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The neurotrophic factors (NTF) hypothesis of depression was postulated nearly a decade ago and is nowadays widely acknowledged. Previous reports suggest that cerebral concentrations of NTF may be reduced in suicide victims who received minimal or no antidepressant pharmacotherapy. Recent evidence suggests that antidepressant treatment may improve or normalise cerebral concentrations of neurotrophic factors. Therefore, we examined the concentration of brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) in different brain regions (cortex, cingulate gyrus, thalamus, hippocampus, putamen and nucleus caudatus) of 21 individuals – 7 patients of which 4 patients with major depressive disorder (MDD) and overall age 86.8 ± 5 years who received antidepressant pharmacotherapy (selective serotonin re-uptake inhibitors [SSRI]; tricyclic antidepressants [TCA]), 3 patients with MDD without antidepressant treatment and overall age 84.3 ± 5 years versus 14 unaffected subjects at age 70.3 ± 13.8. We detected significant elevation of BDNF (parietal cortex) and NT3 (parietal, temporal and occipital cortex, cingulate gyrus, thalamus, putamen and nucleus caudatus regions) in MDD patients who received antidepressant medication compared to MDD untreated patients and controls. Moreover, we detected a significant decrease of NT3 levels in the parietal cortex of patients suffering from MDD non-treated patients without treatment compared to healthy individuals. Although the limited statistical power due to the small sample size in this proof of concept study corroborates data from previous studies, which show that treatment with antidepressants mediates alterations in neuroplasticity via the action of NTF. However, more research using post-mortem brain tissue with larger samples needs to be carried out as well as longitudinal studies to further verify these results.

Objective: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.Results: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics.Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

The prevalence of both Alzheimer's disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders cannot be neglected. Therefore, early diagnosis of metabolic parameters including those relevant for T2DM is required. Moreover, it is possible that therapeutic options utilized today for diabetes treatment may also have an effect on the risk for dementia. T2DM/IRBS contribute to pathological processes in AD and VaD.

Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non-motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety.

Neurotransmission by biogenic monoamines is important for brain function. Biogenic amine turnover employs the enzymes catechol-O-methyltransferase and monoamine oxidase in neuronal and glial cells. Inhibition of these enzymes elevates biogenic amine levels in the synaptic cleft. Subtype selectivity of inhibition is lost during long-term use of 'selective' monoamine oxidase inhibitors. Areas covered: This narrative review discusses use of monoamine oxidase inhibitors in the context with chronic neurodegeneration. Expert opinion: Antidepressant drugs increase synaptic concentrations of biogenic amines. In the aging brain, then one of the two enzymes involved in degrading synaptic amines, catechol-O-methyl transferase, increasingly catalyzes methylation processes. Therefore, metabolism by monoamine oxidase plays an incremental, predominant role in biogenic amine turnover, leading to greater oxidative stress. In patients with chronic neurodegenerative disorders, symptoms, such as depression and apathy, are often treated with drugs that elevate biogenic amine levels. This therapeutic strategy increases biogenic amine turnover, thereby generating neurotoxic aldehydes and enhanced oxidative stress, each of which influence and accelerate the course of neurodegeneration. We propose that antidepressant therapy should be initiated first with monoamine oxidase inhibitors only. If adequate clinical response is not achieved, only then they should be supplemented with a further antidepressant.

Neuromelanin is a complex polymer pigment found primarily in the dopaminergic neurons of human substantia nigra. Neuromelanin pigment is stored in granules including a protein matrix and lipid droplets. Neuromelanin granules are yet only partially characterised regarding their structure and function. To clarify the exact function of neuromelanin granules in humans, their enrichment and in-depth characterization from human substantia nigra is necessary. Previously published global proteome studies of neuromelanin granules in human substantia nigra required high tissue amounts. Due to the limited availability of human brain tissue we established a new method based on laser microdissection combined with mass spectrometry for the isolation and analysis of neuromelanin granules. With this method it is possible for the first time to isolate a sufficient amount of neuromelanin granules for global proteomics analysis from ten 10 μm tissue sections. In total 1,000 proteins were identified associated with neuromelanin granules. More than 68% of those proteins were also identified in previously performed studies. Our results confirm and further extend previously described findings, supporting the connection of neuromelanin granules to iron homeostasis and lysosomes or endosomes. Hence, this method is suitable for the donor specific enrichment and proteomic analysis of neuromelanin granules.

Monoamine oxidase M (MAO-B) inhibitors are used in the symptomatic treatment of Parkinson’s disease (PD) as they prolong the availability and activity of endogenous dopamine in the striatum by blocking its degradation. Two MAO-B inhibitors, rasagiline and selegiline, are currently licensed in Europe and North America. The differences between these agents at the clinical and preclinical level have been much debated. This review critically explores the evidence for preclinical differences between rasagiline and selegiline, and discusses the relevance of these differences for the treatment in PD. Rasagiline is about 10 times more potent in the inhibition of MAO-B than selegiline in ex vivo studies. To achieve similar potency in the clinical setting the doses were adapted. At their selective MAO-B inhibitory dosages, rasagiline and selegiline do not produce the “cheese reaction” and do not cause a potentiation of the effects of L-DOPA combined with the decarboxylase inhibitor carbidopa on blood pressure or heart rate in conscious rats. However, in pithed rats, selegiline but not rasagiline increased noradrenaline and adrenaline release, and pulse rate, and potentiated dopamine pressor response at MAO-B selective dose. It is believed that this difference is the result of their different chemical structure that gives rise to different metabolites with distinct pharmacological properties. Whether this difference is relevant for the clinic in regard to the occurrence of cardiovascular adverse drug reactions is not known, because, it is not known at what concentrations l -amphetamine and l -methamphetamine exert a sympathomimetic effect in vivo, and whether such concentrations are achieved in the blood of PD patients. Rasagiline is superior to selegiline in its potency to prevent spontaneous cell death seen in cell culture, and to reduce accelerated cell death following serum deprivation in vitro. In addition, rasagiline is more effective in regard to its ability to reverse changes in mitochondrial function that lead to apoptosis. Finally, in the lactacystin-treated mouse, rasagiline exerts a neurorestorative effect where selegiline has none. These effects were considered to be independent of the ability of both agents to inhibit MAO-B. It was concluded that these superior effects of rasagiline are attributable to additive effects of the parent active substance and its major metabolite, 1-R-aminoindan, and to possible neurotoxic effects of l -methamphetamine, one metabolite of selegiline. However, it is not known at what concentrations these compounds may exert any protective and neurotoxic effect, respectively, in vivo, and whether respective concentrations are achieved in the brain of PD patients.

