Dopamine and memory consolidation
| ISRCTN | ISRCTN90897064 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN90897064 |
| EudraCT/CTIS number | 2015-002027-26 |
| Secondary identifying numbers | 6 |
- Submission date
- 10/08/2015
- Registration date
- 19/08/2015
- Last edited
- 24/04/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Mental and Behavioural Disorders
Plain English Summary
Current plain English summary as of 06/07/2020:
Background and study aims
Alzheimer’s disease (AD) is the most common type of dementia, which causes problems with memory, thinking and behaviour (cognitive function). AD often develops slowly and the symptoms can be confused with other illnesses. One of these is mild cognitive impairment (MCI) which also causes problems with memory and thinking. People living with MCI have difficulties with certain aspects of daily life, but they are not as severe or noticeable to others as someone with dementia. A person living with MCI is more likely to develop dementia such as AD later in life.
Dopamine is a chemical messenger which carries signals throughout the brain and the body (neurotransmitters). It has been suggested that this neurotransmitter is important for cognitive function, and low levels could play a role in the development of MCI and AD. This study aims to find out whether giving a person medication which increases the activity of dopamine in the brain overnight, will improve memory storage during a good night's sleep. In this preliminary study we test the effect of levodopa in healthy older people and in future we aim to test people with MCI
Who can participate?
Healthy people aged 65 years or older
What does the study involve?
All participants visit the testing centre on three separate occasions. At each visit, the participants are be asked to learn a list of words. They are then given a single dose of medication. The participants are divided into groups who will receive the medications in different orders. On one visit, they are given a single dose of the medication co-beneldopa and on another visit they are given a placebo (dummy pill). The participants then spend the night and have their sleep monitored. After a full night’s sleep, they take a memory recall test of the list of words they learnt at the beginning of the visit. All participants also have a structural magnetic resonance brain scan (MRI) taken, and 24 of the participants will also have a functional imaging (fMRI) scan taken. The memory test is then repeated over the phone 3 days and 5 days later. There is a 7-day gap between visits so that the medication taken on one visit would not interfere with the medication taken on the next visit.
What are the possible benefits and risks of participating?
There are no direct benefits to taking part in this study and every care has been taken to minimise risks. With careful safety screening, MRI is a safe procedure and accidents are extremely rare. EEG recording of sleep is also safe and non-invasive. The drugs in this trial are widely used and generally safe. However, some people experience side effects, such as nausea, and so study volunteers will be given medication to prevent this.
Where is the study run from?
Clinical Research and Imaging Centre Bristol (UK)
When is the study starting and how long is it expected to run for?
September 2015 to September 2019
Who is funding the study?
1. Medical Research Council (UK)
2. Alzheimer's BRACE Bristol (UK)
3. Wellcome Trust (UK)
Who is the main contact?
Dr Elizabeth Coulthard (Scientific)
elizabeth.coulthard@bristol.ac.uk
Ms Hanna Isotalus (Public)
hanna.isotalus@nbt.nhs.uk
Previous plain English summary as of 20/04/2018:
Background and study aims
Alzheimer’s disease (AD) is the most common type of dementia, which causes problems with memory, thinking and behaviour (cognitive function). AD often develops slowly and the symptoms can be confused with other illnesses. One of these is mild cognitive impairment (MCI) which also causes problems with memory and thinking. People living with MCI have difficulties with certain aspects of daily life, but they are not as severe or noticeable to others as someone with dementia. A person living with MCI is more likely to develop dementia such as AD later in life.
Dopamine is a chemical messenger which carries signals throughout the brain and the body (neurotransmitters). It has been suggested that this neurotransmitter is important for cognitive function, and low levels could play a role in the development of MCI and AD. This study aims to find out whether giving a person medication which increases the activity of dopamine in the brain overnight, will improve memory storage during a good night's sleep.
Who can participate?
Seniors with a diagnosis of MCI or mild AD, and age-matched healthy controls
What does the study involve?
