Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome

Evers, L. J. M.; Curfs, Leopold; Bakker, J.; Boot, Erik; Alves, Fabiana da Silva; Abeling, N. G. G. M.; Bierau, Jörgen; Drukker, Marjan; Amelsvoort, Thérèse van

doi:10.1017/s1461145714000376

Cited by 19 publications

(17 citation statements)

References 39 publications

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“…From a research perspective, given the early cognitive decline in 22q11.2DS, this microdeletion syndrome/CNV is an interesting model to investigate possible genes, genetic mechanisms and central neurotransmitter systems in the 22q11.2 region that contribute to cognitive deterioration. A nice illustration of this approach is a recent study by Evers et al []. Their results suggest that a subgroup of adults with 22q11DS may be affected by a neurodegenerative process affecting at least three neurotransmitter systems (serotonin, dopamine and norepinephrine), but the precise mechanism in the cognitive deterioration as seen in 22q11DS, has to be elucidated.…”

Section: Cognitive Phenotype In 22q11 Ds Across Developmentmentioning

confidence: 99%

Developmental trajectories in 22q11.2 deletion syndrome

Swillen¹,

McDonald‐McGinn²

2015

American J of Med Genetics Pt C

190

178

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Chromosome 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic condition, is the most common microdeletion syndrome affecting 1 in 2,000–4,000 live births and involving haploinsufficiency of ∼50 genes resulting in a multisystem disorder. Phenotypic expression is highly variable and ranges from severe life-threatening conditions to only a few associated features. Most common medical problems include: congenital heart disease, in particular conotruncal anomalies; palatal abnormalities, most frequently velopharyngeal incompetence (VPI); immunodeficiency; hypocalcemia due to hypoparathyroidism; genitourinary anomalies; severe feeding/gastrointestinal differences; and subtle dysmorphic facial features. The neurocognitive profile is also highly variable, both between individuals and during the course of development. From infancy onward, motor delays (often with hypotonia) and speech/language deficits are commonly observed. During the preschool and primary school ages, learning difficulties are very common. The majority of patients with 22q11.2DS have an intellectual level that falls in the borderline range (IQ 70–84), and about one-third have mild to moderate intellectual disability. More severe levels of intellectual disability are uncommon in children and adolescents but are more frequent in adults. Individuals with 22q11.2DS are at an increased risk for developing several psychiatric disorders including attention deficit with hyperactivity disorder (ADHD), autism spectrum disorder (ASD), anxiety and mood disorders, and psychotic disorders and schizophrenia. In this review, we will focus on the developmental phenotypic transitions regarding cognitive development in 22q11.2DS from early preschool to adulthood, and on the changing behavioral/psychiatric phenotype across age, on a background of frequently complex medical conditions.

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Section: Cognitive Phenotype In 22q11 Ds Across Developmentmentioning

confidence: 99%

Developmental trajectories in 22q11.2 deletion syndrome

Swillen¹,

McDonald‐McGinn²

2015

American J of Med Genetics Pt C

190

178

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“…Based on our findings regarding glutamatergic alterations in 22q11DS and our earlier observations on dopamine and serotonin (Evers et al 2014a ), it would be interesting to consider new pharmacological strategies. These may include drugs targeting the glutamatergic system, combined with dopaminergic, noradrenergic, and serotonergic action.…”

Section: Discussionmentioning

confidence: 57%

Glutamatergic markers, age, intellectual functioning and psychosis in 22q11 deletion syndrome

