[The White man's burden - a case study caught between bipolar affective disorder and Huntington's disease]. / White Man's Burden - Im Grenzgebiet zwischen bipolarer affektiver Störung und Huntington-Erkrankung.

We report upon a case of a 55 year old patient with a bipolar affective disorder, presenting herself with a depressive symptomatology in addition to a severe motor perturbation. The main emphasis upon admittance was perfecting and improving her latest medication. Four weeks prior to her stay at our clinic a thorough neurological examination had taken place in terms of an invalidity pension trial which did not result in any diagnostic findings. Therefore a neurological disease seemed at first highly unlikely. Even though the prior testing was negative, the ensuing neurological examination at our clinic resulted in movement disorders very much indicative of Huntington's Disease. A detailed investigation in regards to the particular family history of the patient was positive for Huntington's Disease. However, whether the patient's mother had also been a genetic carrier of Huntington's Disease was still unknown at the time the patient was admitted to our clinic. It was nevertheless discovered that her mother had also suffered from a bipolar affective disorder. A genetic testing that followed the neurological examination of the patient proved positive for Huntington's Disease. Neuro-imaging resulted in a bicaudate-index of 2.4 (the critical value is 1.8). In a clinical psychological test battery the ensuing results were highly uncommon for patients with solely a bipolar affective disorder people. Under the medical regimen of Quetiapine, Citalopram and Tiaprid the patient's mood could be stabilized and there was some improvement of her motor pertubation.

Expression and localization of endothelin-1 and endothelin receptors in human meningiomas. Evidence for a role in tumoral growth.

In addition to its well-known homoeostatic actions in the cardiovascular system, ET-1 has been shown to constitute a potent growth regulatory peptide in various tissues. We have studied the expression of ET-1 and its receptors (ET-Ar and ET-Br) in human meningiomas (n = 35) as well as their involvement in cellular growth. By PCR of reverse-transcribed RNA we detected ET-1 mRNA in 91% (32 of 35), ET-Ar mRNA in 82% (29 of 35), and ET-Br mRNA in 42% (15 of 35) of human meningiomas examined. The localization of ET-1 mRNA, ET-Ar mRNA, and ET-1 peptide in tumoral cells was observed by in situ hybridization and immunohistochemistry, whereas ET-Br mRNA was expressed at low level only in cells belonging to blood vessels. In addition, we found that ET-1 stimulated [3H] thymidine incorporation in primary cell cultures of 20 meningiomas and that this effect could be blocked by BQ-123, a specific antagonist for ET-Ar. In contrast, RES-701-3, an antagonist of ET-Br, did not block the proliferative effect of ET-1. In conclusion, our data provide evidence that ET-1 constitutes an important growth factor for meningiomas acting via ET-Ar. We can hypothesize that ET-1, acting in concert with other growth factors and cytokines, is involved in the meningioma tumorigenesis.

Changes of NMDA receptor subunit (NR1, NR2B) and glutamate transporter (GLT1) mRNA expression in Huntington's disease--an in situ hybridization study.

The distribution of NMDA receptor subunit (NR1, NR2B) and glia-bound glutamate transporter (GLT1) mRNAs was investigated in postmortem brains of Huntington's disease (HD) patients and controls by means of in situ hybridization using radiolabeled deoxyoligonucleotides. In the neostriatum of HD, NR1, NR2B and GLT1mRNA decreased in correlation to disease severity. GLT1mRNA was not as low as NR1/NR2BmRNA. Losses were more prominent in putamen than in the distinctly atrophied caudate. NR1/NR2BmRNA decreased corresponding to neuronal loss, GLT1mRNA due to reduced cellular expression. The number of GLT1mRNA expressing cells identified as astrocytes increased in the neostriatum (astrogliosis). In contrast to controls, most of these astrocytes contained glial fibrillary acidic protein. NR1/NR2B and GLT1mRNA expression was not homogeneously lower in the neostriatum; zones with stronger hybridization signals corresponded to the matrix compartment and consisted of a larger number of cells with high mRNA levels. Early in the disease, cellular NR1/ NR2BmRNA levels were higher in these zones than in controls. These findings indicate a loss of neurons with NMDA receptors in the neostriatum of HD. A concomitant proliferation of astrocytes with GLT1 transcripts may represent a compensatory mechanism protecting neostriatal neurons from glutamate excitotoxicity.

