In Vivo Analysis of Microglial Activation and Tau Pathology in Alzheimer's Disease Using [18F]-DPA-714, [18F]-Ro948, and [11C]-UCB-J PET Tracers

The primary objective of this study is to analyze, 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). The study also aims to assess their consequences on synaptic density using [11C]-UCB-J, a recent PET radioligand. Understanding this interaction is clinically relevant as it may provide insights into the pathophysiological mechanisms underlying AD, potentially guiding the development of targeted therapeutic strategies.

Secondary objectives include:

• Longitudinal analysis of the regional alteration of radiotracer binding between baseline and 2-year follow-up imaging.
• Studying the role of global and regional tau deposition on the rapidity of AD progression after one and two-year follow-up.
• Investigating the impact of global and regional synaptic density on AD progression speed over the same period.
• Assessing peripheral and CSF immune biomarkers through broad-spectrum immunophenotyping and functional studies.
• Comparing central and systemic inflammation, tau load, and synaptic density between early and late-onset sporadic AD.
• Determining clinical, biological, and imaging markers of prognosis on disease evolution over a 2-year follow-up.
• Analyzing correlations between clinical/cognitive assessments and molecular PET imaging.
• Examining correlations between clinical and neuropsychological data and the profile of regional atrophy and other MRI markers.
• Exploring the role of ApoE genotypes in molecular imaging and AD progression profile.
• Assessing atrophy of the nucleus basalis of Meynert and locus coeruleus and its relation with cognition at baseline and after 2 years of follow-up.

The clinical trial focuses on **Alzheimer's disease** and involves both male and female participants. The study population includes adults, with a specific emphasis on individuals older than 50 years. Participants are required to be in good general health, without any systemic disorders that could interfere with cognition or PET imaging analysis. The trial includes both patients with early-stage Alzheimer's disease and control subjects. For patients, the onset of Alzheimer's disease is categorized as either early-onset (EOAD) if it occurs at or before 65 years of age, or late-onset (LOAD) if it occurs after 65 years. Control subjects must have normal memory function, as indicated by specific cognitive test scores, and be free from subjective memory problems. The trial does not involve a vulnerable population. Unfortunately, the sponsor has not provided information regarding the total number of participants. Key lifestyle considerations, such as diet and physical activity, are not specified in the available data.

The clinical trial is designed to evaluate the interplay between microglial activation and tau pathology in **Alzheimer's disease** using **Position Emission Tomography (PET)** imaging. This study employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The trial is expected to span from October 2023 to April 2028, with participant involvement lasting up to three months, depending on the specific investigational product administered. The study will utilize radiopharmaceuticals such as **18F-DPA-714**, **[18F]RO6958948**, **[11C]PiB**, and **11C-UCB-J**, administered via **intravenous injection** or **infusion**.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, cognitive function, and absence of systemic disorders. This visit will include a comprehensive medical evaluation and informed consent process. Following successful screening, participants will attend baseline visits where initial imaging and clinical assessments are conducted. Subsequent follow-up visits will occur at regular intervals to monitor the progression of the disease and the effects of the investigational products. The end-of-study visit will involve final assessments to evaluate the primary and secondary endpoints, including the correlation between the tracers and synaptic density changes.

The primary endpoint will assess the degree of correlation at baseline between the tracers expressed in **SUVr** using **Kendall's Tau test**. Secondary endpoints will involve a multivariate approach using the **Mixed Model Repeated Measures (MMRM)** to evaluate the longitudinal evolution of clinical and instrumental parameters. Participants may be withdrawn from the study if they experience adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **18F-DPA-714**, a radiopharmaceutical used for imaging purposes. This compound is provided in the form of an **injection** and is administered via **intravenous injection**. The active substance in 18F-DPA-714 is **N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide**. The maximum daily dose is 60 MBq, with a total maximum dose of 180 MBq over a treatment period of up to 3 days. Participant compliance is monitored through standard clinical trial procedures.

Another investigational product used in the study is **[18F]RO6958948**, also known as **2-(6-[18F]fluoro-pyridin-3-yl)-9H-dipyrido[2,3-b:3',4'-d]pyrrole**. This compound is formulated as a **solution for injection** and is administered intravenously. The maximum daily dose is 90 MBq, with a total maximum dose of 180 MBq over a 3-day period. The administration schedule is designed to ensure optimal imaging results, and adherence is tracked through routine trial assessments.

The study also utilizes **[11C]PiB**, a radioligand provided as a **solution for infusion**. The active substance is **(N-methyl-(11C))2-(4'-methylaminophenyl)-6-hydroxybenzothiazole**. This compound is administered via intravenous injection, with a maximum daily and total dose of 300 MBq, administered over a single day. The infusion is carefully monitored to ensure participant safety and data integrity.

Additionally, **11C-UCB-J** is employed in the trial, formulated as a **solution for injection**. The active substance is **(4R)-1-[(3-(11C)methylpyridin-4-yl)methyl]-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one**. This compound is administered intravenously, with a maximum daily dose of 150 MBq and a total maximum dose of 300 MBq over a 2-day period. Compliance with the dosing schedule is ensured through standard monitoring protocols.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial. The focus is on the investigational radiopharmaceuticals and their role in imaging and assessing synaptic density in Alzheimer's disease. All substances are of chemical origin, and their administration is conducted under strict clinical trial guidelines to ensure participant safety and data accuracy.

The clinical trial aims to assess the efficacy of radiopharmaceutical tracers in evaluating microglial activation and synaptic density in patients with Alzheimer's disease. The primary efficacy endpoint involves measuring the degree of correlation at baseline between the tracers **[18F]-DPA-714**, **[18F]-Ro948**, and **[11C]-UCB-J**. This correlation will be expressed in Standardized Uptake Value ratios (SUVr) and analyzed using Kendall's Tau test. The secondary efficacy endpoint will utilize a multivariate approach with the Mixed Model Repeated Measures (MMRM) to evaluate the longitudinal evolution of clinical and instrumental parameters. These analyses will be adjusted for clinical and demographic characteristics at baseline.