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Thursday, December 20, 2018

Prion Seeds Spotted in Eyes of Sporadic Creutzfeldt-Jakob Disease Patients


Patients with sporadic Creutzfeldt-Jakob disease (sCJD), a rare and fatal brain disorder, typically begin to manifest symptoms when the condition has rapidly progressed. Within a year of diagnosis, most patients die from the neurodegenerative disease. Now, a small postmortem study, published online on November 20 in mBio, suggests eye tests may help detect the early stages of sCJD.

The study authors found high levels of prions in the eyes of 11 deceased patients with sCJD.

"Visual disturbances are a common early presenting symptom of sCJD," but yet the "distribution and levels of prions throughout the eye remain unknown," the researchers, led by Christina J. Sigurdson, DVM, PhD, professor of pathology, director of women in health sciences, and co-director of the Center for Veterinary Sciences and Comparative Medicine at UC San Diego, wrote.

Prions, misfolded proteins that become pathogenic, produce lesions that can induce rapidly progressive neurodegeneration when accumulated in the brain. The sporadic form of the disease, sCJD, accounts for 85 percent of cases.

The 11 sCJD patients, including seven women and four men, had agreed to donate their eyes upon death.  The researchers compared their findings with a control group  of two participants who died from Alzheimer's disease and four others from nonneurological causes.

Using real-time quaking-induced conversion assay (RT-QuIC), the researchers examined PrPSc seeding activity — the cause of prion disease — in extraocular muscle, optic nerve, cornea, lens, vitreous fluid, retina, choroid, and sclera.

The participants who had sCJD also underwent brain magnetic resonance imaging (MR)  and cerebrospinal fluid analysis. These participants had shown clinical signs sCJD for an average of 11 months. Three of the 11 sCJD participants had visual disturbances, such as transient monocular blindness, blurry or double vision, and impaired visuospatial skills.

No visual field deficits were reported.

The study found prion seeding in all cornea samples, with some levels as high as those in the brain. The study also found prion seeding in all other ocular tissues—although at levels up to four-fold lower than in the brain or cornea—including in the lens, ocular fluid, retina, choroid, sclera, optic nerve, and extraocular muscle.

The researchers also confirmed sCJD diagnosis by PRPSc detection in the brain where levels of the protein varied among brain regions in patients. The thalamus and occipital cortex accumulated high levels of PrPSc, while cerebellum contained the lowest levels in eight out of 10 patients.

"The retina consistently showed the highest seed levels, which in some cases were only slightly lower than brain," the researchers wrote.

Overall, they believe their findings indicate that sCJD patients do accumulate prion seeds throughout the eye, and this could be a potential biomarker and diagnostic tool for the disease. The findings also highlights a possible biohazard since surgical equipment can be an avenue for transmission.

The study was supported by National Institutes of Health grants, the Michael J. Homer Family Fund, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), the Equity in Brain Health at the Global Brain Health Institute, and a gift to NIAID from Mary Hilderman Smith, Zoë Smith Jaye, and Jenny Smith Unruh in memory of Jeffrey Smith.

Dr. Sigurdson served on the scientific advisory board of Amydis, Inc.


Orru CD, Soldau K, Cordano C, et al. Prion seeds distribute throughout the eyes of sporadic Creutzfeldt-Jakob disease patients. mBio 2018; Epub 2018 Nov 20.