CIRAANO: Multimodal exploration (including radiopharmaceuticals Amyvid® and Tauvid®) of theater actors, memory athletes, and patients with various memory pathologies: evaluation of mnesic strategies and their cerebral substrates, and contribution to the treatment of memory pathologies.

The primary objective of this trial is to evaluate, in different categories of patients with memory disorders of various origins, the preservation or alteration of memory-related brain networks, associated with different types of memory strategies identified in memory experts. This objective addresses the clinical need to understand the neurobiological substrates underlying mnesic function and dysfunction across diverse patient populations, which may inform therapeutic approaches for memory pathologies.

The secondary objectives include:

• To assess the feasibility of this trial

• To assess the acceptability of the procedures by participants included in Part 1

• To identify the specific characteristics of theatre actors and memory athletes compared to controls, in terms of brain, cognitive, biological, and psycho-affective measures, as well as lifestyle factors, sleep, and alcohol consumption

• To identify the specific characteristics of various patient groups with memory disorders of different etiologies, compared to controls, theatre actors, and memory athletes, in terms of brain, cognitive, biological, and psycho-affective measures, lifestyle factors, sleep, and alcohol consumption, as well as inter-individual differences related to sex, age, and presence of risk factors

• To explore the relationships between brain, biological, cognitive, psycho-affective measures, and lifestyle factors including sleep and alcohol consumption across the different groups in order to deepen understanding of underlying pathophysiological mechanisms

• To identify the mechanisms driving the topography of brain pathology and the factors influencing its propagation over 10 to 20 years, in both controls and patients, with the aim of predicting disease progression using an artificial intelligence model

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population encompasses **adults** aged **18 years or older** across multiple participant categories, with specific age requirements varying by group: certain categories require participants to be aged **60 years or older**, while one category includes individuals aged **50 years or older**. Both **male** and **female** participants are included in the trial. The study population comprises several distinct groups, including healthy controls, memory athletes who have competed at international, European, or national levels, professional or freelance **actors** with at least five years of experience who have performed in theatre within the last three years, individuals with **subjective cognitive decline** in the context of preclinical **Alzheimer's disease**, patients with **mild cognitive impairment** due to Alzheimer's disease, patients with major **neurocognitive disorder** due to probable Alzheimer's disease, individuals with **Lewy body dementia** or prodromal Lewy body dementia, patients with **semantic variant primary progressive aphasia** (semantic dementia), individuals with **alcohol use disorder** who are detoxified and abstinent from psychoactive substances except tobacco and prescribed medication, patients with **organic amnesia syndrome** characterized by severe **episodic memory** deficits, and individuals diagnosed with type 1 **narcolepsy** according to established diagnostic criteria. Participants are recruited from memory clinics, addiction treatment services, hospital services, residential facilities, and the community. All participants must be native French speakers educated in French, have a minimum education level of seven years, be willing to undergo several days of assessments, and adhere to specified lifestyle considerations. Informants aged 18 years or older who spend at least one day per week with participating relatives are also included.

This clinical trial is a multimodal exploratory study investigating memory strategies and their cerebral substrates across multiple participant groups, including healthy controls, theater actors, memory athletes, and patients with various memory pathologies. The study involves the use of two radiopharmaceuticals: florbetapir (18F) and flortaucipir (18F), both administered as solution for injection via intravenous use. The maximum daily and total dose for each radiopharmaceutical is 370 megabecquerels, with a maximum treatment period of one day. The trial is categorized as a physiopathological study utilizing products outside the conditions of their marketing authorization in memory disorders, including healthy volunteers. The study design is classified as Phase IV and is not designated as a low-intervention clinical trial.

The primary objective of Part 2 of the trial is to evaluate the preservation or alteration of memory-related brain networks in different categories of patients with memory disorders of various origins, associated with different types of memory strategies identified in memory experts. The medical conditions under investigation include Alzheimer's disease, Lewy body dementia, semantic variant primary progressive aphasia, alcohol use disorder, organic amnesia syndrome, and narcolepsy. The primary endpoint for Part 2 Objective 1 consists of volume measurements from T1 magnetic resonance imaging and perfusion measurements from early-phase florbetapir (18F) positron emission tomography in four brain networks in each patient group and controls.

The trial includes multiple participant groups with specific eligibility criteria. All participants must be native French speakers educated in French, have a minimum education level of seven years, be affiliated with a French social security scheme, demonstrate willingness to undergo several days of assessments, adhere to lifestyle considerations, and provide signed informed consent. Healthy controls must be aged 18 years or older with neuropsychological performance within the normal range. Memory athletes must be aged 18 years or older and have participated in international, European, or national level memory competitions. Theater actors must be aged 18 years or older and have performed in at least one theater play in the last three years, with at least five years of professional acting experience. Patient groups include individuals with subjective cognitive decline, mild cognitive impairment due to Alzheimer's disease, major neurocognitive disorder due to probable Alzheimer's disease, probable Lewy body dementia or prodromal Lewy body dementia, semantic dementia, alcohol use disorder, non-degenerative amnesic syndromes, and type 1 narcolepsy, each with specific age and clinical criteria requirements.