et al. 2015

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RationalePatients with 22q11 deletion syndrome (22q11DS) have a high prevalence of intellectual disabilities and psychiatric disorders, including psychosis. Haplo-insufficiency of genes in the deleted region may offer a partial explanation for the increased vulnerability for psychosis and intellectual disability. One gene of particular interest is the gene coding for proline dehydrogenase (PRODH), an enzyme responsible for the conversion of proline into glutamate.ObjectivesBecause abnormalities in glutamatergic signaling are thought to be responsible for cognition and psychosis in the general population, we hypothesized that PRODH haplo-insufficiency may underlie some of the cognitive and psychotic features seen in 22q11DS.MethodsIn this explorative study, we investigated the relation between plasma proline, glutamate, and glutamine and age, intelligence, and psychosis in 64 adults with 22q11DS.ResultsHyperprolinemia was found in 31.3 % of subjects with 22q11DS. A relation between glutamine, glutamate, proline, and presence of psychosis was not observed. Regression analysis revealed a positive relation between plasma glutamate and age, a positive relation of glutamate with antipsychotic drugs, a relation of glutamine and gender, and a positive relation of glutamine and mood stabilizing drugs, and a negative relation of the ratio glutamine/glutamate and age. The group with relatively lower IQ had higher glutamate levels compared to the group with relatively higher IQ.ConclusionsOur results suggest that 22q11DS is accompanied by abnormalities in glutamatergic metabolism. Future longitudinal studies are needed to further investigate the glutamatergic system in 22q11DS and how this affects the development of cognitive problems and psychopathology.

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“…An investigation into metabolite biomarkers of schizophrenia revealed that levels of DA, homovanillic acid, NE, vanillylmandelic acid, and serotonin positively correlated with Full Scale Intelligence Quotient scores in patients with chromosome 22q11 deletion syndrome, which results in a higher risk of developing MDD, schizophrenia, and other psychiatric disorders (52). Another report discovered an interaction between an α 2A -AR gene SNP and a specific methylenetetrahydrofolate reductase gene SNP, which encodes for an enzyme involved in DNA methylation, in patients with schizophrenia (53), suggesting a potential role for NE in the epigenetic control relevant to the pathogenesis of schizophrenia.…”

Section: Resultsmentioning

confidence: 99%

“…Several cognitive processes, including attention and working memory, have been shown to be linked to NE activity (5). Indeed, cognitive defects in chromosome 22q11 deletion syndrome are associated with the abnormal function of several neurotransmitters, including NE (52). Furthermore, clonidine may exert dual activity by engaging inhibitory presynaptic α 2 -ARs, and therefore suppressing NE activity, while at the same time directly stimulating prefrontal cortex postsynaptic α 2 -ARs (39).…”

Section: Discussionmentioning

confidence: 99%

The Role of Norepinephrine and Its α-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A Systematic Review

et al. 2017

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Norepinephrine (NE) is recognized as having a key role in the pathophysiology of major depressive disorder (MDD) and schizophrenia, although its distinct actions via α-adrenergic receptors (α-ARs) are not well defined. We performed a systematic review examining the roles of NE and α-ARs in MDD and schizophrenia. PubMed and ProQuest database searches were performed to identify English language papers published between 2008 and 2015. In total, 2,427 publications (PubMed, n = 669; ProQuest, n = 1,758) were identified. Duplicates, articles deemed not relevant, case studies, reviews, meta-analyses, preclinical reports, or articles on non-target indications were excluded. To limit the review to the most recent data representative of the literature, the review further focused on publications from 2010 to 2015, which were screened independently by all authors. A total of 16 research reports were identified: six clinical trial reports, six genetic studies, two biomarker studies, and two receptor studies. Overall, the studies provided indirect evidence that α-AR activity may play an important role in aberrant regulation of cognition, arousal, and valence systems associated with MDD and schizophrenia. Characterization of the NE pathway in patients may provide clinicians with information for more personalized therapy of these heterogeneous diseases. Current clinical studies do not provide direct evidence to support the role of NE α-ARs in the pathophysiology of MDD and schizophrenia and in the treatment response of patients with these diseases, in particular with relation to specific valence systems. Clinical studies that attempt to define associations between specific receptor binding profiles of psychotropics and particular clinical outcomes are needed.

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Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome

Cited by 19 publications

References 39 publications

Developmental trajectories in 22q11.2 deletion syndrome

Developmental trajectories in 22q11.2 deletion syndrome

Glutamatergic markers, age, intellectual functioning and psychosis in 22q11 deletion syndrome

The Role of Norepinephrine and Its α-Adrenergic Receptors in the Pathophysiology and Treatment of Major Depressive Disorder and Schizophrenia: A Systematic Review

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