Background and Objective: The co-morbidity of depressive disorder and chronic kidney failure is remarkably common. However, knowledge about the influence of haemodialysis on the serum concentration of antidepressants is sparse. In this study we examined the influence of haemodialysis on the serum concentrations of the antidepressants amitriptyline (and its active metabolite nortriptyline) and mirtazapine. Methods: The authors retrospectively evaluated therapeutic drug monitoring (TDM)-analyses obtained in eight different regional medical dialysis centres before and after haemodialysis and compared serum concentrations of amitriptyline and mirtazapine using t-tests. Results: Mean serum concentrations of the sum of amitriptyline+nortriptyline (before: 75.52 ng/mL; after: 59.35 ng/mL; p < 0.001) and mirtazapine (before: 53.45 ng/mL; after: 38.31 ng/mL; p < 0.036) decreased significantly with haemodialysis. Haemodialysis patients received rather low doses of amitriptyline (mean 36.5mg; SD 17.6; range 10–75mg) and mirtazapine (mean 24.7mg; SD 9.1; range 15–45mg). Conclusion: For haemodialysis patients with depression an adequate antidepressant drug dosage must be administered. TDM is necessary in order to optimize antidepressant therapy in patients with chronic kidney disease.

Axonal transport of enzymatically active botulinum toxin A (BTX-A) from periphery to the CNS has been described in facial and trigeminal nerve, leading to cleavage of synaptosomal-associated protein 25 (SNAP-25) in central nuclei. Aim of present study was to examine the existence of axonal transport of peripherally applied BTX-A to spinal cord via sciatic nerve. We employed BTX-A-cleaved SNAP-25 immunohistochemistry of lumbar spinal cord after intramuscular and subcutaneous hind limb injections, and intraneural BTX-A sciatic nerve injections. Truncated SNAP-25 in ipsilateral spinal cord ventral horns and dorsal horns appeared after single peripheral BTX-A administrations, even at low intramuscular dose applied (5 U/kg). Cleaved SNAP-25 appearance in the spinal cord after BTX-A injection into the sciatic nerve was prevented by proximal intrasciatic injection of colchicine (5 mM, 2 μl). Cleaved SNAP-25 in ventral horn, using choline-acetyltransferase (ChAT) double labeling, was localized within cholinergic neurons. These results extend the recent findings on BTX-A retrograde axonal transport in facial and trigeminal nerve. Appearance of truncated SNAP-25 in spinal cord following low-dose peripheral BTX-A suggest that the axonal transport of BTX-A occurs commonly following peripheral application.

It has been suggested that the activation of the serotonin (5-hydroxytryptamine, 5-HT) receptor family 5-HT 2 , in particular the subtype 5-HT 2B , is a key step in the progression of drug-induced valvular heart disease (VHD). However, the localisation of 5-HT 2 receptors in human valves have not been reported. Thus, the current study investigated the regional and cellular localization of 5-HT 2 receptors in the tricuspid, mitral, aortic and pulmonary heart valves of six humans ( n = 24 samples) by immunohistochemistry post-mortem. We found that 5-HT 2A and 5-HT 2B receptors are present in all examined heart valves, whereas 5-HT 2C receptors were either not present or scarcely found. Interestingly, we found a uniform pattern of 5-HT 2B receptor numbers in all heart valves examined. Our results confirm patterns reported in echocardiographic investigations in patients with Parkinson’s disease treated with cabergoline and pergolide and suggest that the 5-HT 2 receptor located in heart valves may play a role in the drug-induced VHD.

Piribedil is a non-ergoline, dopamine D(2)/D(3) receptor agonist with α(2) adrenoceptor antagonist properties that has been used in the treatment of Parkinson's disease (PD). Noradrenergic neurotransmission may be involved in the pathogenesis of dyskinesias induced by chronic treatment with L-DOPA (3,4-dihydroxyphenylalanine, levodopa), but its role in the in vivo action of piribedil or on different subclasses of abnormal involuntary movements (AIMs) remains unclear. The aims of this study were therefore (1) to investigate the anti-dyskinetic effects of piribedil on L-DOPA-induced contralateral turning behaviour, locomotive dyskinesias (LD), axial dystonia (AD), orolingual dyskinesia (OD) and forelimb dyskinesia (FD) and (2) to compare these effects to the α(2) adrenoceptor antagonist, idazoxan, or the α(2) adrenoceptor agonist, clonidine. Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and injected intraperitoneally twice daily with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg). After 3 weeks, the effects of piribedil (5, 15, 40 mg/kg), clonidine (0.15 mg/kg), idazoxan (10 mg/kg) and combinations of these drugs were scored during 2 h. Pre-treatment with 5 and 40 mg/kg, but not 15 mg/kg, of piribedil reduced turning behaviour and AD, OD and FD, but piribedil increased LD at the 40 mg/kg doses compared to the L-DOPA group. Idazoxan induced similar effects as piribedil (40 mg/kg), except that it had no effect on LD. Idazoxan blocked the effect of piribedil on AD and FD. Clonidine reduced all AIMs except OD, possibly because of its sedative effect. Clonidine blocked the effect of piribedil on AD, OD and FD. These data suggest a differential involvement of α(2) adrenergic receptors in the action of piribedil on different subclasses of L-DOPA-induced dyskinesias.

