Biological Mechanism-based Neurology and Psychiatry: a BACE1/2 and Downstream Pathway Model

2021 ◽  
Vol 19 ◽  
Author(s):  
Harald Hampel ◽  
Giuseppe Caruso ◽  
Robert Nisticò ◽  
Gaia Piccioni ◽  
Nicola B. Mercuri ◽  
...  

: In Oncology, comprehensive Omics and functional enrichment studies led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor’s clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in Oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields including Psychiatry and Neurology. To illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer’s disease, schizoaffective and autism spectrum disorders. We engage in a speculative intellectual exercise gravitating around the BACE-related science, here used as paradigmatic case, to facilitating a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom agnostic, categorization models in clinical Neurology and Psychiatry for precision medicine solutions. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by high-throughput techniques, embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in Neurology and Psychiatry.

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Patricia Bermudez-Martin ◽  
Jérôme A. J. Becker ◽  
Nicolas Caramello ◽  
Sebastian P. Fernandez ◽  
Renan Costa-Campos ◽  
...  

Abstract Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.


2021 ◽  
Vol 10 (2) ◽  
pp. 366
Author(s):  
Anke Hoffmann ◽  
Dietmar Spengler

Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including ‘humanized’ mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.


2021 ◽  
pp. 1-12
Author(s):  
Gregorio González-Alcaide ◽  
Mercedes Fernández-Ríos ◽  
Rosa Redolat ◽  
Emilia Serra

Background: The study of emotion recognition could be crucial for detecting alterations in certain cognitive areas or as an early sign of neurological disorders. Objective: The main objective of the study is to characterize research development on emotion recognition, identifying the intellectual structure that supports this area of knowledge, and the main lines of research attracting investigators’ interest. Methods: We identified publications on emotion recognition and dementia included in the Web of Science Core Collection, analyzing the scientific output and main disciplines involved in generating knowledge in the area. A co-citation analysis and an analysis of the bibliographic coupling between the retrieved documents elucidated the thematic orientations of the research and the reference works that constitute the foundation for development in the field. Results: A total of 345 documents, with 24,282 bibliographic references between them, were included. This is an emerging research area, attracting the interest of investigators in Neurosciences, Psychology, Clinical Neurology, and Psychiatry, among other disciplines. Four prominent topic areas were identified, linked to frontotemporal dementia, autism spectrum disorders, Alzheimer’s disease, and Parkinson’s and Huntington disease. Many recent papers focus on the detection of mild cognitive impairment. Conclusion: Impaired emotion recognition may be a key sign facilitating the diagnosis and early treatment of different neurodegenerative diseases as well as for triggering the necessary provision of social and family support, explaining the growing research interest in this area.


2021 ◽  
Vol 11 (2) ◽  
pp. 70
Author(s):  
Cristina Panisi ◽  
Franca Rosa Guerini ◽  
Provvidenza Maria Abruzzo ◽  
Federico Balzola ◽  
Pier Mario Biava ◽  
...  

The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called ‘First 1000 Days’) are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.


2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Danilo Garcia ◽  
Henrik Anckarsäter ◽  
Sebastian Lundström

Background. The acronym ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) highlights that children seeking clinical treatment are often multiply impaired, thus requiring treatment from several specialties. The aim was to map and relate, on a population level, ESSENCE to two salient predictors of health and adaptation to adversities, namely, Self-Directedness and Cooperativeness and also to dysfunction and suffering.Methods. Participants were twins(N=1892)aged 9 or 12 whose parents were interviewed with the Autism-Tics, ADHD and other Comorbidities inventory (A-TAC), and the Junior Temperament and Character Inventory (J-TCI). The A-TAC was first used to discern four ESSENCE-related screening diagnoses: autism spectrum disorders, attention deficit hyperactivity disorder, learning disabilities, and developmental coordination disorder; second, to quantify dysfunction and suffering in important social areas.Results. ESSENCE symptoms were continuously and categorically associated with deficiency in Self-Directedness and Cooperativeness and higher ratings of dysfunction and suffering. The impact of ESSENCE symptoms on these measures of mental health was found in a milder form in about 16% of all children and in a severe form in about 2%.Conclusion. Therapeutic interventions focusing on Self-Directedness and Cooperativeness might provide a novel method for child psychiatry in its approach to ESSENCE.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 559-559
Author(s):  
Nina D'Abreo ◽  
Abhinav Rohatgi ◽  
Douglas Kanter Marks ◽  
Heather Kling ◽  
Josien Haan ◽  
...  

