A feasibility study of a participatory designed program for preventing cardiovascular disease in mentally vulnerable patients.

AIM: To test the feasibility of a participatory design intervention aimed at reducing the risk of cardio-vascular disease among patients suffering from alcohol use disorder (AUD) or severe mental illness (SMI). METHODS: The intervention was developed by patients from the Community Mental Health Center and the Alcohol Treatment Facility in Odense, Denmark, and consisted of eight modules (health interviews, screening and treatment, introduction, diet/alcohol, physical activity, smoking, health app, and sleep problems). The intervention was tested using pre- and post-measurements of selected variables, patients' intervention attendance, and interviews and dialogue workshops at the end of the study. RESULTS: A total of 21 out of 42 eligible patients from the Alcohol Treatment Facility and two out of 443 eligible patients from the Community Mental Health Center accepted participation in the study. The two patients from the Community Mental Health Center were not included in the analyses due to General Data Protection Regulation (GDPR). All patients accepted being screened for risk factors at inclusion, and the majority enrolled in at least one of the subsequent modules. The study indicated that the patients followed recommendations from their GPs. CONCLUSIONS: There is a great need for focus on cardio-vascular disease in patients with SMI and those with AUD. Results indicate that the intervention is feasible for patients with AUD, but due to inclusion of too few patients with SMI, nothing can be concluded for this patient group. Patients and staff in the Alcohol Treatment Facility agreed that the intervention has future perspectives.

Dendritic spines and their role in the pathogenesis of neurodevelopmental and neurological disorders.

Since Cajal introduced dendritic spines in the 19th century, they have attained considerable attention, especially in neuropsychiatric and neurologic disorders. Multiple roles of dendritic spine malfunction and pathology in the progression of various diseases have been reported. Thus, it is inevitable to consider these structures as new therapeutic targets for treating neuropsychiatric and neurologic disorders such as autism spectrum disorders, schizophrenia, dementia, Down syndrome, etc. Therefore, we attempted to prepare a narrative review of the literature regarding the role of dendritic spines in the pathogenesis of aforementioned diseases and to shed new light on their pathophysiology.

Does gut brain axis has an impact on Parkinson's disease (PD)?

Parkinson's Disease (PD) is becoming a growing global concern by being the second most prevalent disease next to Alzheimer's Disease (AD). Henceforth new exploration is needed in search of new aspects towards the disease mechanism and origin. Evidence from recent studies has clearly stated the role of Gut Microbiota (GM) in the maintenance of the brain and as a root cause of various diseases and disorders including other neurological conditions. In the case of PD, with an unknown etiology, the GM is said to have a larger impact on the disease pathophysiology. Although GM and its metabolites are crucial for maintaining the normal physiology of the host, it is an undeniable fact that there is an influence of GM in the pathophysiology of PD. As such the Enteroendocrine Cells (EECs) in the epithelium of the intestine are one of the significant regulators of the gut-brain axis and act as a communication mediator between the gut and the brain. The communication is established via the molecules of neuroendocrine which are said to have a crucial part in neurological diseases such as AD, PD, and other psychiatry-related disorders. This review is focused on understanding the proper role of GM and EECs in PD. Here, we also focus on some of the metabolites and compounds that can interact with the PD genes causing various dysfunctions in the cell and facilitating the disease conditions using bioinformatical tools. Various mechanisms concerning EECs and PD, their identification, the latest studies, and available current therapies have also been discussed.

Diversifying autism neuroimaging research: An arterial spin labeling review.

LAY ABSTRACT: Brain function and health depend on cerebral blood flow to secure the necessary delivery of oxygen and nutrients to the brain tissue. However, cerebral blood flow appears to be altered in autistic compared to non-autistic individuals, potentially suggesting this difference to be a cause and potential identification point of autism. Recent technological development enables precise and non-invasive measurement of cerebral blood flow via the magnetic resonance imaging method referred to as arterial spin labeling. However, most neuroimaging studies still prefer using the physiologically indirect measure derived from functional magnetic resonance imaging. Therefore, this review examines the use of arterial spin labeling to further investigate the neurobiology of autism. Furthermore, the review includes a comparison of results from molecular imaging and arterial spin labeling followed by a discussion concerning the future direction and potential of arterial spin labeling. We found that arterial spin labeling study results are consistent with those of molecular imaging, especially after considering the effect of age and sex. In addition, arterial spin labeling has numerous application possibilities besides the quantification of cerebral blood flow. Therefore, we encourage researchers to explore and consider the application of arterial spin labeling for future scientific studies in the quest to better understand the neurobiology of autism.

The neural effects of oxytocin administration in autism spectrum disorders studied by fMRI: A systematic review.

PURPOSE: Oxytocin (OXT) is a hypothalamic neuropeptide that is released from the posterior pituitary gland and at specific targets in the central nervous system (CNS). The prosocial effects of OXT acting in the CNS present it as a potential therapeutic agent for the treatment of aspects of autism spectrum disorder (ASD). In this article, we systematically review the functional MRI (fMRI) literature that reports task-state and resting-state fMRI (rsfMRI) studies of the neural effects of single or multiple dose intranasal OXT (IN-OXT) administration in individuals with ASD. METHOD: We searched four databases for relevant documents (PubMed, Web of Science, Scopus, and Google Scholar) using the keywords "autism spectrum disorder", "Asperger Syndrome", "oxytocin", and "fMRI". Moreover, we made a manual search to assess the quality of our automatic search. The search was confined to English language articles published in the interval February 2013 until March 2021. RESULTS: The search yielded 12 fMRI studies with OXT intervention, including 288 individuals with ASD (age 8-55 years) enrolled in randomized, double-blind, placebo-controlled, parallel designs, within-subject-crossover experimental OXT trials. Studies reporting activation task and rsfMRI were summarized with region of interest (ROI) or whole-brain voxel wise analysis. The systematic review of the 12 studies supported the proposition that IN-OXT administration alters brain activation in individuals with ASD. The effects of IN-OXT interacted with the type of the task and the overall results did not indicate restoration of normal brain activation in ASD signature regions albeit the lack of statistical evidence. CONCLUSION: A large body of evidence consistently indicates that OXT alters activation to fMRI in brain networks of individuals with ASD, but with uncertain implications for alleviation of their social deficits.

DNA Methylation Profiles of GAD1 in Human Cerebral Organoids of Autism Indicate Disrupted Epigenetic Regulation during Early Development.

DNA methylation profiling has become a promising approach towards identifying biomarkers of neuropsychiatric disorders including autism spectrum disorder (ASD). Epigenetic markers capture genetic risk factors and diverse exogenous and endogenous factors, including environmental risk factors and complex disease pathologies. We analysed the differential methylation profile of a regulatory region of the GAD1 gene using cerebral organoids generated from induced pluripotent stem cells (iPSCs) from adults with a diagnosis of ASD and from age- and gender-matched healthy individuals. Both groups showed high levels of methylation across the majority of CpG sites within the profiled GAD1 region of interest. The ASD group exhibited a higher number of unique DNA methylation patterns compared to controls and an increased CpG-wise variance. We detected six differentially methylated CpG sites in ASD, three of which reside within a methylation-dependent transcription factor binding site. In ASD, GAD1 is subject to differential methylation patterns that may not only influence its expression, but may also indicate variable epigenetic regulation among cells.

Proteomic phenotype of cerebral organoids derived from autism spectrum disorder patients reveal disrupted energy metabolism, cellular components, and biological processes.

The way in which brain morphology and proteome are remodeled during embryonal development, and how they are linked to the cellular metabolism, could be a key for elucidating the pathological mechanisms of certain neurodevelopmental disorders. Cerebral organoids derived from autism spectrum disorder (ASD) patients were generated to capture critical time-points in the neuronal development, and metabolism and protein expression were investigated. The early stages of development, when neurogenesis commences (day in vitro 39), appeared to be a critical timepoint in pathogenesis. In the first month of development, increased size in ASD-derived organoids were detected in comparison to the controls. The size of the organoids correlates with the number of proliferating cells (Ki-67 positive cells). A significant difference in energy metabolism and proteome phenotype was also observed in ASD organoids at this time point, specifically, prevalence of glycolysis over oxidative phosphorylation, decreased ATP production and mitochondrial respiratory chain activity, differently expressed cell adhesion proteins, cell cycle (spindle formation), cytoskeleton, and several transcription factors. Finally, ASD patients and controls derived organoids were clustered based on a differential expression of ten proteins-heat shock protein 27 (hsp27) phospho Ser 15, Pyk (FAK2), Elk-1, Rac1/cdc42, S6 ribosomal protein phospho Ser 240/Ser 244, Ha-ras, mTOR (FRAP) phospho Ser 2448, PKCα, FoxO3a, Src family phospho Tyr 416-at day 39 which could be defined as potential biomarkers and further investigated for potential drug development.