Although Alzheimer's disease (AD) is the most common form of dementia in the elderly, its aetiology remains mostly unknown. A potential pathophysiological mechanism for AD arises from the knowledge that insulin is also synthesized independently in the central nervous system and is involved in the regulation of memory formation. AD may represent a brain-specific form of insulin resistance.We used immunohistochemistry to investigate the numbers of cells expressing insulin receptor β-subunit (IRβ) and phosphorylated PPARγ (PPARγ(p)) in human post-mortem tissue from patients with AD; AD combined with type 2 diabetes mellitus (T2DM); just T2DM , and from aged-matched controls. These numbers were evaluated in frontal cortex and in dorsal/ventral parts of the hippocampus.We observed significantly lower numbers of IRβ positive cells in AD cases compared to all other groups in all investigated brain regions. Also significantly more PPARγ(p) positive cells occurred in each patient group compared to control.T2DM and AD may not be directly linked, but may share common histological features including lower numbers of IRβ positive cells and higher numbers of PPARγ(p) positive cells in all investigated brain regions. These observations may at least partially explain the increased frequency of AD in elderly diabetic patients.

Failures in clinical studies that were aimed to prove disease-modifying effects of treatments in Parkinson's disease (PD) raise the question as to whether basic sciences have had an impact in clinical practice. This question implies that despite well-publicized results obtained by intensive genetic and pathogenetic research, e.g. the identification of mutations and cellular biochemical pathways that underlie Parkinson-specific neurodegeneration, no relevant disease-modifying treatment options have been developed. This view neglects the fact that today there are plenty of dopaminergic and non-dopaminergic and surgical treatment options, and that PD was not treatable 50 years ago. This progress was made possible only by basic science. In this review, we underline the success of previous basic science for daily practice in PD and its impact for the understanding and development of an early diagnosis. Early, even pre-symptomatic diagnosis might be key to successfully establish disease-modifying treatments.

Cerebral amyloid angiopathy is manifested as accumulation of amyloid β (Aβ) peptide in the wall of meningeal and cerebral arteries, arterioles and capillaries and is frequently seen post mortem in the brain of sporadic Alzheimer’s disease (sAD) patients. It is difficult to assess when and how cerebral amyloid angiopathy develops and progresses in humans in vivo, which is why animal AD models are used. Streptozotocin- intracerebroventricularly (STZ-icv) treated rats have been recently proposed as the model of sAD which develops insulin resistant brain state preceding Aβ pathology development. Vascular Aβ deposits in the brain of STZ-icv treated rats (3 month-old at the time of icv treatment) were visualized by Thioflavine-S, Congo red staining and Aβ immunohistochemistry. Thioflavine-S and Congo red staining revealed diffuse congophilic deposits in the wall of meningeal and cortical blood vessels both 6 and 9 months after the STZ- icv treatment. Preliminary Aβ1-42 and Aβ1-16 immunohistochemistry experiments showed positive staining in blood vessels 3 and 9 months after the STZ-icv treatment, respectively. Results suggest that cerebral amyloid angiopathy observed 6 and 9 months after the STZ-icv treatment seems to be a continuation and progression of the amyloid pathology observed already 3 months following the STZ-icv treatment in this non-transgenic sAD animal model.

Hintergrund Die Parkinson-Krankheit (PK) ist haufig durch Demenz und Depression gekennzeichnet, die den Krankheitsverlauf erschweren und das Risiko einer Pflegebedurftigkeit zusatzlich erhohen konnen. Uber die genauen Zusammenhange zwischen PK und diesen Komplikationen liegen fur Ambulanzpatienten jedoch bislang keine Zahlen vor.

Von Verwaltungsraten und Mitgliedern von Geschaftsleitungen wird erwartet, dass sie sich in einem anspruchsvollen Umfeld behaupten. Sie sollen die richtigen Strategien wahlen, sich fur die effektivste Organisationsstruktur entscheiden und ihr Fuhrungsteam zu Spitzenleistungen fuhren. Missverstandnisse, Widerstande und Konflikte wirken den Zielsetzungen jedoch oft entgegen. Der Autor beschreibt die Moglichkeiten der Gewaltfreien Kommunikation (GFK), die er als Verwaltungsrat, Fuhrungsperson und Unternehmensberater nutzt.

Manfred Gerlach is the founding editor in chief of this journal. This issue is dedicated to him as an outstanding personality in the fields of developmental child and adolescent as well as adult psychiatry and neurology. His scientific opus represents an extremely broad and unique scientific spectrum from childhood to adulthood bridging the gap between psychiatry and neurology. His multilevel research interests combine developmental aspects with psychopathological behavior and neuropsychiatric symptoms of diseases with brain structure and brain function as well as biochemical and psychophysiological parameters and molecular aspects. Manfred Gerlach was born on May 10, 1954, in Hammelburg, Germany. He studied chemistry and pharmacy at the University of Wurzburg, Germany. He earned the doctorate in 1983. He worked as Scientific Assistant at the Clinical Neurochemistry, Dept. of Neurology, University Wurzburg (1984–1987) and at the Dept. of Neurology, University Bochum (1987–1992). In 1991, he reached habilitation in clinical neurochemistry at the Dept. of Neurology (Head Prof. Dr. Horst Przuntek), University Bochum. In 1998, he became Associate Professor of Clinical Neurochemistry of the University Bochum. From 1992 to 2000 Manfred Gerlach joined as Scientific Assistant at the Clinical Neurochemistry Unit (chaired by Peter Riederer) at the Department of Psychiatry and Psychotherapy at the University of Wurzburg. Since 2000, he is Head of the Clinical Neurobiology and Therapeutic Drug Monitoring Section of the Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy University of Wurzburg with Andreas Warnke (until 2012) and Marcel Romanos (since 2012). Manfred Gerlach initiated and performed a large number of research projects. His research was funded by the German research funding organisation (DFG) and the German Ministry of Education and Research (BMBF). Most projects were performed in close cooperation with his friend and scientific partner Peter Riederer. Colleagues of national and international scientific groups of departments of psychiatry and neurology and of child and adolescent psychiatry are partners in his many research projects. His methodological approach includes experimental methods in the field of biochemistry, pharmacology, genetics, proteomics and brain imaging. His major research topics and findings include

