Search Results - (Author, Cooperation:J. Kornhuber)

2015-04-04

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Alzheimer Disease/*genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Humans ; Male ; Phospholipase D/*genetics

2018-06-22

American Association for the Advancement of Science (AAAS)

0036-8075

1095-9203

Biology

Chemistry and Pharmacology

Geosciences

Computer Science

Medicine

Natural Sciences in General

Physics

Genetics, Medicine, Diseases, Online Only

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Human lumbar CSF patterns of Aβ peptides were analysed by urea-based β-amyloid sodium dodecyl sulphate polyacrylamide gel electrophoresis with western immunoblot (Aβ-SDS–PAGE/immunoblot). A highly conserved pattern of carboxyterminally truncated Aβ1–37/38/39 was found in addition to Aβ1–40 and Aβ1–42. Remarkably, Aβ1–38 was present at a higher concentration than Aβ1–42, being the second prominent Aβ peptide species in CSF. Patients with Alzheimer's disease (AD, n = 12) and patients with chronic inflammatory CNS disease (CID, n = 10) were differentiated by unique CSF Aβ peptide patterns from patients with other neuropsychiatric diseases (OND, n = 37). This became evident only when we investigated the amount of Aβ peptides relative to their total Aβ peptide concentration (Aβ1–x%, fractional Aβ peptide pattern), which may reflect disease-specific γ-secretase activities. Remarkably, patients with AD and CID shared elevated Aβ1–38% values, whereas otherwise the patterns were distinct, allowing separation of AD from CID or OND patients without overlap. The presence of one or two ApoE ε4 alleles resulted in an overall reduction of CSF Aβ peptides, which was pronounced for Aβ1–42. The severity of dementia was significantly correlated to the fractional Aβ peptide pattern but not to the absolute Aβ peptide concentrations.

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1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract : Two-dimensional polyacrylamide gel electrophoresis of CSF has been used in the diagnosis of Creutzfeldt-Jakob disease (CJD). One of the two diagnostic protein spots was identified as isoform(s) of the 14-3-3 family of abundant brain proteins. This has led to the development of one-dimensional 14-3-3 sodium dodecyl sulfate polyacrylamide gel electrophoresis immunoblot, which is currently used to support the diagnosis of CJD. In the present study employing western blot analysis, we have identified the panel of 14-3-3 isoforms that appear in the CSF of 10 patients with CJD compared with 10 patients with other dementias. The results clearly show that the 14-3-3 isoforms β, γ, ε, and η are present in the CSF of patients with CJD and can be used to differentiate other dementias. 14-3-3η also gave a baseline signal in all patients with other dementias, including six patients with Alzheimer's disease. The presence of 14-3-3η in the CSF of a patient with herpes simplex encephalitis was particularly noteworthy. This study has determined that isoform-specific 14-3-3 antibodies against β, γ, and ε should be considered for the neurochemical differentiation of CJD from other neurodegenerative diseases.

Electronic Resource

1369-1600

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

The appetite and weight regulating peptide leptin was associated recently with alcohol craving during withdrawal. Nevertheless, correlations were only significant with craving displayed on the visual analogue scale for maximum craving during the previous week (VAS), and not if assessed with the highly validated Obsessive Compulsive Drinking Scale (OCDS). The objective of the following study, therefore, is to elucidate further the associations between the leptin system and craving concepts during alcohol withdrawal. A sufficiently large sample size should allow multiple statistical subgroup and confounder analyses. We prospectively investigated 102 chronic alcoholic inpatients (23 females, 79 males) during withdrawal on days 0 (admission), 1, 2 and days 7 - 10. In addition to the statistical analysis of the total sample, females and males were to be analysed separately. For detecting associations between leptin levels and craving scores multiple regression analysis was performed. Plasma leptin levels were determined, and craving for ethanol was assessed by both the OCDS and the VAS. Leptin plasma levels significantly increased during alcohol withdrawal compared to day 0, while all craving scores decreased. Body mass corrected leptin plasma levels predicted craving on day 0 in the OCDS total score (R  = 0.55, F  = 7.91, df = 1.19, p  〈 0.05) and in the OCDS obsessive subscore (R  = 0.57, F 〈 = 8.48, df = 1.19, p  〈 0.05) in females. Neither in males nor in the total population did multiple regression analysis reveal any significant results. Leptin levels seem to change during inpatient alcohol withdrawal. In a multivariate model, correlations between leptin levels and the highly validated craving scores of the OCDS can only be assumed in females. Hence, gender differences have to be taken into account when searching for neurobiological models of alcohol craving.

