Investigations of the Pathophysiology of Gilles de la Tourette Syndrome. Part 1: Simultaneous PET and 3T MRI

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Brief Title

Investigations of the Pathophysiology of Gilles de la Tourette Syndrome. Part 1: Simultaneous PET and 3T MRI

Official Title

Combined PET and MR Investigations of the Pathophysiology of Gilles de la Tourette Syndrome. Part 1: Simultaneous PET and 3T MRI

Brief Summary

      Gilles de la Tourette syndrome (GTS; also known as Tourette syndrome) is a congenital
      neuropsychiatric disorder. Characteristic symptoms are so-called tics-rapid, repetitive
      movements (motor tics) or vocalizations (vocal tics) that start suddenly without any apparent
      purpose. Previous research supports the hypothesis of defective regulation (dysregulation) of
      the dopaminergic system, with particular discussion of dysfunction of tonic/phasic dopamine
      release or dopaminergic hyperinnervation. Moreover, given the complex interaction of
      different neurotransmitters, especially in the basal ganglia, it can be assumed that abnormal
      dopaminergic transmission also affects other transmitter systems, such as glutamate (Glu) or
      γ-aminobutyrate (GABA). Furthermore, recent results suggest an abnormality in cerebral iron
      metabolism in GTS. Since iron is accumulated in dopamine vesicles and plays a central role in
      dopamine synthesis, this observation may also be related to dysfunction of the dopaminergic
      system. Therefore, in this multimodal study, the investigators aim to combine positron
      emission tomography (PET), magnetic resonance imaging (MRI), and magnetic resonance
      spectroscopy (MRS) methods comparing patients with GTS and a control cohort.

      In Part 1 of this study, MRI and MRS at 3 Tesla are employed to investigate (i) the binding
      potential of D1 dopamine receptors, (ii) the concentrations of Glu, glutamine and GABA in the
      corpus striatum and the cortex cingularis anterior and (iii) the subcortical iron
      concentration.
    

Detailed Description

      State of the Art

      Gilles de la Tourette Syndrome (GTS) is characterized by the presence of motor and vocal
      tics, which have been defined as rapid, habitual, burst-like movements or utterances that
      typically mimic fragments of normal behavior. Patients often report unpleasant premonitory
      urge sensations preceding tics that are relieved by their execution. Although the therapeutic
      spectrum for GTS has recently been expanding, current treatment strategies are often
      unsatisfactory, thus provoking the need for further elucidation of the underlying
      pathophysiology.

      In current models of GTS pathophysiology, symptoms are thought to arise as a result of the
      inappropriate activation of specific clusters of striatal neurons, which lead to a burst-like
      disinhibition of thalamocortical output. The bulk of current literature suggests a
      dysregulated dopaminergic system. This is supported by clinical evidence of improvements in
      tics following the administration of dopamine antagonists, synthesis blockers or depletion
      drugs, and the exacerbation of symptoms following the administration of dopaminergic
      stimulants. Dopamine drives movement by activating a direct, net excitatory basal ganglia
      pathway involving the dopamine receptor D1 or an indirect, net inhibitory basal ganglia
      pathway involving the dopamine receptor D2. Currently, the vast majority of the
      antipsychotics used for the treatment of tics in GTS aim at the D2 receptor, with
      aripiprazole, risperidone and pimozide being selective D2 receptor antagonists and
      haloperidol being mainly a D2 receptor antagonist. However, recent randomized controlled
      trials further indicate promising results for the selective dopamine receptor D1 antagonist
      ecopipam.

      Methodologically varied work has revealed that patients with GTS exhibit alterations in (i)
      D2 receptor density or binding, (ii) Dopamine Active Transporter (DAT) density/binding, and
      (iii) phasic dopamine transmission in striatal and cortical regions. A very small number of
      post-mortem examinations further suggest potential abnormalities in D1 (and D2 and DAT)
      receptor densities in cortical regions. While this would be in line with the therapeutic
      efficiency of selective D1 receptor antagonists, thorough experimental verification is
      missing. In particular, D1 receptors in GTS patients have not yet been investigated in vivo,
      suggesting a need for additional research.

      Both postsynaptic and presynaptic mechanisms have been postulated to offer explanations of
      the above observations:

        1. Supersensitive postsynaptic dopamine receptors were proposed, in particular to explain
           findings of reduced levels of homovanillic Acid (HVA) in cerebrospinal fluid (CSF) in
           GTS despite the premise of a hyperdopaminergic system. The validity of this view has
           been questioned as HVA levels may be confounded by medication, and previous positron
           emission tomography (PET) studies on dopamine receptors (although likely involved in the
           neurobiology of GTS) have produced inconsistent results.