Postmortem brain tissue has been reported to be suitable to delineate regional pattern of possible disturbances underlying epigenetic functionality. However, from many parameters that have been detected in postmortem brain regions it is noteworthy that an effect of postmortem interval (PMI), storage time and premortem parameters should not be underestimated. Our previous investigation revealed that tryptophan (TRP) levels in postmortem brain tissue is affected by PMI and storage time. Since, alteration in TRP levels are assumed to be due to protein degradation, we further investigated whether TRP correlates to variables such as RNA, proteins and DNA modulators. In addition, we aimed to elucidate whether established postmortem variables may influence epigenetic parameters. These were investigated in well characterized postmortem human brain tissue originating from the European Brain Bank consortium II (BNEII). We could confirm previous findings, in which some protein levels alter because of prolonged PMI. Similarly, we demonstrated an influence of increased storage period on TRP levels, which might indicate degradation of proteins. Still not all proteins degrade in a similar manner, therefore a specific analysis for the protein of interest would be recommended. We found that methyltransferase- and acetyltransferase-activities were relatively preserved with PMI and storage duration. In conclusion, preservation of acetyltransferase- and methyltransferase-activities provides possible evidence of stability for epigenetic studies using postmortem tissue.

Both Alzheimer's disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet β cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal models.

There is ample evidence that impairments in the hypothalamic-pituitary-adrenal (HPA) axis are of etiopathobiochemical importance in a subgroup of patients with "depression", causing hypercortisolaemia as major metabolic effect. Chronic hypercortisolaemia causes insulin resistance. Therefore, it is not surprising that epidemiological studies demonstrate an association of "depression" with diabetes type II and vice versa. Chronic stress and hypercortisolaemia are conditions, which have been suggested to be causal for Alzheimer's disease (AD) as brain insulin resistance is associated with β-Amyloid-accumulation and hyperphosphorylation of tau-protein. Depression is one of the significant symptomatology preceding AD. It is however, not known whether "depression" associated with hypercortisolaemia is the subgroup at risk for AD. In contrast to a subgroup of "depression" and to AD, in Parkinson's disease (PD) there is only weak evidence for an association with diabetes type II and insulin resistance. As "depression" is preceding PD in up to half of such patients, it remains to be elucidated whether this is a subgroup of depressed patients, which is not associated with disturbances of the HPA axis and hypercortisolaemia. Improved clinical and biochemical/molecular knowledge about "depression" associated with AD and PD in comparison to "pure" depression might lead to improved therapeutic strategies and even drug development focusing subtypes of "depression".

For decades, it has been acknowledged that oxidative stress due to free radical species contributes to the pathophysiology of aging and neurodegenerative diseases. Aldehyde dehydrogenases (ALDH) not only transform aldehydes to acids but also act as antioxidant enzymes. However, little is known about the implications of the enzymatic family of ALDH in the context of neurodegenerative processes such as Alzheimer's disease (AD). We therefore examined the enzymatic activity of the mitochondrial ALDH-isoform in different regions of the postmortem brain tissue isolated from patients with AD and controls. We found that the mitochondrial ALDH activity was significantly increased only in the putamen of patients suffering from AD compared to controls. This is of particular interest since mediators of oxidative stress, such as iron, are increased in the putamen of patients with AD. This study adds to the body of evidence that suggests that oxidative stress as well as aldehyde toxicity play a role in AD.

Oxidative stress (OS), is defined as an imbalance of pro- and antioxidants, leading to increased production of free radicals, which can lead to cell damage and death, has been postulated as important factors in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). Most research has concentrated on the antioxidant system, for the first time, this proof of concept study examines the prooxidant system by investigating kinetic parameters of the free radical producing enzyme xanthine oxidase directly in post mortem brain tissue.We determined the Michaelis-Menten constant (K(M)) and the maximal velocity (V(Max)) of xanthine oxidase (XO) in the cortico-limbic system of patients with AD using activity assays.We found the Michaelis-Menton constant of XO significantly decreased in hippocampus of patients with AD compared to controls. None of the other brain regions showed any significant alterations of these parameters.These results add further evidence to the amount of research indicating that OS plays an important role in AD. Moreover, these results should encourage more research in this field and it maybe speculated that this might open new avenues for treatment and prevention in AD.

Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-beta protein precursor derivatives amyloid-beta (Abeta(1-40) and Abeta(1-42/43) lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Abeta as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing diseases that only becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Abeta as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review.

Postmortem human brain tissue is widely used in neuroscience research, but use of tissue originating from different brain bank centers is considered inaccurate because of possible heterogeneity in sample quality. There is thus a need for well-characterized markers to assess the quality of postmortem brain tissue. Toward this aim, we determined tryptophan (TRP) concentrations, phosphofructokinase-1 and glutamate decarboxylase activities in 119 brain tissue samples. These neurochemical parameters were tested in samples from autopsied individuals, including control and pathological cases provided by 10 different brain bank centers. Parameters were assessed for correlation with agonal state, postmortem interval, age and gender, brain region, preservation and freezing methods, storage conditions and storage time, RNA integrity, and tissue pH value. TRP concentrations were elevated significantly (p = 0.045) with increased postmortem interval; which might indicate increased protein degradation. Therefore, TRP concentration might be one useful and convenient marker for estimating the quality of human postmortem brain tissue.

It is generally believed that the cholinergic system plays an important role in normal cognitive functioning. Botulinum toxin is the most potent toxin of the peripheral cholinergic system and today it is used in the treatment of a variety of neurological disorders. However, it is surprising that its effect on cognitive processes has been investigated in only two publications. Short-term effects of the central application of botulinum toxin (BTX) type B have been associated with cognitive impairment in animals, while results with type A are ambiguous. In the present study, we have investigated the duration of memory impairment after an intracerebroventricular administration of BTX-A in rats. Two experiments were performed, lasting 12 and 5 months, respectively. In both experiments, the same dose of BTX-A was applied (2 U/kg) and the Morris water maze test was used in the assessment of memory performance. Results show that a single icv injection of a small dose of BTX-A significantly impairs the water maze performance. In both experiments, impairment was apparently of a slow onset and long lasting (up to 12 months). The length and pattern of attenuation suggest development of dementia-like deficits. In addition to providing a potentially new experimental model of memory impairment, these results question the idea of an intracranial application of BTX in the treatment of CNS disorders.

