Biomarkers of the Locus Coeruleus Nucleus: Links With Early Tau Pathology, Cognition and Alzheimer's Disease Risk

Official title

Biomarkers of the Locus Coeruleus Nucleus: Links With Early Tau Pathology, Cognition and Alzheimer's Disease Risk.

Overview

Alzheimer's disease (AD) is characterized by a long-lasting silent phase. Among initial events, emergence of tau pathology in locus coeruleus (LC) brainstem nucleus, well before the one observed in medial temporal cortex, is highly relevant. LC integrity and function can be assessed in vivo with MRI and pupil measures. The current research proposes to evaluate these LC markers in an aged healthy cohort (n=100, with half APOE4 positive) and to relate these markers with cerebral tau pathology, AD risk and cognitive function.

Detailed description

Early tau pathology in the LC may induce dysfunction of the LC-NA system, contribute to initial cognitive decline and possibly be predictive of future AD occurrence. The present project has the following objectives: 1) to relate different biomarkers of LC function measured in vivo with AD risk and future AD occurrence, in order to evaluate their relevance for earliest AD diagnosis, 2) to investigate how LC biomarkers can account for underlying brain tau pathology in asymptomatic older individuals; a related objective will be to validate LC biomarkers as reliable proxies of tau pathology occurrence, and 3) to study the link between LC biomarkers and cognitive performance.

To complete these objectives, the project will evaluate, in healthy older volunteers from the INSPIRE-T cohort (n=100, \> 60 years old), biomarkers of LC neuronal integrity, LC-forebrain connectivity, and LC tonic and phasic activity. Additionally, a positon emission tomography (PET) exam will be conducted using tau-specific tracer. Detailed cognitive assessment will also be performed, including assessment of a priori NA-dependent and NA-independent cognitive functions. In the studied cohort (n = 100), half volunteers will be recruited based on genetic AD risk (APOE4 positive) and the other half based on the absence of risk (APOE4 negative).

Interventions

• Drug a positon emission tomography (PET) exam
  TEP exam using tau-specific tracer ( Flortaucipir, unique dose 360 MBq)
• Other MRI Contrast
  Data acquisition will include different sequences (anatomical MRI, resting fMRI). The MRI sequences performed will be anatomical imaging (i.e. T1 imaging, FLAIR), a diffusion sequence, a neuromelanin-sensitive sequence and functional imaging at rest (i.e. "the resting state", which allows the functional connectivity within the so-called "default" network to be assessed).
• Other oculometry assessment
  Pupillometry and oculometry will be conducted using an EyeBrain medical device (class IIa). Several cognitive tasks will be submitted to the participant, during which the same measurements will be taken. Different stimuli will be presented on the computer screen (visual scenes, text, geometric shapes) during the eye tracking measurement, and an instruction (cognitive task, such as semantic categorization, free exploration of the gaze, reading, saccade execution) will be associated with each type
• Other cognitive exams
  Cognitive measures will be acquired during an evaluation session through 6 interactive cognitive exercises. These exercises are developed using tools offered by Covirtua Healthcare.

Primary outcome measures

• diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam [Time frame: 24 monnths]

Secondary outcome measures (12)

• diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam for the APOe4- groups [Time frame: 24 months]
• diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam for the APOe4+ groups [Time frame: 24 months]
• The relationship between different LC biomarkers [Time frame: 24 months]
• The link between PET Tau uptake and PET-estimated perfusion changes [Time frame: 24 months]
• The link between PET Tau uptake in oculometry [Time frame: 24 months]
• The link between PET Tau uptake in the structural (neuromelanin) and functional integrity of the LC by MRI [Time frame: 24 months]
• The link between variations in pupillometry [Time frame: 24 months]
• The link between variations in occulometry [Time frame: 24 months]
• The link between variations in the structural (neuromelanin) and functional integrity of the LC by MRI [Time frame: 24 months]
• The relationship between the various LC biomarkers (PET, MRI, pupillometry) and participants' cognitive performance [Time frame: 24 months]
• comparison between APOe4+ and APOe4-: Structural (neuromelanin) and functional integrity of the LC by MRI [Time frame: 24 months]
• comparison between APOe4+ and APOe4: Cognitive performance [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• Participant in the INSPIRE-T cohort
• Normal cognitive assessment
• MMSE score ≥ 27 out of 30 (Mini-Mental State Examination)
• Normal visual abilities (in corrected or uncorrected vision)
• Normal motor skills

Exclusion criteria

• Subjects with a contraindication to MRI exam
• Subjects with a known allergic reaction to the PET radiopharmaceutical (\[18F\] Flortaucipir) or any of its excipients
• Subjects with an ophthalmological pathology making oculometric measurements difficult
• Subjects with a neurodegenerative condition or a history of cerebral ischemia
• Subjects with a psychiatric disorder and a PHQ-9 score > 10 or under treatment with NRI

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

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

France · 1 center

• University Hospital of Toulouse — Toulouse

Identifiers

NCT: NCT07007208 · RC31/23/0371 · 2023-507668-38-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