Showing papers in "Dialogues in Clinical Neuroscience in 2019"

Domains of cognition and their assessment .

Abstract: Cognitive performance is typically conceptualized in terms of domains of functioning. These domains are hierarchical in nature, with the bottom referring to more basic sensory and perceptual processes and the top referring to elements of executive functioning and cognitive control. Domains are not independent of each other and executive functioning exerts control over the utilization of more basic processes. Assessments are typically targeted at subdomains of each ability area and careful combination of tasks can reveal patterns of performance consistent with a variety of different neurological and neuropsychiatric conditions. This review covers the general structures of domains, the patterns of impairments across domains seen in common neuropsychiatric conditions, and use of assessment strategies to differentiate, to the extent possible, between different types of conditions manifesting cognitive impairment. .

Cognitive impairment in psychotic illness: prevalence, profile of impairment, developmental course, and treatment considerations .

Abstract: Despite effective pharmacological treatments for psychotic symptoms (eg, hallucinations, delusions), functional outcomes for people with psychotic disorders are often disappointing. Although it is not included in the diagnostic criteria for psychotic disorders, cognitive impairment is one of the strongest determinants of community functioning in this clinical population, and thus it is an important target for intervention. In this review, we discuss the major areas of research regarding impaired cognition in psychotic illness. The specific topics covered include: (i) the prevalence of cognitive impairment in psychotic disorders; (ii) the profile and magnitude of cognitive impairment in psychotic disorders; (iii) the developmental course of cognitive impairment; (iv) the longitudinal stability of cognitive impairment; and (v) treatment approaches to improve cognitive performance in people with psychotic disorders. .

Epigenetics and depression .

Abstract: The risk for major depression is both genetically and environmentally determined. It has been proposed that epigenetic mechanisms could mediate the lasting increases in depression risk following exposure to adverse life events and provide a mechanistic framework within which genetic and environmental factors can be integrated. Epigenetics refers to processes affecting gene expression and translation that do not involve changes in the DNA sequence and include DNA methylation (DNAm) and microRNAs (miRNAs) as well as histone modifications. Here we review evidence for a role of epigenetics in the pathogenesis of depression from studies investigating DNAm, miRNAs, and histone modifications using different tissues and various experimental designs. From these studies, a model emerges where underlying genetic and environmental risk factors, and interactions between the two, could drive aberrant epigenetic mechanisms targeting stress response pathways, neuronal plasticity, and other behaviorally relevant pathways that have been implicated in major depression. .

Unraveling the epigenetic landscape of depression: focus on early life stress .

Abstract: Depression is a devastating psychiatric disorder caused by a combination of genetic predisposition and life events, mainly exposure to stress. Early life stress (ELS) in particular is known to "scar" the brain, leading to an increased susceptibility to developing depression later in life via epigenetic mechanisms. Epigenetic processes lead to changes in gene expression that are not due to changes in DNA sequence, but achieved via modulation of chromatin modifications, DNA methylation, and noncoding RNAs. Here we review common epigenetic mechanisms including the enzymes that take part in reading, writing, and erasing specific epigenetic marks. We then describe recent developments in understanding how ELS leads to changes in the epigenome that are manifested in increased susceptibility to depression-like abnormalities in animal models. We conclude with highlighting the need for future studies that will potentially enable the utilisation of the understanding of epigenetic changes linked to ELS for the development of much-needed novel therapeutic strategies and biomarker discovery. .

Cognition and addiction .

Abstract: In this targeted review, we summarize current knowledge on substance-use disorder (SUD)-related cognitive deficits, the link between these deficits and clinical outcomes, and the cognitive training, remediation, and pharmacological approaches that have the potential to rescue cognition. We conclude that: (i) people with SUDs have moderate deficits in memory, attention, executive functions, and decision-making (including reward expectancy, valuation, and learning); (ii) deficits in higher-order executive functions and decision-making are significant predictors of relapse; (iii) cognitive training programs targeting reward-related appetitive biases, cognitive remediation strategies targeting goal-based decision-making, and pharmacotherapies targeting memory, attention, and impulsivity have potential to rescue SUD-related cognitive deficits. We suggest avenues for future research, including developing brief, clinically oriented harmonized cognitive testing suites to improve individualized prediction of treatment outcomes; computational modeling that can achieve deep phenotyping of cognitive subtypes likely to respond to different interventions; and phenotype-targeted cognitive, pharmacological, and combined interventions. We conclude with a tentative model of neuroscience-informed precision medicine. .