Increasing evidence has linked inflammatory processes to neurodegenerative disorders, including Alzheimer's and Parkinson's disease (PD). Tumor necrosis factor alpha (TNF-alpha) is a key inflammatory cytokine and several studies linked increased TNF-alpha to dopaminergic cell death in PD. The TNF-alpha promoter sequence contains several CpG dinucleotides located within or next to transcription factor binding sites. To test the hypothesis whether the methylation state of the TNF-alpha promoter contributes to increased expression of TNF-alpha in PD we compared DNA from different brain regions (substantia nigra pars compacta (SNpc) and cortex) of PD patients and neurologically healthy, age and sex matched controls by bisulfite sequencing of the TNF-alpha promoter region. The TNF-alpha promoter DNA from SNpc was significantly less methylated in comparison to DNA from cortex; however both in PD patients and controls. Although there was a tendency for hypomethylation in PD, our analysis of the 10 CpGs in the TNF-alpha core promoter region (−258 to −35 relative to the TSS) revealed no particular pattern in PD patients compared to control and identified no particular hypomethylated position in cortex or SNpc DNA. Electrophoretic mobility shift and luciferase reporter assays showed that methylation of specific solitary CpG in the TNF-alpha promoter resulted in reduced binding of the transcription factors AP-2 and Sp1, respectively, and suppressed TNF-alpha promoter activity. The brain region specific methylation state of solitary CpG in the TNF-alpha promoter thus determines transcription factor binding efficacy and TNF-alpha expression. A lesser degree of methylation of the TNF-alpha promoter in SNpc cells could underlie the increased susceptibility of dopaminergic neurons to TNF-alpha mediated inflammatory reactions.

At most, many protein-misfolding diseases develop as environmentally induced sporadic disorders. Recent studies indicate that the dynamic interplay between a wide repertoire of noncoding RNAs and the environment play an important role in brain development and pathogenesis of brain disorders. To elucidate this new issue, novel animal models which reproduce the most prominent disease manifestations are required. For this, transgenic Drosophila strains were constructed to express small highly structured, non-coding RNA under control of a heat shock promoter. Expression of the RNA induced formation of intracellular aggregates revealed by Thioflafin T in embryonic cell culture and Congo Red in the brain of transgenic flies. Also, this strongly perturbed the brain control of locomotion monitored by the parameters of sound production and memory retention of young 5-day-old males. This novel model demonstrates that expression of non-coding RNA alone is sufficient to trigger neuropathology.

Genetic findings have changed our views on Parkinson's disease (PD) and parkinsonism, which will be collectively referred to as Parkinsonian Syndrome (PS) in the present manuscript. Mutations in several genes are found to cause monogenic forms of the disorder. Point mutations, duplications and triplications in the alpha-synuclein gene cause a rare dominant form of PS in families. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified as a much more common cause for dominant PS, especially in certain ethnic groups, while mutations in the parkin gene, in DJ-1, PINK1 and ATP13A2 cause autosomal recessive parkinsonism of early onset. The monogenic variants are important tools in identifying cellular pathways that also shed light on the molecular pathogenesis of sporadic PS and some of these genes may play a role in the etiology of the common sporadic form of PS. Here we add recent findings to a greatly challenging puzzle.

The resistance of courtship behavior and communicative sound production to heat shock (37°C, 30 min) was studied in wild-type Canton S (CS) male Drosophila melanogaster and males of two strains with defects in the kynurenine pathway of tryptophan metabolism (KPTM) caused by mutations cinnabar (block at the level of kynurenine-3-hydroxylase leading to accumulation of kynurenic acid, a neuroprotective metabolite, in the brain) and cardinal (block at the level of phenoxazinone synthetase causing accumulation of 3-hydroxykynurenine, an oxidative stress generator, in the brain). Males of each strain were divided into four groups. Males from control groups were not exposed to heat shock. The other groups were exposed to heat shock at the late embryonic/early larval (the first instar) developmental stage, when mushroom bodies are formed (HS1 groups); at the prepupal stage, when the brain central complex develops (HS2 groups); or at the imago stage 1 h before the experiment (HS groups). All males were tested at an age of five days. Virgin and fertilized five-day-old CS females served as courtship objects. The courtship behavior and singing of control CS and cinnabar males were similar. Control cardinal males also had high motivation, but their courtship efficiency was lower because of less precise movements (wing vibration was often not accompanied by sound production) and hyperexcitability. Exposure of first-instar larvae to heat shock had almost no effect on behavior or singing of adult males of any strain. In cardinal males exposed to heat shock at the prepupal stage or, especially, at the imago stage 1 h before the test (the HS2 and HS groups), courtship was strongly impaired, and various distortions appeared in their sound signals, which indicated disturbance of coordination between elements of the song center and their interaction with pacemakers. These effects were much milder or absent altogether in HS2 and HS wild-type males and, especially, cinnabar males. Thus, permanent excess of 3-hydroxykynurenine in the male brain dramatically decreased their stress resistance. In contrast, excess of kynurenic acid alleviated the consequences of stress.

Sustained drug delivery providing continuous dopaminergic stimulation is thought to prevent or delay the induction of motor complications (dyskinesia) in Parkinson's disease, whereas pulsatile administration is supposed to promote them. This study investigated the inducibility of sensitization and abnormal involuntary movements (AIMs), comparing continuous and pulsatile administration of rotigotine with pulsatile administration of 3,4-dihydroxy-L-phenylalanine (L-DOPA) for reference. Rats were unilaterally lesioned with 6 hydroxydopamine (6-OHDA). For pulsatile administration, L-DOPA-methylester (10 mg/kg L-DOPA i.p.) or rotigotine (1 mg/kg i.p.) were administered once or twice daily. For continuous administration, a slow release formulation of rotigotine was injected s.c. at a dose of 1 mg/kg every 48 h (experiment I) or every 24 h (experiment II). Pulsatile administration of rotigotine and L-DOPA caused contraversive rotations increasing progressively upon each successive treatment. AIMs started to occur after the second administration of L-DOPA but hardly after pulsatile rotigotine. Continuous rotigotine increased rotations, which reached a plateau after the second administration. No AIMs were observed under continuous administration. The continuous administration of rotigotine did not induce sensitization or AIMs, suggesting that continuous stimulation of dopaminergic receptors by rotigotine has no propensity to induce dyskinesia in this experimental model.

