Mechanisms of Neuronal Resilience in Alzheimer's Disease and Its Focal Variants: a Mri/Tep Study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut National De La Sante Et De La Recherche Medicale

Participant type

Healthy volunteers, Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]

Decision date (initial)

2025-01-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-519995-20-00

EudraCT number

2019-002694-63

ClinicalTrials.gov

NCT04150198

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Diagnosis

- The topographic distribution of tau lesions, thanks to PET brain imaging using
18F-AV-1451 as ligand.
- The correlation between the distribution of these tau lesions and: the cortical volume, the integrity indices of the fascicles of white matter, functional neural networks, as well as the reorganization of the “hubs” of these networks, using structural, diffusion (dMRI) and resting functional (fMRI) MRI imaging.

Secondary objectives 4

1. The correlation between the concentration of tau and tau-phosphorylated proteins in the cerebrospinal fluid (CSF) with the lesion load measured by PET. Indeed, this comparison is a key element in characterizing this new ligand compared to widely validated CSF biomarkers;
2. The correlation between anatomical and functional connectivity, in order to obtain a predictive model of alterations functional on the basis of structural alterations of gray matter and white matter.
3. The markers at the origin of the differences in the evolution of the pathologies studied (slow decliner versus decliner fast)
4. The contribution of cognitive reserve to differences in clinical profiles as well as to the speed of evolution of the disease

Conditions and MedDRA coding

Maladie d' Alzheimer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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.

Exclusion criteria 1

1. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1) The topographic distribution regions of tau lesions, thanks to PET brain imaging using the 18F-AV-1451 as a ligand. 2) The correlation between the distribution of these tau lesions and: the cortical volume, the indices of integrity of the white matter bundles, the functional neural networks, as well as the reorganization of the "hubs" of these networks, thanks to the structural MRI, diffusion (MRI) and functional at rest (fMRI) imaging

Secondary endpoints 1

1. Correlation between the concentration of tau and tau-phosphorylated proteins in cerebrospinal fluid (CSF) with the severity of hypometabolism measured by tau-PET. To establish this correlation the evaluation criterion is represented on one side by the cortico-cerebellar indices of fixation of the tau protein radioligand in PET, on the other side by the concentration of tau proteins in the CSF and tau-phosphorylated. Correlation between anatomical and functional connectivity.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut National De La Sante Et De La Recherche Medicale

Sponsor organisation

Institut National De La Sante Et De La Recherche Medicale

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Institut National De La Sante Et De La Recherche Medicale

Contact name

Raffaella MIGLIACCIO

Public contact point

Organisation

Institut National De La Sante Et De La Recherche Medicale

Contact name

MIGLIACCIO Raffaella

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications