Cholinergic Receptor Imaging in Dystonia

Dystonia is a heterogeneous group of movement disorders characterized by abnormal muscle
contractions resulting in abnormal postures and movements. The spectrum of dystonia includes
focal, segmental, multifocal, and generalized presentations with a broad range of age of
onset. An example of a focal dystonia is cervical dystonia. The pathophysiology of dystonia
is unclear, but prior neuroimaging and neuropathological studies have identified a role for
the basal ganglia. In neuroimaging studies, microstructural changes in the basal ganglia have
been found in voxel based morphometry (VBM) and diffusion tensor imaging (DTI), and abnormal
basal ganglia metabolism has been seen in imaging with fluorodeoxyglucose positron emission
tomography (FDG-PET) in various types of dystonia. Basal ganglia pathology has been observed,
including a case series reporting neuronal loss in the striatum. There is further evidence
implicating the basal ganglia in dystonia from studies of animal models. In animal models,
experimental lesions of the basal ganglia induced dystonia. An abnormality in cholinergic
neurotransmission has been has also been suggested because of a clinical response to
antimuscarinic medications. The striatum is a site of acetylcholine synthesis, and expresses
muscarinic receptors. While antimuscarinic medications are useful in the symptomatic
treatment of dystonia, the role of muscarinic acetylcholine neurotransmission in dystonia is
unclear.

Objective

The objective of this application is to determine the role played by a major basal ganglia
neurotransmitter, acetylcholine, in the pathophysiology of primary dystonia. The central
hypothesis is that cholinergic neurotransmission is deficient in the striatum in dystonia.

Study Population

We plan to examine one group of patients with a form of primary dystonia (cervical dystonia)
to be compared with healthy volunteers without history of neurological or major psychiatric
disorders (stable mild anxiety or stable mild depression are allowed).

Design

This is a case-control study. Using a neuroimaging technique, position emission tomography
(PET), the central hypothesis will be tested by pursuing one specific aim: to map M2
muscarinic acetylcholine receptor binding in cervical dystonia as measured with PET using
[18F]FP-TZTP.

Outcome Measures

This study will determine cholinergic neurotransmitter receptor binding in patients with
cervical dystonia compared with healthy controls. This proposed research study is expected to
advance our understanding of the pathophysiology of dystonia in order to identify possible
targets for potential pharmacological treatments in dystonia and monitor disease progression.

- INCLUSION CRITERIA:

Healthy research volunteers and adult patients with cervical dystonia will be eligible for
the study.

1. Adult patients with cervical dystonia will have clinically documented cervical
dystonia established by history and physical/neurological examination.

--Cervical dystonia patients must not have had received botulinum toxin injections
into neck muscles for at least about 3 months at time of study participation

2. Healthy volunteers will be healthy subjects without neurological or psychiatric
disorders (except for stable mild anxiety or stable mild depression) established by
history and physical/neurological examination.

3. All participants will be at least 18 years of age. There is no maximum age limit.

4. Participants must be able to abstain from tobacco or nicotine replacement for at least
3 days prior to PET scan if participating in both MRI and PET scanning..

5. Participants must be able to abstain from caffeine for at least 24 hours prior to PET
scan if participating in both MRI and PET scanning.

6. Participants must be able to fast for 3 hours before PET scan if participanting in
both MRI and PET scanning.

EXCLUSION CRITERIA:

1. Subjects who are incapable of giving informed consent.

2. Employees of NINDS

3. Pregnant or breastfeeding women. Aside from history obtained at the screening,
pregnancy status in women with childbearing potential is also established by urine
pregnancy testing no more than 24 hours before each MRI and PET scan session.

4. Subjects with past or present medical history of (a) neurological disorders, such as
stroke, movement disorders (other than cervical dystonia in the patient group), brain
tumors, traumatic brain injury with loss of consciousness lasting more than a few
seconds, ataxias, myopathies, myasthenia gravis, demyelinating diseases, alcoholism,
drug dependence; (b) psychiatric disorders besides stable mild anxiety or stable mild
depression, such as schizophrenia, major depressive and/or bipolar disorder,
obsessive-compulsive disorder; (c) ventricular arrhythmias, renal and hepatic
insufficiency, vascular headache, or carcinoid syndrome.

5. Abnormalities in neurological examination other what is typically associated with
cervical dystonia, or any abnormalities in neurological examination in healthy
volunteers.

6. Subjects who are currently taking oral medications known to affect muscarinic
acetylcholine receptor binding in the central nervous system. Of note, some over-the
counter-medications are known to affect muscarinic acetylcholine receptor binding.
Subjects who use medications known to affect muscarinic acetylcholine receptor
binding, such as first generation antihistamines for common cold and allergy symptoms
and sleep aids for insomnia, occasionally on an as needed basis may be enrolled in
this study. Furthermore, these as needed medications should be paused for at least 3
days before PET scanning. This three-day period is equivalent to about 4 to 5 half
lives for these medications. In addition, subjects who use topical antimuscarinic
medications, such as eye drops for glaucoma and inhalers, may be enrolled in this
study because topical antimuscarinic medications have negligible systemic
bioavailability. Subjects who have contraindications to MRI, ferromagnetic objects in
their bodies (e.g., implanted stimulators including deep brain stimulation, aneurysm
clips, prosthesis, artificial heart valves, etc.) that cannot be removed for the
purpose of study participation.

7. Subjects who have claustrophobia.

8. Subjects who are unable to lie comfortably on their back for about one hour for MRI
scanning (and about two hours for PET scanning if participating in both MRI and PET
scanning).

9. Subjects with any radiation exposure in the past year that, together with the research
PET scan, would exceed the NIH Radiation Safety Committee s annual limit (5 rem) if
participating in both MRI and PET scanning.

10. Cervical dystonia patients who have cervical dystonia associated with trauma