Superoxide dismutase isozymes in cerebral organoids from autism spectrum disorder patients.

Autism spectrum disorder is a pervasive neurodevelopmental disorder with a substantial contribution to the global disease burden. Despite intensive research efforts, the aetiopathogenesis remains unclear. The Janus-faced antioxidant enzymes superoxide dismutase 1-3 have been implicated in initiating oxidative stress and as such may constitute a potential therapeutic target. However, no measurement has been taken in human autistic brain samples. The aim of this study is to measure superoxide dismutase 1-3 in autistic cerebral organoids as an in vitro model of human foetal neurodevelopment. Whole brain organoids were created from induced pluripotent stem cells from healthy individuals (n = 5) and individuals suffering from autism (n = 4). Using Pierce bicinchoninic acid and enzyme-linked immunosorbent assays, the protein and superoxide dismutase 1, 2, and 3 concentrations were quantified in the cerebral organoids at days 22, 32, and 42. Measurements were normalized to the protein concentration. Results represented using medians and interquartile ranges. Using Wilcoxon matched-pairs signed-rank test, an abrupt rise in the superoxide dismutase concentration was observed at day 32 and onwards. Using Wilcoxon rank-sum test, no differences were observed between healthy (SOD1: 35.56 ng/mL ± 3.46; SOD2: 2435.80 ng/mL ± 1327.00; SOD3: 1854.88 ng/mL ± 867.94) and autistic (SOD1: 32.85 ng/mL ± 5.26; SOD2: 2717.80 ng/mL ± 1889.10; SOD3: 1690.18 ng/mL ± 615.49) organoids. Cerebral organoids recapitulate many aspects of human neurodevelopment, but the diffusion restriction may render efforts in modelling differences in oxidative stress futile due to the intrinsic hypoxia and central necrosis.

Pharmacological compounds targeting emotional cognition in alcohol use disorder: A systematic review.

Non-emotional (e.g., executive functions) and emotional cognitive (e.g., facial emotion recognition) impairments are a well-known aspect of alcohol use disorder (AUD). These deficits may impede on treatment outcomes, increase the risk of relapse, and lead to socio-occupational disabilities. Previous systematic reviews have examined the effectiveness of cognitive enhancing pharmacological agents (CEPAs) targeting non-emotional, but not emotional, cognition in AUD. Our aim was to systematically review the effectiveness of CEPAs targeting emotional cognition in subclinical and clinical AUD populations. A qualitative synthesis of controlled trials was conducted, and the studies were assessed for risk of bias. Eight studies were eligible (15 ≤ ns ≤ 143), and they all had a moderate risk of bias. Modafinil and nalmefene were the most examined agents, with the findings suggesting a potential beneficial effect of the agents on implicit emotional domains (i.e., reward processing). Methodological shortcomings and heterogeneous findings across the studies do not allow inferences about the effectiveness of these compounds in AUD. Future studies should examine CEPAs targeting emotional cognition in more detail.

The role of multimodal MRI in mild cognitive impairment and Alzheimer's disease.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a prodromal stage of Alzheimer's disease (AD), where neurodegeneration is not as considerable, thereby potentially increasing the effect of treatments. Therefore, highly sensitive and specific classification of subjects with MCI is necessary, where various MRI modalities have displayed promise. METHODS: Structural, diffusion, and resting-state (RS) functional MRI analyses were performed on the AD (n = 26), MCI (n = 5), and healthy control (HC) (n = 14) group. Structural analysis was performed via voxel-based morphometry (VBM) and volumetric subcortical segmentation analysis. Fractional anisotropy and mean diffusivity were estimated during the diffusion analysis. RS analysis investigated seed-based functional connectivity. Classification via support vector machine was performed to evaluate which MRI modality most accurately differentiated the groups. Multiple linear regression was conducted to evaluate the MRI modalities correlation with clinical assessment scores. RESULTS: Classification of MCI and HC displayed highest accuracy based on diffusion MRI, which besides demonstrated high correlation with clinical scores. Classification was equally accurate in AD, when using VBM or diffusion tensor imaging measures. Yet, more variance was explained by VBM measures in the clinical assessment scores of the AD group. CONCLUSIONS: This study highlights the potential of diffusion MRI in differentiating MCI from HC and AD. However, the results need to be interpreted with caution as sample size and artifacts in the MRI data probably influenced the results.

Oxidative Stress in Adults with Autism Spectrum Disorder: A Case Control Study.