Neuromelanin (NM) is a complex polymer pigment found primarily in the dopaminergic neurons of the human substantia nigra. The structure of NM is only partially characterized, and its synthesis pathway remains unknown. We used nuclear magnetic and infrared spectroscopy to examine the structure of human NM isolated from the substantia nigra compared with synthetic dopamine melanins. Biochemical analyses were used to investigate proteinaceous and dopaminergic components in these samples. Following acid hydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety of amino acids were measured. These findings suggest a peptide component in NM structure. NM also appears to contain a variety of unidentified structural components possibly derived from the oxidation of dopamine. Human NM differs structurally from synthetic dopamine melanin, but both human and synthetic NM include an aromatic backbone. It is interesting that both human NM and synthetic melanin also contain a large proportion of aliphatic structures. Our results suggest that NM is a more complex pigment than synthetic dopamine melanin formed via dopamine autoxidation alone.

A central role of iron in the pathogenesis of Parkinson's disease (PD), due to its increase in substantia nigra pars compacta dopaminergic neurons and reactive microglia and its capacity to enhance production of toxic reactive oxygen radicals, has been discussed for many years. Recent transcranial ultrasound findings and the observation of the ability of iron to induce aggregation and toxicity of α-synuclein have reinforced the critical role of iron in the pathogenesis of nigrostriatal injury. Presently the mechanisms involved in the disturbances of iron metabolism in PD remain obscure. In this review we summarize evidence from recent studies suggesting disturbances of iron metabolism in PD at possibly different levels including iron uptake, storage, intracellular metabolism, release and post-transcriptional control. Moreover we outline that the interaction of iron with other molecules, especially α-synuclein, may contribute to the process of neurodegeneration. Because many neurodegenerative diseases show increased accumulation of iron at the site of neurodegeneration, it is believed that maintenance of cellular iron homeostasis is crucial for the viability of neurons.

Extensive research has revealed a complex pathophysiology in Parkinson’s disease, with different factors contributing to the progressive neurodegeneration. Within this complex pathophysiology, a central role of iron and iron-induced oxidative stress has been discussed for many years, as elevated tissue iron levels, especially within the substantia nigra, have been detected by different techniques in a number of postmortem studies. These findings could be verified intra vitam by advancing MRI techniques, and more recently transcranial ultrasound. Different causes, such as disruption of the BBB, local changes in the normal iron-regulatory system, release of iron from intracellular storages or intraneuronal transportation from iron-rich areas, as well as genetic variations leading to changes in brain iron metabolism, are being discussed to be responsible for the increased tissue iron levels. Although it is still not clear whether increased iron levels constitute a primary or secondary phenomenon in the etiology of Parkinson’s disease, its interaction with many pathophysiologcial cascades and contribution to all forms of Parkinson’s disease, idiopathic as well as monogenetic, stresses the importance of further elucidating the mechanism of brain iron homeostasis and its possible alterations to finally develop pharmacological interventions that may disrupt the chain of pathological events leading to neurodegeneration.

Sporadic Parkinson's disease (PD) constitutes 99% of the disorder, while the remaining 1% of the cases is of familial (genetic) origin. The mutations reported to be associated with familial PD indicate impairment in protein processing and misfolding, as is handled by the ubiquitin-proteasome system (UPS), and in mitochondrial function. For these reasons, we have recently applied, for the first time, Affymetrix oligonucleotide microarray technique in the substantia nigra pars compacta of sporadic parkinsonian patients for studying global gene expression analysis and comparison to the alterations identified in inherited PD. This study identified decreased expression of 68 genes and elevation of 69 genes. Classification into functional groups revealed that the downregulated genes are related to signal transduction, protein degradation (e.g., ubiquitin-proteasome subunits), dopaminergic transmission/metabolism, iron transport, protein modification/phosphorylation, and energy pathways/glycolysis functional classes. A major finding is the decreased expressions of 5 subunits of the UPS, SKP1A, a member of the SCF (E3) ubiquitin ligase complex, and chaperone HSC-70, which can lead to a wide impairment in the function of an entire repertoire of proteins. The upregulated genes are clustered in cell adhesion/cytoskeleton, extracellular matrix components, cell cycle, protein modification/phosphorylation, protein metabolism and transcription, and inflammation/hypoxia (e.g., key iron and oxygen sensor EGLN1) classes. The study shows, for the first time, a convergence in the pathogenic processes that are observed in hereditary (familial) and sporadic PD, where abnormal iron metabolism, oxidative stress, and aggregation of proteins occur. An additional breakthrough in this research is the identification of a number of previously unsuspected crucial gene players that are also involved in the process of neurodegeneration, which can serve as specific biomarkers for PD and novel drug development.

Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.

Parkinson's disease (PD) is characterized by selective depletion of nigral dopamine (DA) neurons containing neuromelanin (NM), suggesting the involvement of NM in the pathogenesis. This study reports induction of apoptosis by NM in SH-SY5Y cells, whereas protease-K-treated NM, synthesized DA- and cysteinyl dopamine melanin showed much less cytotoxicity. Cell death was mediated by mitochondria-mediated apoptotic pathway, namely collapse of mitochondrial membrane potential, release of cytochrome c, and activation of caspase 3, but Bcl-2 over-expression did not suppress apoptosis. NM increased sulfhydryl content in mitochondria, and a major part of it was identified as GSH, whereas dopamine melanin significantly reduced sulfhydryl levels. Western blot analysis for protein-bound GSH demonstrated that only NM reduced S-glutathionylated proteins in mitochondria and dissociated macromolecular structure of complex I. Reactive oxygen and nitrogen species were required for the deglutathionylation by NM, which antioxidants reduced significantly with prevention of apoptosis. These results suggest that NM may be related to cell death of DA neurons in PD and aging through regulation of mitochondrial redox state and S-glutathionylation, for which NM-associated protein is absolutely required. The novel function of NM is discussed in relation to the pathogenesis of PD.

