Biomedical subjects

P Riederer

Publications and source records attributed to P Riederer.

At least 19 recordsLinked to original sources

PubMed2006

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

Brain↗

PubMed2006

From benefit to damage. Glutamate and advanced glycation end products in Alzheimer brain.

The glutamatergic system is the most widespread neurotransmitter system in the mammalian brain. It is connected to the acetylcholinergic neurotransmitter system to form the glutamatergic/aspartatergic-acetylcholinergic circuit, which is the morphobiochemical basis of learning, memory and cognition assisted by the glutamatergic N-methyl-D-aspartate receptor, which mediates long-term potentiation as the fundamental molecular mechanisms of these mental capacities. Glutamate and acetylcholine as ligands of the two neurotransmitter systems are products of the neuronal glucose metabolism as holds true also for advanced glycation end products (AGEs), which are markers of damaged and/or aged proteins. During normal aging, both the neurotransmitters glutamate and acetylcholine undergo strong functional variations. Their synthesis was found to be reduced as a common feature. In contrast, basal release of acetylcholine and receptor number decrease, whereas basal release of glutamate and receptor number increase. AGEs increase during aging obviously preferentially in glutamatergic pyramidal neurons in cerebral cortical layers prone to neurodegeneration. In sporadic Alzheimer disease (SAD), glutamate concentration was shown to fall since it may serve as a substitute for lacking glucose in the beginning of the disease. In contrast, glutamate receptor density was found to be much less involved indicating an excessive activation of the glutamatergic neurotransmitter system particularly via the NMDA receptor, mediating endogenous excitotoxicity. The morphological hallmarks of SAD neuritic plaques and neurofibrillary tangles have been demonstrated to crosslink with AGEs causing an increased rate of free radical production. First data from animal studies and investigations on human beings may indicate that the NMDA receptor antagonist memantine may have beneficial effects on the course of SAD and its clinical symptoms.

Acetylcholine↗

PubMed2006

Proteomics of the human brain: sub-proteomes might hold the key to handle brain complexity.

Proteomics is a promising approach, which provides information about the expression of proteins and increasingly finds application in life science and disease research. Meanwhile, proteomics has proven to be applicable even on post mortem human brain tissue and has opened a new area in neuroproteomics. Thereby, neuroproteomics is usually employed to generate large protein profiles of brain tissue, which mostly reflect the expression of highly abundant proteins. As a complementary approach, the focus on sub-proteomes would enhance more specific insight into brain function. Sub-proteomes are accessible via several strategies, including affinity pull-down approaches, immunoprecipitation or subcellular fractionation. The extraordinary potential of subcellular proteomics to reveal even minute differences in the protein constitution of related cellular organelles is exemplified by a recent global description of neuromelanin granules from the human brain, which could be identified as pigmented lysosome-related organelles.

Brain Chemistry↗

PubMed2006

Association study of BDNF and CNTF polymorphism to depression in non-demented subjects of the "VITA" study.

BACKGROUND: Neurotrophic factors are known to play an important role in the survival and differentiation of many types of neurons during development. Both brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) may act cooperatively in modulating the development and functioning of synapses. Both these neurotrophic factors were intensely investigated with regard to depression without conclusive results. METHODS: We have investigated the possible use of both CNTF null-mutation and BDNF polymorphism C270T as biomarkers for depression in the Vienna Transdanube Aging (VITA) study. The VITA is a prospective community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. RESULTS: We found no association between CNTF null-mutation and BDNF C270T polymorphism to any depressive symptoms after exclusion of demented subjects. CONCLUSION: These results call in question the hypothesis that either BDNF or CNTF can be used as molecular markers for depression or late onset depression in the elderly.

Age Factors↗

PubMed2006

Investigation of the lipid component of neuromelanin.

OBJECTIVE: Neuromelanin (NM) is different to other melanins in that its ultrastructure includes a lipid component. The objectives of this study were to identify and quantify lipids associated with NM. RESULTS: Quantification of the lipid component associated with the pigment on electron micrographs demonstrated that this component comprises 35% of the NM granule volume in the normal brain. The irregular ultrastructural appearance of the NM granules was quite different to the round regular boundary of melanin granules. Using reversed phase high performance liquid chromatography (HPLC) coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry we demonstrated that the isoprenoid dolichol accounted for approximately 12% of total NM pigment mass. Low levels of other lipids were detectable (cholesterol, ubiquinone-10 and alpha-tocopherol) and account for <0.05% of NM lipid, in contrast to cholesterol accounting for 35% of total brain lipids. CONCLUSION: Unlike other melanins, a substantial proportion of NM volume is comprised of lipid and the major type of lipid associated with NM granules is the isoprenoid dolichol.