All participants visit the testing centre on three separate occasions. At each visit, the participants are be asked to learn a list of words. They are then given a single dose of medication. The participants are divided into groups who will receive the medications in different orders. On one visit, they are given a single dose of the medication co-beneldopa and on another visit they are given a placebo (dummy pill). The participants then spend the night and have their sleep monitored. After a full night’s sleep, they take a memory recall test of the list of words they learnt at the beginning of the visit. All participants also have a structural magnetic resonance brain scan (MRI) taken, and 24 of the healthy participants will also have a functional imaging (fMRI) scan taken. The memory test is then repeated over the phone 3 days and 5 days later. There is a 7-day gap between visits so that the medication taken on one visit would not interfere with the medication taken on the next visit.
What are the possible benefits and risks of participating?
There are no direct benefits to taking part in this study and every care has been taken to minimise risks. With careful safety screening, MRI is a safe procedure and accidents are extremely rare. EEG recording of sleep is also safe and non-invasive. The drugs in this trial are widely used and generally safe. However, some people experience side effects, such as nausea, and so study volunteers will be given medication to prevent this.
Where is the study run from?
Clinical Research and Imaging Centre Bristol (UK)
When is the study starting and how long is it expected to run for?
September 2015 to September 2019
Who is funding the study?
1. Medical Research Council (UK)
2. Alzheimer's BRACE Bristol (UK)
3. Wellcome Trust (UK)
Who is the main contact?
Dr Elizabeth Coulthard (Scientific)
elizabeth.coulthard@bristol.ac.uk
Ms Hanna Isotalus (Public)
hanna.isotalus@nbt.nhs.uk
Previous plain English summary:
Background and study aims
Alzheimer’s disease (AD) is the most common type of dementia, which causes problems with memory, thinking and behaviour (cognitive function). AD often develops slowly and the symptoms can be confused with other illnesses. One of these is mild cognitive impairment (MCI) which also causes problems with memory and thinking. People suffering from MCI have difficulties with certain aspects of daily life, but they are not as severe or noticeable to others as someone with dementia. It is thought that a person suffering from MCI is more likely to develop dementia such as AD later in life.
Dopamine is a chemical messenger which carries signals throughout the brain and the body (neurotransmitters). It has been suggested that this neurotransmitter is important for cognitive function, and low levels could play a key role in the development of MCI and AD. This study aims to find out whether giving a person medication which increases the activity of dopamine in the brain overnight, will improve memory storage during a good night's sleep.
Who can participate?
Seniors with a diagnosis of MCI or mild AD, and age-matched healthy controls
What does the study involve?
All participants visit the testing centre on four separate occasions. At each visit, the participants are be asked to learn a list of words. They are then given a single dose of medication. The participants are divided into groups who will receive the medications in different orders. On one visit, they are given a single dose of the medication co-beneldopa, on another visit they are given ropinirole and on another visit they are given a placebo (dummy pill). The participants then spend the night and have their sleep monitored. After a full night’s sleep, they take a memory recall test of the list of words they learnt at the beginning of the visit. All participants also have a structural magnetic resonance brain scan (MRI) taken, and 24 of the healthy participants will also have a functional imaging (fMRI) scan taken. This test is then repeated over the phone 3 days and 5 days later. There is a 7-day gap between visits so that the medication taken on one visit would not interfere with the medication taken on the next visit.
What are the possible benefits and risks of participating?
There are no direct benefits to taking part in this study and every care has been taken to minimise risks. With careful safety screening, MRI is a safe procedure and accidents are extremely rare. EEG recording of sleep is also safe and non-invasive. The drugs in this trial are widely used and generally safe. However, some people experience side effects, such as nausea, and so study volunteers will be given medication to prevent this.
Where is the study run from?
Clinical Research and Imaging Centre Bristol (UK)
When is the study starting and how long is it expected to run for?
September 2015 to September 2019
Who is funding the study?
1. Medical Research Council (UK)
2. Alzheimer's BRACE Bristol (UK)
3. Wellcome Trust (UK)
Who is the main contact?
