Understanding the basic molecular mechanisms and developing effective therapies for the core social- communicative symptoms of autism spectrum disorder (ASD) is a public health priority. Because the mechanisms of ASD neuropathology are poorly understood, there are no FDA approved medications to treat these core social-communicative symptoms of the disorder. This proposed research project applies novel molecular neuroimaging methods to directly investigate metabotropic glutamate receptor 5 (mGluR5) density and to provide mechanistic information about excitatory processes in the brains of individuals with ASD. We propose to use positron emission tomography (PET) imaging with the mGluR5 tracer, [18F]FPEB, to study, for the first time, whether a molecular marker can be used to identify glutamate differences in ASD via mGluR5 receptor availability in vivo. This directly addresses a central issue in ASD, whether mGluR5 is a viable molecular and treatment target (Aim 1) and whether this directly relates to the social-communicative deficits (Aim 2).
For Aim 1, we will compare the magnitude and regional pattern of potential mGluR5 receptor availability in ASD with measurements of the volume of distribution, VT, between 20 adult ASD and 20 demographically matched healthy control (HC) subjects. Our hypothesis is that ASD subjects will express higher [18F]FPEB binding in brain areas of high mGluR5 density that are implicated in functional deficits in ASD (e.g., medial prefrontal cortex and fusiform gyrus).
In Aim 2 we will examine interrelationships among mGluR5 receptor availability with social-communicative deficits. We predict that lower [18F]FPEB binding in the studied brain regions will be associated with (a) higher social-communicative function and (b) reduced symptom severity as assessed by our behavioral and clinical measures. ASD subjects will be recruited from the Yale Autism Program, using subjects 18-35 years who completed clinical assessments. Inclusion/exclusion criteria will be the same for both groups and will include medical and psychiatric examination (including ECG and laboratory studies) to determine study eligibility. Subjects eligible to participate will also receive behavioral testing, an anatomical MRI for co-registration (and partial volume corrections) and a High Resolution Research Tomography (HRRT) PET scan with the radiotracer [18F]FPEB. This is the highest resolution human brain scanner available and allows us the ability to investigate subcortical brain areas crucial in ASD, such as the amygdala. This innovative research investigates, for the first time, in-vivo estimation of mGluR5 in ASD, a potentially high impact endeavor that (a) will provide preliminary data to clarify whether mGluR5 changes exist in ASD, something that that has not been established and is necessary to validate whether it is a mechanism of autistic symptomatology and a promising avenue for treatment and (b) will allow potential mGluR5 changes to be directly related to quantifiable clinical measures (i.e., social-communicative deficit) with the novel combination of behavioral and clinical measures and PET in ASD.

Public Health Relevance

At present, the neuropathology of autism spectrum disorder (ASD) is poorly understood at the molecular level and this study will investigate glutamate receptor (mGluR5) density, a putative mechanism for autistic dysfunction, with strong supporting evidence from animal models, genetic research, post-mortem studies, and related single-gene disorders. By relating this information to a detailed assessment of social- communicative dysfunction, this research will provide the first data supporting inference of mechanistic dysfunction from the molecular level to neural systems to clinical behavior. This is a critical objective as there are no clinical ASD biomarkers and because there are extant medications to regulate glutamate receptors, an understanding of mGluR5 differences in ASD has important and direct implications for treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH113955-02
Application #
9696006
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gilotty, Lisa
Project Start
2018-06-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code