GliSyn: Impact of Microglial Activation on Synaptic Density in Alzheimer's Disease

Sponsor

Centre Hospitalier St Anne (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05911178

Collaborator

Roche Pharma AG (Industry)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study aims to analyse, in vivo, the interplay between microglial activation and tau pathology in Alzheimer's disease (AD) using [18F]-DPA-714 and [18F]-Ro948 tracers by Position Emission Tomography (PET), and their consequences on synaptic density using [11C]-UCB-J, a recent PET radioligand.

By coupling advanced neuroimaging techniques in AD patients, while comparing them to controls, we will be able to study, for the first time in humans, the interaction between neuroinflammation, tau pathology, synaptic density, and their impact on AD progression. Joint analyses of peripheral immune biomarkers, carried out as a secondary objective, will further aim at defining peripheral correlates of this interplay.

Overall, we aim to refine AD subgroup classification in order to improve and to refine the design of new therapeutic trials.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Radiation: [11C]-UCB-J Radiation: [18F]-DPA-714 Radiation: [18F]-RO-948 Radiation: [11C]-PiB	N/A

Detailed Description

The present study aims to reevaluate the interplay between microglial activation, tau pathology, and synaptic density. It is an interventional, comparative, controlled, non-randomized study in which AD patients will be matched to controls. In order to better our current understanding of pathophysiological processes of neuroinflammation in AD, we will analyze regional microglial activation, cortical tau deposition, and synaptic dysfunction by employing multiple PET radioglands and MRI. The hybrid images will be acquired at baseline and at two years.

This study design opens the door to a multimodal study; first transversal (by determining whether the level and the extent of DPA-714 binding are associated with synaptic loss and tau deposition) then longitudinal (after a two-year follow-up based on PET/MRI, cognitive and clinical assessment and peripheral immune biomarkers). By using PET imaging at baseline and at two years, we will investigate the neuroinflammation dynamics in sporadic AD and its consequences on neurodegenerative biomarkers as well as its clinical repercussions.

Conservative diagnosis criteria based on clinical and CSF biomarkers have been established to avoid risks of misdiagnosis for the patients. The controls will undergo, at inclusion, an additional PiB-PET imaging to avoid bias and to identify amyloid positive controls.

A complete clinical and cognitive evaluation will accompany the image acquisation at baseline. The subjects will be followed up clinically at one year. At two years, another set of PET/MRIs will be performed as well as a cogntive evaluation. The image acquisations will be planned within 6 months of each clinical visit at baseline and at two years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Early and late onset AD subjects, matched to controls for age and education level, will be followed up for two years, allowing both longitudinal and cross-sectional comparisons.Early and late onset AD subjects, matched to controls for age and education level, will be followed up for two years, allowing both longitudinal and cross-sectional comparisons.

Masking:

None (Open Label)

Masking Description:

This is a non-randomized, open label study including three groups; early onset AD, late onset AD, healthy controls.

Primary Purpose:

Screening

Official Title:

Impact of Microglial Activation on Synaptic Density in Alzheimer's Disease

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2027

Anticipated Study Completion Date :

Jul 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early Onset Alzheimer's Disease (EOAD) Patients who have been diagnosed with AD according to clinical and biomarker criteria. Early onset AD is considered as having an age of onset of symptoms younger than 65 years. Age of onset ≤ 65 years	Radiation: [11C]-UCB-J PET tracer binding to "SV2A" protein, used to study synaptic vesiscle density. Radiation: [18F]-DPA-714 PET tracer binding to "TSPO" protein, used to study microglial activation. Radiation: [18F]-RO-948 PET tracer binding to "tau" protein, used to study the topograhpy of tau deposition.
Experimental: Late Onset Alzheimer's Disease (LOAD) Patients who have been diagnosed with AD according to clinical and biomarker criteria. Late onset AD is considered as having an age of onset of symptoms older than 65 years. Age of onset > 65 years	Radiation: [11C]-UCB-J PET tracer binding to "SV2A" protein, used to study synaptic vesiscle density. Radiation: [18F]-DPA-714 PET tracer binding to "TSPO" protein, used to study microglial activation. Radiation: [18F]-RO-948 PET tracer binding to "tau" protein, used to study the topograhpy of tau deposition.
Experimental: Controls Healthy control subjects will be matched to patients for age and education level.	Radiation: [11C]-UCB-J PET tracer binding to "SV2A" protein, used to study synaptic vesiscle density. Radiation: [18F]-DPA-714 PET tracer binding to "TSPO" protein, used to study microglial activation. Radiation: [18F]-RO-948 PET tracer binding to "tau" protein, used to study the topograhpy of tau deposition. Radiation: [11C]-PiB PET tracer binding to Aβ40 and Aβ42 fibrils and insoluble plaques containing the aforementioned Aß peptides, used to study the topography of amyloid deposition.

Arm

Intervention/Treatment

Experimental: Early Onset Alzheimer's Disease (EOAD)

Patients who have been diagnosed with AD according to clinical and biomarker criteria. Early onset AD is considered as having an age of onset of symptoms younger than 65 years. Age of onset ≤ 65 years

Radiation: [11C]-UCB-J

PET tracer binding to "SV2A" protein, used to study synaptic vesiscle density.

Radiation: [18F]-DPA-714

PET tracer binding to "TSPO" protein, used to study microglial activation.

Radiation: [18F]-RO-948

PET tracer binding to "tau" protein, used to study the topograhpy of tau deposition.

Experimental: Late Onset Alzheimer's Disease (LOAD)

Patients who have been diagnosed with AD according to clinical and biomarker criteria. Late onset AD is considered as having an age of onset of symptoms older than 65 years. Age of onset > 65 years

Radiation: [11C]-UCB-J

PET tracer binding to "SV2A" protein, used to study synaptic vesiscle density.

Radiation: [18F]-DPA-714

PET tracer binding to "TSPO" protein, used to study microglial activation.

Radiation: [18F]-RO-948

PET tracer binding to "tau" protein, used to study the topograhpy of tau deposition.

Experimental: Controls

Healthy control subjects will be matched to patients for age and education level.

Radiation: [11C]-UCB-J

PET tracer binding to "SV2A" protein, used to study synaptic vesiscle density.

Radiation: [18F]-DPA-714

PET tracer binding to "TSPO" protein, used to study microglial activation.

Radiation: [18F]-RO-948

PET tracer binding to "tau" protein, used to study the topograhpy of tau deposition.

Radiation: [11C]-PiB

PET tracer binding to Aβ40 and Aβ42 fibrils and insoluble plaques containing the aforementioned Aß peptides, used to study the topography of amyloid deposition.

Outcome Measures

Primary Outcome Measures

Change in regional microglial activation and tau pathology from baseline at 24 months [24 months]
The first primary endpoint will be evaluated and compared to baseline across all participants (patients and controls). The microglial activation and tau pathology will be measured respectively with [18F]-DPA-714 and [18F]-RO-948 binding rate at baseline and again at 24 months. The change will be calculated by comparing the baseline and 24-month uptake ratios.
Change in regional synaptic density from baseline at 24 months [24 months]
The second primary endpoint will be evaluated and compared to baseline across all participants (patients and controls). The synaptic density will be measured with [11C]-UCB-J. We hypothesize that both tau pathology and microglial activation will modulate regional synaptic density, which is responsible for clinical symptoms. The change will be calculated by comparing the baseline and 24-month uptake ratios.