Dr Elizabeth Coulthard (Scientific)
elizabeth.coulthard@bristol.ac.uk
Ms Hanna Isotalus (Public)
hanna.isotalus@nbt.nhs.uk
Contact information
Scientific
Clinical Neurosciences
University of Bristol, Level 1 Learning and Research Building BS10 5NB
Bristol
BS10 5NB
United Kingdom
| Phone | +44 (0) 117 41 47801 |
|---|---|
| elizabeth.coulthard@bristol.ac.uk |
Scientific
Clinical Neurosciences
University of Bristol, Level 1 Learning and Research Building BS10 5NB
Bristol
BS10 5NB
United Kingdom
| Phone | +44 (0) 117 41 47801 |
|---|---|
| hanna.isotalus@nbt.nhs.uk |
Study information
| Study design | Single-centre placebo-controlled double-blind randomised cross-over study with single doses |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet. |
| Scientific title | Targeting dopamine to treat impaired memory consolidation in neurodegenerative disease |
| Study acronym | DOPAMIND |
| Study hypothesis | Current study hypothesis as of 06/07/2020: When dopaminergic drugs, as opposed to placebo, are administered overnight, memory of episodic, associative and reward information will be improved 12 hours, 3 and 5 days later in older healthy adults (65+ years). Previous study hypothesis as of 20/04/2018: 1. When dopaminergic drugs, as opposed to placebo, are administered overnight, memory of episodic, associative and reward information will be improved 12 hours, 3 and 5 days later in older healthy adults (65+ years). 2. When dopaminergic drugs, as opposed to placebo, are administered overnight, memory of episodic, associative and reward information will be improved 12 hours, 3 and 5 days later in those living with MCI or AD. Original study hypothesis: 1. When dopaminergic drugs, as opposed to placebo, are administered overnight, memory of episodic, associative and reward information will be improved 12 hours, 3 and 5 days later in older healthy adults (65+ years). 2. When dopaminergic drugs, as opposed to placebo, are administered overnight, memory of episodic, associative and reward information will be improved 12 hours, 3 and 5 days later in those living with MCI or AD. 3. Both patients and healthy adults will experience a greater improvement in memory on cobeneldopa than on ropinirole, due to its ability to increase D1 receptor activity. |
| Ethics approval(s) | South West - Central Bristol Ethics Committee, 13/04/2016, REC ref: 16/SW/0028 |
| Condition | Healthy ageing, amnesic mild cognitive impairment and mild to moderate Alzheimer's dementia. |
| Intervention | Current interventions as of 06/07/2020: A cohort of healthy control participants undergo block randomisation into groups, who will receive each treatment in a different order. Participants will visit the testing facility on three occasions. At each visit they will receive either a single dose of co-beneldopa 200mg or a single dose of placebo, with at least a 7-day wash-over period between dosing. These groups are as follows: 1. 1st visit placebo, 2nd visit co-beneldopa 2. 1st visit co-beneldopa, 2nd visit placebo Each testing visit entails a learning phase, followed by a single-dose of a drug, an early recall and a late recall after a full night’s sleep. After dosing, the participants will stay at the research facility overnight and have their sleep monitored using sleep electroencephalography (EEG), to examine the relationship between memory performance, dopamine and sleep architecture. All participants will have a structural magnetic resonance brain scan (MRI) taken, and a subset of 24 healthy controls will also undergo functional imaging (fMRI). A recall of the verbal learning task will be performed over the phone after 3 and 5 days. Previous interventions as of 20/04/2018: Three groups of patients (healthy control, Alzheimer's disease and Mild Cognitive Impairment) undergo block randomisation into further groups, who will receive each treatment in a different order. Participants will visit the testing facility on three occasions. At each visit they will receive either a single dose of co-beneldopa 200mg or a single dose of placebo, with at least a 7-day wash-over period between dosing. These groups are as follows: 1. 1st visit placebo, 2nd visit co-beneldopa 2. 