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

Primary Purpose

Alzheimer Disease

Status

Not yet recruiting

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

[11C]-UCB-J

[18F]-DPA-714

[18F]-RO-948

[11C]-PiB

About this trial

This is an interventional screening trial for Alzheimer Disease focused on measuring Neuroinflammation, Microglial activation, Synaptic density, Tau pathology, Peripheral immunity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

CHU de Lille
GHU Saint Anne Psychiatrie & Neurosciences
CHU de Rouen

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Early Onset Alzheimer's Disease (EOAD)

Late Onset Alzheimer's Disease (LOAD)

Controls

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Change in regional microglial activation and tau pathology from baseline at 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

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

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

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

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

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

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.

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

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.

Full Information

NCT ID

NCT05911178

First Posted

June 12, 2023

Last Updated

June 12, 2023

Sponsor

Centre Hospitalier St Anne

Collaborators

Roche Pharma AG

1. Study Identification

Unique Protocol Identification Number

NCT05911178

Brief Title

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

Acronym

GliSyn

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

July 1, 2023 (Anticipated)

Primary Completion Date

July 2027 (Anticipated)

Study Completion Date

July 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Centre Hospitalier St Anne

Collaborators

Roche Pharma AG

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer Disease

Keywords

Neuroinflammation, Microglial activation, Synaptic density, Tau pathology, Peripheral immunity

7. Study Design

Primary Purpose

Screening

Study Phase

Not Applicable

Interventional Study Model

Sequential Assignment

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.

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.

Allocation

Non-Randomized

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Early Onset Alzheimer's Disease (EOAD)

Arm Type

Experimental

Arm Description

Arm Title

Late Onset Alzheimer's Disease (LOAD)

Arm Type

Experimental

Arm Description

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

Arm Title

Controls

Arm Type

Experimental

Arm Description

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

Intervention Type

Radiation

Intervention Name(s)

[11C]-UCB-J

Intervention Description

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

Intervention Type

Radiation

Intervention Name(s)

[18F]-DPA-714

Intervention Description

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

Intervention Type

Radiation

Intervention Name(s)

[18F]-RO-948

Intervention Description

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

Intervention Type

Radiation

Intervention Name(s)

[11C]-PiB

Intervention Description

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

Primary Outcome Measure Information:

Title

Change in regional microglial activation and tau pathology from baseline at 24 months

Description

Time Frame

24 months

Title

Change in regional synaptic density from baseline at 24 months

Description

Time Frame

24 months

Secondary Outcome Measure Information:

Title

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

Description

Global and regional cortical [18F]-DPA-714 uptake ratio.

Time Frame

24 months

Title

Identification of peripheral and CSF immune biomarkers across all participants at baseline, at 1 year, and at 2 years

Description

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.

Time Frame

24 months

Title

Rate of clinical disease progression as impacted by global and regional tau deposition at baseline, at 1 years, and at 2 years

Description

Time Frame

24 months

Title

Rate of clinical disease progression as impacted by global and regional synaptic density at baseline, at 1 years, and at 2 years

Description

Time Frame

24 months

Title

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

Description

Global and regional cortical [18F]-DPA-714 uptake ratio across the patient groups.

Time Frame

24 months

Title

Correlation of the rate of clinical decline with the rate of PET tracer uptake increase at 24 months across all patients.

Description

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

Time Frame

24 months

Title

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

Description

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.

Time Frame

24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Khaoussou SYLLA, MD, PhD

Phone

01 45 65 76 78

k.sylla@ghu-paris.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Viviane Awassi

Phone

01 45 65 84 86

v.awassi@ghu-paris.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Marie SARAZIN, MD, Prof

Organizational Affiliation

GHU Sainte-Anne

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Guillaume DOROTHEE, PhD

Organizational Affiliation

INSERM UMRS 938

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Michel BOTTLAENDER, PhD

Organizational Affiliation

Service Hospitalier Frédéric Jolit / CEA

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Marie Claude POTIER, PhD

Organizational Affiliation

Institut du Cerveau et de la Moelle épinière, Hôpital Pitié-Salpêtrière

Official's Role

Study Chair

Facility Information:

Facility Name

CHU de Lille

City

Lille

Country

France

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Thibaud LEBOUVIER, MD

thibaud.lebouvier@chu-lille.fr

First Name & Middle Initial & Last Name & Degree

Thibaud LEBOUVIER, MD

Facility Name

GHU Saint Anne Psychiatrie & Neurosciences

City

Paris

Country

France

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Simge OKSUM, MA

simge.oksum@ghu-paris.fr

First Name & Middle Initial & Last Name & Degree

Viviane AWASSI

Phone

01 45 65 84 86

v.awassi@ghu-paris.fr

First Name & Middle Initial & Last Name & Degree

Marie SARAZIN, MD, Prof

First Name & Middle Initial & Last Name & Degree

Pauline OLIVIERI, MD

First Name & Middle Initial & Last Name & Degree

Julien LAGARDE, MD

Facility Name

CHU de Rouen

City

Rouen

Country

France

Facility Contact:

First Name & Middle Initial & Last Name & Degree

David WALLON, MD

david.wallon@chu-rouen.fr

First Name & Middle Initial & Last Name & Degree

David WALLON, MD

12. IPD Sharing Statement

Learn more about this trial

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

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