Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the negative effects of HFD. Thus, physical exercise, by modulating adult neurogenesis in the hippocampus, might represent a potential preventive approach for treating cognitive impairments associated with adolescent obesity.

[The significance of depot medication in the long-term-treatment of schizophrenia]. / Stellenwert von Depotformulierungen in der Langzeittherapie der Schizophrenie.

Relapse prevention in schizophrenia is a key aim in therapy. However, it is estimated that approximately 75% of patients with schizophrenia relapse within five years. Each relapse might worsen the disease and increase the risk of psychosocial and work-related disadvantages. A continuous long-term therapy is able to reduce this risk, but medical non-adherence, which is influenced by numerous factors, is a limitation. Naturalistic studies show that depot-antipsychotics compared with oral antipsychotics lead consistently to a better outcome, for example by reducing relapse rates or hospitalisation. Numerous meta-analyses of randomised controlled trials comparing oral versus depot-antipsychotics also show this advantages. However these results are not consistent in all meta-analyses. Results of controlled studies do not appropriately reflect the reality of daily practice. The advantages of depot-antipsychotics are shown more distinctly in naturalistic studies. The following review reflects the current therapy of schizophrenia and discusses adequately a broad application of depot-antipsychotics based on existing data. In addition, concerns and prejudices of physicians and patients against antipsychotic long-term therapy and depot-formulation are discussed and a recommendation is provided.

Changes of serum concentrations of brain-derived neurotrophic factor (BDNF) during treatment with venlafaxine and mirtazapine: role of medication and response to treatment.

INTRODUCTION: Depression, stress and antidepressant treatment have been found to modulate the expression of brain-derived neurotrophic factor (BDNF). Recent research suggests that serum BDNF concentration is reduced in depression and that antidepressant treatment leads to an increase in serum BDNF concentration. METHODS: We studied depressed patients receiving a randomized antidepressant treatment with either mirtazapine (n=29) or venlafaxine (n=27) for 28 days in a prospective design. Changes in the concentrations of serum neurotrophins in response to antidepressant treatment were assessed. RESULTS: There was a significant "treatment" by "medication" interaction effect on BDNF serum concentrations that indicated a decline of BDNF in venlafaxine-treated patients (7.82±3.75-7.18±5.64 ng/mL), while there was an increase in mirtazapine-treated patients (7.64±6.23-8.50±5.37 ng/mL). There was a trend for a "treatment" by "remission" interaction with a favourable clinical course being related to increasing serum BDNF. DISCUSSION: Changes in BDNF serum concentrations as a result of antidepressant therapy depend on the antidepressant and potentially on the clinical course.

[The development of depression: the role of brain-derived neurotrophic factor]. / Entstehung von Depression : Die Rolle des "brain-derived neurotrophic factor"

An association between the presence of psychosocial stress, its pathological processing and the development of depression is well documented. This review reports and discusses studies suggesting a reduced release of brain-derived neurotrophic factor (BDNF) under stress as a possible mechanism. The studies show a reduction of BDNF secretion in stressful situations, a decreased blood concentration in depression and a normalization of BDNF by successful antidepressant therapy. As a possible mechanism of BDNF action, a reactivation of neuroplasticity is being discussed, especially in hippocampal and cortical networks. On the other hand, methodological limitations, such as the impossibility of determining the cerebral BDNF concentration in vivo and ruling out a variety of possible confounders, may restrict the significance of the studies. The question of whether the ascertained changes of BDNF levels are causally involved in the pathophysiology of depression or whether they are just an epiphenomenal result of depression-induced stress is still under debate.

[Assessment of benefits of drug therapies: memantine for Alzheimer's disease as an example]. / Zur Bewertung des Nutzens medikamentöser Therapieoptionen am Beispiel von Memantin bei Alzheimer Demenz.

After the approval of a drug, which represents a first assessment, independent institutions and medical professional associations provide further evaluations. Here, the question is to be asked whether common or diverging evaluation methods exist that can have an impact on the result. In principle, two methods are used: meta-analyses and responder analyses. Meta-analyses and the resulting effect sizes have to be interpreted according to the field of application (for example, the type and severity degree of a disease) with medical expertise. Omitting this can lead to incorrect evaluations and to a discrepancy of evaluation results. In the case of memantine, the merely biometric evaluation of meta-analyses performed by the IQWiG led to a denial of the benefit, while the same data, considering clinical routine, led professional associations to recommend memantine for moderate to severe Alzheimer´s disease. In contrast to meta-analyses, responder analyses directly show the benefit of a therapy option in the presence of significant group differences, as the selected responder criteria are based on the indication. The corresponding results of the responder analyses on memantine were also acknowledged by the IQWiG and led to a positive evaluation of memantine. This discrepancy of evaluation results illustrates the fact that statistical procedures are necessary when evaluating drug and non-drug therapy options but, that the interpretation of the results with medical expertise is essential.