1st visit co-beneldopa, 2nd visit placebo Each testing visit entails a learning phase, followed by a single-dose of a drug, an early recall and a late recall after a full night’s sleep. After dosing, the participants will stay at the research facility overnight and have their sleep monitored using sleep electroencephalography (EEG), to examine the relationship between memory performance, dopamine and sleep architecture. All participants will have a structural magnetic resonance brain scan (MRI) taken, and a subset of 24 healthy controls will also undergo functional imaging (fMRI). A recall of the verbal learning task will be performed over the phone after 3 and 5 days. Previous interventions: Three groups of patients (healthy control, Alzheimer's disease and Mild Cognitive Impairment) undergo block randomisation into further groups, who will receive each treatment in a different order. Participants will visit the testing facility on four occasions. At each visit they will receive either a single dose of ropinirole 8mg, a single dose of co-beneldopa 200mg or a single dose of placebo, with at least a 7-day wash-over period between dosing. These groups are as follows: 1. 1st visit ropinirole, 2nd visit co-beneldopa, 3rd visit placebo 2. 1st visit ropinirole, 2nd visit placebo, 3rd visit co-beneldopa 3. 1st visit placebo, 2nd visit co-beneldopa, 3rd visit ropinirole 4. 1st visit placebo, 2nd visit ropinirole, 3rd visit co-beneldopa 5. 1st visit co-beneldopa, 2nd visit placebo, 3rd visit ropinirole 6. 1st visit co-beneldopa, 2nd visit ropinirole, 3rd visit placebo Each testing visit entails a learning phase, followed by a single-dose of a drug, an early recall and a late recall after a full night’s sleep. After dosing, the participants will stay at the research facility overnight and have their sleep monitored using sleep electroencephalography (EEG), to examine the relationship between memory performance, dopamine and sleep architecture. All participants will have a structural magnetic resonance brain scan (MRI) taken, and a subset of 24 healthy controls will also undergo functional imaging (fMRI). A recall of the verbal learning task will be performed over the phone after 3 and 5 days. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Current drug names as of 20/04/2018: Co-beneldopa (200 mg dose) Original drug names: 1. Ropinirole (8 mg dose) 2. Co-beneldopa (200 mg dose) |
| Primary outcome measure | The change in behavioural performance on memory and learning tasks (number of words recalled) after 12 hours and after 3 and 5 days after medication. |
| Secondary outcome measures | 1. Time spent (in minutes) in different sleep stages as measured from EEG of sleep during the night following administration 2. Hippocampal subfield volume and shape to be measured using MRI and fMRI. Structural MRI is taken at baseline, fMRI is taken between 1 and 3 hours following drug administration 3. White matter tractography as measured by diffusion weighted imaging 4. Functional correlativity (Pearson's r) between VTA BOLD and hippocampus BOLD signals 5. Sensory preconditioning/reinforcement learning task the ratio of choices of rewarded actions compared to non-rewarded 6. Attention and motor learning tasks raw reaction times measured at baseline, 30 minutes after dosing, 12 hours after dosing |
| Overall study start date | 01/09/2015 |
| Overall study end date | 01/09/2019 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Senior |
| Sex | Both |
| Target number of participants | 90 |
| Total final enrolment | 35 |
| Participant inclusion criteria | Current participant inclusion criteria as of 06/07/2020: 1. Native or fluent English speakers (highly proficient in English language) 2. Normal or corrected to normal vision 3. Aged 65 years or older 4. Participants must have mental capacity to consent, and score above 11/30 in the Montreal Cognitive Assessment test Previous participant inclusion criteria: 1. Native or fluent English speakers (highly proficient in English language) 2. Normal or corrected to normal vision 3. Aged 65 years or older (may recruit younger patients if age-matched healthy control can be found) 4. Diagnosis of Mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD) 5. Participants must have mental capacity to consent, and score above 11/30 in the Montreal Cognitive Assessment test |