Electronic Resource

0165-0327

Cell mediated immunity ; Clinical recovery ; Glucocorticoid receptor ; Lymphocyte transformation test ; Major depression

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Psychology

Electronic Resource

0165-0327

Antidepressants ; Binding ; Depression ; Glucocorticoid receptors

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Psychology

Electronic Resource

0165-0327

Cell-mediated immunity ; Glucocorticoid receptor ; Glucocorticoids ; Lymphocyte transformation test ; Major depression

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Psychology

Electronic Resource

1435-1463

Aspartate ; glutamate ; postmortem ; human brain ; putamen ; ontogenesis ; aging

Springer Online Journal Archives 1860-2000

Medicine

Summary We have previously reported that the developmental regulation of NMDA receptor expression in human brain is characterized by a sharp postnatal increase peaking at about age 1 year. We have now extended this work by measuring concentrations of L-glutamate and L-aspartate in the putamen from 45 human autopsy specimens. Both amino acids increased steeply within the first postnatal year after which they remained fairly constant throughout life. There was no impact on glutamate and aspartate levels in putamen of sex, side of the brain, postmortem time and storage time of brain tissue.

Electronic Resource

1435-1463

Keywords: Genetic, association, affective disorders, angiotensin converting enzyme, insertion/deletion polymorphism, mood disorders.

Springer Online Journal Archives 1860-2000

Medicine

Summary. The insertion/deletion polymorphism of the gene of angiotensin-converting enzyme (ACE) was investigated in a case-control study including 169 patients with suffering from either bipolar disorder type I or unipolar recurrent major depression (DSM-IV) and 169 healthy controls. No significant association was found with bipolar disorder type I or unipolar recurrent depression and the polymorphism of the ACE gene. A previously reported genetic association (Arinami et al., 1996) was not confirmed by the present study.

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1435-1463

Pyruvate dehydrogenase complex (PDHc) ; rat brain ; [3H]Quinuquidinylbenzilate ([3H]QNB) ; energy-rich phosphates ; bromopyruvate ; animal model ; dementia of Alzheimer type (DAT)

Springer Online Journal Archives 1860-2000

Medicine

Summary Pyruvate dehydrogenase complex (PDHc), a link between carbohydrate and acetylcholine metabolism, is a regulatory enzyme for glucose and neurotransmitter metabolism in the brain and is reduced in Alzheimer-diseased brain. To study functional consequences of an inhibition of PDHc on muscarinic receptor binding, bromopyruvate, a suicide inhibitor of PDHc, was injected intracerebroventricularly (icv) in rats. Bromopyruvate caused a reduction of PDHc activity in the 3 brain regions examined, however, reaching significance only in the cerebral cortex and the hippocampus and not in the striatum, 24h after injection. 3, 6, and 12 weeks later, there was a normalization or transiently increased activity, respectively, of PDHc in these brain regions. No changes in concentrations of energy-rich phosphates could be demonstrated in the cerebral cortex 12 weeks after brompyruvate injection. The number of muscarinic receptors was significantly reduced in the cerebral cortex 12 weeks after injection. the data indicate that a transient reduction of brain PDHc activity in vivo is associated with a long-lasting reduction in muscarinic cholinergic receptors. Because comparable changes of PDHc and muscarinic receptors are found in dementia of Alzheimer type, the model of bromopyruvate inhibition of PDHc in rats is suggested to be useful for experimental dementia research.