Extrahypothalamic neurophysin-containing perikarya, fiber pathways and fiber clusters in the rat brain.

Immunoreactive neurophysin (Np) is demonstrated by the immunoperoxidase technique not only within neurones of the classical hypothalamo-neurohypophyseal system, but also in extrahypothalamic perikarya and fibers. Np-positive perikarya are found in the triangular nucleus of the septum. Np fibers join the stria terminalis (ST) at the level of the anterior hypothalamus, and course medially in the ST to the central nucleus of the amygdala. Np fibers are found in the brain stem and spinal cord. Fine caliber Np fibers from the suprachiasmatic nucleus ascend to the medial dorsal thalamus and lateral septum. The presence of Np within neurones implies the presence of either vasopressin or oxytocin. Np-positive fibers in extrahypothalamic sites may interact with non-neurosecretory neurones involved in neuroendocrine regulation, or may serve as yet unknown functions.

Heterogeneous dopamine D2 receptor subtype messenger ribonucleic acid expression in clinically nonfunctioning pituitary adenomas.

Little is known about differences in the expression, localization, and function of the two dopamine D2 receptor subtypes, D2short and D2long (D2s and D2l), in either normal or adenomatous pituitary. We investigated the messenger RNA (mRNA) expression of the D2 receptor (D2R) subtypes in clinically nonfunctioning pituitary adenomas by in situ hybridization using subtype-specific oligonucleotides. The five normal pituitaries studied expressed similar ratios of D2R subtypes mRNA with a predominant expression of the D2l isoform. In 2 of 18 clinically inactive adenomas no D2R mRNA was found, whereas in 16 a heterogeneous expression of D2R isoforms was observed. Six adenomas expressed only the D2l and 2 adenomas only the D2s subtype mRNA; the remaining 8 expressed extremely varying proportions of the two subtypes. The D2R was found only in a subset of the nonfunctioning adenoma cells. In gonadotropin-immunopositive adenomas, the D2R was mainly localized in LH- and FSH-immunopositive cells. Probably because of the heterogeneous D2R subtype expression, suppression of cell proliferation was observed in only 3 of 9 adenoma cell cultures in which the growth inhibitory effect of bromocriptine was studied. Although there is some evidence that the presence of the D2s receptor subtype favors the growth inhibitory response to bromocriptine, further studies with a larger number of inactive adenomas are needed to confirm this speculation.

Identification of parvocellular vasopressin and neurophysin neurons in the suprachiasmatic nucleus of a variety of mammals including primates.

The presence of parvocellular vasopressin- and neurophysin-containing neurons in the suprachiasmatic nucleus (SCN) was investigated in 13 mammalian species representing six mammalian orders (marsupials, rodents, lagomorphs, artiodactyls, carnivores, and primates), using specific antisera to vasopressin and neurophysin in the unlabelled antibody=enzyme immunoperoxidase method. In all mammals examined, including man, parvocellular vasopressin and neurophysin neurons were found in the SCN. Only a portion of SCN neurons contain vasopressin and neurophysin, the number varying with species. Cell counts comparing the number of immunoreactive to Nissl-stained neurons showed averages of 17% immunopositive neurons in the rat SCN, and 31% in the human SCN. No oxytocin-containing SCN neurons were observed. These findings suggest that parvocellular vasopressin and neurophysin neurons are widely represented in mammals.

CSF somatostatin is elevated in patients with postzoster neuralgia.

We evaluated the concentration of the neuropeptide somatostatin (SOM) in the CSF of patients with several neurologic diseases. Since SOM is localized in high concentrations in primary sensory pathways, such as the dorsal root ganglia and dorsal horn of the spinal cord, it might be involved in conditions of chronic pain due to functional alterations of nociceptive neurons, such as postinfectious zoster neuralgia. Our study indicated a marked elevation of SOM in patients suffering from postzoster neuralgia compared with controls. Comparison with other neurologic diseases revealed decreased CSF SOM levels in Parkinson's and Alzheimer's disease, unchanged values in patients with amyotrophic lateral sclerosis, and increased concentrations in patients with brain tumors. In neurodegenerative disorders, SOM levels in CSF seemed to reflect the anatomic distribution as well as a reduction or preservation of the peptide in certain brain areas affected by the disease process. In postzoster patients, postinfectious degeneration of dorsal root ganglia cells might cause deafferentation of dorsal horn neurons and activation of SOM-containing systems with increased release either locally from neurons in the dorsal horn of the spinal cord or from descending fiber projections. The results suggested that SOM may take part in the modulation of nociceptive responses.