Psychedelic drugs-a new era in psychiatry? .

Abstract: This article covers the renaissance of classical psychedelic drugs such as psilocybin and LSD plus 3,4-methylene dioxymethamphetamine (MDMA-ecstasy) in psychiatric research. These drugs were used quite extensively before they became prohibited. This ban had little impact on recreational use, but effectively stopped research and clinical treatments, which up to that point had looked very promising in several areas of psychiatry. In the past decade a number of groups have been working to re-evaluate the utility of these substances in medicine. So far highly promising preliminary data have been produced with psilocybin in anxiety, depression, smoking, alcoholism, and with MDMA for post-traumatic stress disorder (PTSD) and alcoholism. These findings have led to the European Medicines Agency approving psilocybin for a phase 3 study in treatment-resistant depression and the Food and Drug Administration for PTSD with MDMA. Both trials should read out in 2020, and if the results are positive we are likely to see these medicines approved for clinical practice soon afterwards. .

Metacognitive and cognitive-behavioral interventions for psychosis: new developments .

Abstract: This review describes four cognitive approaches for the treatment of schizophrenia: cognitive-behavioral therapy for psychosis (CBTp), metacognitive therapy, metacognitive training, and metacognitive reflection insight therapy (MERIT). A central reference point of our review is a seminal paper by James Flavell, who introduced the term metacognition ("cognition about cognition"). In a way, every psychotherapeutic approach adopts a metacognitive perspective when therapists reflect with clients about their thoughts. Yet, the four approaches map onto different components of metacognition. CBTp conveys some "metacognitive knowledge" (eg, thoughts are not facts) but is mainly concerned with individual beliefs. Metacognitive therapy focuses on unhelpful metacognitive beliefs about thinking styles (eg, thought suppression). Metacognitive training brings distorted cognitive biases to the awareness of patients; a central goal is the reduction of overconfidence. MERIT focuses on larger senses of identity and highlights metacognitive knowledge about oneself and other persons. For CBTp and metacognitive training, meta-analytic evidence supports their efficacy; single studies speak for the effectiveness of MERIT and metacognitive therapy. .

A review of epigenetic contributions to post-traumatic stress disorder .

Abstract: Post-traumatic stress disorder (PTSD) is a syndrome which serves as a classic example of psychiatric disorders that result from the intersection of nature and nurture, or gene and environment. By definition, PTSD requires the experience of a traumatic exposure, and yet data suggest that the risk for PTSD in the aftermath of trauma also has a heritable (genetic) component. Thus, PTSD appears to require both a biological (genetic) predisposition that differentially alters how the individual responds to or recovers from trauma exposure. Epigenetics is defined as the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself, and more recently it has come to refer to direct alteration of DNA regulation, but without altering the primary sequence of DNA, or the genetic code. With regards to PTSD, epigenetics provides one way for environmental exposure to be "written" upon the genome, as a direct result of gene and environment (trauma) interactions. This review provides an overview of the main currently understood types of epigenetic regulation, including DNA methylation, histone regulation of chromatin, and noncoding RNA regulation of gene expression. Furthermore, we examine recent literature related to how these methods of epigenetic regulation may be involved in differential risk and resilience for PTSD in the aftermath of trauma. .

Physical activity for cognitive health: what advice can we give to older adults with subjective cognitive decline and mild cognitive impairment?

Abstract: Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are common conditions in older age and are associated with an increased risk of future cognitive decline and dementia. As there is currently no effective pharmacological treatment available for SCD and MCI, modifiable risk factors for cognitive decline and dementia have received increasing attention in the literature as a focus for clinical trials. Physical activity (PA) is one of the strongest protective lifestyle factors. This clinical review aims to highlight the accumulating evidence about the benefits of PA for SCD and MCI. Whilst there is agreement that at least 150 minutes of moderate aerobic PA per week in combination with additional resistance training is necessary to support brain health in people with SCD and MCI, future research is required to help inform specific advice on type of exercise, intensity, "dose" and effective strategies to encourage behavior change.

