This research proposes to investigate physiological and cognitive markers of locus coeruleus (LC) neuronal integrity and function in cognitively-healthy participants over 60 years old. The locus coeruleus is a brainstem nucleus, sole source of noradrenaline for the brain. Tau pathology appears in neurons of this nucleus, which may induce initial cognitive changes. The study aims at relating locus coeruleus markers, assessed with MRI and eye-tracking techniques, with cognitive function.
The LC is a small brainstem nucleus, sole source of noradrenaline (NA) to the brain. NA is involved in the physiological arousal response: LC neuronal activity is closely related with pupil dilation, and pupil size is now considered a reliable and easy-access biomarker of LC function. NA-dependent cognitive functions include attention, flexibility and memory, which are selectively impaired with age. Accordingly, LC-NA system dysfunction may occur and contribute to initial cognitive changes during old age. The study will assess, in cognitively-healthy older volunteers from the INSPIRE cohort (n=100, over 60 years old), MRI and pupillometry markers of LC integrity, LC-forebrain connectivity and LC activity. We aim at investigating the relationship between LC biomarkers and cognitive status. Four experimental visits will be conducted by each participant, every 6 months over an 18-month period. Visits V1 and V4 will include MRI, eye-tracking and detailed cognitive exams. Visits V2 and V3 will include a detailed cognitive exam.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
100
MRI examinations will be conducted on the 3T MRI technical platform. During the MRI examination, images reflecting the integrity of the LC (quantification of neuromelanin as well as its functional connections with the different brain regions (resting functional MRI) will be acquired. High-resolution T1 and T2 weighted images of the the entire brain will also be acquired for the volumetry of cerebral areas.
Eye tracking examinations will be conducted using an EyeBrain medical device (class IIa) developed by Suricog. This eye tracker will be installed in a box, in an experimental room. The eye tracker is combined with a computer to present visual cognitive tasks. Pupillary dilation/constriction measurements will be acquired at rest (when fixing a cross presented on the screen) and during the performance of different cognitive tasks (exploration and processing of scenes visuals, reading texts, making saccades or anti-saccades when presenting visual targets). These pupillary measurements will then be linked to the memorization of the stimuli presented, this recognition being tested at the end of the exam.
University Hospital
Toulouse, France
RECRUITINGImaging contrast between the LC nucleus and the pontine tegmentum region
The outcome will be measured with brainstem anatomical MRI (no unit) at visits V1 (immediately after inclusion) and V4 (18 months after inclusion).
Time frame: 18 months
Z-score of the LC-forebrain connectivity at rest
It will be assessed with resting-state functional MRI (no unit) at visits V1 (immediately after inclusion) and V4 (18 months after inclusion).
Time frame: 18 months
Amplitude of the phasic pupil response during completion of cognitive tasks
It will be assessed with eye-tracking (in millimeter) at visits V1 (immediately after inclusion) and V4 (18 months after inclusion).
Time frame: 18 months
Latency of saccadic eye movements during completion of cognitive tasks
It will be assessed with eye-tracking (in milliseconds) at visits V1 (immediately after inclusion) and V4 (18 months after inclusion).
Time frame: 18 months
Amplitude of saccadic eye movements during completion of cognitive tasks
It will be assessed with eye-tracking (in millimeter) at visits V1 (immediately after inclusion) and V4 (18 months after inclusion).
Time frame: 18 months
Composite cognitive (executive and memory) score
It will be assessed (no unit) at visits V1 (immediately after inclusion), V2 (6 months after inclusion), V3 (12 months after inclusion) and V4 (18 months after inclusion).
Time frame: 18 months
Levels of blood phospho-Tau
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Cognitive measures will be acquired during an evaluation session through interactive cognitive exercises. These exercises are developed using tools offered by Covirtua Healthcare (Covirtua Cognition software). Some exercises will test cognitive systems a priori dependent on NA release (episodic memory, working memory, selective attention, selective inhibition, planning) and other a priori independent of NA (semantic memory: categorization, naming).
It will be assessed by single-molecule array (Simoa) technology (picogram/ml)
Time frame: 18 months