Oxidative stress has been proposed as being important in the pathophysiology of autism spectrum disorders (ASD), and heightened levels of oxidative stress has found in children with ASD. Our aim was to investigate, whether this change is temporary or persist into adulthood. We included 89 adult patients with ASD and sex and age matched controls. Plasma levels of antioxidants superoxide dismutase 1 (SOD1) and superoxide dismutase 2 (SOD2) and pro-oxidant xanthine oxidase (XO) were measured. Individuals with ASD had higher levels of SOD1, which furthermore correlated with autism severity as measured by autism quotient-score. We found no difference regarding SOD2 and XO between ASD group and controls. However, SOD1 and SOD2 were elevated in males compared to females.

Brain+ AlcoRecover: A Randomized Controlled Pilot-Study and Feasibility Study of Multiple-Domain Cognitive Training Using a Serious Gaming App for Treating Alcohol Use Disorders.

Background: Patients with alcohol use disorder (AUD) exhibit deficits in various cognitive domains, including executive functioning, working memory, and learning and memory, which impede the effectiveness of conventional AUD treatment and enhance relapse. Mobile health (mHealth) services are promising in terms of delivering cognitive training in gamified versions. So far, studies examining the effects of mHealth-based cognitive training in AUD patients have, however, focused on specific rather than multiple cognitive domains and overlooked the importance of clinical outcomes. Furthermore, research has yet to investigate the acceptability and feasibility of this type of cognitive training. Aims: The aims of this pilot study are to examine (1) whether using smartphone-based, multi-domain cognitive training with gamified elements as part of conventional treatment for AUD indicate effect, and (2) whether the intervention is acceptable and feasible as a part of conventional treatment for AUD. Methods: Patients from the alcohol outpatient clinic, Odense Municipality, Denmark will be invited to participate in the study on a consecutive basis until a total of 60 patients have been recruited. The study will be performed as a combined parallel randomized controlled trial (RCT) and qualitative feasibility study. The patients will be randomly assigned to one of two groups. The intervention group (n = 30) will receive smartphone-based, multi-domain cognitive training with gamified elements together with treatment as usual (TAU). The active control group (n = 30) will receive a sham version of the same cognitive training together with TAU. Cognitive outcomes will be assessed via the training application at baseline and post-treatment. Clinical outcomes will be assessed at baseline, post-treatment, and at 6-month follow-up using the Addiction Severity Index. Furthermore, the 30 patients randomized to the intervention group will be invited to participate in the second phase, that is the feasibility study, at post-treatment. A questionnaire inquiring about the use of mHealth treatment in general will be administered. Further, feedback regarding functionality and meaningfulness of the application in addition to other qualitative aspects relating to the use of the application will be collected. The patients will also be asked to provide suggestions about how to improve and potentially implement the tool. Implications: It is anticipated that this pilot study will provide tentative evidence for the effectiveness of smartphone-based, multi-domain cognitive training as well as information about the usability and feasibility of this type of training, including acceptability and compliance. The study will also contribute with feedback derived from the patients about how to improve and implement the tool. If promising, the findings will be used to plan a large-scale RCT. Since cognitive deficits are not addressed in current treatments for AUD, gamified cognitive training delivered through smartphones may increase the effectiveness of current treatment for AUD as well as introduce more mHealth-based treatment that is both accessible and cost-effective.

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins.

Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like APOBEC3G, H6PD, SLC45A1, GRIN3B, and PDE4D were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the SLC45A1 gene, which was upregulated with increasing cognitive function. Linear models found only H6PD and SLC45A1, the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which CTCF and REST were activated and SP3, SRF, and XBP1 were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.

Differential lncRNA expression profiling of cognitive function in middle and old aged monozygotic twins using generalized association analysis.

Cognitive impairment is the most prominent symptom in neurodegenerative disorders affecting quality of life and mortality. However, despite years of research, the molecular mechanism underlying the regulation of cognitive function and its impairment is poorly understood. This study aims to elucidate the role of long non-coding RNAs (lncRNAs) expression and lncRNA-mRNA interaction networks, by analyzing lncRNA expression in whole blood samples of 400 middle and old aged monozygotic twins in association with cognitive function using both linear models and a generalized correlation coefficient (GCC) to capture the diverse patterns of correlation. We detected 13 probes (p < 1e-03) displaying nonlinear and 7 probes (p < 1e-03) showing linear correlations. After combining the results, we identified 20 lncRNA probes with p < 1e-03. The top lncRNA probes were annotated to genes, along with the non-coding MALAT1, that play roles in neurodegenerative diseases. The top lncRNAs were linked to functional clusters including peptidyl-glycine modification, vascular smooth muscle cells, mitotic spindle organization and protein tyrosine phosphatase. In addition, mapping of the top significant lncRNAs to the lncRNA-mRNA interaction network detected significantly enriched biological pathways involving neuroactive ligand-receptor interaction, proteasome and chemokines. We show that GCC served as a complementary approach in detecting lncRNAs missed by the conventional linear models. A combination of GCC and linear models identified lncRNAs of diverse patterns of association enriched for GO biological and molecular functions meaningful in cognitive performance and cognitive decline. The novel lncRNA regulatory network further contributed to detect significant pathways implicated in cognition.

Pharmacological enhancing agents targeting cognition in patients with alcohol-induced neurocognitive disorders: A systematic review.

Debilitating neurocognitive deficits are seen in alcohol use disorders (AUD) and Wernicke-Korsakoff's syndrome (WKS). These shared characteristics suggest a spectrum of alcohol-induced neurocognitive disorders (AIND). Cognitive pharmacological enhancing agents (CPEA) have been examined in the treatment of other psychiatric disorders, but little is known about the effects of these agents on AINDs. Our aim was to synthesize the evidence for the effectiveness of CPEAs on AINDs. Databases were searched for controlled trials examining CPEAs on AUD, WKS, and alcohol-related dementia (ARD). Eligible studies were included in a qualitative synthesis and a quality assessment was conducted. The search identified 23 studies (4 ≤ ns ≤ 98). Evidence suggests that modafinil may improve executive functions in AUD and ARD, but this effect may only be present in patients with severe deficits. The studies were rated as having a moderate risk of bias. Despite the promising effects of modafinil, small samples and inconsistent evidence deem the results preliminary. More research is warranted examining the effects of transdiagnostic CPEAs on deficits across AINDs.

Establishment of an induced pluripotent stem (iPS) cell line (SDUKIi006-A) from a 21-year old male patient diagnosed with atypical autism disorder.

Autism is a complex neuropsychiatric disorder defined by significant challenges in communication skills and social behavior as well as repetitive conduct and interests. Recent advances in stem cell technologies allow in vitro modeling of the underlying molecular disease mechanisms. Using integration-free episomal plasmids, we have generated a novel iPS cell line (SDUKIi006-A) from a patient diagnosed with atypical autism ("FYNEN cohort" of Southern Denmark). Characterization of the established cell line validated its expression of pluripotency markers, differentiation into the three germ layers, and the absence of chromosomal abnormalities.

Generation of autism spectrum disorder patient-derived iPSC line SDUKIi004-A.

Autism is a heterogeneous neurodevelopmental disorder defined by deficits in socialization, communication, and patterns of behavior. Using stem cells to model brain disordersmay yield new understanding about the underlying neuropathological processes and could prove essential for drug development. We present here a newhuman inducedpluripotentstem cell (iPSC) line (SDUKIi004-A) generated from skin fibroblasts derived from a 21-year old male patient diagnosed with Pervasive DevelopmentalDisorder-Not Otherwise Specified (PDD-NOS)("FYNEN-cohort"). Reprogramming of the fibroblasts was accomplished using integration-free episomal plasmids. Characterization validated the expression of pluripotency markers, differentiation into the three germ layers, and absence of chromosomal abnormalities.

Multiple Sclerosis Atlas: A Molecular Map of Brain Lesion Stages in Progressive Multiple Sclerosis.

Introduction: Multiple sclerosis (MS) is a chronic disorder of the central nervous system with an untreatable late progressive phase. Molecular maps of different stages of brain lesion evolution in patients with progressive multiple sclerosis (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. Materials and Methods: The MS Atlas database comprises comprehensive high-quality transcriptomic profiles of 98 white matter (WM) brain samples of different lesion types (normal-appearing WM [NAWM], active, chronic active, inactive, remyelinating) from ten progressive MS patients and 25 WM areas from five non-neurological diseased cases. Results: We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate on a lesion basis. The MS Atlas gives means for testing research hypotheses, validating biomarkers and drug targets. It comes with a user-friendly web interface, and it fosters bioinformatic methods for de novo network enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures and demonstrate the interface of MS Atlas. Conclusion: This compendium of mechanistic PMS WM lesion profiles is an invaluable resource to fuel future MS research and a new basis for treatment development.