Abstract

Although dysregulation of metabotropic glutamate receptor subtype 5 (mGluR5)-mediated signaling has consistently been confirmed in preclinical and clinical studies of fragile X syndrome (FXS) and other subtypes of autism spectrum disorder (ASD), studies of mGluR5 expression yielded conflicting findings. Clinical trials to modulate mGluR5-mediated signaling have been hindered by the absence of a tool to measure mGluR5 expression in the living human brain. We sought to measure mGluR5 expression in people with FXS, ASD, and typical development (TD). Two teams of investigators independently administered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB), a novel, specific mGluR5 positron emission tomography (PET) ligand to quantitatively measure the density and the distribution of mGluR5s, to participants of both sexes with ASD and TD and to men with FXS including 1 man with FXS allele size mosaicism (FXS-M). Behavioral psychologists provided mock scanner training to participants with FXS before undergoing scans. In order to maximize the size effect, we report the combined sample of participants with ASD (N = 7, age [mean ± SD] 19.71 years ± 2.06), FXS (N = 10, age 29.7 years ± 10.39), and TD (N = 19, age 34.89 years ± 14.57). In contrast to participants with TD, mGluR5 expression was increased in cortical regions of participants with ASD and reduced in all regions of men with FXS. For example, mGluR5 uptake (mean ± SD) in the temporal lobe was 1.72 ± 0.65 (95% CI, 1.18-2.26) for FXS, 2.97 ± 1.04 (95% CI, 2.47-3.47) for TD, and 4.01 ± 0.63 (95% CI, 3.42-4.6) for ASD. Additionally, mGluR5 uptake in deep nuclei was lower in participants with FXS than in participants with ASD and TD with equivalent uptake in ASD and TD. For example, mGluR5 uptake in the thalamus was 0.87 ± 0.31 (95% CI, 0.65-1.09) for FXS, 1.52 ± 0.47 (95% CI, 1.29-1.75) for TD, and 1.5 ± 0.17 (95% CI, 1.34-1.66) for ASD. PET with [18F]FPEB with mock scanner training by behavioral psychologists provides a promising tool to measure cerebral mGluR5 expression of people with FXS and other subtypes of ASD. Expression of mGluR5 was reduced throughout the brains of men with FXS and elevated in cortical regions of people with ASD. This protocol provides the means to measure mGluR5 expression in people with FXS and other subtypes of ASD for rigorous clinical trials.

Highlights

  • The persistence rate over the 9-month period was highest with DR/ ER-MPH at 33% (n 1⁄4 10,371), compared to 26% for lisdexamfetamine dimesylate (LDX) (n 1⁄4 384,144), 22% for generic ER amphetamine (ER AMP) (n 1⁄4 463,429), 20% for branded ER MPH or ER AMP analogs (n 1⁄4 79,663), and 17% for generic ER MPH (n 1⁄4 427,396; p < 0.01 for all)

  • Conclusions: not adjusted for comorbidities or other baseline characteristics, individuals showed higher persistence and adherence over 9 months with DR/ER-MPH compared to other ER stimulants, which may be a result of its unique evening administration and/or dose-dependent duration effect

  • Correlations were determined between Connors’ Global Index–Parent (CGI-P) Emotional lability (EL) scores and the following measures/items: Clinical Global Impression–Severity (CGIS), CGI–Improvement (CGI-I), Caregiver Strain Questionnaire (CGSQ), and the “arguing/struggling” items in the Morning and Evening subscales of the Parent Rating of Evening and Morning Behavior–Revised (PREMB-R) scale

Read more

Summary

Objectives

Dysregulation of metabotropic glutamate receptor subtype 5 (mGluR5)-mediated signaling has consistently been confirmed in preclinical and clinical studies of fragile X syndrome (FXS) and other subtypes of autism spectrum disorder (ASD), studies of mGluR5 expression yielded conflicting findings. We sought to measure mGluR5 expression in people with FXS, ASD, and typical development (TD). Results: In contrast to participants with TD, mGluR5 expression was increased in cortical regions of participants with ASD and reduced in all regions of men with FXS. Conclusions: PET with [18F]FPEB with mock scanner training by behavioral psychologists provides a promising tool to measure cerebral mGluR5 expression of people with FXS and other subtypes of ASD. Expression of mGluR5 was reduced throughout the brains of men with FXS and elevated in cortical regions of people with ASD. This protocol provides the means to measure mGluR5 expression in people with FXS and other subtypes of ASD for rigorous clinical trials. Journal of the American Academy of Child & Adolescent Psychiatry Volume 60 / Number 10S / October 2021 www.jaacap.org

Results
Findings
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call