Adult↗

PubMed2006

[Therapeutic drug monitoring (TDM) of psychotropic drugs: a consensus guideline of the AGNP-TDM group].

In psychiatry, therapeutic drug monitoring (TDM) is an established procedure for most psychotropic drugs. However, as its use in everyday clinical practice is far from optimal, the AGNP-TDM group has worked out consensus guidelines to assist psychiatrists and laboratories involved in drug analysis. Based on a thorough analysis of available literature, 5 levels of recommendation were defined with regard to TDM of psychoactive drugs, from 1) (strongly recommended) to 5) (not recommended). A list of indications for TDM, alone or in combination with pharmacogenetic tests is presented. Instructions are given with regard to preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM.

Drug Monitoring↗

PubMed2006

Structural investigations of neuromelanin by pyrolysis-gas chromatography/mass spectrometry.

Pyrolysis combined with gas chromatography and mass spectrometry (Py-GC/MS) was applied for structural investigations of the human substantia nigra neuromelanin. Using synthetic neuromelanins, we have demonstrated that Py-GC/MS is suitable for identification and differentiation of both eumelanin (dopamine-derived) and pheomelanin (cysteinyldopamine-derived) component of the pigment. Structural information on melanin monomers was inferred from their pyrolytic markers. When the human neuromelanin was subjected to pyrolysis, none of the heterocyclic, sulfur-containing markers of pheomelanin component was detected among the thermal degradation products. We have concluded that nigral pigment isolated from normal brain tissue does not contain benzothiazine-type monomers, and that cysteinyldopamine-originated units may be incorporated into the polymer in uncyclized form. The most abundant pyrolysis product was identified as limonene, which indicates that nigral pigment is tightly associated with an isoprenoid-type compound. Pyrolysis in the presence of the methylating reagent allowed identification of high levels of saturated and monounsaturated straight-chain C14-C18 fatty acid species chemically bound to the pigment macromolecule.

Gas Chromatography-Mass Spectrometry↗

PubMed2006

Subcellular proteomics reveals neuromelanin granules to be a lysosome-related organelle.

The powerful combination of subcellular fractionation and protein identification by electrospray ionization tandem mass spectrometry (ESI-MS/MS) pioneered the molecular elucidation of neuromelanin (NM) granules. We recently isolated NM granules from the human brain and succeeded in the establishment of the first protein profile of this compartment. NM granules are pigmented organelles, which are mainly found in the catecholaminergic neurons of the human substantia nigra (SN) pars compacta and the locus coeruleus. These granules contain the insoluble pigment NM, which is regarded as the most important iron storage system in these neurons. A global examination of NM granules, however, has so far been hampered due to the lack of a pigmented brain stem in rodents, the absence of an appropriate experimental system and their scarcity in the human brain. 'Subcellular proteomics', which increasingly emerges as the method of choice to characterize cellular compartments and to elucidate their biogenesis, has recently been shown to be an adequate approach to tackle a thorough description of NM granules. Thereby, NM granules could be described as a 'lysosome-related organelle'. This indicates a genetic program underlying a biogenesis of NM rather than its autoxidative formation.

Cytoplasmic Granules↗

PubMed2006

Evidence for specific phases in the development of human neuromelanin.

Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. Here we describe the age-related development and regulation of neuromelanin within these dopamine neurons. 10 microm sections from formalin-fixed midbrain from 29 people spanning the ages of 24 weeks to 95 years old were either stained with a basic Nissl substance stain (0.5% cresyl violet), or processed unstained. After locating the substantia nigra using the stained sections, digital photos were taken of individual ventral substantia nigra neurons in the unstained sections, and the cellular area occupied by pigment, and optical density were measured using computer software. These measurements demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.

Adolescent↗

PubMed2006

The effect of neuromelanin on the proteasome activity in human dopaminergic SH-SY5Y cells.

In Parkinson's disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mitochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.

Blotting, Western↗

PubMed2006

Potential sources of increased iron in the substantia nigra of parkinsonian patients.

