[Acceptance of psychosocial bridging measures in dementia : Treatment observation during the COVID-19 pandemic]. / Akzeptanz psychosozialer Überbrückungsmaßnahmen im Rahmen demenzieller Erkrankungen : Behandlungsbeobachtung während der COVID-19-Pandemie.

BACKGROUND: In the event of a COVID-19-related absence from an outpatient treatment program, patients suffering from dementia and their caregivers were offered support from a distance. The aim was to examine the extent of the participants' burden as well as how the offer was accepted and evaluated. MATERIAL AND METHODS: All participants (n = 63) were offered supportive telephone contact over a period of 8 weeks at varying frequencies (weekly, fortnightly). In addition patients received cognitive and physical tasks by mail every 2 weeks. In order to examine the acceptance of the support, data collected from clinical routine were included in a treatment observation. Additionally, all participants were asked to evaluate the support retrospectively. RESULTS: Out of 63 contacted participants, 45 were included in the treatment observation. The telephone support was very well accepted and a tendency towards higher agreement could be ascertained by caregivers. The experience of burden remained stable at a moderate level for all participants; however, caregivers were significantly more burdened. CONCLUSION: The present treatment observation shows the acceptance of a location-independent psychosocial treatment program for dementia for future pandemics or treatment failure as well as for the routine care, e.g. for patients with restricted mobility or those living in rural areas without direct hospital connection. In particular, our data strengthen the importance of programs for caregivers in order to alleviate their burden.

[Potentials and limits of aging cohort studies for geriatric psychiatry]. / Potenziale und Grenzen von Alternskohortenstudien für die Gerontopsychiatrie.

The sizeable number of population-based cohort studies of aging in Germany have provided highly valuable contributions for the specification of risk factors and predictors for frequent mental disorders in old age, especially dementia and depression. The results from these cohort studies enable the specification of mechanisms for the development of and preventative interventions for common mental disorders in old age. On the other hand, there is a significant paucity of clinical cohort studies investigating disease trajectories and possible markers for specific individualized interventions of frequent mental disorders in old age. In this article, we report selected key findings from cohort studies of aging and discuss novel approaches for the integration and harmonization of population-based and clinical cohort studies.

Ziprasidone--not haloperidol--induces more de-novo neurogenesis of adult neural stem cells derived from murine hippocampus.

INTRODUCTION: Here, we present a stem-cell based study on the de-novo generation of beta-III-tubulin-positive neurons after treatment with the classic antipsychotic drug haloperidol or after treatment with the second-generation antipsychotic (SGA) ziprasidone. METHODS: Adult neural stem cells (ANSC) dissociated from the adult mouse hippocampus were expanded in cell culture with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). ANSC differentiated upon withdrawal of EGF and bFGF. RESULTS AND DISCUSSION: Ziprasidone generated significantly more beta-III-tubulin-positive neurons than haloperidol during the differentiation of adult neural stem cells isolated from murine hippocampus (ANSC). We assume that this net increase in neurogenesis by ziprasidone relies on this drug's 5-HT1A receptor affinity, which is not present in the haloperidol molecule, since the inactivation by WAY100621 impeded this process. These data could possibly suggest a clinical relevance for studying antipsychotic drugs in the stem cell paradigm employed in this study.

PET imaging in a case of the semantic variant of primary progressive aphasia.

A 64-year-old right-handed Caucasian presented with a four-year history of word-finding deficits and otherwise fluent speech production. Neurological examination remained unremarkable apart from the word finding impairment. Likewise, neuropsychological evaluation confirmed significantly reduced semantic word fluency. While brain MRI depicted only discrete anterior temporal atrophy, 18-fluorodeoxyglucose PET showed clear hypometabolism of the anterior temporal pole bilaterally with left predominance. An imaging-supported diagnosis of the semantic variant of primary progressive aphasia was established in close accordance to recently published diagnostic criteria.The PET findings can be regarded as typical for this condition and PET imaging proved helpful to delineate other variants (non-fluent and logopenic) of primary progressive aphasia.

Current application of neurochemical biomarkers in the prediction and differential diagnosis of Alzheimer's disease and other neurodegenerative dementias.

In light of the dramatically increasing prevalence of Alzheimer's disease (AD) to be expected in the future, the development of novel therapeutics, improved differential and early diagnostics, and means for the identification of individuals at risk are urgently needed. At present, instruments for a reliable differential diagnosis in clinical dementia, mild cognitive impairment, or prodromal stages have direct practical implications for differentiating secondary dementias from neurodegenerative conditions and for treatment decisions. It may also be reasonable to enforce the incorporation of biomarkers into clinical studies as surrogate outcome parameters and as an attempt to optimize recruitment criteria. Recently, revised research criteria increasingly rely on the interpretation of biomarker patterns, including neuroimaging and CSF-based neurochemical dementia diagnosis (NDD) in supporting the clinical diagnosis. Here, we review the performance of current core CSF biomarkers (Aß(42) peptide, total tau protein and phosphorylated tau species) and try to define objectives for prospective markers, also considering blood-based tests, which would increase the acceptance and wide application of NDD. Moreover, we evaluate the role and the limitations of genotyping in the predictive diagnosis of AD.

[Advances in the diagnostics of Alzheimer's disease]. / Fortschritte in der Diagnostik der Alzheimer-Demenz.

Due to the demographic developments, diagnosis and treatment, dementia constitutes an increasing medical challenge and is likely to have an increasing socioeconomic impact. Dementia does not reflect a single disease but encompasses a variety of underlying conditions, heterogeneous clinical courses and therapeutic approaches, among which Alzheimer's disease represents the most common cause. Therefore, a thorough differential diagnosis of dementia is of major importance. To date the current diagnosis of dementia according to ICD-10/DMS-IV is based on clinical criteria. In addition, the concept of mild cognitive impairment comprises early cognitive dysfunction without clinically apparent dementia. Alzheimer's disease is more and more conceptualized as a disease continuum with mild cognitive impairment as an early and manifest dementia as the later stage of the disease. This review gives an overview on the current diagnostic approaches and the proposed revisions of diagnostic and research criteria for Alzheimer's disease.

Adult neurogenesis in serotonin transporter deficient mice.

Serotonin (5-HT) is a regulator of morphogenetic activities during early brain development and neurogenesis, including cell proliferation, migration, differentiation, and synaptogenesis. The 5-HT transporter (5-HTT, SLC6A4) mediates high-affinity reuptake of 5-HT into presynaptic terminals and thereby fine-tunes serotonergic neurotransmission. Inactivation of the 5-HTT gene in mice reduces 5-HT clearance resulting in persistently increased concentrations of synaptic 5-HT. In the present study, we investigated the effects of elevated 5-HT levels on adult neurogenesis in the hippocampus of 5-HTT deficient mice, including stem cell proliferation, survival, and differentiation. Using an in vivo approach, we showed an increase in proliferative capacity of hippocampal adult neural stem cells in aged 5-HTT knockout mice (approximately 14.5 months) compared to wildtype controls. In contrast, in vivo and additional in vitro analyses of younger adult 5-HTT knockout mice (approximately 7 weeks and approximately 3.0 months) did not reveal significant changes in proliferation of neural stem cells or survival of newborn cells. We showed that the cellular fate of newly generated cells in 5-HTT knockout mice is not different with respect to the total number and percentage of neurons or glial cells from wildtype controls. Our findings indicate that elevated synaptic 5-HT concentration throughout early development and later life of 5-HTT deficient mice does not induce adult neurogenesis in adult mice, but that elevated 5-HT levels in aged mice influence stem cell proliferation.

Enhanced calcium responses to serotonin receptor stimulation in T-lymphocytes from schizophrenic patients--a pilot study.