Electronic Resource

1435-1463

Excitatory amino acid receptors ; ontogeny ; human brain ; Sudden Infant Death Syndrome ; schizophrenia ; Fetal Alcohol Syndrome

Springer Online Journal Archives 1860-2000

Medicine

Summary The early appearance of neurotransmitters in brain tissue refers to their regulative functions on the neuronal circuits. Many neurotransmitters have direct effects on neuronal outgrowth and differentiation during brain development, which precede their role in synaptic information coding. Both the neurotrophic and neurotoxic properties of excitatory amino acids (EAAs) have focused special interest on glutamatergic neurotransmission during brain development. Therefore, this work intends to review and discuss developmental alterations of the EAA neurotransmitter system in the human brain, their relation to human brain maturation and implications for pathological processes during early human brain development.

Electronic Resource

1435-1463

Glutamate ; N-methyl-D-aspartate (NMDA) ; amantadine ; neuroleptic malignant syndrome (NMS)

Springer Online Journal Archives 1860-2000

Medicine

Summary Schizophrenia and Parkinson's disease have been considered inversely related neuropsychiatric disorders since the former has been attributed to increased dopaminergic transmission while the latter is thought to result from loss of dopaminergic neurons. It is in line with this concept that the classical neuroleptic (anti-schizophrenic) drugs cause as a side effect a drug-induced type of Parkinsonism. Most etiopathogenetic models hold that the “neuroleptic malignant syndrome” may result from “overtherapy” of schizophrenia, causing too widespread a block of dopaminergic transmission. The same clinical condition can be triggered by rapid discontinuation of dopaminergic medication in Parkinson's disease. Further, neuroleptic malignant syndrome shares key clinical features such as extrapyramidal motor disturbances and hyperthermia with a severe form of clinical deterioration in Parkinson's disease patients, the akinetic Parkinsonian crisis. Both conditions, neuroleptic malignant syndrome and Parkinsonian crisis, are resistant to anticholinergic treatment but may well respond to drugs with N-methyl-D-aspartate (NMDA) antagonistic properties such as amantadine and memantine. We advocate the use of NMDA receptor antagonists in these medical emergencies and link their clinical efficacy to the common pathophysiological pathway of increased excitatory aminoacid neurotransmitter activity in neuroleptic malignant syndrome, Parkinsonian crisis, and dopamine agonist withdrawal states.

Electronic Resource

1435-1463

D2 receptor ; schizophrenia ; spiperone ; tardive dyskinesia ; neuroleptic drugs

Springer Online Journal Archives 1860-2000

Medicine

Summary In post-mortem putamen samples from 27 schizophrenics and 27 controls D2 receptors were measured by Scatchard analysis using3H-spiperone as a ligand. Maximum number of binding sites (Bmax) and apparent dissociation constant (KD) were significantly increased only in patients in whom neuroleptic medication had been given within a three-month period before death. When the neuroleptic medication had been withdrawn at least 3 month before death, there was a slight, but not significant, reduction in Bmax values and unchanged KD values. Withdrawal of neuroleptic drugs was followed by a normalization of the KD values within 2 weeks and a slower reduction of Bmax values. There were 6 schizophrenic patients with mainly positive schizophrenic symptoms and 17 patients with mainly negative symptoms; positive schizophrenic symptoms were not related to higher Bmax values. There was no difference in3H-spiperone binding between patients with and without movement disorders (tardive dyskinesia or extrapyramidal symptoms).

Electronic Resource

1435-1463

Human brain ; excitatory amino acids ; N-methyl-D-aspartate (NMDA) ; [3H]MK-801 ; schizophrenia

Springer Online Journal Archives 1860-2000

Medicine

Summary [3H]MK-801 binding was used as a marker for the NMDA receptor-ion channel complex in postmortem brain samples from the frontal cortex, hippocampus, putamen, entorhinal region, and amygdala of schizophrenic patients and controls. In schizophrenia [3H]MK-801 binding levels were increased in all brain regions investigated reaching significance in the putamen.

