Tourette syndrome (TS) is a common childhood-onset neurodevelopmental disorder characterized by multiple motor and phonic tics. TS is accompanied commonly by behavioral co-morbidities, including obsessive compulsive disorder (OCD) and attentional deficits. The pathogenesis and pathophysiology of TS are understood only poorly. Converging evidence points to striatal dysfunction in TS and a modest amount of post-mortem data suggests deficits in some populations of striatal interneurons, notably cholinergic interneurons. Striatal cholinergic interneurons are important actors within the basal ganglia. This relatively sparse population of interneurons may serve a synchronizing role across large volumes of the striatum. Deficient striatal cholinergic interneurons are a plausible substrate for tics and related manifestations of TS and we hypothesize diminished striatal cholinergic interneurons in TS. It has not been previously feasible to quantify striatal cholinergi interneuron integrity in vivo. Our group developed a novel positron emission tomography (PET) tracer, [18F]FEOBV, a ligand for the vesicular acetylcholine transporter (VChT), that allows accurate quantification of striatal cholinergic terminals in humans. We propose to evaluate striatal cholinergic neuron terminal integrity in TS and control subjects. We will recruit TS and age-matched control subjects for study with [18F]FEOBV. Subjects will undergo a standard clinical evaluation including assessment of tic severity and character, obsessive-compulsive behaviors, and attentional deficits. Primary analysis will be comparison of striatal [18F]FEOBV binding between TS and control subjects. Secondary analyses will include correlation of striatal [18F]FEOBV binding with clinical ratings and assessment of cholinergic terminal integrity in other brain regions. Validation of this hypothesis would point to a specific anatomic - neurochemical system deficit in TS. This would facilitate research on understanding the developmental basis for TS. Cholinergic systems offer multiple potential targets for pharmacologic intervention and validation of this hypothesis would initiate a new approach to experimental therapeutics in TS.

Public Health Relevance

Tourette syndrome is a common neurologic disorder of childhood characterized by tics and associated behavioral problems. The brain changes responsible for TS are not understood. Some data suggests that loss of a specific type of nerve cells, cholinergic interneurons, in one part of the brain, the striatum, are associated with TS. We developed a new brain imaging method, FEOBV PET, allowing measurement of this group of neurons in living individuals. We will study TS and control subjects with FEOBV PET to determine if striatal cholinergic neurons are diminished in TS. This experiment may identify the first clear brain change in TS and suggest new approaches to treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS088302-01
Application #
8751951
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Gwinn, Katrina
Project Start
2014-06-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$194,375
Indirect Cost
$69,375
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109