Secondary Outcome Measures

Change in neuroimmune reaction as assessed by [18F]-DPA-714 PET global cortical index and regional cortical binding at baseline and at 24 months across all participants [24 months]
Global and regional cortical [18F]-DPA-714 uptake ratio.
Identification of peripheral and CSF immune biomarkers across all participants at baseline, at 1 year, and at 2 years [24 months]
Peripheral and CSF immune biomarkers will be identified by broad spectrum immunophenotyping in order to determine biological markers of prognosis on disease evolution over 1 and 2 years of follow-up.
Rate of clinical disease progression as impacted by global and regional tau deposition at baseline, at 1 years, and at 2 years [24 months]
Clinical presentation of symptoms will be mainly evaluated by the changes in MMSE (total score out of 30) and CDR (total score out of 3) scores. And it will be compared with the topography of tau deposition (measured by [18F]-RO-948) for each patient.
Rate of clinical disease progression as impacted by global and regional synaptic density at baseline, at 1 years, and at 2 years [24 months]
Clinical presentation of symptoms will be mainly evaluated by the changes in MMSE (total score out of 30) and CDR (total score out of 3) scores. And it will be compared with the synaptic density (measured by [11C]-UCB-J) for each patient.
Comparison of the rate of central and systemic inflammation between sporadic AD groups assessed by [18F]-DPA-714 PET global cortical index and regional cortical binding at baseline and at 24 months [24 months]
Global and regional cortical [18F]-DPA-714 uptake ratio across the patient groups.
Correlation of the rate of clinical decline with the rate of PET tracer uptake increase at 24 months across all patients. [24 months]
Global and regional uptake ratios will be compared to the rate of clinical decline as assessed by changes in MMSE (x/30) and CDR (x/3) scores
Correlation between the rate of clinical decline and the rate of regional atrophy as assessed by MRI scans at baseline and at 24 months across all participants [24 months]
Clinical decline is assessed by the changes in MMSE (x/30) and CDR (x/3) scores. MRI scans are performed simultaneously during hybrid PET-MRI scans.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

General Inclusion Criteria:

Adult (older than 18 years)
Women old enough to procreate under effective contraception
Signed consent
Absence of general or systemic disorders that may interfere with cognition.

Inclusion criteria for EOAD and LOAD patients:

Progressive amnestic syndrome, associated or not with other cognitive impairments,
CDR = 0.5 or 1 for EOAD; CDR = 0.5 for LOAD
Absence of general or systemic disorders that may interfere with cognition or PET imaging analysis,
Absence of brain lesions as determined by MRI carried out within the framework of usual care.
Presence of CSF biomarkers profile suggestive of AD
If the patient is under guardianship or curatorship, then the consent will be signed by the guardian or curator will be informed

Inclusion criteria for controls:

absence of subjective problems with memory and normal scores on the MMSE (MMSE > 27) with no more than one word missing.
older than 50 years old.
Scores on the Free and Cued Selective Reminding Test (FCSRT) of >25 for free recall and >44 for total recall.
absence of general or systemic disorders that may interfere with cognition at follow-up.

Controls will be matched to AD patients for age and education level.

Exclusion Criteria:

Subject with a psychiatric evolutionary and/or poorly checked pathology (left to the judgement of the investigator).
Subject with a grave, severe or unstable pathology (left to the judgement of the investigator) the nature of which can interfere with the variables of evaluation.
Current auto-immune disease
Subject presenting contraindications to the 3T MRI
Known or supposed histories (≤5 years) of severe alcoholism or misuse of drugs
Vascular, inflammatory or expansive, visible lesion in the MRI which can interfere on the criteria of diagnosis.
No health insurance
Pregnant, breast-feeding woman or planning a pregnancy in two years of follow-up.
Diagnosis or history of other possible etiology of dementia, including but not limited to other neurodegenerative disorders.
Person placed under the protection of justice

Contacts and Locations

Locations

	Site	City	Country
1	CHU de Lille	Lille	France
2	GHU Saint Anne Psychiatrie & Neurosciences	Paris	France
3	CHU de Rouen	Rouen	France

Sponsors and Collaborators

Centre Hospitalier St Anne
Roche Pharma AG

Investigators

Principal Investigator: Marie SARAZIN, MD, Prof, GHU Sainte-Anne
Study Chair: Guillaume DOROTHEE, PhD, INSERM UMRS 938
Study Chair: Michel BOTTLAENDER, PhD, Service Hospitalier Frédéric Jolit / CEA
Study Chair: Marie Claude POTIER, PhD, Institut du Cerveau et de la Moelle épinière, Hôpital Pitié-Salpêtrière