Biomarker discovery in attention deficit hyperactivity disorder: RNA sequencing of whole blood in discordant twin and case-controlled cohorts

McCaffrey, Timothy A.; Laurent, Georges St.; Shtokalo, Dmitry; Антонец, Денис; Vyatkin, Yuri; Jones, Dan; Battison, Eleanor; Nigg, Joel T.

doi:10.1186/s12920-020-00808-8

Cited by 15 publications

(6 citation statements)

References 106 publications

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“…Other studies suggested that polymorphic loci in RGS2 seem to predict the severity of schizophrenia symptoms (Campbell et al, 2008 ), or they can be associated with the risk of extrapyramidal symptoms induced by typical neuroleptics-haloperidol (Gareeva et al, 2013 ). Recently, RGS2 has also been associated with attention deficit hyperactivity disorder (ADHD; McCaffrey et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Reduced Blood RGS2 Expression in Mild Cognitive Impairment Patients

Milanesi

Cucos

Matías‐Guiu

et al. 2021

Front. Aging Neurosci.

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Regulator of G protein signaling 2 (RGS2) is a gene involved in neuronal plasticity and synaptic signaling, whose expression in the brain is altered in neuropsychiatric and neurodegenerative disorders. Microarray data from large datasets suggested reduced RGS2 mRNA levels in the post-mortem brain tissue and blood of Alzheimer’s disease (AD) patients. The results were previously confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) only ex vivo in lymphoblastoid cell lines derived from AD patients and controls. In this study, we compared RGS2 mRNA levels in peripheral blood samples from 69 mild cognitive impairment (MCI) patients to 50 age- and sex-matched non-cognitively impaired controls, out of which 25 patients were monitored at 1 year. We found that RGS2 was indeed downregulated in the peripheral blood of these patients (FR = −1.60, p < 0.001), and despite disease-specific therapy, RGS2 transcript levels continued to decrease at 1 year. The results suggest that RGS2 seems to be involved in AD pathology and progression and can be introduced in a panel of blood AD biomarkers.

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Section: Discussionmentioning

confidence: 99%

Reduced Blood RGS2 Expression in Mild Cognitive Impairment Patients

Milanesi

Cucos

Matías‐Guiu

et al. 2021

Front. Aging Neurosci.

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“…For the present ADHD study-case, RNAseq records from the entry GSE159104 ( 43 ) were selected, where two cohorts of patients were already identified and labeled as control (healthy) and ADHD (case-disease). The variability within the genes or proteins involved in the ADHD molecular definition (see Supplementary Methods in Supplementary Material 1 ; Supplementary Tables A, B in Supplementary Material 2 ) was evaluated for the 154 samples (78 control, 76 ADHD) included in the GEO experiment.…”

Section: Methodsmentioning

confidence: 99%

Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate

et al. 2021

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Regulatory agencies encourage computer modeling and simulation to reduce the time and cost of clinical trials. Although still not classified in formal guidelines, system biology-based models represent a powerful tool for generating hypotheses with great molecular detail. Herein, we have applied a mechanistic head-to-head in silico clinical trial (ISCT) between two treatments for attention-deficit/hyperactivity disorder, to wit lisdexamfetamine (LDX) and methylphenidate (MPH). The ISCT was generated through three phases comprising (i) the molecular characterization of drugs and pathologies, (ii) the generation of adult and children virtual populations (vPOPs) totaling 2,600 individuals and the creation of physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models, and (iii) data analysis with artificial intelligence methods. The characteristics of our vPOPs were in close agreement with real reference populations extracted from clinical trials, as did our PBPK models with in vivo parameters. The mechanisms of action of LDX and MPH were obtained from QSP models combining PBPK modeling of dosing schemes and systems biology-based modeling technology, i.e., therapeutic performance mapping system. The step-by-step process described here to undertake a head-to-head ISCT would allow obtaining mechanistic conclusions that could be extrapolated or used for predictions to a certain extent at the clinical level. Altogether, these computational techniques are proven an excellent tool for hypothesis-generation and would help reach a personalized medicine.

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“…Anti-sense transcript to the HLA- DQB1 locus on chromosome 6 is elevated roughly twofold in people with ADHD 174 …”

Section: Plausible Explanation Models For Orx-s Dysfunction Pathways ...mentioning

confidence: 99%

Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations)

Knez¹,

Stevanović²,

Fernell³

et al. 2022

NDT

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Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE) is an umbrella term covering a wide range of neurodevelopmental difficulties and disorders. Thus, ESSENCE includes attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and other neurodevelopmental disorders (NDDs) and difficulties, with a variety of symptoms in cognitive, motor, sensory, social, arousal, regulatory, emotional, and behavioral developmental domains, frequently co-occurring and likely having partly common neurobiological substrates. The ESSENCE concept is a clinical paradigm that promotes organizing NDDs in everyday clinical practice according to their coexistence, symptom dimensions overlapping, and treatment possibilities. Despite increased knowledge regarding NDDs, the neurobiological mechanisms that underlie them and other ESSENCE-related problems, are not well understood. With its wide range of neural circuits and interactions with numerous neurotransmitters, the orexin/hypocretin system (Orx-S) is possibly associated with a variety of neurocognitive, psychobiological, neuroendocrine, and physiological functions and behaviors. Dysfunction of Orx-S has been implicated in various psychiatric and neurological disorders. This article provides an overview of Orx-S dysfunctions' possible involvement in the development, presentation, and maintenance of ESSENCE. We provide a focused review of current research evidence linking orexin neuropeptides with specific clinical NDDs symptoms, mostly in ADHD and ASD, within the Research Domain Criteria (RDoC) framework. We propose that Orx-S dysfunction might have an important role in some of these neurodevelopmental symptom domains, such as arousal, wakefulness, sleep, motor and sensory processing, mood and emotional regulation, fear processing, reward, feeding, attention, executive functions, and sociability. Our perspective is presented from a clinical point of view. Further, more thorough systematic reviews are needed as well as planning of extensive new research into the Orx-S’s role in ESSENCE, especially considering RDoC elements.

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Biomarker discovery in attention deficit hyperactivity disorder: RNA sequencing of whole blood in discordant twin and case-controlled cohorts

Cited by 15 publications

References 106 publications

Reduced Blood RGS2 Expression in Mild Cognitive Impairment Patients

Reduced Blood RGS2 Expression in Mild Cognitive Impairment Patients

Methods to Develop an in silico Clinical Trial: Computational Head-to-Head Comparison of Lisdexamfetamine and Methylphenidate

Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations)

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