on account of their typical pattern of lipofuscin pigmentation. As an additional feature some of the multipolar neurons exhibit intracytoplasmic acidophilic granules. At the ultrastructural level, these granules reveal a homogeneous substructure, and they are occasionally located within mitochondria. The percentage of large multipolar neurons displaying acidophilic granules varies in a topographical manner (medial septal nucleus and vertical limb nucleus of the diagonal band: 10%, horizontal limb nucleus of the diagonal band and anteromedial subnucleus of the basal nucleus: 36%, posterolateral subnucleus of the basal nucleus: 54%). In parkinsonian cases a significant decrease of granule-bearing neurons within the posterolateral subnucleus of the basal nucleus is noted. This decrease might be associated with the appearance of neurons containing Lewy-bodies. It is also conceivable that the granule-bearing neurons show a higher vulnerability and underlie neuronal death. Analyzing the lipofuscin pigmentation within the two subnuclei of the basal nucleus in parkinsonian cases, one notices that the number of large multipolar neurons displaying pigment granules in a dendritic stem is significantly higher than in controls. Moreover, it is apparent that the degree of this pigment penetration is more pronounced in cases of Parkinson's disease. These alterations may be interpreted as a sign of plasticity of this neuronal population.

Light microscopic evidence for a substance P-containing innervation of the human nucleus basalis of Meynert.

A two color histochemical/immunohistochemical method was used to demonstrate substance P and acetylcholinesterase in sections of the human nucleus basalis of Meynert (nbM). Substance P-immunoreactive terminal-like structures were found to make contact with magnocellular, acetylcholinesterase-positive perikarya and primary dendrites throughout all subdivisions of the nbM. This apparent innervation of nbM neurons was in most cases a relatively sparse one, but a small percentage of these neurons appeared to be recipients of a very heavy innervation which covered their perikarya and primary dendrites.

A comparison of somatostatin and neuropeptide Y distribution in monkey brain.

The concentrations of both somatostatin-like immunoreactivity (SLI) and neuropeptide Y-like immunoreactivity (NPYLI) were measured in all major cortical and subcortical regions of monkey brain. High concentrations of both SLI and NPYLI were found in cerebral cortex where they were significantly correlated, supporting a colocalization of the two peptides in cortical neurons. There were no significant differences between the right and left hemispheres. Subdissections of the basal ganglia showed that concentrations of both SLI and NPYLI were 3-fold higher in the nucleus accumbens than in the remainder of the striatum, where concentrations of the peptides were evenly distributed. SLI and NPYLI levels were significantly correlated in the striatum, supporting a colocalization of the two neuropeptides in striatal neurons. Concentrations were low in the globus pallidus. Limbic system nuclei including the amygdala, bed nucleus of the stria terminalis and substantia innominata had relatively high concentrations of both SLI and NPYLI. In several subcortical regions concentrations of the neuropeptides were dissociated, suggesting separate neuronal populations. The distribution of both neuropeptides in monkey brain closely resembles that in human brain. The high levels in cerebral cortex and basal ganglia suggest that somatostatin and neuropeptide Y may play a role both in cognition and in normal motor function.

Alzheimer's disease: monoamines and spiperone binding reduced in nucleus basalis.

Levels of dopamine and serotonin, and of their precursors and metabolites, were measured in the nucleus basalis of Meynert (nbM) of patients with Alzheimer's disease and control patients. [3H]Spiperone binding to membrane homogenates of the nbM, indicative of both dopaminergic and serotonergic receptors, was also measured. The nbM from patients with Alzheimer's disease showed significant decreases in both spiperone binding and in the levels of dopamine and serotonin but no decrease in either tyrosine or tryptophan levels. These data indicate a loss of both dopaminergic and serotonergic synapses in the nbM of patients with Alzheimer's disease.

Substance P in the human brain.

The distribution of substance P immunoreactive sites was investigated by immunoenzymatic methods in a large series of paraffin embedded human brain sections from the collection assembled by Oscar and Cécile Vogt several decades ago, as well as from more recent post-mortem material. These studies demonstrated that substance P immunoreactivity was preserved in archival material permitting a detailed account of the localization of immunoreactive cell bodies, fibre networks and tracts in the human brain. Previous observations made on experimental animals and man were confirmed and extended. Additionally, substance P immunoreactive cell bodies were seen in most cortical areas and novel features were noted in the distribution of substance P-containing elements in the tuberal region, corpus striatum, substantia nigra (particularly in relationship to blood vessels) and in association with melanin-containing cells. Reconstruction of some substance P pathways was attempted by the analysis of semi-serial sections in more than one plane. Immunocytochemistry, in combination with image analysis, enabled some measurements of the differential concentrations of substance P immunoreactive material to be made and allowed a close correlation of this with defined anatomical landmarks or enkephalin immunoreactive sites.

Somatostatin immunoreactivity in cortical and some subcortical regions in Alzheimer's disease.

Reverse phase HPLC analysis of somatostatin immunoreactivity in the cerebral cortex in elderly normal individuals revealed that the majority of the immunoreactivity co-eluted with synthetic somatostatin-14. While an immunoreactive peak corresponding to somatostatin-28 was not detected there was a peak of immunoreactivity which eluted after somatostatin-14. In cases of senile dementia of Alzheimer type (SDAT), where abundant neurofibrillary tangles and senile plaques (density greater than 30 per 1.3-mm2 field) were present in the cerebral cortex, somatostatin immunoreactivity was found to be significantly decreased in either the frontal or temporal cortex. Chromatographic analysis, however, revealed that both the major immunoreactive peaks detected in the normal group were reduced in SDAT in the temporal and frontal cortex. Using a punch microdissection technique somatostatin immunoreactivity has been assessed in the nucleus of Meynert and amygdala of SDAT and elderly normal cases. While there was no change in somatostatin immunoreactivity in the nucleus of Meynert in the SDAT group, tissue punches taken from the amygdala revealed a selective decrease in somatostatin immunoreactivity in the basal nucleus, in the SDAT cases.

Characterization of proenkephalin B-derived opioid peptides in the human hypothalamo-neurohypophyseal axis.

Proenkephalin B-derived opioid peptides, such as dynorphin1-17, dynorphin1-8, dynorphin B, alpha-neo-endorphin and beta-neo-endorphin in the human hypothalamo-neurohypophyseal tract were quantitated and characterized by the combined use of various radioimmunoassays, gel filtration, high performance liquid chromatography and enzymatic cleavage. Chromatographic analysis of immuno-reactive peptide levels determined that, in each case, these were comprised almost exclusively of the authentic peptides both in the neurohypophysis and hypothalamus. Concentrations of authentic proenkephalin B-peptides were 100-5000-fold lower in the human as compared to the rat neurohypophysis. However, in the paraventricular nucleus (PVN), supraoptic nucleus (SON) and certain other nuclei of the human hypothalamus concentrations of authentic peptides were found to be in the same range as those in the rat hypothalamus. The ratio of proenkephalin B-peptides in PVN and SON to those of the neurohypophysis in the rat was ca. 1:50. Conversely, in man these ratios were shown to be 80:1 for dynorphin B, 6:1 for alpha-neo-endorphin and 1:1 for all other peptides evaluated. Examination of postmortem degradation of peptides indicated that these lower levels in the neurohypophysis are not due to a higher rate of postmortem breakdown. Since levels of both vasopressin and beta-endorphin were very high, these deficits in proenkephalin B-peptides were selective and do not represent a generalized property of the human pituitary. Experiments involving enzymatic cleavage demonstrated the occurrence of higher molecular weight forms containing the Leu-enkephalin sequence which were not recognized by the antisera employed.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for the existence of serotonin type-2 receptors on cholinergic terminals in rat cortex.

Levels of serotonin type-2 receptors and choline acetyltransferase (ChAT) were measured in various rat brain regions following unilateral lesions of the nucleus basalis magnocellularis (nBM). As expected, lesions of the nBM markedly decrease cortical ChAT activity. Moreover, [3H]ketanserin (serotonin type-2) binding is significantly decreased in lamina IV of the anterior and middle cortex on the lesioned vs control side. [3H]ketanserin binding in the striatum is not affected by lesions of the nBM. Autoradiograms of [3H]ketanserin binding in lesioned animals show similar results. This suggests that at least a certain proportion of serotonin type-2 receptor binding sites are located on cholinergic terminals in lamina IV of the rat cortex. Therefore, further investigations on cholinergic-serotonergic interactions in the cortex and their possible involvement in senile dementia of the Alzheimer's type appear to be highly relevant.

Relationship between pigment accumulation and age in Alzheimer's disease and Down syndrome.

The amount of lipofuscin pigment within nerve cells of the nucleus basalis of Meynert and that of melanin pigment with nerve cells of locus ceruleus was measured in seven patients with Down syndrome, in 22 patients with Alzheimer's disease and in 18 controls ranging from 30 to 88 years of age. No significant differences in amount of either pigment in these cells at any age were noted between the patient groups and their age controls.