Clinical trial NCT07007208: 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.
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Alzheimer Disease
Keywords: PET
MRI
occulometry
locus coeruleus
Alzheimer disease
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2025-06-05
Enrollment: 100
Sex: ALL
Minimum age (years): 60
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single group with ApoE4 carriers (n=50) and non-ApoE4 carriers (n=50)
Primary purpose: DIAGNOSTIC

Brief summary: 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).

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 neurological or psychiatric pathologies

Primary outcomes:
measure: diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam
timeFrame: 24 monnths
Secondary outcomes:
measure: diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam for the APOe4- groups
timeFrame: 24 months
measure: diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam for the APOe4+ groups
timeFrame: 24 months
measure: The relationship between different LC biomarkers
timeFrame: 24 months
measure: The link between PET Tau uptake in pupillometry
timeFrame: 24 months
measure: The link between PET Tau uptake in oculometry
timeFrame: 24 months
measure: The link between PET Tau uptake in the structural (neuromelanin) and functional integrity of the LC by MRI
timeFrame: 24 months
measure: The link between variations in pupillometry
timeFrame: 24 months
measure: The link between variations in occulometry
timeFrame: 24 months
measure: The link between variations in the structural (neuromelanin) and functional integrity of the LC by MRI
timeFrame: 24 months
measure: The relationship between the various LC biomarkers (PET, MRI, pupillometry) and participants' cognitive performance
timeFrame: 24 months
measure: comparison between APOe4+ and APOe4-: Structural (neuromelanin) and functional integrity of the LC by MRI
timeFrame: 24 months
measure: comparison between APOe4+ and APOe4: Cognitive performance
timeFrame: 24 months
measure: comparison between APOe4+ and APOe4-: Pupillometry and oculometry
timeFrame: 24 months
measure: The reliability of the amplitude of the phasic pupil response during completion of cognitive tasks
timeFrame: 24 months
measure: The reliability of the latency of saccadic eye movements during completion of cognitive tasks
timeFrame: 24 months
measure: The reliability of the amplitude of saccadic eye movements during completion of cognitive tasks
timeFrame: 24 months
Other outcomes:
Locations:
city: Toulouse
country: France
facility: University Hospital of Toulouse
Study officials:
References: