Eye Testing May Aid Early Diagnosis of Creutzfeldt-Jakob Disease

Damian McNamara

November 28, 2018

Eye examinations may aid clinicians in the diagnosis of sporadic Creutzfeldt-Jacob disease (sCJD), results of a small postmortem study show.

In an evaluation of the eyes and brains of 11 sCJD patients, investigators found prion seeding in all eyes they tested, finding the highest levels of the infectious protein in the retina.

"In more than half the cases, prion seeding activities in retina were remarkably high and approached levels in brain, consistent with efficient prion conversion in neural tissue," the investigators, 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, write.

"Patients with prion disease often have visual symptoms, so neurologists and other physicians may consider these findings useful for developing new methods to diagnose prion disease," Sigurdson told Medscape Medical News.  

The study was published online November 20, 2018, in mBio.

Visual Symptoms, Blindness

CJD is the most common of the rapidly progressive neurodegenerative prion conditions. The sporadic form is caused by expression of PrPSc, an infectious misfolded and aggregated form of the cellular prion protein PrPC.

Visual disturbances can include diplopia, supranuclear palsies, and loss of vision.

By late stage disease, approximately 25% to 42% of sCJD patients develop blindness. Loss of eyesight may stem from spongiform lesions and PrPSc deposits in the lateral geniculate component of the thalamus and the primary visual cortex, the researchers note.

"Since the eyes are windows into the brain, we wanted to know whether prions were spreading from the brain into the eyes where they could potentially be detected in early stages of disease. We found that all patients with sporadic prion disease, 11 of 11, had accumulated prions in the eye, often at quite high levels," Sigurdson added.

For the study the investigators measured the frequency and level of prions in the eye to understand the transmission risk and determine the potential for diagnostic assays.

All patients presented to the UC San Francisco Memory and Aging Center for rapidly progressive neurologic disease. The prospective study ran between July 2015 and July 2017.

Mean age at disease onset was 63 years. The research included seven women and four men with sCJD who underwent brain MRI and cerebrospinal fluid analysis for 14-3-3, neuron-specific enolase and total tau. Participants experienced clinical neurologic signs for a mean of 11 months.

The investigators also enrolled a control group of one woman and five men, with a mean age of 70 years. Unlike the sCJD cohort, two control participants died from Alzheimer's disease, and four others died of nonneurologic causes.

Three of 11 cases had visual disturbances, experiencing transient monocular blindness, blurry or double vision, and impaired visuospatial skills. No patients had visual field deficits.

Highest Prion Levels in the Retina

Diffusion MRI showed focal regions of high cortical intensity with restricted diffusion in all patients. Three patients had cortical ribboning in the occipital cortex.

The researchers confirmed sCJD diagnosis biochemically by PrPSc detection in the brain. Levels of this folded protein in brain regions varied among patients.

For example, the thalamus and occipital cortex commonly accumulated high levels of PrPSc, whereas the lowest levels were detected in the cerebellum in 8 of 10 cases examined.

Prion seed levels in the retina were significantly higher than the extraocular muscles, optic nerve, cornea, lens, vitreous fluid, and sclera.

The investigators found high prion seeding activities in the optic nerve that correlated with high levels in the retina, but not with high levels in the cornea.

"These differences may reflect prion entry by multiple cranial nerves transporting PrPSc, as prions may be spreading from prion-infected brain into the eye by retrograde axonal transport," they write.

The researchers also report distinctions between prions in the eyes and brains.

"The prions in the retina have a very different appearance as compared to the brain, in that the prions appear to be intracellular and very regularly distributed in the synaptic layer, versus extracellular aggregates in brain," Sigurdson said.

"We also do not see the spongiform pathology that is so typical in the brain with a prion infection," she added.

The investigators found no correlation between seeding activity in the retina and age, gender, disease duration, PRNP genotype, or sCJD subtypes.

Revolutionary Assay

Unlike previous studies using different detection techniques, Sigurdson and colleagues used the "highly sensitive" real-time quaking induced conversion assay (RT-QuIC). They examined PrPSc seeding activity using this advanced technology in extraocular muscle, optic nerve, cornea, lens, vitreous fluid, retina, choroid, and sclera.

"The development of RT-QuIC analysis has revolutionized very sensitive and specific detection of extraordinarily low levels of prions," Sigurdson said.

In terms of aiding future clinical diagnosis, PrPSc aggregates were highly visible in the posterior retina.

This is "an accessible [central nervous system] window that could potentially be exploited for the early diagnosis of CJD," the researchers note. For example, researchers could develop an electroretinogram as a noninvasive diagnostic tool to reveal early electrical abnormalities.

The findings may also carry implications for other neurodegenerative conditions. Because other protein aggregates such as amyloid-β, α-synuclein, and tau may also spread from the brain to the retina, "it would also be important to evaluate eyes from patients having more common neurodegenerative diseases, such as Alzheimer's disease, synucleinopathies, and tauopathies," the researchers note.

"Our hope is that it may be possible someday to visualize prions in the retina using fluorescent probes. We are engaged in an NIH-funded study with the company Amydis to determine whether retinal prions can be labelled and visualized," Sigurdson said.

"In addition to developing diagnostic assays to detect prions in the eye, we are also working to understand when and how prions gain access into the eye, as understanding how prions spread may lead us to therapies to halt the infection," she added.

"Corneal grafts from patients with prion disease can transmit prion infection to the recipient, so encouraging the development of biosynthetic corneal substitutes would be worthwhile," Sigurdson noted.

The findings also carry implications for surgical instruments as a potential mode of transmission. For this reason, she said, "disposable instruments are recommended for ophthalmological surgical procedures on prion disease patients."

Prion-contaminated corneal grafts, dura mater transplants, and human cadaveric growth hormone are other potential sources of CJD transmission.

'Important Implications'

Commenting on the findings for Medscape Medical News, Raymond P. Roos, MD, professor of neurology at the University of Chicago and a fellow of the American Academy of Neurology, said the study findings suggest "a prion assay of eye tissues—or perhaps even of tears—may help with the diagnosis of CJD."

The study also "emphasizes the importance of using disposable instruments," including those that contact the eye, such as tonometers, added Roos, who was not involved in the research.

The results carry important implications on public health, he said. Transplant guidelines presently disallow donations from individuals with CJD or from individuals who have a family member with CJD.

"The finding of prions in eye tissue from CJD patients suggests the advisability of using a sensitive assay such as RT-QuIC in order to identify prions in donor tissues from individuals with unsuspected presymptomatic or early CJD. Presumably even safer would be to replace human corneas for transplantation with biosynthetic corneas."

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 supported the study. Sigurdson disclosed she is on the scientific advisory board of Amydis, Inc, a company developing amyloid protein assays. Roos has disclosed no relevant financial relationships.

mBio. Published online November 20, 2018. Full text

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