The Generative Brain

Orru CD et al. 2018, Prion seeds distribute throughout the eyes of sporadic Creutzfeldt-Jakob disease patients (mBio 9:e02095-18)

A postmortem study from NIAID Rocky Mountain Laboratories, UC San Diego and the UCSF Memory and Aging Center that measured prion seeding activity with RT-QuIC in eight parts of the eye in 11 people who died of sporadic CJD and 6 controls. Every sCJD eye had seeding activity, the retina carried the most (in some cases close to brain levels), and every cornea had a low to moderate amount, while all control tissues were negative. The authors read this as a reason to explore the retina for diagnosis in life and to treat eye instruments and donated corneas with care. It is one of the main sources the atlas uses on prion seeding in the eye, and later work on retinal deposits, corneal graft risk and tear fluid testing cites it. Information only, not medical advice.

Key facts

  • Published in mBio volume 9 issue 6 as article e02095-18 on 20 November 2018 (received 2 October, accepted 4 October 2018); open access as PMC6247090, PMID 30459197.
  • Joint first authors were Christina Orru (NIAID Rocky Mountain Laboratories) and Katrin Soldau (UC San Diego); Michael Geschwind, Byron Caughey and Christina Sigurdson were corresponding authors, with Bradley Groveman, Jiri Safar and Jonathan Lin among the co-authors.
  • The series was 11 neuropathologically confirmed sCJD cases from the UCSF Memory and Aging Center with no PRNP mutation and no known iatrogenic exposure (codon 129 MM 5, MV 5, VV 1), plus 6 non-prion controls.
  • One eye per person was frozen for RT-QuIC on extraocular muscle, optic nerve, cornea, lens, vitreous, retina, choroid and sclera, and the other was fixed for immunohistochemistry; RT-QuIC used a hamster recombinant PrP substrate with endpoint dilution to estimate seeding doses.
  • Seeding activity was found in all 11 sCJD eyes and in none of the control tissues; the retina was highest, between 10 and 10,000 fold below brain, and close to brain in some cases.
  • All corneas had low to moderate seeding with little spread between people; the lens was negative in 3 cases and the vitreous in 1.
  • Immunohistochemistry found disease-associated PrP in the outer plexiform layer of the retina in 9 of 11 cases and in no other eye tissue; retinal seed level did not track age, sex, disease length, codon 129 genotype, subtype or visual symptoms.
  • The authors argue for single-use instruments or proper decontamination in eye procedures, support the WHO grouping of parts of the eye as high infectivity tissue, and call for research on synthetic corneal substitutes; they stress that seeding activity is not the same as measured infectivity and the samples are end-stage autopsy tissue.
  • Funding came from NIH grants, the NIAID intramural program, a family fund and a donation; Caughey declared an RT-QuIC patent licensed to Amprion.
  • Europe PMC listed 47 citing articles at read time, including work on retinal deposits, retinal imaging tracers, corneal transplant risk, ophthalmic surgery and tear fluid seeding.
  • A 2022 UC San Diego and Stanford follow-up in 14 sCJD cases confirmed that retinal prion deposits sit in the outer plexiform layer and differ in shape from brain deposits, and proposed this as a guide for eye imaging.
  • A 2020 US modelling study, which cites this paper, estimated that about 3.8 corneas from donors with undiagnosed CJD entered the 2018 US transplant pool and counted 10 reported corneal transmission cases worldwide; these are model estimates.
  • In 2026 the Goettingen group reported tear fluid RT-QuIC sensitivity of 85% in sCJD with a human E200K substrate, an eye surface sample route the 2018 authors had only pointed toward.
  • UK national CJD infection control guidance from the ACDP TSE subgroup includes an ophthalmology annex and guidance for ophthalmologists; no link from that guidance to this paper was checked.

Timeline

  1. 2018Manuscript received on 2 October and accepted on 4 October 2018.
  2. 2018Published in mBio on 20 November 2018.
  3. 2020Corneal transplant risk analysis citing the paper published in Ophthalmology and Therapy.
  4. 2022Retinal deposit morphometry study in 14 sCJD cases published in Experimental Eye Research.
  5. 2026Tear fluid RT-QuIC with a human E200K substrate published by the Goettingen reference centre.
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