[The importance of depressive syndromes for incipient Alzheimer-type dementia in advanced age]. / Die Bedeutung depressiver Syndrome bei beginnender Demenz vom Alzheimer-Typ im höheren Lebensalter.

Based on epidemiological data on the risk for dementia conveyed by depression, we report recent findings on the effects of depressive disorders on cognition in later life and its relationship to incipient Alzheimer's disease. We review the current literature on possible mechanisms underlying the depression-dementia association. The findings summarized in this review underline the central importance of depressive disorders for the diagnosis and treatment of psychiatric disorders in later life.

Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats.

INTRODUCTION: The neurotrophin brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are a central part of the molecular concepts on neuroplastic changes associated with stress, anxiety and depression. An increasing number of studies uses serum BDNF levels as a potential indicator for central nervous system alterations. METHODS: To analyze the relationship between brain tissue and serum BDNF and NGF levels, we used electroconvulsive shocks (ECS), an animal model of electroconvulsive therapy, and studied the temporal profile of neurotrophin expression in the hippocampus, prefrontal cortex and serum. 88 male Sprague-Dawley rats received single or serial ECS treatments and were killed between 3 hours and 14 days after the last treatment. RESULTS: We found a 2.8-fold rise for BDNF (1.3-fold for NGF) in the prefrontal cortex, and a 2.2-fold rise (1.2-fold for NGF) in the hippocampus after 5 ECS sessions. The temporal expression profile and correlation analyses between tissue and serum BDNF indicate that BDNF crosses the blood-brain barrier. No such correlation was found for NGF. DISCUSSION: The time course of central and peripheral BDNF changes may significantly differ. However, we demonstrate substantial evidence that it can be justified to measure serum BDNF levels with a time delay to monitor brain tissue neurotrophin alterations.

High-fat Diet and Physical Exercise Differentially Modulate Adult Neurogenesis in the Mouse Hypothalamus.

The hypothalamus has emerged as a novel neurogenic niche in the adult brain during the past decade. However, little is known about its regulation and the role hypothalamic neurogenesis might play in body weight and appetite control. High-fat diet (HFD) has been demonstrated to induce an inflammatory response and to alter neurogenesis in the hypothalamus and functional outcome measures, e.g. body weight. Such modulation poses similarities to what is known from adult hippocampal neurogenesis, which is highly responsive to lifestyle factors, such as nutrition or physical exercise. With the rising question of a principle of neurogenic stimulation by lifestyle in the adult brain as a physiological regulatory mechanism of central and peripheral functions, exercise is interventionally applied in obesity and metabolic syndrome conditions, promoting weight loss and improving glucose tolerance and insulin sensitivity. To investigate the potential pro-neurogenic cellular processes underlying such beneficial peripheral outcomes, we exposed adult female mice to HFD together with physical exercise and evaluated neurogenesis and inflammatory markers in the arcuate nucleus (ArcN) of the hypothalamus. We found that HFD increased neurogenesis, whereas physical exercise stimulated cell proliferation. HFD also increased the amount of microglia, which was counteracted by physical exercise. Physiologically, exercise increased food and fat intake but reduced HFD-induced body weight gain. These findings support the hypothesis that hypothalamic neurogenesis may represent a counter-regulatory mechanism in response to environmental or physiological insults to maintain energy balance.

NGF receptor-mediated reduction in axonal NGF uptake and retrograde transport following sciatic nerve injury and during regeneration.

Injury to the rat sciatic nerve leads to the induction of nerve growth factor (NGF) receptors on the denervated Schwann cells and their disappearance on the regenerating axons of the axotomized, normally NGF-sensitive sensory and sympathetic neurons. This disappearance in the axonal expression and retrograde transport of NGF receptors is associated with a similarly dramatic reduction in the axonal uptake and retrograde transport of NGF following axotomy and during regeneration. In view of the massive NGF synthesis occurring in the injured nerve, these results suggest that, while sensory and sympathetic neurons are the primary targets of NGF in the normal peripheral nervous system, the denervated Schwann cells may become its primary target in the aftermath of nerve injury.

Age-dependent time course of cerebral brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 in APP23 transgenic mice.

Neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), have repeatedly been shown to be involved in the pathophysiology of Alzheimer's disease (AD). Recent studies have claimed that these neurotrophic factors are important tools for therapeutic intervention in neurodegenerative diseases. So far, little is known about the age- and disease-modulated time course of cerebral neurotrophins. Therefore, we have studied protein concentrations of BDNF, NGF, and NT-3 in different brain areas and sciatic nerve, a neurotrophin-transporting peripheral nerve, in a well-characterized AD model of amyloid precursor protein-overexpressing rodents (APP23 mice) at the ages of 5.0, 10.5, and 20.0 months. In APP23 mice, there was a significant increase of BDNF and NGF in the frontal and occipital cortices (for BDNF also in the striatum) of old 20.0-month-old mice (with respect to median values up to 8.2-fold), which was highly correlated with amyloid concentrations of these brain areas. Median values of NGF and NT-3 showed up to a 6.0-fold age-dependent increase in the septum that was not detectable in APP23 mice. Hippocampus, olfactory bulb, and cerebellum (except NT-3) did not show substantial age- or genotype-related regulation of neurotrophins. In the sciatic nerve, BDNF and NGF levels are increased in5-month-old APP23 mice and decrease with age to control levels. In conclusion, APP23 mice show a genotype-dependent increase of cortical BDNF and NGF that is highly correlated with amyloid concentrations and may reflect an amyloid-related glia-derived neurotrophin secretion or an altered axonal transport of these neurotrophic factors.

Impaired detection and differentiation of briefly presented facial emotions in adults with high-functioning autism and asperger syndrome.

Although deficits in the recognition of emotional facial expressions are considered a hallmark of autism spectrum disorder (ASD), characterization of abnormalities in the differentiation of emotional expressions (e.g., sad vs. angry) has been rather inconsistent, especially in adults without intellectual impairments who may compensate for their deficits. In addition, previous research neglected the ability to detect emotional expressions (e.g., angry vs. neutral). The present study used a backward masking paradigm to investigate, a) the detection of emotional expressions, and b) the differentiation of emotional expressions in adults diagnosed with high functioning autism or Asperger syndrome (n = 23) compared to neurotypical controls (n = 25). Compensatory strategies were prevented by shortening the stimulus presentation time (33, 67, and 100 ms). In general, participants with ASD were significantly less accurate in detecting and differentiating emotional expressions compared to the control group. In the emotion differentiation task, individuals with ASD profited significantly less from an increase in presentation time. These results reinforce theoretical models that individuals with ASD have deficits in emotion recognition under time constraints. Furthermore, first evidence was provided that emotion detection and emotion differentiation are impaired in ASD.

Neurotrophic factors--a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases?

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) belong to the protein family of neurotrophins. They both display profound neuromodulatory functions and are essentially involved in the survival and homeostatic maintenance of central and peripheral neurons during development and adulthood. Moreover, NGF and BDNF are known to modulate immune cell function and thus serve as mediators in the reciprocal cross talk between neurons and immune cells. Neurotrophic factors have been implicated in pathophysiological mechanisms of many diseases of the nervous and the immune system, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), neuropathy, pain, allergic bronchial asthma (BA) and neurotrophic keratitis. For all these diseases research has reached the point of creating strategies for therapeutic intervention with neurotrophins. In this review, we present an overview of the pathophysiology, therapeutic interventions and strategies concerning NGF and BDNF in the mentioned diseases.

Clinical relevance of nerve growth factor serum levels in patients with atopic dermatitis and psoriasis.