The secondary endpoints encompass a comprehensive range of assessments. Part 1 Objective 1 evaluates the number of participants successfully completing all examinations necessary for the main judgment criterion. Additional secondary endpoints include acceptability scores, behavioral data from questionnaires, raw and composite scores from neuropsychological tests, directed forgetting task performance, ranking positions in memory sports classifications, theater experience metrics, gray matter volume measurements, hippocampal and thalamic volume and subfield analyses, locus coeruleus intensity values, cerebral perfusion measurements, diffusion tensor imaging parameters including fractional anisotropy and mean diffusivity, white matter lesion characteristics, functional brain connectivity, beta-amyloid burden measured using florbetapir (18F), neurofibrillary tangle or abnormally phosphorylated tau protein burden measured using flortaucipir (18F), functional magnetic resonance imaging brain activity during text learning tasks, electroencephalography data during passive listening and resting states, subjective and objective sleep measures including actigraphy and polysomnography, blood biomarkers, anthropometric and physical measures including electrocardiogram analysis, liver fibrosis measurement using Fibroscan, and informant-provided data regarding participants.

The estimated recruitment start date is November 2025, with an estimated study completion date of March 2036, indicating an overall trial duration of approximately 10 years. The expected length of participant involvement varies depending on the group and assessment schedule, requiring multiple days of comprehensive evaluations including neuropsychological testing, neuroimaging procedures with both radiopharmaceuticals, sleep studies, and various physiological measurements. Conditions that may lead to early termination from the study are not explicitly specified in the available data.

The investigational medicinal products utilized in this clinical trial consist of two radiopharmaceutical agents administered as diagnostic imaging tracers. Flortaucipir (18F) is formulated as a solution for injection and administered via intravenous use. The maximum daily dose is 370 megabecquerels (MBq), which also represents the maximum total dose per administration. The maximum treatment period is 1 day. This radiopharmaceutical tracer contains flortaucipir (18F) as the active substance of chemical origin and is employed for imaging purposes in volunteers as part of the multimodal exploration protocol.

Florbetapir (18F) is the second radiopharmaceutical agent used in this trial, also formulated as a solution for injection and administered via intravenous use. The dosing parameters are identical to flortaucipir (18F), with a maximum daily dose of 370 MBq and a maximum total dose of 370 MBq. The maximum treatment period is similarly 1 day. Florbetapir (18F) serves as an active substance of chemical origin and functions as a diagnostic imaging tracer for use in volunteers within the study framework.

Both radiopharmaceutical products are classified as test medications in this trial and are utilized for the evaluation of memory-related brain networks in various study populations. The single-day administration schedule reflects the diagnostic nature of these imaging agents, which are employed to assess cerebral substrates associated with memory strategies and pathologies.

Efficacy will be assessed through measurements of brain network volume and cerebral perfusion in patient groups and controls. Volume measurements will be obtained from T1 MRI, while perfusion measurements will be derived from early-phase Florbetapir (18F) PET imaging. These parameters will be evaluated across four brain networks in each patient group and in control participants.

Secondary assessments will include gray matter volume measured in each voxel of the brain, volume of the hippocampus and hippocampal subfields, volume of the thalamus and thalamic subregions, and mean intensity value of the locus coeruleus. Cerebral perfusion will be measured in each voxel of the brain. Additional imaging parameters will comprise fractional anisotropy, mean diffusivity, and mean kurtosis in each voxel of the brain, as well as the number, size, and location of white matter lesions. Functional brain connectivity will be evaluated. Beta-amyloid burden will be measured using Florbetapir (18F) in each voxel of the brain and as an overall mean in gray matter. Burden of neurofibrillary tangles or abnormally phosphorylated Tau protein will be assessed using Flortaucipir (18F), measured in each voxel of the brain and as an overall mean in the temporal region.

Neuropsychological and behavioral assessments will include raw scores from neuropsychological tests, composite scores by cognitive function and domain calculated from standardized z-scores, and scores from the directed forgetting task. Brain activity measured by fMRI will be evaluated during recall, encoding, and learning from the text learning task compared to control tasks. Data collected during EEG recording associated with passive listening tasks and spontaneous oscillatory activity in a resting state will be analyzed. Sleep measures will be obtained through sleep questionnaires, actigraphy, polysomnographic recordings, and the SomnoArt device. Blood measures, anthropometric and physical measures, and measurement of liver fibrosis using Fibroscan will be performed. Behavioral data will be collected using various questionnaires, and scores will be obtained on the acceptability scale.