Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects

Background: Obesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D-2/D-3 receptor [D2/3R] availability is lower in morbidly obese subjects. Methods: To confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [I-123]IBZM SPECT, in 15 obese women and 15 non-obese controls. Results: Striatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women. Conclusion: This study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesit

AMPT-induced monoamine depletion in humans: evaluation of two alternative [123I]IBZM SPECT procedures

Purpose Acute monoamine depletion paradigms using alpha-methyl-para-tyrosine (AMPT) combined with single photon emission computed tomography (SPECT) have been used successfully to evaluate disturbances in central dopaminergic neurotransmission. However, severe side effects due to relatively high doses (4,500 to 8,000 mg) of AMPT have been reasons for study withdrawal. Thus, we assessed the effectiveness and tolerability of two alternative procedures, using lower doses of AMPT. Methods Six healthy subjects underwent three measurements of striatal dopamine D2 receptor (D2R)-binding potential (BPND) with SPECT and the selective radiolabeled D2R antagonist [123I]IBZM. All subjects were scanned in the absence of pharmacological intervention (baseline) and after two different depletion procedures. In the first depletion session, over 6 h, subjects were administered 1,500 mg of AMPT before scanning. In the second depletion session, over 25 h, subjects were administered 40 mg AMPT/kg body weight. We also administered the Subjective Well-being Under Neuroleptic Treatment Scale, a self-report instrument designed to measure the subjective experience of patients on neuroleptic medication. Results We found no change of mean D2R BPND after the first and short AMPT challenge compared to the baseline. However, we found a significant increase in striatal D2R BPND binding after the AMPT challenge adjusted for bodyweight compared to both other regimen. Although subjective well-being worsened after the prolonged AMPT challenge, no severe side effects were reported. Conclusions Our results imply a low-dosage, suitable alternative to the common AMPT procedure. The probability of side effects and study withdrawal can be reduced by this procedure

Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan’s unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = −0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = −0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = −0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = −0.02, p < 0.001) and frontal white matter Glx (z = −0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies

Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects

The 22q11.2 deletion syndrome is caused by non‐allelic homologous recombination events during meiosis between low copy repeats (LCR22) termed A, B, C, and D. Most patients have a typical LCR22A‐D (AD) deletion of 3 million base pairs (Mb). In this report, we evaluated IQ scores in 1,478 subjects with 22q11.2DS. The mean of full scale IQ, verbal IQ, and performance IQ scores in our cohort were 72.41 (standard deviation‐SD of 13.72), 75.91(SD of 14.46), and 73.01(SD of 13.71), respectively. To investigate whether IQ scores are associated with deletion size, we examined individuals with the 3 Mb, AD (n = 1,353) and nested 1.5 Mb, AB (n = 74) deletions, since they comprised the largest subgroups. We found that full scale IQ was decreased by 6.25 points (p = .002), verbal IQ was decreased by 8.17 points (p = .0002) and performance IQ was decreased by 4.03 points (p = .028) in subjects with the AD versus AB deletion. Thus, individuals with the smaller, 1.5 Mb AB deletion have modestly higher IQ scores than those with the larger, 3 Mb AD deletion. Overall, the deletion of genes in the AB region largely explains the observed low IQ in the 22q11.2DS population. However, our results also indicate that haploinsufficiency of genes in the LCR22B‐D region (BD) exert an additional negative impact on IQ. Furthermore, we did not find evidence of a confounding effect of severe congenital heart disease on IQ scores in our cohort

Post-traumatic stress in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden

Post-traumatic stress in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden

Post-traumatic stress in adults with 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.2DS) is associated with an elevated genetic risk of several psychiatric disorders. However, the prevalence of post-traumatic stress disorder (PTSD) in individuals with 22q11.2DS has been reported to be only 0.9%; this is lower than that of the general population (3.9%). We explored the occurrence of PTSD and traumatic events in a Dutch cohort of 112 adults with 22q11.2DS, and found PTSD in 8.0%, traumatic events in 20.5% and trauma-focused treatment in 17.9% of patients. Our novel findings suggest that PTSD may be underdiagnosed in individuals with 22q11.2DS. Clinicians and other caregivers should be alert to trauma in this population in order to enable treatment and minimise psychiatric burden

Triple X syndrome:psychiatric disorders and impaired social functioning as a risk factor

Women with triple X syndrome (TXS) have an extra X chromosome. TXS appeared to be associated with psychiatric disorders in biased or underpowered studies. Aim This study aims to describe the prevalence of psychiatric disorders in adults with TXS in a relatively large and less biased group of participants. Method In this cross-sectional study, data were collected from 34 women with TXS (mean age = 32.9; s.d. = 13.1) and 31 controls (mean age = 34.9; s.d. = 13.7). Psychiatric disorders were assessed using the MINI International Neuropsychiatric Interview (MINI) and the adult behavior checklist (ABCL). Trait and state anxiety were assessed using the State–Trait Anxiety Inventory. Results In the TXS group, MINI results showed a higher prevalence of major depressive episodes (43.3%), psychotic disorders (29.4%), and suicidality (23.5%). Only 50% of the TXS group earned a normal score for the total syndrome score using the ABCL. In addition, levels of trait anxiety were higher in the TXS group. Only three women in each group received psychotropic medication. Impaired social functioning appeared to represent a major risk factor in TXS as regards psychotic, affective disorders, trait anxiety, and low self-esteem. Conclusions Women with TXS are vulnerable to developing psychiatric disorders, and women with both TXS and impaired social functioning are even more vulnerable

Startle reactivity and prepulse inhibition of the acoustic startle response are modulated by catechol-O-methyl-transferase Val158 Met polymorphism in adults with 22q11 deletion syndrome

22q11 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22, which includes the gene coding for catechol-O-methyl-transferase (COMT). High dopamine (DA) levels due to COMT haplo-insufficiency may be associated with the increased risk of developing schizophrenia in adults with 22q11DS. Reduced prepulse inhibition (PPI) of the acoustic startle response has been associated with schizophrenia and with disrupted DAergic transmission in the prefrontal cortex (PFC). COMT Val(158)Met polymorphism has been shown to influence PPI. We report the first study in adults with 22q11DS to examine PPI of the acoustic startle response and its modulation by COMT Val(158)Met polymorphism. Startle reactivity (SR) and PPI of the acoustic startle response were measured in 23 adults with 22q11DS and 21 healthy controls. 22q11DS subjects were genotyped for the functional COMT Val(158)Met polymorphism. 22q11DS Met hemizygotes showed reduced SR and PPI compared with 22q11DS Val hemizygotes. The effect of COMT Val(158)Met polymorphism on PPI was no longer significant when controlling for baseline SR. Met hemizygosity in 22q11DS is associated with reduced SR and influences PPI indirectly. Decreased PFC functioning following excessive PFC DA levels may be one of the mechanisms by which the Met genotype in 22q11DS disrupts S

Parkinsonism in Genetic Neurodevelopmental Disorders: A Systematic Review

Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism