The Generative Brain

Natural history study of preclinical genetic CJD, Tel Aviv (NCT05746715)

A single-site natural history study at Tel Aviv Medical Center of E200K genetic CJD patients and their first-degree healthy relatives, carriers and non-carriers. It sits in the largest known at-risk E200K population and follows participants yearly for four years with MRI and lumbar puncture. It requires willingness to undergo genetic testing and does not share individual data.

Status as of 2026-10-16. Please check the study registry for the latest position.

Key facts

  • One site (Cognitive Neurology Unit, Tel Aviv Medical Center), recruiting; principal investigator Noa Bregman; individual participant data sharing is listed as no.
  • Population: the largest genetic CJD cluster is in Jews of Libyan and Tunisian ancestry carrying E200K; about 200,000 Libyan Jews live in Israel, the largest at-risk population in the world (the protocol's own estimate).
  • The Israeli National CJD database lists 423 patients with E200K of Libyan ancestry and 27 of Turkish ancestry, a second cluster, suggesting E200K arose on several independent haplotypes worldwide.
  • Groups and eligibility: genetic CJD patients and first-degree healthy relatives (carriers and non-carriers) of E200K patients; willingness to undergo genetic testing is required; relatives must be 50 or older (patients 18 or older); excluded are another clinically significant neurological disorder on prior MRI, MRI contraindications, anticoagulant use, conditions preventing a safe lumbar puncture and active malignancy (2023 protocol; current registry criteria not checked).
  • Procedures: healthy relatives have an in-depth visit at baseline and at the end of each year for four years (clinical evaluation, blood and urine, gait, 3T MRI, lumbar puncture, polysomnography) plus brief visits every six months; patients have a single in-depth visit.
  • First results (JNNP 2025): of 60 healthy relatives, 30 (50 percent) carried E200K; diffusion MRI abnormalities along white matter tracts were found in carriers with raised CSF total tau (above 290 pg/mL; 8 of the 23 carriers who had a lumbar puncture), but there were no significant differences between carriers and non-carriers overall and only six symptomatic patients were included; the authors suggest the changes may be an early biomarker and say longer follow-up is needed.
  • The protocol states the mutation is not necessarily sufficient for the formation and accumulation of abnormal prion protein (elsewhere it describes penetrance as approaching 100 percent), suggesting other genetic and non-genetic factors affect age at onset; the study aims to find biomarkers of preclinical CJD and risk factors for phenoconversion.
  • Earlier Israeli imaging work enrolled healthy carriers and non-carrier relatives to study the earliest brain changes (the 2005 abstract reports first results from seven participants), showing a long-running research tradition in this community.
  • The JNNP study was funded by Ionis Pharmaceuticals; competing interests are listed as none declared, and the protocol paper says Ionis funds the study through a centre grant without involvement in design, data collection, analysis or publication decisions.

Timeline

  1. 2005Earlier imaging study of healthy carriers described.
  2. 2022Israeli National CJD database report (423 Libyan and 27 Turkish E200K patients).
  3. 2023Registry listing updated.
  4. 2023BMC Neurology protocol published.
  5. 2025JNNP paper on white matter and tau in healthy E200K carriers.
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