A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial)

Background

There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.

Methods and Findings

Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.

Conclusions

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).     

Inhibition of hyaluronan export attenuates cell migration and metastasis of human melanoma

When secreted from malignant cells, hyaluronan facilitates tumor invasion and metastasis, as inhibition of its export by zaprinast inhibited metastasis formation in mice. However, the precise steps of the metastatic cascade, which were influenced by zaprinast, have not been identified as yet. Here we analyzed the cell biological effects of the inhibitor on three human melanoma cell lines that differed in their hyaluronan production and their metastatic capability when xenografted into SCID mice. We measured the influence of zaprinast on cellular hyaluronan export, surface coat formation, proliferation, random migration, colony formation in soft agar, adhesion, and transepithelial resistance. Concentrations of zaprinast not affecting cell proliferation, adhesion and transepithelial resistance, nevertheless reduced hyaluronan export by 50%, surface coat formation, random migration, and colony formation in soft agar. These results indicate that hyaluronan enhances metastasis formation primarily in those steps of the metastatic cascade, which involves tumor cell migration.     

Impaired daily glucocorticoid rhythm in Per1 Brd mice

Biological clocks have evolved in all kinds of organisms in order to anticipate and adjust to the daily light–dark cycle. Within the last decade, the molecular machinery underlying the circadian system was unraveled. In the present study, the impact of the loss of the Per1 or Per2 genes, key components of the core clock oscillator, on body mass, food and water intake, glucose metabolism, and hypothalamic-pituitary-adrenal axis, was investigated in the Per1 ^Brd and Per2 ^Brd mouse models. The results reveal that the lack of Per1 but not Per2 has severe consequences for the regulation of these parameters. Specifically, in Per1 ^Brd animals, we found an impaired daily glucocorticoid rhythm, with markedly elevated levels during the day compared to control animals. In addition, Per1 ^Brd mice showed significant differences in body mass as well as food and water intake. Although the Per1 ^Brd are lighter than wildtype mice, food and water intake per gram body mass is elevated. In addition, the Per1 ^Brd mice exhibit an increased glucose metabolism after i.p. injection with glucose. In conclusion, our study presents first evidence for a link between an altered metabolism in Per1 and Per2 deficient mice, which in the case of the Per1 ^Brd animals might be due to an impaired corticosterone rhythm.     

High-throughput Flow Cytometry Cell-based Assay to Detect Antibodies to N-Methyl-D-aspartate Receptor or Dopamine-2 Receptor in Human Serum

Over the recent years, antibodies against surface and conformational proteins involved in neurotransmission have been detected in autoimmune CNS diseases in children and adults. These antibodies have been used to guide diagnosis and treatment. Cell-based assays have improved the detection of antibodies in patient serum. They are based on the surface expression of brain antigens on eukaryotic cells, which are then incubated with diluted patient sera followed by fluorochrome-conjugated secondary antibodies. After washing, secondary antibody binding is then analyzed by flow cytometry. Our group has developed a high-throughput flow cytometry live cell-based assay to reliably detect antibodies against specific neurotransmitter receptors. This flow cytometry method is straight forward, quantitative, efficient, and the use of a high-throughput sampler system allows for large patient cohorts to be easily assayed in a short space of time. Additionally, this cell-based assay can be easily adapted to detect antibodies to many different antigenic targets, both from the central nervous system and periphery. Discovering additional novel antibody biomarkers will enable prompt and accurate diagnosis and improve treatment of immune-mediated disorders.     

Disturbances catalyze the adaptation of forest ecosystems to changing climate conditions

The rates of anthropogenic climate change substantially exceed those at which forest ecosystems – dominated by immobile, long‐lived organisms – are able to adapt. The resulting maladaptation of forests has potentially detrimental effects on ecosystem functioning. Furthermore, as many forest‐dwelling species are highly dependent on the prevailing tree species, a delayed response of the latter to a changing climate can contribute to an extinction debt and mask climate‐induced biodiversity loss. However, climate change will likely also intensify forest disturbances. Here, we tested the hypothesis that disturbances foster the reorganization of ecosystems and catalyze the adaptation of forest composition to climate change. Our specific objectives were (i) to quantify the rate of autonomous forest adaptation to climate change, (ii) examine the role of disturbance in the adaptation process, and (iii) investigate spatial differences in climate‐induced species turnover in an unmanaged mountain forest landscape (Kalkalpen National Park, Austria). Simulations with a process‐based forest landscape model were performed for 36 unique combinations of climate and disturbance scenarios over 1000 years. We found that climate change strongly favored European beech and oak species (currently prevailing in mid‐ to low‐elevation areas), with novel species associations emerging on the landscape. Yet, it took between 357 and 706 years before the landscape attained a dynamic equilibrium with the climate system. Disturbances generally catalyzed adaptation and decreased the time needed to attain equilibrium by up to 211 years. However, while increasing disturbance frequency and severity accelerated adaptation, increasing disturbance size had the opposite effect. Spatial analyses suggest that particularly the lowest and highest elevation areas will be hotspots of future species change. We conclude that the growing maladaptation of forests to climate and the long lead times of autonomous adaptation need to be considered more explicitly in the ongoing efforts to safeguard biodiversity and ecosystem services provisioning.     

Molecular chaperones in biology and medicine at Obernai

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