Striatal dopamine D2 receptors in patients with narcolepsy measured with PET and 11C-raclopride.

We investigated in vivo D2 receptor binding using 11C-raclopride and PET in the striatum of 17 subjects with the narcoleptic syndrome. Putamen and caudate nucleus 11C-raclopride uptake was comparable in the total patient group and controls, and the tracer uptake was similar in the HLA-DR2-positive (n = 12) and HLA-DR2-negative (n = 5) narcoleptic subjects. There was a significant increase in 11C-raclopride uptake in the putamen of narcoleptic subjects older than 31 years (n = 11) when compared with age-matched controls (n = 15). There was no evidence of involvement of the striatal D2 dopaminergic neurotransmitter system in the basic pathophysiology of the narcoleptic syndrome despite an age-related increase in putaminal 11C-raclopride uptake.

Increased cerebral iron uptake in Wilson's disease: a 52Fe-citrate PET study.

UNLABELLED: Toxicity of abundant copper is the main cause of brain and liver tissue damage in patients with Wilson's disease (WD). However, there is also evidence of a disturbed iron metabolism in this genetically determined disorder. This PET study was undertaken to assess cerebral iron metabolism in WD patients. METHODS: We used 52Fe-citrate, which converts to 52Fe-transferrin in blood plasma, to study basic pharmacokinetic features of the cerebral iron transport in 6 WD patients and in 16 healthy volunteers (control subjects). A 2-tissue-compartment model and multiple time graphic plotting were used to calculate 52Fe-transferrin distribution volumes and transport rates. RESULTS: Net iron uptake (Ki) from plasma into brain tissue was significantly (P < 0.001) higher in WD patients (Ki [mean +/- SEM] = 15.1E-05 +/- 7.13E-05 [1/min]) than in healthy volunteers (Ki = 2.66E-05 +/- 0.351E-05 [1/min]). There was no difference of tracer iron distribution in the cerebral plasma volume between patients and healthy volunteers. Iron uptake values resulting from 2 methods to model PET data of patients and healthy volunteers were highly correlated (P < 0.001). CONCLUSION: An abnormally increased cerebral 52Fe-transferrin uptake was found in WD patients.

Somatostatin in the brain of the turtle Testudo hermanni Gmelin. An immunohistochemical mapping study.

An immunohistochemical mapping study in the brain and upper spinal cord of the turtle Testudo hermanni Gmelin revealed a wide distribution of somatostatin perikarya and fibres. Within the telencephalon, somatostatin perikarya are present in the anterior olfactory nucleus, in the medial, dorsomedial and dorsal cortex, in the pallial thickening, in the piriform cortex, paleostriatum augmentatum, in the dorsoventricular ridge, core nucleus of the dorsoventricular ridge, in area c and d, and in the amygdala. In the diencephalon, the periventricular nucleus of the hypothalamus contains many somatostatin perikarya. Cerebrospinal fluid contacting somatostatin perikarya of the infundibular nucleus terminate with club-like endings in the ventricular cavity. Some somatostatin perikarya are present in the nu. reuniens of the thalamus and in the lateral habenular nucleus of the epithalamus. Within the mesencephalon somatostatin perikarya are located in the interpeduncular nucleus, area tegmentalis ventralis and in the nu. reticularis isthmi. In the rhombencephalon, somatostatin perikarya are encountered in the nu. raphe superior, nu. reticularis magnus, periventricular grey matter, bed nucleus of the fasciculus longitudinalis medialis and in the nu. solitarius-vagus complex. Somatostatin fibres form a circular band in the olfactory bulb. In the telencephalon, dense aggregations of somatostatin fibres are present in the anterior olfactory nucleus, in the pallial thickening, in the parahippocampal gyrus, cortex medialis, dorsomedialis, dorsalis and piriformis, in the dorsal ventricular ridge, paleostriatum augmentatum, area c and d, in the septum, nu. diagonalis of Broca, in the amygdala and in the anterior commissure. In the diencephalon, somatostatin fibres terminate at the vessels of the organum vasculosum of the lamina terminalis. A dense band of somatostatin fibres surrounds the rostral third ventricle. Somatostatin fibres terminate in the infundibulum at portal capillaries, and in the neural lobe. Somatostatin fibres are found in the periventricular, ventromedial and lateral nucleus of the hypothalamus. In the thalamus, the area triangularis, the dorsomedial and dorsolateral area and the nu. reuniens contain somatostatin fibres. Somatostatin fibres are very dense in the lateral habenular nucleus. At the mesencephalic level, somatostatin fibres are found in the pretectal nucleus, in the deep layers of the tectum, in the nu. tori semicircularis lateralis, in the interpeduncular nucleus, area tegmentalis ventralis, nu. ruber, substantia nigra and periventricular grey.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuropeptide Y-like immunoreactive neurons in the human olfactory bulb.

Neuropeptide Y-like (NPY) immunoreactivity was localized in the adult human olfactory bulb by the unlabeled antibody enzyme (peroxidase anti-peroxidase; PAP) technique in vibratome sections. The majority of NPY-immunoreactive somata was localized in the white matter surrounding the anterior olfactory nucleus. Immunoreactive neurons were less numerous within the anterior olfactory nucleus and within the olfactory bulb layers. NPY-immunoreactive fibres were present in the white matter, the anterior olfactory nucleus, and in the olfactory bulb layers. Fibres within the white matter were generally aligned in a straight path parallel to the long axis of the olfactory bulb and tract. Fibres within the anterior olfactory nucleus showed no clear orientation and displayed numerous branching points. Coiled plexus of NPY-immunoreactive fibres were present in the glomerular layer of the olfactory bulb. Additional characteristics of the NPY-immunoreactive neurons were studied after decolouring the chromogen and restaining the sections with aldehydefuchsin to demonstrate the presence of lipofuscin granules and also with gallocyanin chrome alum to stain the Nissl substance. This analysis showed that the neurons belong to the class of non-pigmented nerve cells.

Progressive degeneration of dopamine system functions after transient cerebral oligemia in rats.

A reduction in cerebral blood flow to oligemic levels was achieved in pentobarbital-anesthetized adult rats by clamping both carotid arteries (BCCA) for 60 min. To assess the extent to which the animals' dopaminergic system was affected over an increasing time span, their spontaneous locomotor activity in an unfamiliar environment and in response to the subcutaneous administration of apomorphine was tested at various times after either BCCA or sham operation. Eight to 14 days after the operation, it was possible to observe a diminished locomotor activity in response to apomorphine injection in BCCA as compared with sham-operated animals, while oral stereotypical behavior such as licking was increased. At 3 months, there was only a subtle decrease in apomorphine-induced locomotor activity, and stereotypical behavior was similar in both groups. At 7 months, the BCCA rats covered shorter distances than sham-operated controls during the habituation phase; after apomorphine injection, more stereotypic movements, such as, e.g., sniffing, were observed, and less running. Twelve months after surgery, no further differences could be observed between the two groups during the habituation phase, but the injection of apomorphine led to increased stereotypic sniffing movements, rearing and locomotor activity in BCCA animals to a greater extent than in the controls. At 12 months, sensorimotor disturbances elicited by the rota rod test, which were only transiently observed at 11 weeks and 7 months, did not appear any different from the normal age-related motor decline of the sham-operated controls. The animals' motor co-ordination in the chimney test was not significantly disturbed during the time between 7 and 12 months after surgery. At 15 months, nocturnal locomotor activities in BCCA rats were significantly decreased. In situ hybridization (ISH) histochemistry revealed decreased D1 receptor mRNA (D1RmRNA) in striatal neurons 19 months after surgery, while D2 receptor mRNA (D2RmRNA) and the neuronal number remained the same. The present results show that just as is already known for the immature rat brain, the adult rat brain, too, reacts to a transient decrease in its blood supply by appearance of long-lasting alterations in function, and that even a single oligemic episode is capable of inducing progressive dopaminergic dysfunctions and ultimately the partial loss of striatal D1RmRNA.

Co-localization of choline acetyltransferase and postsynaptic glycine receptors in motoneurons of rat spinal cord demonstrated by immunocytochemistry.

Male rats were perfused with paraformaldehyde and picric acid. The cervical spinal cord was cryosectioned and immunostained with a monoclonal antibody against the postsynaptic receptor for the neurotransmitter glycine. The anterior horn contained glycinoceptive neurons of varying morphology. Cholinergic cells were identified in the same tissue sections when subsequently immunostained with a monoclonal antibody against choline acetyltransferase, the biosynthetic enzyme of acetylcholine. Immunoreactivity for the glycine receptor was detected in the plasma membrane and for choline acetyltransferase in the perikaryal cytoplasm of identical anterior horn cells, classified as small, medium and large motoneurons. This suggests that motoneurons have receptors for glycine on their cell surface.

The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease.

According to the excitotoxicity hypothesis, neurotoxicity due to glutamate is regarded as potential factor in the progredient neurodegeneration of Huntington's disease (HD). Memantine, as a glutamate receptor antagonist, should counteract this mechanism. Its effectiveness (up to 30 mg/day) with regard to retardation of progression was thus examined in 27 HD patients in a two year, open and multicentre trial. The results suggest that memantine treatment of HD may be useful in terms of retardation of the progression of the disorder.

Immunohistochemical studies on opioid peptides in the human placenta.

The demonstration of the immunoreactive proopiomelanocortin (POMC) peptides beta-endorphin (beta-E), beta-lipotropin (beta-LPH), alpha-melanotropin (alpha-MSH), and corticotropin (ACTH) in the human placenta or in tissue cultures of placental origin using radioimmuno-, bio-, or radioreceptor assay suggested that opioid peptide hormones or their precursors are synthesized in the placenta. In order to test this hypothesis, we tried to localize opioid peptides immunohistochemically. On neighbouring sections of the placenta which were incubated with antisera against beta-E, beta-LPH, alpha-MSH, ACTH, BAM-12 P, BAM-22 P, Heptapeptide, alpha-Neoendorphin and Dynorphin 1-17, the immunoperoxidase method was used. The placenta and the pituitary of perfusion-fixed rats were used for controls. The negative immunohistochemical findings in the human and rat placenta do not support the view that beta-E, beta-LPH, alpha-MSH and ACTH are synthesized in the syncytiotrophoblast of this organ. The site of origin of proopiomelanocortin peptides which are present in the maternal and the fetal plasma most likely is the maternal and fetal pituitary.

Opioid peptide-like immunoreactivity localized in GABAErgic neurons of rat neostriatum and central amygdaloid nucleus.

Opioid peptide-like (OPL)-immunoreactivity and (the GABA-biosynthetic enzyme) glutamic acid decarboxylase-like (GAD)-immunoreactivity were localized in rat neostriatum and central amygdaloid nucleus (ACE) using a polyclonal sheep antiserum to rat brain GAD and a monoclonal mouse antibody to the N-terminus of beta-endorphin (3-E7) as primary antisera. PAP-immunohistochemistry revealed GAD-immunoreactivity in the majority of neurons in neostriatum and ACE. OPL-immunoreactivity was observed in numerous neurons in ACE, but only in few neostriatal nerve cells. In double immunofluorescence in the same section OPL- and GAD-immunoreactivity colocalized in few medium size cells in the neostriatum, but in numerous neurons in ACE. The existence of opioid peptide containing GABAergic neurons in ACE and neostriatum is demonstrated.

Somatostatin-like immunoreactivity in non-pyramidal neurons of the human isocortex.