Histopathological, biochemical and in vivo brain imaging techniques, such as magnetic resonance imaging and transcranial sonography, revealed a consistent increase of substantia nigra (SN) iron in Parkinson's disease (PD). Increased iron deposits in the SN may have genetic and non-genetic causes. There are several rare movement disorders associated with neurodegeneration, and genetic abnormalities in iron regulation resulting in iron deposition in the brain. Non-genetic causes of increased SN iron may be the result of a disturbed or open blood-brain-barrier, local changes in the normal iron-regulatory systems, intraneuronal transportation of iron from iron-rich area into the SN and release of iron from intracellular iron storage molecules. Major iron stores are ferritin and haemosiderin in glial cells as well as neuromelanin in neurons. Age- and disease dependent overload of iron storage proteins may result in iron release upon reduction. Consequently, the low molecular weight chelatable iron complexes may trigger redox reactions leading to damage of biomolecules. Additionally, upon neurodegeneration there is strong microglial activation which can be another source of high iron concentrations in the brain.

Animals↗

PubMed2006

Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder.

The basal ganglia form a forebrain system that collects signals from a large part of the neocortex, redistributes these cortical inputs both with respect to one another and with respect to inputs from the limbic system, and then focuses the inputs of this redistributed, integrated signals into particular regions of the frontal lobes and brainstem involved in aspects of motor planning and motor memory. Movement disorders associated with basal ganglia dysfunction comprise a spectrum of abnormalities that range from the hypokinetic disorder (from which Parkinson's disease, PD, is the best-known-example) at one extreme to the hyperkinetic disorder (exemplified by Huntington's disease and hemiballism) at the other. In addition to disorders of movement, major mental disorders including schizophrenic-like states and attention deficit hyperactivity disorder (ADHD) have been linked to abnormalities in the basal ganglia and their allied nuclei. In this paper we discuss recent evidence indicating that a dopamine-induced dysbalance of basal ganglia neurocircuitries may be an important pathophysiological component in PD, schizophrenia and ADHD. According to our model, the deprivation of dopaminergic nigro-striatal input, as in PD, reduces the positive feedback via the direct system, and increases the negative feedback via the indirect system. The critical consequences are an overactivity of the basal ganglia output sites with the resulting inhibition of thalamo-cortical drive. In schizophrenia the serious cognitive deficits might be partly a result of a hyperactivity of the inhibitory dopamine D(2) transmission system. Through this dysinhibition, the thalamus exhibits hyperactivity that overstimulates the cortex resulting in dysfunctions of perception, attention, stimulus distinction, information processing and affective regulation (inducing hallucinations and delusions) and motor disabilities. Recent studies have strongly suggested that a disturbance of the dopaminergic system is also involved in the pathophysiology of ADHD. The most convincing evidence comes from the demonstration of the efficacy of psychostimulants such as the dopamine transporter (DAT) blocker methylphenidate in the symptomatic treatment of ADHD. Genetic studies have shown an association between ADHD and genes involved in dopaminergic neurotransmission (for example the dopamine receptor genes DRD4 and DRD5, and the DAT gene DAT1). DAT knockout mice display a phenotype with increased locomotor activity, which is normalized by psychostimulant treatment. Finally, imaging studies demonstrated an increased density of DAT in the striatum of ADHD patients. Which system is disturbed and whether this system is hyper- or hypoactive is not unambiguously known yet.

Antipsychotic Agents↗

PubMed2006

Evidence for specific phases in the development of human neuromelanin.

Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. The age-related development and regulation of neuromelanin within these dopamine neurons has not been previously described. Optical density and area measurements of unstained neuromelanin in ventral substantia nigra neurons from 29 people spanning the ages of 24 weeks to 95 years old, demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.

Adolescent↗

PubMed2005

Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome.

Parkinson's disease is characterized by the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin. Involvement of neuromelanin in the pathogenesis may be either cytotoxic or protective. Recently we found that neuromelanin reduces the activity of 26S proteasome. In this paper, the detailed mechanisms behind the reduced activity were studied using neuromelanin isolated from the human brain. Neuromelanin increased the oxidative stress, but synthetic melanin did not. Superoxide dismutase and deferoxamine completely suppressed the increase, indicating that superoxide produced by an iron-mediated reaction plays a central role. Iron was shown to reduce in situ 26S proteasome activity in SH-SY5Y cells and the reduction was protected by antioxidants. These results suggest that iron released from neuromelanin increases oxidative stress in mitochondria, and then causes mitochondrial dysfunction and reduces proteasome function. The role of neuromelanin is discussed in relation to the selective vulnerability of dopamine neurons in Parkinson's disease.