        2. Dopamine hyperinnervation, that is, an overabundance of striatal dopamine terminals was
           suggested to reflect observations of generally increased binding to the DAT and to the
           vesicular monoamine transporter type 2 (VMAT2).

        3. Tonic-phasic dysfunction assumes reduced tonic dopamine levels as well as a
           hyperresponsive (spike-dependent) phasic dopaminergic system. A low tonic dopamine tone
           could be caused by an overactive DAT preventing efficient spillage to the extrasynaptic
           space and/or altered presynaptic dopamine D2 autoreceptor binding.

      Apart from such considerations specific to dopamine one can postulate that if a dopaminergic
      abnormality were present, other neurotransmitter systems would exhibit perturbations as well.
      In particular, this is suggested by (i) the close synergy exhibited between excitatory,
      inhibitory and modulatory neurotransmitter systems within the striatum and throughout the
      brain; and (ii) the interdependent metabolic relationship exhibited between glutamate (Glu),
      and γ-aminobutyric acid (GABA) via the non-neuroactive metabolic intermediate glutamine
      (Gln). Moreover, an irregular afferent modulation of dopaminergic nuclei would have profound
      effects on tonic/phasic dopaminergic release in the striatum and the control of subsequent
      thalamocortical output. Consistently, separate groups have demonstrated that adult patients
      with GTS exhibit alterations within the GABAergic system in cortical regions using in vivo
      proton (1H) magnetic resonance spectroscopy (MRS) and subcortical regions using PET.
      Employing 1H MRS, the investigators recently found reductions in striatal concentrations of
      Gln and the sum of Glu plus Gln (Glx) in GTS patients as well as negative correlations
      between striatal Gln and actual tic severity and between thalamic Glu and premonitory urges.
      While these findings do not rule out alternative mechanisms, they lend support to the
      hypothesis of an alteration in the dynamics of the tonic/phasic dopaminergic signaling
      because chronic perturbations in the subcortical GABA-Glu-Gln cycle flux could lead to
      spatially focalized alterations in excitatory and inhibitory neurotransmitter ratios.

      Another aspect of dopamine neurobiology that has recently gained interest in the context of
      neuroimaging is the relation to brain iron. Besides supporting myelination and cellular
      respiration, brain iron is crucial for the synthesis of neurotransmitters, in particular
      dopamine. It is stored primarily as ferritin and co-localizes with dopamine vesicles having
      the greatest concentration in the dopamine-rich basal ganglia and midbrain. As the major
      brain iron compounds have (super)paramagnetic properties, they can be detected via
      susceptibility-sensitive magnetic resonance (MR) techniques, such as quantitative
      susceptibility mapping (QSM) or measurements of the effective or the reversible transverse
      relaxation rates, R2* or R2', respectively. Recent multimodal imaging targeted at (normal)
      developmental changes of the striatal dopamine system demonstrated that R2'-based estimates
      of tissue iron content were associated with carbon-11 [11C]dihydrotetrabenazine PET of
      presynaptic vesicular dopamine. This suggests that susceptibility-sensitive MR imaging (MRI),
      which does not require an intravenously applied radiotracer, might serve as a proxy for
      obtaining information on dopamine that could substitute measurements of HVA in CSF without
      sharing the same confounds. More recently, the investigators already obtained preliminary
      indications of disturbed iron homeostasis in GTS patients as evidenced by reduced serum
      ferritin and magnetic susceptibility in the striatum and further subcortical structures.

      Objectives and Hypotheses

      In continuation of previous investigations, the investigators plan to perform examinations
      with MRI and MRS in GTS patients in comparison to age- and sex-matched healthy controls
      within Part 2 of this combined study. This includes (indirect) information on the interplay
      of different neurotransmitter systems (Glu, and GABA), as well as on the role of brain iron
      in GTS.

      In particular, the investigators plan to use (i) iron-sensitive MRI techniques, such as QSM
      and R2* mapping, for obtaining indirect information on presynaptic dopamine availability;
      (ii) [11C]SCH23390 PET measures of cortical D1 receptor binding/densities in vivo in GTS
      patients; and (iii) 1H MRS with standard single-voxel techniques and spectral-editing
      methods, for obtaining neurochemical profiles and quantitative information on Glu, Gln, and
      GABA in the striatum and cortical areas.

      Neuropsychological tests:

      At the time of the MR and/or PET exams, an established, comprehensive test battery will be
      performed with all patients for a detailed clinical assessment, including the severity of
      tics or the presence of comorbidities. These tests may be performed online as a video
      conference questionnaire and include:

        -  DSM-IV-symptom list for attention deficit hyperactivity disorder (ADHD), rage attack
           questionnaire (RAQ), Pittsburgh sleep quality index (PSQI);

        -  Clinical ratings : Yale global tic severity scale (YGTSS-R), Yale-Brown
           obsessive-compulsive scale (Y-BOCS), clinical global impression scale (CGI).

