A Natural History Study of Preclinical Genetic Creutzfeldt-Jakob Disease (CJD)

Study Overview
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Brief Summary
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Creutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrPsc), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion. The study includes two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year (for 4 years), healthy participants are invited for an in-depth visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture, and Polysomnography sleep lab (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a brief visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one in-depth visit, similar to the baseline visit of healthy relatives.

Official Title
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A Natural History Study of Preclinical Genetic Creutzfeldt-Jakob Disease (CJD)

Conditions
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Creutzfeldt-Jakob Disease (CJD)

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First--degree relative of an E200K gCJD patient. Age 50 years or older at baseline. Willingness to undergo genetic testing. Ability to provide written informed consent under GCP, ICH, and local regulations. Willingness and ability to comply with scheduled visits, required study procedures, and laboratory tests. Exclusion Criteria: a clinical diagnosis of CJD Any other medical or psychiatric condition or laboratory abnormality, which in the opinion of the investigator might preclude participation. Previously obtained MRI scan with evidence of clinically significant neurological disorder other than CJD. Current anticoagulant treatment (e.g Non-vitamin K Antagonist Oral Anticoagulants (NOACs), Warfarin, Low Molecular weight Heparin) that might preclude safe completion of LP. Conditions that preclude the safe performance of LP, such as severe lumbar spinal disease, bleeding diathesis, or clinically significant coagulopathy or thrombocytopenia. Conditions that preclude the safe performance of MRI scannings such as subjects who have a pacemaker, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin, or body, or any other known contra-indication for MRI. Active malignant disease.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| genetic Creutzfeldt-Jakob Disease (CJD) patients<br>A group of patients diagnosed with CJD, who are carriers of E200K mutation in the PRNP gene (gCJD) | |
| Healthy first degree relatives<br>A group of first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Existence of pathological Prion Protein (PrP) in CSF of mutation carriers | CSF fluid obtained through yearly lumbar puncture of healthy relatives will be explored for the existence of PrP using RTQuic | 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Diffusion Tensor Imaging collected using yearly MRI scans in healthy relatives | Analysis of Diffusion Tensor Imaging (DTI) is expected to reveal lower diffusivity and higher fraction anisotropy in prodromal gCJD | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Creutzfeldt-Jakob Disease, Prion disease, E200K mutation