559 Background: Lymphovascular invasion (LVI), the passage of carcinoma cells through lymphatic and blood vessels, is an important early step in metastasis; however, LVI is excluded from most breast cancer (BC) clinical risk assessments. Previous studies assessed the prognostic value of LVI to estimate clinical outcomes. To gain understanding of the molecular basis of LVI, we evaluated differentially expressed genes (DEGs) between tumors with LVI versus those without LVI, stratified by the 70-gene signature (MammaPrint/MP) and 80-gene molecular subtyping signature (BluePrint/BP). Methods: The prospective, observational FLEX Study (NCT03053193) includes stage I-III BC patients who receive MP/BP testing and consent to full transcriptome and clinical data collection. Patients with LVI (n=581) and without LVI (n=600, randomly selected), enrolled from 2017 to present, were included. LVI was assessed by local pathology laboratories. Differential gene expression analysis of 44k Agilent microarray data was performed with R limma package. DEGs were compared within all samples, BP Luminal subtype, MP risk groups (Low Risk [LR]/Luminal A and High Risk [HR]/Luminal B), and by lymph node (LN) status. DEGs with FDR<0.05 were considered significant. Results: Of tumors with LVI (LVI+), 66% were MP HR; notably, 51% of tumors without LVI (LVI-) were MP HR. LVI was associated with larger T stage, LN involvement, high grade, negative ER status by IHC, and younger patient age (LVI+ vs. LVI-, p<0.05 for all comparisons). Patient ethnicity, obesity, and tumor type did not differ by LVI status; however, prevalence of type 2 diabetes trended higher in patients with LVI+ HR tumors (21%), compared with LVI- HR (15%, p=0.09) and LVI+ LR (11%, p=0.004). There were significant transcriptomic differences between LVI+ and LVI, with most DEGs evident in the Luminal B subset. DEGs in LVI+, LN-negative (LN-) tumors overlapped substantially with the overall Luminal group analysis. Functional enrichment analysis showed dysregulation of cell cycle, extracellular matrix (ECM) organization, cell adhesion, and cytokine receptor pathways. Gene sets related to insulin growth factor pathways were also enriched in LVI+ tumors. Conclusions: DEGs associated with LVI were primarily found in MP HR Luminal, LN-negative tumors; enrichment analysis suggested dysregulation of ECM organization and cell adhesion pathways, consistent with previous reports. DEGs were not associated with LVI presence in LN+ tumors, suggesting that LVI assessment may be less relevant in LN+ breast cancer. Future studies will assess clinical outcomes, as well as LVI-associated gene expression in BP Basal- and HER2-type tumors. However, the current analysis indicates few DEGs in LVI+ MP LR tumors; thus, the potential prognostic information gained from LVI-associated gene expression is likely already captured by the MP and BP signatures. Clinical trial information: NCT03053193.


Author(s):  
Judy Joohye Lee ◽  
Laura Dryjanska

Technological advances have led to a variety of positive outcomes and benefits. This chapter aims to discuss the different kinds of therapeutic interventions, clinical methods, and approaches in the field of psychology that have resulted from the advance in digital and virtual technology. In particular, this chapter focuses on avatars and virtual technology as a component of media literacy. Additionally, the chapter explores, in detail, how avatars are used across various clinical settings with diverse populations such as individuals with autism spectrum disorder, individuals with schizophrenia, prison settings, and the criminal justice system. Furthermore, the chapter highlights the significant implications avatars have in regards to education. Lastly, controversies and challenges are discussed regarding the efficacy of digital technology within clinical settings (e.g., telepsychology).


2020 ◽  
Vol 12 (1) ◽  
pp. 59-66
Author(s):  
T. V. Kozhanova ◽  
S. S. Zhilina ◽  
T. I. Mescheryakova ◽  
E. G. Luk`yanova ◽  
K. V. Osipova ◽  
...  

Autism spectrum disorders (ASDs) are a group of complex disintegrative disorders of mental development, characterized by a lack of ability to social interaction, communication, stereotyped behavior, leading to social maladaptation. We present a rare clinical case of a delay in psychomotor and speech development, specific facial dysmorphia, impaired behavior, and a detected mutation in the ADNP gene. When conducting targeted exomic sequencing, we revealed a previously undescribed variant of the nucleotide sequence in the ADNP gene (p.Ala1017fs). Mutations in the ADNP gene in a heterozygous state were described for patients with Helsmoortel-van der Aa syndrome (OMIM: # 615873). Mutations in the ADNP gene are the genetic cause of ASD in 0.17% of cases. When interpreting the data of new generation sequencing (NGS) in patients with epileptic encephalopathy, ASD, and characteristic phenotype, it is advisable to take into account that the ADNP gene is one of the key genes responsible for embryonic neurodevelopment.


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