Dietary Interventions in Mild Cognitive Impairment and Dementia

Abstract: Dietary intervention is an enticing approach in the fight against cognitive impairment. Nutritional supplements and dietetic counseling are relatively easy and benign interventions, but research has not yet yielded irrefutable evidence as to their clinical utility. Heterogeneity in the results of available clinical studies, as well as methodological and practical issues, does not allow replication and generalization of findings. The paper at hand reviews only randomized clinical trials of single nutrients, multi-nutrient formulations and dietary counseling in mild cognitive impairment and dementia of the Alzheimer's type focusing on both cognitive and functional outcomes. Thus far, folate, vitamin E, Ω-3 fatty acids, and certain multi-nutrient formulations have shown some preliminary promising results; larger, well-designed trials are needed to confirm these findings before nutritional elements can be incorporated in recommended clinical guidelines.

The epigenetics of perinatal stress

Abstract: Early life adversity is associated with long-term effects on physical and mental health later in life, but the mechanisms are yet unclear. Epigenetic mechanisms program cell-type-specific gene expression during development, enabling one genome to be programmed in many ways, resulting in diverse stable profiles of gene expression in different cells and organs in the body. DNA methylation, an enzymatic covalent modification of DNA, has been one of the principal epigenetic mechanisms investigated. Emerging evidence is consistent with the idea that epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioral phenotypes. Whereas there is evidence supporting this hypothesis in animal studies, human studies have been less conclusive. A major problem is the fact that the brain is inaccessible to epigenetic studies in humans and the relevance of DNA methylation in peripheral tissues to behavioral phenotypes has been questioned. In addition, human studies are usually confounded with genetic and environmental heterogeneity and it is very difficult to derive causality. The idea that epigenetic mechanisms mediate the life-long effects of perinatal adversity has attractive potential implications for early detection, prevention, and intervention in mental health disorders will be discussed. .

Epigenetics as a key link between psychosocial stress and aging: concepts, evidence, mechanisms .

Abstract: Psychosocial stress-especially when chronic, excessive, or occurring early in life-has been associated with accelerated aging and increased disease risk. With rapid aging of the world population, the need to elucidate the underlying mechanisms is pressing, now more so than ever. Among molecular mechanisms linking stress and aging, the present article reviews evidence on the role of epigenetics, biochemical processes that can be set into motion by stressors and in turn influence genomic function and complex phenotypes, including aging-related outcomes. The article further provides a conceptual mechanistic framework on how stress may drive epigenetic changes at susceptible genomic sites, thereby exerting systems-level effects on the aging epigenome while also regulating the expression of molecules implicated in aging-related processes. This emerging evidence, together with work examining related biological processes, begins to shed light on the epigenetic and, more broadly, molecular underpinnings of the long-hypothesized connection between stress and aging. .

Antidiabetic therapies and Alzheimer disease.

Abstract: Given current lack of therapies for dementia, there is substantial interest in identifying potentially modifiable risk factors. Clarifying the potential of these factors to mitigate risk as well as determining the mechanisms that link these factors to dementia is expected to lead to new approaches for both preventing and treating neurodegenerative diseases such as Alzheimer disease. Modifiable factors include cardiovascular risks as well as related lifestyle-centric factors such as diet and physical activity (reviewed in this issue). Given reports that type 2 diabetes and associated features increase the risk for developing dementia, there has been tremendous interest in exploring whether use of antidiabetic medications may impact the risk of dementia, as well as whether antidiabetic medications could be used to prevent or treat dementia, particularly Alzheimer disease. This review will briefly cover the known links between diabetes and risk for dementia, the state of evidence linking antidiabetic treatments with either protection against dementia or possibly increased risk for cognitive dysfunction, and provide a brief overview of what has been learned from clinical trials testing antidiabetic treatments in Alzheimer disease.

Transcriptional mechanisms of drug addiction .

Abstract: Drugs of abuse can modify gene expression in brain reward and motivation centers, which contribute to the structural and functional remodeling of these circuits that impacts the emergence of a state of addiction. Our understanding of how addictive drugs induce transcriptomic plasticity in addiction-relevant brain regions, particularly in the striatum, has increased dramatically in recent years. Intracellular signaling machineries, transcription factors, chromatin modifications, and regulatory noncoding RNAs have all been implicated in the mechanisms through which addictive drugs act in the brain. Here, we briefly summarize some of the molecular mechanisms through which drugs of abuse can exert their transcriptional effects in the brain region, with an emphasis on the role for microRNAs in this process. .

