The Locus Coeruleus and Memory

Study Overview
=================
Brief Summary
-----------------
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: 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. 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). 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.

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

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Other: 7 Tesla MRI with memory task and non-invasive neurostimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Magnetic Resonance Imaging, Noradrenaline, locus coeruleus, memory