Investigation of Neuronal Resilience Mechanisms in Alzheimer's Disease Using 18F-AV-1451 PET and MRI Imaging Techniques

Trial ID: 2024-519995-20-00
Protocol: C19-40
Sponsor: Institut National De La Sante Et De La Recherche Medicale

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of this study is to evaluate the **topographic distribution** of tau lesions in Alzheimer's disease using PET brain imaging with the ligand 18F-AV-1451. This is clinically relevant as it aims to correlate the distribution of tau lesions with cortical volume, integrity indices of white matter fascicles, functional neural networks, and the reorganization of network "hubs" through structural, diffusion (dMRI), and resting functional (fMRI) MRI imaging. Understanding these correlations is crucial for advancing the knowledge of Alzheimer's pathology and potentially improving diagnostic and therapeutic strategies.

Secondary objectives include:

The correlation between the concentration of tau and tau-phosphorylated proteins in the cerebrospinal fluid (CSF) with lesion load measured by PET, which is essential for characterizing the new ligand compared to validated CSF biomarkers.
The correlation between anatomical and functional connectivity to develop a predictive model of functional alterations based on structural changes in gray and white matter.
Identifying markers responsible for differences in the progression of the studied pathologies, distinguishing between slow and fast decliners.
Assessing the contribution of cognitive reserve to variations in clinical profiles and the rate of disease progression.

Participants

The clinical trial involves participants diagnosed with **Alzheimer's disease**, focusing on the topographic distribution of tau lesions. The study population includes both male and female subjects, with an age range that encompasses middle-aged to older adults. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on specific inclusion criteria, such as in vivo proof of Alzheimer's pathology through cerebrospinal fluid analysis or a positive PET-amyloid imaging test. The trial also includes a control group with normal neurological and neuropsychological examinations, matched in age to the patients. The study population is considered vulnerable, and lifestyle factors such as diet and physical activity are not detailed in the available data.

Plans and Procedures

The clinical trial is designed to investigate the **mechanisms of neuronal resilience** in Alzheimer's disease and its focal variants through a combination of MRI and PET imaging. The study employs a **randomized, double-blind, controlled** trial design to ensure the reliability and validity of the results. The trial is expected to span from April 2022 to December 2028, with participant involvement lasting up to two years. The primary objective is to map the topographic distribution of tau lesions using PET brain imaging with **18F-AV-1451** as a ligand and to correlate these findings with various neuroimaging metrics, including cortical volume and white matter integrity.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as in vivo proof of Alzheimer's pathology and neuropsychological assessments. Follow-up visits will be scheduled periodically to monitor the progression of the disease and the effects of the intervention. These visits will include imaging assessments and evaluations of cognitive function. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to gather comprehensive data on the trial's endpoints.

The expected length of participant involvement is contingent upon adherence to the study protocol, with conditions for early termination including adverse reactions to the investigational product or withdrawal of consent. The trial's primary endpoints focus on the distribution of tau lesions and their correlation with neuroimaging findings, while secondary endpoints examine the relationship between tau protein concentrations in cerebrospinal fluid and hypometabolism severity. The trial is not classified as low intervention and is categorized as a Phase II study, emphasizing its exploratory nature in understanding Alzheimer's disease pathology.

Treatment

The clinical trial involves the administration of **18F-AV-1451**, a radiopharmaceutical used for positron emission tomography (PET) imaging. The active substance in this experimental medication is **flortaucipir (18F)**, a chemical compound designed to bind to tau protein deposits in the brain, which are characteristic of Alzheimer's disease. The pharmaceutical form of **18F-AV-1451** is a **solution for injection**, and it is administered via **intravenous injection**. The dosing regimen specifies a maximum daily dose of 240 MBq/ml and a maximum total dose of 480 MBq/ml, with a treatment period not exceeding two days. The administration of this compound is intended to facilitate the visualization of tau lesions in the brain, aiding in the study of neuronal resilience mechanisms in Alzheimer's disease and its focal variants.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the investigational use of **18F-AV-1451** to achieve the trial's objectives. Participant compliance with the dosing schedule is monitored to ensure the accuracy and reliability of the imaging results. The trial aims to correlate the distribution of tau lesions with various brain imaging indices, including cortical volume and the integrity of white matter fascicles, using advanced MRI techniques.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on the topographic distribution of **tau lesions** using PET brain imaging with 18F-AV-1451 as a ligand. Additionally, the correlation between the distribution of these tau lesions and various brain structures and functions will be evaluated. This includes assessing cortical volume, the integrity of white matter fascicles, functional neural networks, and the reorganization of network "hubs" using structural MRI, diffusion MRI (dMRI), and resting functional MRI (fMRI) imaging.