An automated high performance liquid chromatography with column-switching and ultraviolet detection was developed for the analysis of risperidone and 9-hydroxyrisperidone. The method needs minimum sample preparation and is useful for the detection down to a limit of 1 ng mL−1. Sample clean-up of serum was carried out on a CN 20 μm SPE-column using 8% (v/v) acetonitrile in water. Chromatographic separation was performed on ODS Hypersil C18 material with 38% (v/v) acetonitrile and 0.4% (v/v) TEMED in water. Application of the method to the analysis of serum samples confirmed its suitability for therapeutic drug monitoring of risperidone and 9-hydroxyrisperidone.

Despite its toxicity, botulinum neurotoxin type A (BTX-A) is a valuable therapeutic agent for several motor, autonomic and pain disorders. Numerous studies have described its peripheral as well as central effects. Using reversed-phase High Performance Liquid Chromatography with Electrochemical Detection (HPLC-ED) and gradient elution, we quantified the concentrations of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and their metabolites in 10 brain regions, ipsilateral and contralateral from the site of unilateral BTX-A administration (5 U/kg) into the rat whisker pad. In regions associated with nociception and pain processing we also examined possible BTX-A effects in combination with formalin-induced inflammatory orofacial pain. The dominant BTX-A effects on the monoamines and their metabolites were insignificant. The only significant increase caused by BTX-A alone was that of NA in striatum and serotonin in hypothalamus. While antinociceptive effects of BTX-A are most probably not related to central monoamine concentrations, the localized increased NA and 5-HT concentrations might play a role in reported BTX-A efficacy for the treatment of depression.

OBJECTIVE: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).METHODS: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.RESULTS: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics.CONCLUSIONS: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD).Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.The present article (Part I) summarises findings on potential biomarkers in neuroimaging studies, including structural brain morphology, functional magnetic resonance imaging and techniques for measuring metabolic changes, including positron emission tomography and others. Furthermore, this review reports on the clinical and molecular genetic findings of family, twin, linkage, association and genome-wide association studies. Part II of the review focuses on neurochemistry, neurophysiology and neurocognition.Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high-quality research has accumulated that will improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.

Die Rolle von Neurotransmittersystemen in der Physiologie der Gehirnfunktionen ist ebenso unbestritten wie deren Beteiligung an pathologischen Veranderungen, die letztlich zu den Symptomen psychischer Krankheiten fuhren. Neurotransmitterhypothesen psychischer Storungen sind sowohl in der Pathogeneseforschung als auch in der Psychopharmakotherapie Ausgangspunkte der wissenschaftlichen Bemuhungen um ein besseres Verstandnis der neurobiochemischen Grundlagen psychischer Erkrankungen. Einfache Monotransmitterhypothesen haben adaquateren Gleichgewichtstheorien weichen mussen, die von einer komplizierten Interaktion der verschiedensten Neurotransmitter ausgehen, neuroanatomische Strukturierungen („funktionelle Systeme“) berucksichtigen und auch Effekte in die Uberlegungen miteinbeziehen, die uber die reine Synapsenwirkung hinausgehen (Signaltransduktoren, Transkriptionsfaktoren etc.). Die Neurotransmittersysteme des Gehirns sind so komplex, dass bislang nur die Grundzuge ihrer Funktionsweisen bekannt sind. Es ware vermessen anzunehmen, dass aus der Kenntnis dieser Prozesse ein Verstandnis der menschlichen Psyche erwachsen konnte. Die Tatsache, dass Storungen der Neurotransmittersysteme eine Grundlage psychischer Erkrankungen darstellen konnen, darf nicht dazu fuhren, hierin die alleinige Ursache psychischer Storungen zu erblicken. Ein solcher einseitiger reduktionistischer und simplifizierender Biologismus wird weder im wissenschaftlichen Sinn dem komplexen System der menschlichen Psyche noch im arztlichen Sinn den Bedurfnissen psychisch kranker Patienten gerecht. Erst in der interdisziplinaren Verbindung mit neuroanatomischen, neuropsychologischen und klassisch-klinischen, psychopathologischen Bemuhungen konnen neurobiochemische Hypothesen wie die Neurotransmittertheorien dazu beitragen, psychische Storungen besser zu verstehen und optimierte therapeutische Strategien zu entwickeln.

N-methyl-D-aspartate (NMDA) receptor activation is involved in the pathogenetic cascades of neurodegenerative disorders including human immunodeficiency virus (HIV) dementia. Memantine, an uncompetitive NMDA receptor antagonist, which has been recently approved for the treatment of Alzheimer's disease, is being discussed as a potential adjunctive therapeutic substance for HIV dementia. We used simian immunodeficiency virus-infected rhesus macaques to assess the effects of memantine on brain dysfunction and brain pathology within 3-5 months after initial infection during early asymptomatic stage of disease. We had shown previously that within this time frame, marked changes were evident in the dopaminergic systems. Memantine was administered two weeks post infection, at peak viremia, in order to prevent early NMDA receptor activation due to immune mediators. We found that memantine prevented onset of dopamine deficits in the brains of SIV-infected macaques, without affecting early brain pathology or peripheral course of infection. Memantine specifically upregulated mRNA and protein expression of the neurotrophic factor brain-derived neurotrophic factor (BDNF), suggesting that the protective effect of memantine on dopamine function may be mechanistically remote from NMDA receptor antagonism. This novel pharmacological action of memantine may also be relevant for other neurodegenerative disorders and supports the involvement of neurotrophic factors in adult brain neuroprotection.

