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The main objective of this study is to investigate the central and peripheral inflammatory, as well as the spontaneous Aβ-specific, immune responses at the asymptomatic stage and early stages of AD by combining molecular imaging techniques with blood biomarker analyses. The early and preclinical stages of AD will be studied in the relatives of patients with PSEN1, PSEN2 or APP mutations that are at-risk (50%) to be mutation carriers. This study will evaluate the contribution of Inflammatory and immune anti-Aβ responses (I2ARs) in AD progression. Inclusion of sporadic and familial forms of AD will aid in studying the chronology of pathological events. Clinical follow-ups will be conducted annually for two years and will include an MRI and a blood draw on the last visit. We expect I2ARs to appear in the early stages of the disease and to constitute new prognostic factors. I2ARs could also become therapeutic markers for the assessment of novel anti-amyloid treatments and may offer new insights to the development of Aβ-specific immunotherapy strategies.
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Introduction: Alzheimer's disease (AD) is characterized by abnormal β-amyloid deposition associated with Tau-based neurofibrillary tangles. The metabolism of these proteins is modulated by the individuals physiological background. In addition to genetic factors, early brain inflammation and the presence of a spontaneous beta amyloid (Aβ)-specific immune response are likely to have an important influence on amyloid pathogenesis, as demonstrated in recent neuropathological and experimental studies. In vivo measurements of the β-amyloid load and brain inflammation have become available with the development of new tracers for positron emission tomography (PET) imaging. So far, tracers for brain inflammation have had a limited ability to detect changes in the expression of peripheral benzodiazepine receptors (PBR), which are mainly present on the surface of activated microglial cells. The recently developed [18F]DPA-714 was found to be a better ligand for PBR than previous tracers. Inflammatory and immune anti-Aβ responses (I2ARs) are likely to occur very early in the pathogenic protein cascade. They could thus constitute early markers for AD diagnosis and also play key roles in its phenotypic presentation and as prognostics. Comparing sporadic AD and familial forms of AD caused by APP, PSEN1 or PSEN2 mutations (in both symptomatic and at-risk non-symptomatic relatives) will aid in establishing the chronology of pathological events and defining their clinical impact.
The main objective of this study is to investigate the central and peripheral inflammatory, as well as the spontaneous Aβ-specific, immune responses at the asymptomatic stage and early stages of AD by combining molecular imaging techniques with blood biomarker analyses. The early and preclinical stages of AD will be studied in the relatives of patients with PSEN1, PSEN2 or APP mutations that are at-risk (50%) to be mutation carriers.
The secondary objectives are
Methodology : We propose to conduct a multimodal study, first transversal, then longitudinal with a two year follow-up, based on
Recruitment of sporadic AD patients and controls will occur at the Pitie-Salpetriere Hospital. Teams of geneticists from Paris and Rouen will recruit patients with known mutations and at-risk asymptomatic first-degree relatives. Every subject will undergo the following examinations: (a) at the Pitie-Salpetriere Hospital, a clinical and neuropsychological assessment, a 3T multimodal research MRI, and a blood draw 8 for studying a panel of plasmatic markers, measuring the blood level of anti-Aβ antibodies, evaluating Aβ-specific T lymphocyte responses and studying potential genetic modifiers; and (b) at the ORSAY Hospital, two PET scans will be performed on the same day: first an [11C]-PIB PET scan, followed 3 hours later by an [18F]DPA-714 imaging. Clinical follow-ups will be conducted annually for two years and will include an MRI and a blood draw on the last visit.
The previous study BIOMAGE, funded by the French National Research Agency (ANR 2007), has demonstrated the logistical feasibility of the project as well as the efficiency of patient and control recruitment. The subjects that were included in BIOMAGE will be invited to participate in this research project, thus utilizing this cohort for DPA imaging and I2AR markers. The duration of the research will be four years.
Expected results and perspectives: This study will evaluate the contribution of I2ARs in AD progression. Inclusion of sporadic and familial forms of AD will aid in studying the chronology of pathological events. We expect I2ARs to appear in the early stages of the disease and to constitute new prognostic factors. I2ARs could also become therapeutic markers for the assessment of novel anti-amyloid treatments and may offer new insights to the development of Aβ-specific immunotherapy strategies.
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Inclusion and exclusion criteria
Inclusion criteria :
Sporadic AD patients at a prodromal stage:
Be older than 30 years old.
Progressive amnestic syndrome of the hippocampal type, defined by a free recall score
≤ 18 and a total recall score ≤ 40 on the Free and Cued Selective Recall Reminding Test (FCSRT).
Absence of overt dementia.
CDR (Clinical Dementia Rating Scale) = 0.5.
No impact on activities of daily living, or only one item impaired at the first level of the Instrumental Activity of Daily Living Scale.
Absence of general or systemic disorders that may interfere with cognition.
Absence of brain lesions as determined by MRI that may account for part of the clinical presentation.
Sporadic AD patients at a mild to moderate dementia stage:
Normal controls :
Familial symptomatic AD patients with PSEN1, PSEN2 or APP mutations:
Relatives at 50% risk of familial AD:
Familial frontotemporal dementia (FTD) patients :
Concomitant therapy :
Subjects taking acetylcholinesterase inhibitor or memantine will be admitted.
Exclusion criteria :
125 participants in 5 patient groups
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Data sourced from clinicaltrials.gov
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