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

NCT05911178 | Recruiting

• 1 other identifier: D23-P006
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 3

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.

Conditions

Alzheimer Disease

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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.

  24 months

• 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.

  24 months

Secondary Outcomes (7)

• 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

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

  24 months

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

  24 months

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

  24 months

• 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

Study Arms (3)

Early Onset Alzheimer's Disease (EOAD)

EXPERIMENTAL

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; Radiation: [18F]-DPA-714; Radiation: [18F]-RO-948

Late Onset Alzheimer's Disease (LOAD)

EXPERIMENTAL

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; Radiation: [18F]-DPA-714; Radiation: [18F]-RO-948

Controls

EXPERIMENTAL

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

Radiation: [11C]-UCB-J; Radiation: [18F]-DPA-714; Radiation: [18F]-RO-948; Radiation: [11C]-PiB

Interventions

[11C]-UCB-J RADIATION

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

Controls; Early Onset Alzheimer's Disease (EOAD); Late Onset Alzheimer's Disease (LOAD)

[18F]-DPA-714 RADIATION

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

Controls; Early Onset Alzheimer's Disease (EOAD); Late Onset Alzheimer's Disease (LOAD)

[18F]-RO-948 RADIATION

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

Controls; Early Onset Alzheimer's Disease (EOAD); Late Onset Alzheimer's Disease (LOAD)

[11C]-PiB RADIATION

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

Controls

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Progressive amnestic syndrome, associated or not with other cognitive impairments,
• CDR = 0.5 or 1
• 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
• 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.

You may not qualify if:

• 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
• Patient under guardianship or curatorship

Sponsors & Collaborators

• Centre Hospitalier St Anne: lead
• Roche Pharma AG: collaborator

Study Sites (3)

CHU de Lille

Lille, France

NOT YET RECRUITING

GHU Saint Anne Psychiatrie & Neurosciences

Paris, France

RECRUITING

CHU de Rouen

Rouen, France

NOT YET RECRUITING

MeSH Terms

Conditions

Alzheimer Disease; Neuroinflammatory Diseases

Interventions

1-((3-(methylpyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; 2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Marie SARAZIN, MD, Prof

  GHU Sainte-Anne

  PRINCIPAL INVESTIGATOR

• 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

  STUDY CHAIR

Central Study Contacts

Khaoussou SYLLA, MD, PhD

CONTACT

01.45.65.76.78; k.sylla@ghu-paris.fr

Viviane Awassi

CONTACT

v.awassi@ghu-paris.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This is a non-randomized, open label study including three groups; early onset AD, late onset AD, healthy controls.
• Purpose: SCREENING
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 12, 2023
• First Posted: June 20, 2023
• Study Start: October 18, 2023
• Primary Completion (Estimated): February 17, 2028
• Study Completion (Estimated): April 17, 2028
• Last Updated: June 13, 2024

Record last verified: 2024-06

Locations

FR (3)