Ethical issues in early diagnosis and prevention of Alzheimer disease.

Abstract: This paper considers ethical issues related to early diagnosis and all forms of prevention of Alzheimer disease and related conditions. It offers a critical view of the current state of scientific, clinical, and social responses to the growing number of older people with cognitive challenges, and suggests how priorities going forward should be different from those receiving most attention today. We begin with a review of global policy efforts, consider the fundamental goals of prevention, examine issues surrounding early diagnosis, explore more deeply values associated with efforts to prevent age associated cognitive decline, and conclude by considering often unexplored ethical issues that contextualize the field and should influence our approaches to the future.

Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer's disease .

Abstract: Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs. .

Effects of computer gaming on cognition, brain structure, and function: a critical reflection on existing literature

Abstract: Video gaming as a popular form of leisure activity and its effect on cognition, brain function, and structure has come into focus in the field of neuroscience. Visuospatial cognition and attention seem to benefit the most, whereas for executive functions, memory, and general cognition, the results are contradictory. The particular characteristics of video games driving these effects remain poorly understood. We critically discuss major challenges for the existing research, namely, the lack of precise definitions of video gaming, the lack of distinct choice of cognitive ability under study, and the lack of standardized study protocols. Less research exists on neural changes in addition to cognitive changes due to video gaming. Existing studies reveal evidence for the involvement of similar brain regions in functional and structural changes. There seems to be a predominance in the hippocampal, prefrontal, and parietal brain regions; however, studies differ immensely, which makes a meta-analytic interpretation vulnerable. We conclude that theoretical work is urgently needed. .

Pharmacological treatment of cognitive deficits in nondementing mental health disorders .

Abstract: Evidence for pharmacological remediation of cognitive deficits in three major psychiatric disorders-attention deficit- hyperactivity disorder (ADHD), schizophrenia, and depression-is reviewed. ADHD is effectively treated with the stimulant medications methylphenidate and d-amphetamine, as well as nonstimulants such as atomoxetine, implicating cognitive enhancing effects mediated by noradrenaline and dopamine. However, the precise mechanisms underlying these effects remains unclear. Cognitive deficits in schizophrenia are less effectively treated, but attempts via a variety of neurotransmitter strategies are surveyed. The possibility of treating cognitive deficits in depression via antidepressant medication (eg, selective serotonin reuptake inhibitors) and by adjunctive drug treatment has only recently received attention because of confounding, or possibly interactive, effects on mood. Prospects for future advances in this important area may need to take into account transdiagnostic perspectives on cognition (including neurodegenerative diseases) as well as improvements in neuropsychological, neurobiological, and clinical trial design approaches to cognitive enhancement. .

Assessing behavior and cognition in rodents, nonhuman primates, and humans: where are the limits of translation? .

Abstract: New psychopharmacological treatments are needed for affective and nonaffective psychoses, especially for the associated negative and cognitive symptoms. Earlier developments mostly failed, probably partly because of limitations in behavioral models used for validation. Now, deeper understanding of the genetics underlying disease pathogenesis and progress in genetic engineering will generate many rodent models with increased construct validity. To improve these models' translational value, we need complementary data from nonhuman primates. We also have to improve and streamline behavioral test systems to cope with increased demand. Here, we propose a comprehensive neurocognitive test battery that should overcome the disadvantages of single tests and yield cognitive/behavioral profiles for modeling subsets of patient symptoms. Further, we delineate a concept for classifying disease-relevant cognitive endophenotypes to balance between face and construct validity and clinical diagnostics. In summary, this review discusses new concepts and the limitations and future potential of translational research on cognition in psychiatry. .

Dementia prevention and reserve against neurodegenerative disease.

Abstract: Similar to other complex disorders, the etiology of Alzheimer disease is multifactorial and characterized by an interplay of biological and environmental risk and protective factors. Potentially modifiable risk factors have emerged from epidemiological research and strategies to prevent neurodegeneration and dementia are currently being tested, including multimodal interventions aiming to reduce several risk factors at once. The concept of reserve was developed based on the observation that certain individual characteristics, such as life experiences, lifestyles, and neurobiological parameters, are associated with a higher resilience against neurodegeneration and its symptoms. Coordinated research is required to maximize the use of available human and financial resources to better understand the underlying neurobiological mechanisms of reserve and to translate research findings into effective public health interventions.

Potential immunotherapy for Alzheimer disease and age-related dementia.

Abstract: Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

Dementia treatment versus prevention.

Abstract: Alzheimer disease (AD) and dementia are becoming increasingly prevalent due to the aging of the global populations. Currently available treatment options, including acetylcholinesterase inhibitors and memantine, only have symptomatic effects and no drugs with disease-modifying properties are available. Research on the amyloid cascade indicates that amyloid-β (Aβ) clearance from the brain may be the main pathophysiological change in late-onset AD and the key driver of neurodegeneration, which ultimately results in progressive cognitive deterioration and dementia. Most new AD drug candidates target different aspects of Aβ clearance, eg, using passive anti-Aβ immunization, but so far, all efforts to develop more effective drugs have failed. In parallel, nonpharmacological prevention trials are being conducted to modify dementia risk associated with known epidemiological risk factors. Some initial results are promising, but replication across independent cohorts remains a challenge.

The synaptic pathology of cognitive life

Abstract: Prospective, community-based studies allow evaluation of associations between cognitive functioning and synaptic measures, controlled for age-related pathologies. Findings from >400 community-based participants are reviewed. Levels of two presynaptic proteins, complexin-I (inhibitory terminals), and complexin-II (excitatory terminals) contributed to cognitive variation from normal to dementia. Adding the amount of protein-protein interaction between two others, synaptosome-associated protein-25 and syntaxin, explained 6% of overall variance. The presynaptic protein Munc18-1 long variant was localized to inhibitory terminals, and like complexin-I, was positively associated with cognition. Associations depended on Braak stage, with the level of complexin-I contributing nearly 15% to cognitive variation in stages 0-II, while complexin-II contributed 7% in stages V-VI. Non-denaturing gels identified multiple soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein-protein (SNARE) complexes in frontal and in temporal lobes, making specific contributions to cognitive functions. Multiple mechanisms of presynaptic plasticity contribute to cognitive function during aging. .

How evolutionary psychiatry can advance psychopharmacology .

Abstract: The prevailing paradigm for psychopharmacology focuses on understanding brain mechanisms as the key to finding new medications and improving clinical outcomes, but frustration with slow progress has inspired many pleas for new approaches. Evolutionary psychiatry brings in an additional basic science that poses new questions about why natural selection left us vulnerable to so many mental disorders, and new insights about how drugs work. The integration of neuroscience with evolutionary psychiatry is synergistic, going beyond reductionism to provide a model like the one used by the rest of medicine. It recognizes negative emotions as symptoms, that are, like pain and cough, useful defenses whose presence should initiate a search for causes. An integrative evolutionary approach explains why agents that block useful aversive responses are usually safe, and how to anticipate when they may cause harm. More generally, an evolutionary framework suggests novel practical strategies for finding and testing new drugs. .

Drug discovery in psychopharmacology: from 2D models to cerebral organoids .

Abstract: Psychiatric disorders are a heterogeneous group of mental illnesses associated with a high social and economic burden on patients and society. The complex symptomatology of these disorders, coupled with our limited understanding of the structural and functional abnormalities affecting the brains of neuropsychiatric patients, has made it difficult to develop effective medical treatment strategies. With the advent of reprogramming technologies and recent developments in induced pluripotent stem (iPS) cell-based protocols for differentiation into defined neuronal cultures and 3-dimensional cerebral organoids, a new era of preclinical disease modeling has begun which could revolutionize drug discovery in psychiatry. This review provides an overview of iPS cell-based disease models in psychiatry and how these models contribute to our understanding of pharmacological drug action. We also propose a refined iPSC-based drug discovery pipeline, ranging from cell-based stratification of patients through improved screening and validation steps to more precise psychopharmacology. .

Dysfunctional neurocognition in individuals with clinically significant psychopathic traits .

Abstract: The main goal of this review is to consider the main forms of dysfunctional neurocognition seen in individuals with clinically significant psychopathic traits (ie, reduced guilt/empathy and increased impulsive/antisocial behavior). A secondary goal is to examine the extent to which these forms of dysfunction are seen in both adults with psychopathic traits and adolescents with clinically significant antisocial behavior that may also involve callous-unemotional traits (reduced guilt/empathy). The two main forms of neurocognition considered are emotional responding (to distress/pain cues and emotional stimuli more generally) and reward-related processing. Highly related forms of neurocognition, the response to drug cues and moral judgments, are also discussed. It is concluded that dysfunction in emotional responsiveness and moral judgments confers risk for aggression across adolescence and into adulthood. However, reduced reward-related processing, including to drug cues, is only consistently found in adolescents with clinically significant antisocial behavior, not adults with psychopathy. .