Electronic Resource

0165-1781

Alzheimer's disease ; Glucocorticoid receptors ; aging

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

1433-0407

Schlüsselwörter Advanced glycation endproducts ; AGE ; Alzheimer-Erkrankung ; Ätiologie ; Biochemische Hypothesen ; Key words Advanced glycation endproducts ; Alzheimer's disease ; Biochemical hypotheses ; Etiology

Springer Online Journal Archives 1860-2000

Medicine

Summary Despite intense efforts, it has not yet been possible to clarify the etiopathogenesis of Alzheimer's dementia. There are, however, hypotheses which focus on certain aspects of this type of dementia, characterized by particular neuropathological alterations and clinical correlates. Recently, evidence has accumulated that advanced glycation endproducts (AGEs) could play an important role in the etiology of the Alzheimer's syndrome. AGEs are generated by an irreversible reaction through the non-enzymatic, long-term glycosylation of proteins. They are strongly resistent to proteolytic processes and induce protein crosslinking. They could thus inhibit the physiological functions of many proteins. Moreover, it is suggested that they contribute to the transformation of the soluble form of β-amyloid into its unsoluble version. AGEs are also demonstrable in neurofibrillary tangles (NFTs). A further mechanism by which AGEs might be pathogenic is via their induction of oxidative stress. AGEs probably exert their pathological effects not only directly because of their chemical properties, but also by indirect receptor-mediated mechanisms. Further investigation of AGE-mediated mechanisms should reveal their role in the etiopathogenesis of the Alzheimer's syndrome and, finally, lead to the development of new pharmacological strategies aimed at inhibiting protein cross-linking.

Zusammenfassung Trotz intensiver Bemühungen ist es bislang nicht gelungen, die Ätiopathogenese des Alzheimer-Syndroms endgültig aufzuklären. Es existieren Hypothesen, die zumindest Teilaspekte dieser mit charakteristischen neuropathologischen Veränderungen und typischer klinischer Symptomatik einhergehenden Demenzerkrankung erklären können. In jüngster Zeit häufen sich Hinweise darauf, daß AGE (advanced glycation endproducts) in der Krankheitsentstehung des Alzheimer-Syndroms eine wichtige Rolle spielen könnten. AGE entstehen in einer irreversiblen Reaktion durch nicht-enzymatische, über einen längeren Zeitraum verlaufende Glykosylierung von Proteinen. Sie sind sehr resistent gegenüber proteolytischen Prozessen und induzieren Proteinvernetzungen (crosslinking). Dadurch können sie die physiologische Funktion vieler Proteine hemmen. Darüber hinaus wird vermutet, daß sie zur Umwandlung der löslichen Form des β-Amyloids in die unlösliche Form beitragen können. Auch in den neurofibrillären Tangles (NFT) konnten AGE nachgewiesen werden. Ein weiterer Pathomechanismus der AGE könnte in der Induktion von oxidativem Streß bestehen. Pathologische Effekte üben die AGE vermutlich nicht nur direkt aufgrund ihrer chemischen Eigenschaften aus, sondern auch über indirekte rezeptorvermittelte Mechanismen. Eine verstärkte Erforschung der Bedeutung von AGE in der Ätiopathogenese des Alzheimer-Syndroms könnte auch zur Entwicklung neuer pharmakotherapeutischer Strategien beitragen.

Electronic Resource

1433-0407

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1433-0407

Springer Online Journal Archives 1860-2000

Medicine

Electronic Resource

1432-0533

Key words Amantadine ; Human ; N-methyl-d-aspartate ; Phencyclidine ; Postmortem brain

Springer Online Journal Archives 1860-2000

Medicine

Abstract Low doses of N-methyl-d-aspartate (NMDA)-type glutamate receptor antagonists induce morphological alterations in neurons of the cingulate gyrus and retrosplenial cortex of the rat. Neuronal cell death may result at higher doses. These effects are a major concern with regard to the introduction of new NMDA receptor antagonists into clinical trials. Amantadine is an uncompetitive NMDA receptor antagonist, which has been in clinical use for many years. In the present study we have looked for possible morphological alterations like necrosis in postmortem human brain tissue of patients previously treated with amantadine. Formalin-fixed tissue samples were taken from the hippocampus, cingulate gyrus, and retrosplenial cortex of 8 patients on previous amantadine medication and of 11 controls. Histopathological examination of sections was performed blind. All brains except one revealed either nonspecific age-related or cerebrovascular changes or other neurodegenerative disorders including Alzheimer’s, Parkinson’s or Lewy body disease. In conclusion, histopathological examination of the hippocampus, retrosplenial cortex, and cingulate gyrus of human brain did not reveal changes suggested to be specific for previous amantadine treatment.

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