        -  Self-assessment questionnaires: adult tic questionnaire (ATQ), Beck depression inventory
           (BDI), Beck anxiety inventory (BAI), Conners' adult ADHA rating scales (CAARS), autism
           spectrum quotient (AQ); premotory urge for tics scale (PUTS), GTS quality of life scale
           (GTS-QOL).

      MR exams within Part 1 (Simultaneous PET and 3T MR):

      PET investigations of D1 receptor binding/density will be performed with the 11C-based tracer
      [11C]SCH23390, which has already revealed abnormalities in cortical D1 receptor in other
      neuropsychiatric disorders. Before starting the PET measurement, the subject is positioned on
      the scanner's patient table and asked to relax for several minutes while an intravenous line
      is in-serted into an arm vein for injection of the radionuclide. Subsequently, [11C]SCH23390
      is administered during 90 s following established procedures for the specific radionuclide.
      The administered radioactivity varies around 500 MBq, depending on the specific activity and
      the subject's body mass. Following injection, dynamic emission data are collected for approx.
      90 min. The acquired frames (4 during 15 s, 4 during 1 min, 5 during 2 min, 5 during 5 min,
      and 5 during 10 min) are reconstructed into a series of three-dimensional (3D) PET images for
      evaluations of the D1 receptor distribution volume ratio and binding potential.

      Simultaneous MR scanning at 3 Tesla (3 T) will be performed during PET scanning. These
      acquisitions are based on a protocol that has been established in previous investigations of
      GTS patients comprising the following acquisitions:

        -  Scout acquisition for automated alignment of imaging or spectroscopy volumes ("auto
           align").

        -  Structural MR scan ("MP2RAGE") for image registration, tissue segmentation, morphometry
           of cortical and subcortical structures, and for measuring the longitudinal relaxation
           time T1 to obtain information on myelin and brain iron content.

        -  Susceptibility-sensitive acquisition ("multi-echo FLASH") for measurements of the
           magnetic susceptibility (QSM) and R2* to obtain information on brain iron and myelin.

        -  Single-voxel proton MRS of the basal ganglia and the anterior cingulate cortex to
           measure metabolic profiles, in particular to obtain concentration estimates of local Glu
           and Gln (or Glx).

        -  Resting-state functional MRI acquisition to extract information on functional
           connectivity.

        -  Diffusion-weighted MRI to extract information on structural connectivity. The total time
           for the combined PET/MR acquisitions including preparations and patient positioning will
           not exceed 100 min. From all subjects (GTS patients and healthy controls) 10ml of venous
           blood will be collected at the time of the exam for subsequent measurement of blood
           ferritin levels. These levels will be compared with the results from
           susceptibility-related measures of brain iron.

           10ml of venous blood will be collected from all subjects (GTS patients and healthy
           controls) at the time of the exam for subsequent measurement of blood ferritin levels.
           These levels will be compared with the results from susceptibility-related measures of
           brain iron.
    


Study Type

Observational


Primary Outcome

D1 receptor availability

Secondary Outcome

 Plasma ferritin level

Condition

Gilles de la Tourette Syndrome

Intervention

PET/MR scanner

Study Arms / Comparison Groups

 GTS patient group
Description:  Cohort of adult GTS patients, males and females, age range 18 to 50 years

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

40

Start Date

February 2022

Completion Date

January 2023

Primary Completion Date

July 2022

Eligibility Criteria

        GTS Group:

        Inclusion Criteria:

          -  GTS according to DSM-IV-TR criteria

          -  mild or moderate tics

          -  drug-free for a minimum of 4 weeks prior to the exam

        Exclusion Criteria:

          -  severe tics of the head and/or face

          -  psychiatric medication within 4 weeks prior to the exam

          -  consumption of alcohol during 24 hours prior to the exam

          -  consumption of cannabis during 24 hours prior to the exam • pregnancy

          -  general contra-indications for MRI exams

        Control Group:

        Inclusion Criteria:

        • no known neurological or psychiatric disease

        Exclusion criteria:

          -  psychiatric medication within 4 weeks prior to the exam

          -  consumption of alcohol during 24 hours prior to the exam

          -  consumption of cannabis during 24 hours prior to the exam • pregnancy

          -  general contra-indications for MRI exams
      

Gender

All

Ages

18 Years - 50 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Harald E Möller, PhD, +49 341 9940-2212, [email protected]

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT05232955

Organization ID

PETMR_GTS_1-PETMR


Responsible Party

Sponsor

Study Sponsor

Max Planck Institute for Human Cognitive and Brain Sciences

Collaborators

 Leipzig University Medical Center

Study Sponsor

Harald E Möller, PhD, Principal Investigator, Max Planck Institute for Human Cognitive and Brain Sciences


Verification Date

February 2022