In Vivo Involvement of the Cholinergic and Dopaminergic Systems in the Pathophysiology of Apathy.

Overview

Apathy is a neurocognitive syndrome characterized by reduced goal-directed behaviors, contributing to decreased patient and caregiver quality of life. Apathy pathophysiology involves disruption of cortico-striato-thalamo-cortical loops, modulated by several neurotransmitter systems including dopamine and acetylcholine, thus complexifying pharmacological management. Post-stroke apathy (PSA) can provide a proper in vivo model to study the underlying neurochemical substrates of apathy as a syndrome. The present project aims to provide a better characterization of the cholinergic and dopaminergic functioning in apathy as a syndrome. In order to precise the respective alterations of these two systems, investigators will use a positron emission tomography (PET) molecular imaging of dopaminergic (with \[18F\]-FDOPA, a marker of the decarboxylating enzyme of dopamine) and - for the first time in apathetic patients - cholinergic (with \[18F\]-FEOBV, a marker of the vesicular acetylcholine transporter) transmissions in 15 apathetic and 15 unapathetic patients 3 months after stroke, without overlapping depression. This dual imaging study may provide help in guiding therapeutic management of PSA. The functional network analysis allowed by functional MRI is crucial to complement regional neurotransmitter deficits observed with PET. Altogether, a multimodal approach in apathy, combining PET and MRI, can allow identifying which circuits of the cortico-striato-thalamo-cortical loops are disrupted and how these circuits are modulated by other neurotransmitters.

Interventions

• Drug Positron Emission Tomography (PET) with [18F]-FDOPA
  Positron Emission Tomography (PET) with \[18F\]-FDOPA
• Drug Positron Emission Tomography (PET) with [18F]-FEOBV
  Positron Emission Tomography (PET) with \[18F\]-FEOBV
• Device Magnetic Resonnance Imaging (MRI)
  MRI protocol will be performed on the same day that the \[18F\]-FEOBV PET imaging, using a 3T scanner (Philips Medical System). Different types of images will be acquired.
• Other Neuropsychological evaluation
  Neuropsychological evaluation will be performed, consisting in an assessment of apathy by actigraphy (social or physical activities will be recorded during seven days) and a complementary assessment of apathy using the Lille Apathy Rating Scale (LARS)

Primary outcome measures

• [18F]-FDOPA SUVr [Time frame: Between 7 and 30 days after first visit]
• [18F]-FEOBV SUVr [Time frame: First visit (Day 0)]

Secondary outcome measures (8)

• Apathy Inventory Score [Time frame: First visit (Day 0)]
• Beck Anxiety Inventory (BAI) Score [Time frame: First visit (Day 0)]
• Lille Apathy Rating Scale (LARS) Score [Time frame: First visit (Day 0)]
• Multidimensional Fatigue Inventory (MFI) Score [Time frame: First visit (Day 0)]
• Center of Epidemiology Studies Depression Scale (CES-D) Score [Time frame: First visit (Day 0)]
• Fractional anisotropy [Time frame: First visit (Day 0)]
• Mean diffusivity [Time frame: First visit (Day 0)]
• Cerebral blood flow maps [Time frame: First visit (Day 0)]

Eligibility criteria

Inclusion criteria

• Patient of legal age and younger than 75 years
• Patient with a Rankin score less then or equal to 2 and with or without apathy, demonstrated by AI scales at 3 months after stroke (apathetic patient = AI scale score > 2)
• Affiliate or beneficiary of a social security scheme
• Subjects (female study subjects and female partners of male participants) using highly effective contraceptive methods (intra-uterine device, progestin or estrogen-progestin contraceptive, sterilization)
• Free, informed and written consent signed by the participant and the investigator (at the latest on the day of inclusion and before any examination required by the research)

Exclusion criteria

• Patients over 75 years old
• Taking of any pharmacological treatment likely to affect cholinergic systems at the time of PET-scan: Amitriptyline, Atropine, Brompheniramine, Chlorphenamine, Chlorpromazine, Clomipramine, Clozapine, Dimenhydrinate, Diphenhydramine, Doxepine, Hyoscyamine, Imipramine, Meclozine, Nortriptyline, Oxybutynine, Promethazine, Scopolamine, Trimipramine, Hydroxyzine.
• Taking of any pharmacological treatment likely to affect dopaminergic systems at the time of PET-scan: glucagon, haloperidol, reserpin
• Taking of any selective serotonine reuptake inhibitors treatment
• White matter T2 hyperintense lesions (Fazekas score > 3)
• NYHA Class III to IV Heart Failure Patient
• Patients with allergy or conter-indication to entacapone
• Subjects with positive pregnancy test (BHCG dosage and Urine dipstick), and/or currently breast-feeding
• Patients unable to come back to hospital for at least 2-follow-up visits
• Patient with a chronic neurological disorder or severe psychiatric disorder
• Patient with cognitive impairment (MoCA<24) and depression (CES-D score > 17 for men and >23 for women)
• Patient presenting a counter-indication for MRI
• Patient presenting a counter-indication for TEP with \[18F\]-FEOBV or \[18F\]-FDOPA (known allergy)
• Patient who underwent a PET examination in the previous month
• Patient with state of health not allowing a displacement in the department of imaging of the CHU: bedridden state, state of health very deteriorated
• Patient deprived of liberty by judicial or administrative decision
• Patient under legal protection or unable to express its own consent
• Subject within exclusion period from another clinical trial

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

France · 1 center

• Bordeaux University Hospital — Bordeaux

Identifiers

NCT: NCT03998852 · CHUBX 2017/22

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