BACKGROUND: Nerve growth factor (NGF) is known to act as a potent mediator in neuroinflammatory processes. Recent studies point to a role of NGF in the skin pathophysiology of atopic dermatitis (AD) and psoriasis. Hereby, NGF was found to interact with the major cellular components (mast cells and eosinophils) of both skin diseases. OBJECTIVES: In order to investigate NGF serum levels as a possible clinical marker of disease activity and immunological status, we determined serum NGF, eosinophil cationic protein (ECP), total IgE and score of AD (SCORAD) in 57 patients with AD as well as NGF and the psoriasis area and severity index (PASI) in 17 patients with psoriasis. Fifty healthy subjects served as controls. METHODS: We used a highly sensitive improved fluorometric two-site ELISA system for serum NGF detection. IgE and ECP were measured by CAP-FEIA and radioimmunoassay. RESULTS: We did not find a significant correlation between NGF and either ECP, total IgE, or severity of disease assessed by SCORAD. Also in patients with psoriasis, there was no significant correlation with disease activity determined by PASI. CONCLUSION: Even though there is increasing evidence showing NGF to be involved in the local inflammatory pathophysiology of AD within skin lesions, our findings suggest that NGF systemic serum concentration is not a suitable parameter to estimate the clinical or immunological status of AD or psoriasis patients. This result is inconsistent with some previous studies showing a positive correlation of serum NGF with AD severity, which might be, for example, due to the fact that the present results are corrected for unspecific binding.

Beta/A4-Amyloid increases nerve growth factor production in rat primary hippocampal astrocyte cultures.

Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons (BFCN). In processes of chronic degeneration of BFCN like in Alzheimer's disease (AD), characterized among others by amyloid containing plaques, NGF has been shown to improve cognitive decline and rescue BFCN but also to reduce survival of hippocampal neurons via p75 neurotrophin receptor (p75). Little is known about the mechanisms of NGF regulation in glial cells under pathological conditions in AD. This study investigates the influence of amyloid administration on the NGF protein secretion in rat primary hippocampal astrocytes. Astrocytes were stimulated with "aged" beta/A4-Amyloid (1-40), and NGF was measured in different fractions, such as supernatant, vesicles, and cytosol fraction. Treatment with amyloid at a final concentration of 10 microM for 72 h led to increased NGF protein levels up to 30-fold increase compared to unstimulated controls. This observation may be an endogenous neuroprotective mechanism possibly contributing to a delay of amyloid-dependent loss of cholinergic neurons or contribute to accelerated neuronal death by activation of p75 within Alzheimer pathology.

Effects of aerobic exercise on brain metabolism and grey matter volume in older adults: results of the randomised controlled SMART trial.

There is mounting evidence that aerobic exercise has a positive effect on cognitive functions in older adults. To date, little is known about the neurometabolic and molecular mechanisms underlying this positive effect. The present study used magnetic resonance spectroscopy and quantitative MRI to systematically explore the effects of physical activity on human brain metabolism and grey matter (GM) volume in healthy aging. This is a randomised controlled assessor-blinded two-armed trial (n=53) to explore exercise-induced neuroprotective and metabolic effects on the brain in cognitively healthy older adults. Participants (age >65) were allocated to a 12-week individualised aerobic exercise programme intervention (n=29) or a 12-week waiting control group (n=24). The main outcomes were the change in cerebral metabolism and its association to brain-derived neurotrophic factor (BDNF) levels as well as changes in GM volume. We found that cerebral choline concentrations remained stable after 12 weeks of aerobic exercise in the intervention group, whereas they increased in the waiting control group. No effect of training was seen on cerebral N-acetyl-aspartate concentrations, nor on markers of neuronal energy reserve or BDNF levels. Further, we observed no change in cortical GM volume in response to aerobic exercise. The finding of stable choline concentrations in the intervention group over the 3 month period might indicate a neuroprotective effect of aerobic exercise. Choline might constitute a valid marker for an effect of aerobic exercise on cerebral metabolism in healthy aging.

[Prevalence and role of psychiatric disorders in disability]. / Prävalenz und Rolle psychiatrischer Erkrankungen bei Einschränkung der beruflichen Leistungsfähigkeit.