It is believed that oxidative stress (OS) plays a central role in the pathogenesis of metabolic diseases like diabetes mellitus (DM) and its complications (like peripheral neuropathy) as well as in neurodegenerative disorders like sporadic Alzheimer's disease (sAD). Representative experimental models of these diseases are streptozotocin (STZ)-induced diabetic rats and STZ-intracerebroventricularly (STZ-icv) treated rats, in which antioxidant capacity (AC) against peroxyl (ORAC(-ROO) (*)) and hydroxyl (ORAC(-OH) (*)) free radicals (FR) was measured in three different brain regions: the hippocampus (HPC), the cerebellum (CB), and the brain stem (BS) by means of oxygen radical absorbance capacity (ORAC) assay. In the brain of both STZ-induced diabetic and STZ-icv treated rats decreased AC has been found demonstrating regionally specific distribution. In the diabetic rats these abnormalities were not associated with the development of peripheral diabetic neuropathy (PDN). Also, these abnormalities were not prevented by the intracerebroventricularly (icv) pretreatment of glucose transport inhibitor 5-thio-D: -glucose (TG) in the STZ-icv treated rats, suggesting different mechanism of STZ-induced central effects from those at the periphery. Similarities of the OS alterations in the brain of STZ-icv rats and humans with sAD could be useful in the search for the new drugs in the treatment of sAD that have antioxidant activity. In the STZ-induced diabetic animals the existence of PDN was tested by the paw pressure test, 3 weeks following the diabetes induction. Mechanical nociceptive thresholds were measured three times at 10-min intervals by applying increased pressure to the hind paw until the paw-withdrawal or overt struggling was elicited. Only those diabetic animals which demonstrated decreased withdrawal threshold values in comparison with the control non-diabetic animals (C) were considered to have developed the PDN.

Prefrontal cortical (PFC) and hippocampal (HI) volume reductions have been consistently found in patients with recurrent depressive disorder (DD). Here we examine the possibility that oxidative stress, widely implicated in neuronal cell damage, may contribute to these brain structural changes. We compared manganese (Mn) and copper/zinc (Cu/Zn) superoxide dismutase (SOD) coenzyme concentrations in postmortem PFC and hippocampal brain tissue from 7 patients with DD and 7 neuropsychiatrically healthy controls using sandwich-type enzyme-linked immunosorbent assay (ELISA) technique. The concentration of Cu/Zn-SOD was significantly increased in the PFC but not in the hippocampus of patients. There was no significant change in Mn-SOD enzyme concentration in either region. Our findings contribute to the growing body of evidence implicating oxidative stress in the pathophysiology of depressive disorder.

The intracerebroventricular (icv) application of streptozotocin (STZ) in low dosage was used in 3-month-old rats to explore brain insulin system dysfunction. Three months following STZ icv treatment, the expression of insulin-1 and -2 mRNA was significantly reduced to 11% in hippocampus and to 28% in frontoparietal cerebral cortex, respectively. Insulin receptor (IR) mRNA expression decreased significantly in frontoparietal cerebral cortex and hippocampus (16% and 33% of control). At the protein/activity level, different abnormalities of protein tyrosine kinase activity (increase in hippocampus), total IR beta-subunit (decrease in hypothalamus) and phosphorylated IR tyrosine residues (increase) became apparent. The STZ-induced disturbance in learning and memory capacities was not abolished by icv application of glucose transport inhibitors known to prevent STZ-induced diabetes mellitus. The discrepancy between reduced IR gene expression and increase in both phosphorylated IR tyrosine residues/protein tyrosine kinase activity may indicate imbalance between phosphorylation/dephosphorylation of the IR beta-subunit causing its dysfunction. These abnormalities may point to a complex brain insulin system dysfunction after STZ icv application, which may lead to an increase in hyperphosphorylated tau-protein concentration. Brain insulin system dysfunction is discussed as possible pathological core in the generation of hyperphosphorylated tau protein as a morphological marker of sporadic Alzheimer's disease.

Background: Neuromelanin-containing neurons of the substantia nigra are highly vulnerable to degenerate in Parkinson’s disease. Inhibition of the respiratory chain or formation of reactive oxygen species (ROS) by intracellular neuromelanin and triggering of inflammatory processes by extracellular neuromelanin emanating from melanized neurons after their demise are thought to be causally implicated in the high vulnerability of melanized neurons. Objective: We addressed the direct effect of purified neuromelanin on mitochondrial complex I activity, and its influence on ROS production and survival of primary mesencephalic neurons in the presence or absence of glia. Methods: Neuromelanin was isolated from midbrain of postmortem human brains. The content in iron and other elements was measured by inductively coupled mass spectrometry. The effect of neuromelanin on mitochondrial complex I activity was analyzed in post-nuclear extracts. Primary neuronal enriched and neuron-glia mixed cultures from midbrain were treated with different concentrations of neuromelanin. The generation of ROS was determined by fluorochrome detection. MAP2-positive and TH-positive neuronal viability was analyzed. Results: Neuromelanin did not affect complex I activity, but concentration-dependently increased ROS production in neurons and reduced the number of MAP2-positive and TH-positive cultured neurons. Glia protected neurons against the neuromelanin toxicity. Conclusion: Extracellular neuromelanin is detrimental to neurons implicating a mechanism of intracellular ROS production, but not complex I inhibition. ROS formation may be catalyzed by iron, which was sensitively identified in purified neuromelanin (3.3 mg/g). Importantly, we demonstrate that glial cells have the potential to mitigate the neurotoxic effect of neuromelanin.

The objectives of this study is to clarify whether there are phases critical for the infection of the central nervous system (CNS) as defined by active viral replication in the cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV) infection. One hundred and nine HIV-1-positive homo- and bisexual patients in early and late disease stages with or without highly active antiretroviral therapy (HAART) were included in the cross-sectional, diagnostic (phase I) multicenter study. No patients had any overt neurological deficits; all underwent venous and lumbar puncture as well as neuropsychological testing. In untreated early-stage patients, cerebrospinal fluid (CSF) viral load correlated with inflammatory parameters, but not significantly with neuropsychological abnormalities. CSF viral load and inflammatory reactions were suppressed in HAART-treated early-stage patients. In HAART-treated late-stage patients, there was a weak correlation between CSF viral load and CSF cell count as well as a moderate correlation with immune activation markers and with distinct cerebral deficits independent of CSF viral load. Seventeen of the 109 patients had higher CSF than plasma viral loads and marked inflammatory reactions and immune activation. In patients with greater plasma than CSF viral loads, the factors contributing to cerebral deficits still need to be identified. The results suggest not only that there is an early "set point" for CSF/central nervous system (CNS) infection, but also that there is a subgroup of patients in whom intrathecal viral replication correlates with cerebral deficits. Lumbar puncture should be performed in all positive patients to identify members of this subgroup and to ascertain what characteristic factors they have in common in order to improve therapy.