The distribution of somatostatin-immunoreactive cell bodies and axons throughout the human isocortex and subjacent white matter was examined. Vibratome sections of cortical tissue (30-40 micrometers thick) obtained at surgery were treated to reveal the antigen by the unlabelled antibody enzyme method. Two types of somatostatin-immunoreactive axons were present: short, coiled axons and extended ones that follow a straight course in various directions. Somatostatin immunoreactive nerve cell bodies were encountered in layers II-VI and in the subjacent white matter. The majority of labelled cells were found in the white matter and layer VI, and then in layers II and III. The immunoreactive perikarya were fusiform, triangular or multipolar in shape and did not show preferential orientation of their long axis. Frequently, the fusiform neurons in layer VI and in the white matter were aligned parallel to radiate bundles of myelinated fibres. The immunoreactive neurons gave rise to a few thick dendrites. Often thin axon-like processes could also be recognized, originating either from the cell body or from a thicker dendrite. After destaining of the chromogen and counterstaining with aldehydefuchsin and gallocyanin chromealum, the formerly immunoreactive neurons displayed a light and eccentrically located nucleus. The soma contained only a sparse amount of basophilic substance and was nearly devoid of lipofuscin granules. In electron micrographs, the cisterns of the rough endoplasmic reticulum (RER) were localized near the periphery of the soma. Immunoreactivity occurred along membranes of the RER cistern, outer mitochondrial membrane, and in particles 120-150 micrometers in diameter. Rounded areas (up to a diameter of 1 micrometer) lacked immunoreactivity. Furthermore, there were a few tiny lysosomes.

Is motilin a cerebellar peptide in the rat? A radioimmunological, chromatographic and immunohistochemical study.

Motilin was demonstrated by the immunoperoxidase technique in endocrine cells of the gastrointestinal tract using several specific antisera. Motilin-like immunoreactivity could only be demonstrated with one of these antisera and was observed in Purkinje cells and dendrites of the cerebellum, in pyramidal cells and dendrites of the cerebral cortex and in dendrites of the CA 3 field of the hippocampus of the rat. Very low motilin-like immunoreactivity was found in cerebellum as well as in cerebral cortex using radioimmunoassay. However, using reverse phase liquid chromatography combined with UV-detection and radioimmunoassay, no peak of a peptide corresponding to synthetic motilin was detectable in rat cerebellar extracts, in contrast to findings in rat duodenum. The results do not suggest that motilin is an intrinsic neuroactive substance of the cerebellum.

Distribution of neuropeptide Y in the prosencephalon of man and cotton-head tamarin (Saguinus oedipus): colocalization with somatostatin in neurons of striatum and amygdala.

The presence, chromatographic properties and localization of neuropeptide Y was demonstrated in postmortem human brain areas of neurologically and neuropsychiatrically normative controls using immunocytochemistry and high performance liquid chromatography combined with radioimmunoassay. NPY-immunoreactivity was found in many regions of the prosencephalon. Numerous perikarya and fibers were present in the neocortex, basal ganglia and limbic-hypothalamic areas. A moderate number of neurons and fibers was observed in the basal forebrain, including the septal complex. A comparative immunohistochemical investigation in perfusion-fixed brains of the old-world ape Saguinus oedipus revealed an almost identical distribution of NPY-immunoreactivity with only minor differences. Colocalization experiments on 1-2 microns thin consecutive paraffin sections revealed a large number of NPY neurons throughout the human neostriatum and amygdaloid complex that were also positive for somatostatin. Our findings indicate that detection of neuropeptides in fresh or fixed post-mortem human tissue by different immunochemical methods may actually reflect the in vivo conditions. In addition, the wide distribution of NPY throughout the human brain and its colocalization with other neurotransmitters suggests a physiological role as neuroactive substance, i.e. neuromodulator in the primate central nervous system.

Demonstration of atrial natriuretic peptide/cardiodilatin (ANP/CDD)-immunoreactivity in the salt gland of the Pekin duck.

A novel peptide hormone, atrial natriuretic factor/cardiodilatin (ANP/CDD), was recently isolated and characterized from mammalian heart. Its presence has been demonstrated in several organs that contribute to water and sodium homeostasis, such as salivary glands. This study demonstrates the presence of ANP/CDD immunoreactivity in the salt gland of Pekin ducks by high performance liquid chromatography, radioimmunoassay and immunocytochemistry, using a specific antibody against atriopeptide I. A small number of distinct, ovoid or cuboid shaped ANP/CDD-immunoreactive cells were localized in the connective tissue surrounding and separating the central secretory tubules, whereas no immunostaining was observed in the peripheral tubules. Salt glands of ducks that were adapted to salt water revealed a significant hypertrophy of their secretory lobules. However, no differences were found between the number or localization of immunoreactive cells in the salt gland of salt water-acclimatized ducks and nonstimulated glands of ducks that were housed with ad libitum access to fresh water. Our results indicate that ANP/CDD may play a role in the regulation of sodium secretion in the salt gland of aquatic birds.