Common risk factors for the receipt of disability income (DI) are psychiatric diagnosis at the time of conscription, showing low personal responsibility and job satisfication, unemployment after graduation, low rating on an "IQ" test, low educational level, part-time employment, isolation, separation, smoking, problem drinking, poor subjective state of health and well-being. Psychiatric diagnoses are considered to be the main reason for disability income in women and rank third in men. With average retirement age of 39 for males and 42 for females, schizophrenia is the most important single reason for early retirement before age 40. Major depression has been shown to be the fourth leading cause of DI worldwide. Personality disorders, which display primarily antisocial, histrionic, emotionally unstable and narcissistic behaviour (Cluster B personality disorders) have been associated with an earlier age of work disability, and borderline personality has been associated with failure to return to work. A dependent, schizoid, paranoid and antisocial personality tends to be associated with an increased risk of developing disability. A subtype of adaptation disorder that is characterised primarily by lasting embitterment after exceptional life events, which violate basic beliefs, namely post-traumatic embitterment disorder, shows up highly the development of DI. However, most of the patients applying for a DI have neither been sufficiently diagnosed nor received adequate psychiatric and/or psychotherapeutic treatment when they claim on their DI policy. Thus, the prognosis of the diseases listed above could well be improved at least for some patients depending on their disease (10-80 %).

Treatment of intractable non-rapid cycling bipolar affective disorder with high-dose thyroxine: an open clinical trial.

Six patients with very severe forms of non-rapid cycling bipolar affective illness whose symptoms had previously been refractory to all current antidepressant and/or prophylactic medications were treated with supraphysiological doses of thyroxine (250 to 500 micrograms/day) as an adjuvant to their previous medications. The mean follow-up period was 27.8 +/- 12.8 months (range 12 to 46). The mean number of relapses during the follow-up period of each patient declined from 5.3 +/- 3.1 to 0.8 +/- 0.8 and the mean duration of hospitalization from 10.0 +/- 5.6 to 0.8 +/- 1.2 months as compared to the same length of time for each patient before the start of treatment with high-dose thyroxine (T4). Three of the patients had no further relapses at all. Thus, for these patients, who had previously been severely ill and therapy-resistant, high-dose T4 administration proved to have excellent effects on the course of the illness. However, in five of these patients the effect of the T4 was strong enough only when it was administered in combination with a prophylactic and antidepressant and/or neuroleptic drug, of which in some cases high doses were also needed. The side effects were negligible. Mechanisms that may possibly underlie the beneficial effects of high-dose T4 in bipolar affective disorder are discussed.

Treatment of refractory depression with high-dose thyroxine.

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T4) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 +/- 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 +/- 72 micrograms/day. The patients' scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 +/- 4.7 prior to the addition of T4 to 11.6 +/- 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of < or = 9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 +/- 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T4 proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.

Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures.

Apolipoprotein E isoforms may have differential effects on a number of pathological processes underlying Alzheimer's disease. Recent studies suggest that the amount, rather than the type, of apolipoprotein E may also be an important determinant for Alzheimer's disease. Therefore, understanding the regulated synthesis of apolipoprotein E is important for determining its role in Alzheimer's disease. We show here that in rat primary hippocampal astrocyte cultures, dibutyryl-cAMP increased apolipoprotein E secretion with time in a dose-dependent manner (to 177% at 48 h) and that retinoic acid potentiated this effect (to 298% at 48 h). Dibutyryl-cAMP also gave a rapid, albeit transient, increase of apolipoprotein E mRNA expression (to 200% at 1 h). In contrast, the protein kinase C activator phorbol 12-myristate 13-acetate decreased both apolipoprotein E secretion (to 59% at 48 h) and mRNA expression (to 22% at 1 h). Phorbol 12-myristate 13-acetate also reversed the effects of dibutyryl-cAMP. Apolipoprotein E secretion was also modulated by receptor agonists for the adenylyl cyclase/cAMP pathway. Isoproterenol (50 nM, a beta-adrenoceptor agonist) enhanced, while clonidine (250 nM, an alpha2-adrenoceptor agonist) decreased, secreted apolipoprotein E. We also analysed the effects of agonists for the phospholipase C/protein kinase C pathway. Arterenol (1 microM, an alpha1-adrenoceptor agonist) and serotonin (2.5 microM) enhanced, whereas carbachol (10 microM, an acetylcholine muscarinic receptor agonist) decreased secreted apolipoprotein E. The effects of these non-selective receptor agonists were modest, probably due to effects on different signalling pathways. Arterenol also potentiated the isoproterenol-mediated increase. We also show that phorbol 12-myristate 13-acetate and dibutyryl-cAMP have opposite effects on nerve growth factor, as compared to apolipoprotein E, secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis. We conclude that astrocyte apolipoprotein E production can be regulated by factors that affect cAMP intracellular concentration or activate protein kinase C. Alterations in these signalling pathways in Alzheimer's disease brain may have consequences for apolipoprotein E secretion in this disorder.