The Locus Coeruleus and Memory (LOCUS)

Focus on the Locus Coeruleus Network With 7 T MRI: Link to Memory (Dys)Function

The cause of Alzheimer's disease, the most common form of dementia, remains unknown. Neuropathological studies suggest that a small area in the brainstem, the locus coeruleus, might be the site of the onset of the disease. This area is the sole source of noradrenalin to the brain, a neurotransmitter involved in arousal, but also cognitive functions. Animal and pharmacological studies have hinted towards an important role of this area in memory functioning. However, these studies were hampered by the limited spatial resolution, making it hard to clearly localize the locus coeruleus in the brain. New developments in brain imaging allow now to visualize the brain with stunning precision. Furthermore, a non-invasive new stimulation method, transcutaneous vagus nerve stimulation, is believed to excite the locus coeruleus and thereby influencing neuronal networks and memory functioning.

There are three aims in this project:

1. To investigate how the functional interaction between the locus coeruleus and other brain areas, in particular the medial temporal lobe areas, during memory processes (encoding, consolidation and retrieval) change with development of Alzheimer's disease.
2. To investigate associations between noradrenaline, memory performance and brain functioning. The investigators aim to investigate how acute noradrenalin levels change during the different memory processes and whether or not this is beneficial for performance. Furthermore, the investigators will investigate whether this interaction between noradrenalin, memory performance and brain functioning is different healthy older individuals (n =35) or patients with prodromal Alzheimer's disease (n =35).
3. To investigate the underlying neural network changes during transcutaneous vagus nerve stimulation. The investigators will focus on differences in functional connectivity between the locus coeruleus and the medial temporal lobe areas in healthy older individuals and prodromal Alzheimer's disease patients. An experimental condition will be compared with a sham condition in a pseudo-randomized cross-over design.

Study Overview

• Status: Unknown
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Other: 7 Tesla MRI with memory task and non-invasive neurostimulation

• Study Type: Observational
• Enrollment (Anticipated): 70

Contacts and Locations

Study Locations

• Netherlands
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

35 healthy older individuals and 35 patients with prodromal Alzheimer's disease

Description

Inclusion Criteria:

For the patients:

• diagnosis of prodromal Alzheimer's disease based on the latest research criteria (clinical assessment at the memory clinic : presence of at least a memory impairment, memory complaints expressed by the patient or informant, no problems in daily life functioning, no dementia and presence of biomarkers
• Clinical Dementia Rating score of 0.5 (
• Mini-Mental State Examination (MMSE) ≥ 23 and being mentally competent (in general, individuals with a MMSE ≥ 18 are considered mentally competent)
• Age: between 60 and 85 years old
• 50% female
• Right-handedness
• Average level of education
• Informed consent before participation in the study

For the healthy older individuals:

• Average neuropsychological test results, in accordance with normative data, corrected for age, education and gender
• No substantial memory complaints (according to the participant)
• Age: between 60 and 85 years old
• 50% female
• Right-handedness
• Average level of education
• Informed consent before participation in the study

Exclusion Criteria:

• Reduced vision
• Psychoactive medication use
• Abuse of alcohol and drugs
• Cognitive impairment due to alcohol/drug abuse or abuse of other substances
• Past or present psychiatric or neurological disorders (major depression, schizophrenia, bipolar disorder, psychotic disorder (or treatment for it), epilepsy, stroke, Parkinson's disease, multiple sclerosis, brain surgery, brain trauma, electroshock therapy, kidney dialysis, Menière's disease, brain infections)
• Major vascular disorders (e.g. stroke)
• Heart diseases or pacemakers
• Contraindications for scanning (e.g. brain surgery, cardiac pacemaker, metal implants, claustrophobia, body tattoos)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Other

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy older controls; 7 Tesla MRI with memory task and non-invasive neurostimulation	Other: 7 Tesla MRI with memory task and non-invasive neurostimulation; This is not an intervention, we investigate the neural mechanisms
Prodromal Alzheimer's disease patients; 7 Tesla MRI with memory task and non-invasive neurostimulation	Other: 7 Tesla MRI with memory task and non-invasive neurostimulation; This is not an intervention, we investigate the neural mechanisms

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood Oxygen Level Dependent (BOLD) response during a memory task	BOLD response contrasts during encoding and retrieval. For encoding: comparing neutral versus emotional, comparing old versus prodromal AD and the interaction emotional level by group. For retrieval: correctly remembered versus those incorrectly remembered; neutral versus emotional faces; lures, mistakes and hits. These contrasts will be investigated comparing both groups. BOLD responses during the memory task will also be compared across sessions (sham versus stimulation) for both groups. Consolidation: task-free, so the BOLD response in the locus coeruleus will be correlated with the BOLD response in any other voxel of the grey matter of the brain over time (seed-based resting-state analyses).	60 minutes
Performance on the memory task	Mean reaction times and accuracy levels during encoding and retrieval for emotional and neutral face-name associations and for old and prodromal AD patients. Mean reaction times and accuracy levels will also be compared across sessions: sham versus stimulation for both groups Mean reaction times and accuracy levels will also be correlated with BOLD responses during the memory task.	60 minutes
Noradrenalin levels during the memory task	Noradrenalin levels will be measured 7 times: double baseline, before encoding, after encoding, before retrieval, after retrieval and follow-up. Noradrenalin levels will be correlated with BOLD responses during the memory task.	60 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grey matter volume of the locus coeruleus	manual measurement of the number of voxels of the locus coeruleus: to compare groups	5 mintues
shape properties of the locus coeruleus	Correspondence of the location between triangle meshes (shape of the locus coeruleus) will be compared between groups	5 minutes
Performance on neuropsychological tests	Total score on the mini-mental state examination, fluency test, letter-digit-substitution test, concept shifting task, stroop color word test and the word learning task will be compared across groups. For the stroop color word task and the concept shifting task we will also compare reaction times between both groups. These scores will be correlated to the grey matter volume of the locus coeruleus and the shape properties of the locus coeruleus.	30 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Basic descriptives	gender, date of birth, socio-economic status, educational level, medical history, medication use: will be used descriptively	15 minutes
Vascular measurements	Mean arterial blood pressure, cardiovascular risk factors and vascular pathology will be assessed descriptively and could also lead to exclusion of participants.	15 min
Alpha-peak frequency	the individual mean alpha-peak frequency will be assessed with rest EEG to determine stimulation parameters.	30 minutes
Side effects	via a questionnaire we will collect the level of side effects after stimulation (scale 1-5)	10 min
Blood pressure and heart rate	Blood pressure and heart rate will be measured before and after the sessions (seated and standing) in order to monitor response to the stimulation.	20 minutes

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Netherlands Organisation for Scientific Research
• Investigators: Study Director: Frans Verhey, Prof, Maastricht University Medical Centre

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2017
• Primary Completion (Anticipated): December 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: February 4, 2015
• First Submitted That Met QC Criteria: February 13, 2015
• First Posted (Estimate): February 16, 2015

Study Record Updates

• Last Update Posted (Actual): February 28, 2020
• Last Update Submitted That Met QC Criteria: February 26, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: memory; Magnetic Resonance Imaging; locus coeruleus; Noradrenaline
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: NL51297.068.14