Genomics and the future of psychopharmacology: MicroRNAs offer novel therapeutics .

Abstract: MicroRNAs (miRNAs) are short, noncoding RNAs functioning as regulators of the transcription of protein-coding genes in eukaryotes. During the last two decades, studies on miRNAs indicate that they have potential as diagnostic and prognostic biomarkers for a wide range of cancers. Research interest in miRNAs has moved to embrace further medical disciplines, including neuropsychiatric disorders, comparing miRNA expression and mRNA targets between patient and control blood samples and postmortem brain tissues, as well as in animal models of neuropsychiatric disorders. This manuscript reviews recent findings on miRNAs implicated in the pathology of mood disorders, schizophrenia, and autism, as well as their diagnostic potential, and their potential as tentative targets for future therapeutics. The plausible contribution of X chromosome miRNAs to the larger prevalence of major depression among women is also evaluated. .

Use of the epigenetic toolbox to contextualize common variants associated with schizophrenia risk .

Abstract: Schizophrenia is a debilitating psychiatric disorder with a complex genetic architecture and limited understanding of its neuropathology, reflected by the lack of diagnostic measures and effective pharmacological treatments. Geneticists have recently identified more than 145 risk loci comprising hundreds of common variants of small effect sizes, most of which lie in noncoding genomic regions. This review will discuss how the epigenetic toolbox can be applied to contextualize genetic findings in schizophrenia. Progress in next-generation sequencing, along with increasing methodological complexity, has led to the compilation of genome-wide maps of DNA methylation, histone modifications, RNA expression, and more. Integration of chromatin conformation datasets is one of the latest efforts in deciphering schizophrenia risk, allowing the identification of genes in contact with regulatory variants across 100s of kilobases. Large-scale multiomics studies will facilitate the prioritization of putative causal risk variants and gene networks that contribute to schizophrenia etiology, informing clinical diagnostics and treatment downstream. .

Nonpharmacological treatment of dyscognition in schizophrenia: effects of aerobic exercise .

Abstract: Cognitive symptoms are a core feature of schizophrenia and are related to an unfavorable disease outcome. So far, there are no satisfactory pharmacological approaches to address cognitive symptoms. For some time now, aerobic exercise has been demonstrated in various trials to be a promising candidate for this indication. The aim of this brief qualitative review was to present the most recent meta-analyses regarding the capacity of exercise to improve cognition in schizophrenia patients. Additionally, we give a short overview of the effects in other conditions, like healthy subjects and patients with major depression. We conducted a focused literature search using the PubMed database, concentrating on meta-analyses which are based on a systematic search. The most recent meta-analysis investigating the efficacy of aerobic exercise on cognitive impairments in schizophrenia patients provides evidence that exercise has positive effects on cognitive functioning in this population. However, the effect seems not to be specific; there were positive findings regarding healthy subjects and patients with depressive disorders as well, even if they were less consistent. As most available trials have a small to modest sample size and have no consensus with regard to the intervention regime, nor to the assessment of cognition, the findings are difficult to generalize. In the future, standardized clinical trials focusing on the long-term effects of exercise are needed to evaluate whether the improvements in cognition are sustainable.

What are we trying to prevent in Alzheimer disease

Abstract: Within aging societies, the number of individuals suffering from Alzheimer disease (AD) is constistently increasing. This is paralleled by intense research aimed at improving treatment options and potentially even fostering effective prevention. The discussion on relevant outcomes of such interventions is ongoing. Here, different types of currently applied outcomes in the treatment of AD at the dementia stage, but also at the pre-dementia stages of mild cognitive impairment (MCI) and asymptomatic preclinical AD are discussed. Regulatory agencies require effects on the clinical measures of cognition and function. In novel disease-modifying therapy trials, biological markers are used as secondary and exploratory outcomes. Additional outcomes of great relevance for the individual patients are neuropsychiatric symptoms, quality of life, and goal attainment. In addition, costs and cost-benefit ratios are of interest for the reimbursement of interventions.