Acrolein↗

PubMed2005

Region specific distribution of levomepromazine in the human brain.

OBJECTIVE: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time. METHODS: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus). Mean values of drug concentrations in these larger brain areas were used in a repeated measurement ANOVA to analyze for region specific distribution. The elimination half-life in brain tissue was estimated with a NONMEM population kinetic analysis using the mean value of all brain regions of an individual case. RESULTS: Levomepromazine and desmethyl-levomepromazine appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia (mean 316 ng/g) and lowest values in the cortex cerebri (mean 209 ng/g). The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine. CONCLUSIONS: Levomepromazine shows a region-specific distribution in the human brain with highest values in the basal ganglia. This might be the consequence of low expression of the metabolic enzyme Cyp2D6 in the basal ganglia. If this finding is true also for other neuroleptic drugs it might increase our understanding of preferential toxicity of neuroleptic drugs against basal ganglia structures and higher volumes of basal ganglia of neuroleptic-treated patients. Furthermore, patients exposed to levomepromazine cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Aged↗

PubMed2005

Brain aging phenomena in migrating sockeye salmon Oncorhynchus nerka nerka.

Aging, a process occurring in all vertebrates, is closely related to a loss in physical and functional abilities. There is widespread interest in clarifying the relevance of environmental, metabolic, and genetic factors for vertebrate aging. In the Pacific salmon a dramatic example of aging is known. Looking for changes in the salmon brain, perhaps even in the role of initiating the aging processes, we investigated several biochemical parameters that should reflect brain functional activity and stress response such as the neurotransmitters dopamine, and serotonin, and two of their respective metabolites 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole acetic acid, as well as glutathione, glutathione disulfide, and the extent of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labelling. The aging of migrating sockeye salmon (Oncorhynchus nerka nerka) is accompanied by gradual increase in dopamine and serotonin turnover and a gradual decrease of brain total protein and glutathione levels. There appears to be an increased need for detoxification of reactive biological intermediates since activities of superoxide dismutase and catalase increase with age. However, our data do not support a major increase in apoptotic cell death during late aging but rather implicate an age related downward regulation of protein and glutathione synthesis and proteolysis increasing the need for autophagocytosis or heterophagocytosis in the course of cell death.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Central administration of alloxan impairs glucose tolerance in rats.

By means of oral glucose tolerance test (OGTT), we investigated glucose tolerance in rats pre-treated with intracerebroventricular and subcutaneous non-diabetogenic dose of betacytotoxic drug alloxan 7 days before OGTT. Being normoglycemic and normoinsulinemic pre-OGTT, at 30 minutes post-OGTT, alloxan intracerebroventricularly-treated rats had a lower glucose and a higher insulin plasma levels in comparison with controls or alloxan subcutaneously treated animals. Centrally administered alloxan seems to have brain related effect on the regulation of peripheral glucose tolerance and insulin secretion.

Alloxan↗

PubMed2005

Oxidative stress related markers in the "VITA" and the centenarian projects.

Oxidative stress seems to play an important role in the pathophysiology of Alzheimer's disease (AD). At present there are no easily accessible biochemical markers for AD. We performed activity assays for platelet MAO-B and erythrocyte Cu/Zn-SOD as well as Western blotting for these two proteins. Moreover, we assessed plasma lactoferrin and performed RFLP-analysis for the MAO-B-intron-13-polymorphism in patients from the Vienna-Transdanube Aging (VITA) and from the so called centenarian project. The first one, VITA, is a community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. The centenarian project investigates chronic care in-old patients suffering from AD. In both sexes platelet MAO-B activity increased significantly in the AD group, and Cu/Zn-SOD activity decreased, but the latter effect was significant only in females. No significant difference was found regarding plasma lactoferrin. No correlation was found between MAO-Bi13 and MAO-B platelet activity or allele MAO-Bi13 and disease frequency. These results point to the possibility that a combination of MAO-B and SOD activity levels might be useful tools for an early diagnosis of AD.

Aged↗