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

Phase 2

Not yet recruiting

• Conditions: Alzheimer Disease
• Interventions: Drug: a positon emission tomography (PET) exam; Other: MRI Contrast; Other: oculometry assessment; Other: cognitive exams

• Registration Number: NCT07007208
• Lead Sponsor: University Hospital, Toulouse

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).

Study Timeline

• Status Verified: 2025-05
• Study First Submitted: 2025-05-12
• Study First Submitted QC: 2025-05-28
• Last Update Submitted: 2025-05-28
• Study Start: 2025-06-01
• Study First Posted: 2025-06-05
• Last Update Posted: 2025-06-05
• Primary Completion: 2029-01-31
• Study Completion: 2029-01-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 100

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
experimental arm	a positon emission tomography (PET) exam	TEP exam, MRI exam, oculometry assessment and cognitive tasks
experimental arm	MRI Contrast	TEP exam, MRI exam, oculometry assessment and cognitive tasks
experimental arm	oculometry assessment	TEP exam, MRI exam, oculometry assessment and cognitive tasks
experimental arm	cognitive exams	TEP exam, MRI exam, oculometry assessment and cognitive tasks

Primary Outcome Measures

Name	Time	Method
diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam	24 monnths	The diagnostic capabilities (sensitivity, specificity and AUC) of each of the elements of oculometry (pupillary response, number, latency and amplitude of ocular saccades), functional MRI (LC-hippocampus and LC-prefrontal cortex) and structural MRI (LC intensity) for a positive PET-Tau examination

Secondary Outcome Measures

Name	Time	Method
diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam for the APOe4- groups	24 months	The diagnostic capabilities (sensitivity, specificity and AUC) of each of the elements of oculometry (pupillary response, number, latency and amplitude of ocular saccades), functional MRI (LC-hippocampus and LC-prefrontal cortex) and structural MRI (LC intensity) for a positive PET-Tau examination in APOe4- patients
diagnostic capabilities of Locus Coeruleus biomarkers for a positive PET-Tau exam for the APOe4+ groups	24 months	The diagnostic capabilities (sensitivity, specificity and AUC) of each of the elements of oculometry (pupillary response, number, latency and amplitude of ocular saccades), functional MRI (LC-hippocampus and LC-prefrontal cortex) and structural MRI (LC intensity) for a positive PET-Tau examination in APOe4+ patients
The relationship between different LC biomarkers	24 months	this will be evaluated by correlation and regression. The correlations will be performed both together and separately in the APOe4 status. The impact will be assessed by linear and logistic regression and will also take into account age, gender, and education level.
The link between PET Tau uptake in pupillometry	24 months	this will be assessed by the correlation between variations expressed in absolute value or as a proportion of the baseline value and Tau marking, and by regression at 12 and 24 months.. The correlations will be performed both together and separately in the APOe4 status, and the regression will also take into account age, gender, and education level.
The link between PET Tau uptake in oculometry	24 months	this will be assessed by the correlation between variations expressed in absolute value or as a proportion of the baseline value and Tau marking, and by regression. The correlations will be performed both together and separately in the APOe4 status, and the regression will also take into account age, gender, and education level.
The link between PET Tau uptake in the structural (neuromelanin) and functional integrity of the LC by MRI	24 months	this will be assessed by correlating variations expressed as absolute values or as a proportion of the baseline value with PET Tau, and by regression at 12 and 24 months.
The link between variations in pupillometry	24 months	this will be assessed by the correlation between variations expressed in absolute value or as a proportion of the baseline value, and by regression at 12 and 24 months.. The correlations will be performed both together and separately in the APOe4 carrier and non-carrier groups, and the regression will also take into account age, gender, and education level.
The link between variations in occulometry	24 months	this will be assessed by the correlation between variations expressed in absolute value or as a proportion of the baseline value, and by regression at 12 and 24 months. The correlations will be performed both together and separately in the APOe4 carrier and non-carrier groups, and the regression will also take into account age, gender, and education level, at 12 and 24 months
The link between variations in the structural (neuromelanin) and functional integrity of the LC by MRI	24 months	this will be evaluated by correlation between variations expressed as absolute values or as a proportion of the baseline value and by regression at 12 and 24 months
The relationship between the various LC biomarkers (PET, MRI, pupillometry) and participants' cognitive performance	24 months	this will be assessed both at inclusion and at 12 and 24 months, using regressions that take into account age, gender, level of education and APOe4 status.
comparison between APOe4+ and APOe4-: Structural (neuromelanin) and functional integrity of the LC by MRI	24 months	this Will be assessed both at inclusion, at 12 months, and at 24 months, through regressions that will take into account age, gender, and education level.
comparison between APOe4+ and APOe4: Cognitive performance	24 months	this Will be assessed both at inclusion, at 12 months, and at 24 months, through regressions that will take into account age, gender, and education level.
comparison between APOe4+ and APOe4-: Pupillometry and oculometry	24 months	this Will be assessed both at inclusion, at 12 months, and at 24 months, through regressions that will take into account age, gender, and education level.
The reliability of the amplitude of the phasic pupil response during completion of cognitive tasks	24 months	This will be validated by intraclass correlation between baseline value and value at one month (test-retest) in a subgroup of 30 participants.
The reliability of the latency of saccadic eye movements during completion of cognitive tasks	24 months	This will be validated by intraclass correlation between baseline value and value at one month (test-retest) in a subgroup of 30 participants.
The reliability of the amplitude of saccadic eye movements during completion of cognitive tasks	24 months	This will be validated by intraclass correlation between baseline value and value at one month (test-retest) in a subgroup of 30 participants.

Trial Locations

Locations (1)

University Hospital of Toulouse; 🇫🇷 Toulouse, France