| Participant exclusion criteria | Current exclusion criteria as of 20/04/2018: 1. The participants must not have: 1. 1. Clinically significant neurological or psychiatric diagnoses, other than MCI or mild AD for the patient group. This will be assessed by self-report and questionnaires during the screening visit 1.2. Known posterior cortical atrophy (mainly relevant for MCI and AD, who will have had a brain scan as a part of the diagnostic procedure) 1.3. Clinically significant sleep problems in the past year 1.4. An undiagnosed skin lesion. Participants will be asked about this. 1.5. Known sensitivity to levodopa, ropinirole, benserazide, or domperidone 1.6. Known lactose intolerance, galactosemia or glucose/galactose malabsorption 1.7. Known galactose intolerance 1.8. Known Lapp lactase deficiency 1.9. Diagnosis of Huntington’s Chorea 1.10. Intention tremor. This will be screened for by a trained investigator 1.11. Known prolactin-releasing pituitary tumour (prolactinoma) 1.12 Diagnosis of glaucoma 1.13 A history of, or current, malignant melanoma 1.14 Diagnosed diabetes 1.15 Known osteomalacia 1.16 Severe endocrine, hepatic, renal, pulmonary, or cardiac disorder 1.17 Diagnosed electrolyte disturbances 1.18 Known peptic ulcers 1.19 History of a heart-attack or prolongation of cardiac conduction intervals, or any other cardiac problems as taking domperidone increases risk of said problems. An ECG will be taken at the screening visit and heart-rate and blood pressure will be monitored before and after drug administration, as specified elsewhere in this protocol. 1.20. Current cancer treatment 1.21. End stage renal disease or severe renal impairment 1.22. Diagnosed hepatic impairment 1.23 Pregnant women and women of childbearing potential not using adequate contraception will be excluded in line with the Madopar SmPC 2. The participant must not be taking: 2.1 Dopaminergic medications 2.2 Noradrenergic, serotonergic, or anticholinergic medications, except if the participant has been on stable treatment (at least 3 months) for pain or mood disorders 2.3 Monoamine oxidase inhibitors (MAO-I), except if selective MAO-A or MAO-B inhibitors are given. MAO-A and MAO-B inhibitors given together are equivalent to non-selective MAO-inhibition and therefore volunteers taking both MAO-A and MAO-B will not be included in this study 2.4. Cholinesterase inhibitors, except if the participant has been on stable treatment (at least 3 months) 2.5. Antihypertensive (blood pressure) drugs containing reserpine 2.6. Ferrous sulphate on the day of testing 2.7. Opioids or sympathomimetics (e.g. amphetamines, epinephrine/adrenaline) 2.8. Diazepam 2.9 Ketoconazole, erythromycin or CYP3A4 inhibitors (e.g. fluoconazole, voriconazole, clarithromycin, amiodarone, telithryomycin) 2.10. Antibiotics 2.11. Hormone replacement therapy 2.12. Anti-fungal agents (pentamidine) 2.13. Anti-malarial agents 2.14. Gastro-intestinal medicines 2.15. Antihistaminics 2.16. AIDS/HIV medications 2.17. If a participant takes antacids or antisecretory agents they should not be taken at the same time as domperidone (but these participants can be included if the medication can be taken at a different time) 2.18. Any medication known to interfere with co-beneldopa or domperidone Original exclusion criteria: 1. The participants must not have: 1. 1. Clinically significant neurological or psychiatric diagnoses, other than MCI or mild AD for the patient group. This will be assessed by self-report and questionnaires during the screening visit 1.2. Known posterior cortical atrophy (mainly relevant for MCI and AD, who will have had a brain scan as a part of the diagnostic procedure) 1.3. Clinically significant sleep problems in the past year 1.4. An undiagnosed skin lesion. Participants will be asked about this. 1.5. Known sensitivity to levodopa, ropinirole, benserazide, or domperidone 1.6. Known lactose intolerance, galactosemia or glucose/galactose malabsorption 1.7. Known galactose intolerance 1.8. Known Lapp lactase deficiency 1.9. Diagnosis of Huntington’s Chorea 1.10. Intention tremor. This will be screened for by a trained investigator 1.11. Known prolactin-releasing pituitary tumour (prolactinoma) 1.12 Diagnosis of glaucoma 1.13 A history of, or current, malignant melanoma 1.14 Kiagnosed diabetes 1.15 Known osteomalacia 1.16 Severe endocrine, hepatic, renal, pulmonary, or cardiac disorder 1.17 Diagnosed electrolyte disturbances 1.18 Known peptic ulcers 1.19 History of a heart-attack or prolongation of cardiac conduction intervals, or any other cardiac problems as taking domperidone increases risk of said problems. An ECG will be taken at the screening visit and heart-rate and blood pressure will be monitored before and after drug administration, as specified elsewhere in this protocol. 1.20. Current cancer treatment 1.21. End stage renal disease or severe renal impairment 1.22. Diagnosed hepatic impairment 1.23 Pregnant women and women of childbearing potential not using adequate contraception will be excluded in line with the Madopar SmPC 2. The participant must not be taking: 2.1 Dopaminergic medications 2.2 Noradrenergic, serotonergic, or anticholinergic medications, except if the participant has been on stable treatment (at least 3 months) for pain or mood disorders 2.3 Monoamine oxidase inhibitors (MAO-I), except if selective MAO-A or MAO-B inhibitors are given. MAO-A and MAO-B inhibitors given together are equivalent to non-selective MAO-inhibition and therefore volunteers taking both MAO-A and MAO-B will not be included in this study 2.4. Cholinesterase inhibitors, except if the participant has been on stable treatment (at least 3 months) 2.5. Antihypertensive (blood pressure) drugs containing reserpine 2.6. Ferrous sulphate on the day of testing 2.7. Opioids or sympathomimetics (e.g. amphetamines, epinephrine/adrenaline) 2.8. Diazepam 2.9 Ketoconazole, erythromycin or CYP3A4 inhibitors (e.g. fluoconazole, voriconazole, clarithromycin, amiodarone, telithryomycin) 2.10. Antibiotics 2.11. Hormone replacement therapy 2.12. Anti-fungal agents (pentamidine) 2.13. Anti-malarial agents 2.14. Gastro-intestinal medicines 2.15. Antihistaminics 2.16. AIDS/HIV medications 2.17. If a participant takes antacids or antisecretory agents they should not be taken at the same time as domperidone (but these participants can be included if the medication can be taken at a different time) 2.18. Any medication known to interfere with co-beneldopa, ropinirole or domperidone |
| Recruitment start date | 01/11/2015 |
| Recruitment end date | 01/09/2018 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
60 St Michael's Hill
Bristol
BS2 8DX
United Kingdom
Sponsor information
University/education
Senate House, Tyndall Ave, Bristol, City of Bristol
Bristol
BS8 1TH
England
United Kingdom
| Phone | 0117 928 9000 |
|---|---|
| red-office@bristol.ac.uk | |
| Website | http://www.bristol.ac.uk/ |
"ROR" |
https://ror.org/0524sp257 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
No information available
Private sector organisation / International organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/12/2019 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | The results of this trial will be published in a scientific journal and written as a part of a PhD thesis. They will also be presented at national and international scientific meetings and conferences. 2020 results in preprint in https://doi.org/10.1101/2020.05.23.112375 (added 30/11/2020) |
| IPD sharing plan | Not provided at time of registration |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | 05/04/2023 | 24/04/2023 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
24/04/2023: Publication reference and total final enrolment added.
30/11/2020: The following changes have been made:
1. Preprint added to the publication and dissemination plan.
2. The plain English summary has been updated to reflect the previous changes to the inclusion criteria and revised aims of the study.
06/07/2020: The following changes have been made:
1. The study hypothesis has been updated.
2. The interventions have been updated.
3. The participant inclusion criteria have been updated.
4. The plain English summary has been updated.
20/04/2018: The following changes have been made to reflect that the trial will no longer administer ropinirole because of adverse events (nausea and vomiting) experienced by the first 5 participants who received ropinirole:
1. The plain English summary has been changed.
2. The protocol/serial number has been changed from "4" to "6".
3. The study hypothesis has been changed.
4. The interventions have been changed.
5. "Ropinirole 8 mg" has been removed from the drug names.
6. The participant exclusion criteria have been changed.
29/04/2016: Ethics approval information added.