Secondary endpoints will involve the correlation between the concentration of tau and tau-phosphorylated proteins in cerebrospinal fluid (CSF) and the severity of hypometabolism as measured by tau-PET. This correlation will be established by comparing cortico-cerebellar indices of tau protein radioligand fixation in PET with the concentration of tau proteins in the CSF. Additionally, the study will examine the correlation between anatomical and functional connectivity.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Affiliation to a social security insurance or beneficiary Informed consent form signed by the participant or his / her legal/ - In vivo proof of Alzheimer's pathology: Determination of specific proteins on the cerebrospinal fluid (CSF, a routine care procedure). The values considered pathological (AD) are Aβ1-42 peptide <500 (μg / ml), and / or tau protein> 450 and phosphorylated tau protein> 60, IATI index <1, tau / Aβ protein ratios > 1.23 as well as phosphorylated tau protein / Aβ1-42> 0.211. And / or a positive PET-amyloid imaging test. Early-onset episodic memory deficit (<65 years), progressive onset with evidence of hippocampal amnesic syndrome at neuropsychological assessment. In memory tests, the amnesic hippocampal syndrome is defined by: a deficit of the free recall despite a reinforced encoding, an effectiveness of the indexing or an impairment of the recognition capabilities, the presence of intrusions. The presence during the tests of false memories spontaneous (intrusions) or provoked (false recognitions) is also very contributive to the definition of amnesic syndrome of the hippocampal type. PCA group selection Patients with a clinical and cognitive profile suggestive of PCA, characterized by: an in vivo proof of the Alzheimer pathology (see selection of the AD-Y group) a specific impairment of neuro-visual abilities, in the absence of major disorders of episodic memory (hippocampal) and executive functions. Two possible variants: occipito-temporal variant: visuo-perceptive deficit in the foreground, early onset and progressive worsening; lack of visual identification of objects, symbols, words or faces; biparietal variant: visuospatial deficit in the foreground, early settlement and progressive worsening; Gerstmann syndrome; Balint syndrome; gestural apraxia; visual-spatial neglect. Selection of the control subjects group Normal neurological and neuropsychological examinations. Control subjects will be matched in age to patients.

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Exclusion Criteria

Medical history of torsade de pointe or risk of torsade de pointes Contraindication to radiopharmaceutical injection: For precautions of safety of use of the radiopharmaceutical, a blood sample allowing to check the renal and hepatic functions will be realized before imagery. The delay between the sampling and the neuroimaging visit is left to the investigator's discretion based on the patient's biological results. In particular, the glomerular filtration rate will be calculated from the results obtained. In the event of renal insufficiency (GFR 30mL / min / 1.73m2), hepatic insufficiency or any other biological anomaly of grade 3 or higher detected during these analyzes, the participant will not be able to carry out PET imaging. In this case, the results of the analyzes will be sent to the doctor indicated by the participant. This evaluation, which involves a determination of serum creatinine, is part of the standard routine biological assessment performed in the context of cognitive disorders Inability to provide informed consent by participant or legal representative: Patient deprived of liberty by decision of justice or not benefiting from social cover. Person in the process of participating in another therapeutic research or in a period of exclusion from another research. Participants with a contraindication to MRI: pacemaker or cardiac defibrillator, implanted equipment activated by an electrical, magnetic or mechanical system, haemostatic clips of intracerebral aneurysms or carotid arteries , carriers of orthopedic implants. Contraindication to radiopharmaceutical injection: known hypersensitivity to the active substance or to any of the excipients, renal impairment (GFR 30mL / min / 1.73m2), hepatic insufficiency or any other biological abnormality of grade 3 or higher Person suffering from claustrophobia. Pregnancy (for women of childbearing age, a urine pregnancy test will be performed on the day of the inclusion visit and the PET-MRI examination). Any symptoms or biological values suggestive of a systemic disorder (renal, hepatic, cardiovascular, pulmonary) or any other medical conditions that could interfere with the interpretation of test results or compromise the health of patients. Person subject to a legal safeguard. Specific non-inclusion criteria for AD-Y and PCA patients: Sudden appearance of cognitive deficits. Gait disturbances, convulsions, major behavior modification. Focal alterations to neurological examination, extrapyramidal signs, hallucinations, fluctuations. cognitive. Psychiatric, cerebrovascular, metabolic, inflammatory pathology. Specific non-inclusion criteria for control subjects: Pathological neurological examination History of neurological disease (in particular ischemic stroke or neurodegenerative disease) or psychiatric illness (particularly severe depression, psychosis, or bipolar illness still requiring drug treatment at the time of inclusion) Physical affection that is serious or can interfere with cognitive functions.