Even if more extensively investigated in affective disorders, the serotonergic system is likely to be also implicated in modulating the pathogenesis of schizophrenia, where it closely interacts with the dopaminergic and glutamatergic system. To substantiate this notion, we studied the intensity and dynamics of cellular Ca(2+) responses to serotonin (5-hydoxytryptamine, 5-HT) in peripheral lymphocytes taken from currently non-psychotic schizophrenic patients. To this aim, peripheral lymphocytes were freshly obtained from healthy controls and a naturalistic collective of patients with schizophrenia in remission. Intracellular Ca(2+) responses were recorded in real-time by ratiometric fluorometry after 5-HT or phythaemagglutinin (PHA) stimulation, which served as an internal reference for Ca(2+) responsivity to non-specific stimulation. The intracellular Ca(2+) peak early after applying the 5-HT trigger was significantly elevated in schizophrenic patients. No significant differences of Ca(2+) peak levels were seen in response to stimulation with the mitogenic agent PHA, although responses to 5-HT and PHA were positively correlated in individual patients or controls. In conclusion, the serotonergic response patterns in peripheral lymphocytes from schizophrenic patients seem to be elevated, if employing sensitive tools like determination of intracellular Ca(2+) responses. Our observations suggest that the participation of serotonergic neurotransmitter system in the pathogenesis of schizophrenia may deserve more interest, even if it should only act as a modulator on the main pathology in the dopaminergic and glutamatergic systems. We hope that this pilot study will prompt further studies with larger patient collectives to revisit this question.

Two different forms of p53 localized differently within cells of urogenital tumours.

We analyzed the subcellular localization of p53 in prostate and bladder carcinoma cells. Using laser scanning microscopy and PAb1620, a monoclonal antibody recognizing the wildtype conformation of p53, and another monoclonal antibody directed against the mutant conformation of the protein (PAb240), we found two different subsets of p53 within the same cell. The wildtype subgroup was found in the nucleolus, whereas the mutant protein was confined to the nucleus. The results obtained by immunofluorescence were verified by Western blot analysis and immunoprecipitation. Thus, our findings demonstrate an unusual subcellular localization pattern of p53 in prostate and bladder cancer cells which may indicate another mechanism of inactivation of p53.

Disturbed function of GABAergic interneurons in schizophrenia: relevance for medical treatment?

For decades treatment of schizophrenia was restricted to drugs, which mainly target positive symptoms by interfering with the dopaminergic neurotransmission. Since a large body of experimental and clinical data implicate that schizophrenia may primarily be a consequence of an imbalance in the glutamatergic system, specifically the networks containing GABAergic interneurons (γ-amino butyric acid), new drugs modulating glutamatergic neurotransmission are being developed. Targeting this dysfunction may follow different strategies, including application of direct or indirect NMDA (N-methyl-D-aspartate) receptor agonists or drugs modulating the function of metabotropic glutamate receptors. Meanwhile, the first substances have proven to be effective in animal models of schizophrenia and now enter the stage of clinical trials. The most promising data have been obtained in studies employing agonists of the metabotropic glutamate receptor. A choice of these substances is presented in this review.

Systems biology and complex neurobehavioral traits.

There is evidence for a strong genetic component in the etiology of schizophrenia, as demonstrated by family, twin and adoption studies suggesting a heritability of about 80%. There are several approaches in the search for genetic risk factors such as linkage or association studies. Additionally, much effort was done in refining the phenotype including neuropsychology, neurophysiology, imaging or the generation of animal models. Genes becoming associated with schizophrenia have to be tested for functionality including e.g. metabolomics, transcriptomics, proteomics, generation of transgenic mice, analysis of protein-protein interactions, allele-specific RNA expression analysis, analysis of neuronal and stem cell cultures, as well as post mortem studies and behavioral studies in rodents. This amount of data requires complex data analysis. A system's perspective can help in the analysis of the structural and functional complexity of the brain. New tools will be needed for a more complex and systemic view. The systems biology approach could be a pivotal tool in understanding of complex behavior and diseases in future.

When cells become depressed: focus on neural stem cells in novel treatment strategies against depression.

Clinical neuroscience enters a new era in understanding the pathophysiology of depressive illness and the mode of action of antidepressant therapy. While elucidation of factors that lead to depression is still in its infancy, biochemical malfunctions appear to have well defined morphological correlations, especially in the hippocampus. Hippocampus is one of the main sites in the brain habouring neural stem cells. Cytokines and neurotrophic factors like brain-derived neurotrophic factor (BDNF) play a pivotal role in neural plasticity and potentially influence growth and migration of these progenitors. Not surprisingly, antidepressant drugs interfering with neurotransmitters such as serotonin (5-HT) influence neurotrophins like BDNF, since 5-HT homeostasis is essential for brain development, neurogenesis, and neuroplasticity as well as complex behavior. In this review, the new area of neural stem cell research and the avenues of ongoing and future research sustaining the development of novel treatments for depression will be explored.

Association analysis of the functional monoamine oxidase A gene promotor polymorphism in migraine.

Migraine affects about 15% of the adult population. Serotonergic and dopaminergic systems are believed to be involved in its pathophysiology. One of the key enzymes in the degradation of serotonin and to a lesser extent of dopamine is monoamine oxidase A (MAO-A). In this study we investigated a functionally relevant gene-linked polymorphic repetitive sequence (LPR) located approximately 1.2 kb upstream of the ATG codon in the MAO-A-promotor gene. 119 patients with migraine and 229 controls were tested. The allelic distribution of the controls and the migraine patients did not show significant differences with respect to the low- and high-activity alleles. Moreover, effectiveness of the potent serotonergic antimigraine agents, triptans, which are metabolized by MAO-A, was clinically not affected by the MAO-A-LPR in our patients. These findings thus indicate that there is no association between the functional MAO-A-LPR and susceptibility to migraine.

Quantitation of 5HT3 receptors in forebrain of serotonin transporter deficient mice.

Mice deficient in the serotonin transporter (5HTT) display highly elevated extracellular 5HT levels. 5HT exerts ist effects via at least fourteen different cloned 5HT receptors located pre- and postsynaptically. In contrast to the other 5HT receptors, the 5HT3 receptor is a ionotropic receptor with ligand-gated cation channel function. Since G-protein-coupled 5HT receptors show extensive adaptive changes in 5HTT-deficient mice, we investigated whether 5HT3 receptors are also altered in these mice. Using quantitative autoradiography, we found that 5HT3 receptors are upregulated in frontal cortex (+46%), parietal cortex (+42%), and in stratum oriens of the CA3 region of the hippocampus (+18%) of 5HTT knockout mice. Changes in 5HT3 receptor mRNA expression, as determined by quantitative in situ hybridisation, were less pronounced. The adaptive changes of 5HT3 receptor expression constitute a part of the complex regulatory pattern of 5HT receptors in 5HTT knockout mice.

Increased hippocampal DNA oxidation in serotonin transporter deficient mice.

The serotonin transporter (5HTT) is the molecule responsible for the high-affinity reuptake of 5HT from the synaptic cleft. Mice lacking the 5HTT exhibit highly elevated extracellular concentrations of 5HT. We assessed whether the glutathione detoxification system is altered in 5HTT-deficient mice. While levels of reduced and oxidized glutathione were unchanged, glutathione metabolising enzymes showed a differential pattern of modulation. Glutathione peroxidase was reduced in frontal cortex, brainstem, and cerebellum of 5HTT-deficient mice, though not to a statistically significant extent, while a putative isoform of the detoxifying enzyme glutathione-S-transferase pi was decreased in a number of brain regions, especially in brainstem. At the level of the DNA, we found an increase of oxidative DNA adducts in the hippocampus of 5HTT-deficient mice. Given the importance of the hippocampus in learning and memory, this may be the most important neurochemical consequence of the absence of the 5HTT.