New skin test detects prion infection before symptoms appear

Prions can infect both humans and animals, causing Creutzfeldt-Jakob disease (CJD) in humans, mad cow disease in cattle, and chronic wasting disease in elk and deer. The infectious, misfolded protein particles often go undetected as they destroy brain tissue, causing memory loss, mobility issues, and ultimately death. Preclinical detection of prions has proven difficult, but new research suggests skin samples hold early signs of prion disease that precede neurologic symptoms. 

"Currently a definitive diagnosis of Creutzfeldt-Jakob disease is dependent on the examination of diseased brain tissue obtained at biopsy or autopsy. It has been impossible to detect at the early preclinical stage," said an associate professor of pathology.

In a ground-breaking study, an international team of researchers successfully used two methods to detect prions in skin samples collected from inoculated rodents. The study provides the first proof-of-concept evidence that readily accessible skin samples could be used to detect prion disease early—before clinical symptoms appear.

In the new study, the researchers successfully detected prions in rodent skin samples as early as two weeks post-infection. They also detected prions in the skin of uninoculated rodents that were housed alongside inoculated cage mates, demonstrating that prion transmission can occur between cohabitating rodents.

Prions were detected in skin samples from the inoculated rodents before they showed any clinical signs of prion disease. The researchers first inoculated the brains of hamsters and humanized transgenic mice with rodent or human prion samples, respectively. Then, they collected skin and brain samples at different time points, and used two different methods to detect disease-associated prion proteins in the tissues. In both hamsters and mice, the researchers detected prions in skin before they could be detected in brain tissue. The researchers concluded that skin prions could serve as a useful biomarker for preclinical diagnosis of prion diseases.

The study compared two highly-sensitive prion detection methods: RT-QuIC (real-time quaking-induced conversion) and sPMCA (serial protein misfolding cyclic amplification). "Both assays were able to efficiently amplify trace amounts of disease-associated prion protein found in the skin tissues of infected animals," said the study's first author. The tests use prions in tissue samples as a template and either normal brain tissue or synthetic prion protein as "building blocks" to dramatically amplify minute amounts of prions to detectable levels.

One of the methods, RT-QuIC, has been used to detect prion particles in symptomatic CJD patients. However, it normally requires invasive cerebrospinal fluid (CSF) sampling that may be contraindicated for certain patients. Additionally, "The CSF-based prion test results could be uncertain in some cases and not all CSF specimens from patients with prion disease are RT-QuIC positive," said an associate professor of pathology. "Although skin samples may not replace CSF in routine RT-QuIC-based prion disease diagnosis, they may be helpful when prion disease is suspected but CSF is either unavailable or RT-QuIC-negative."

The study results build upon previous work by the researchers showing that autopsy skin samples from human prion disease patients exhibit prion seeding and infectivity. The next step will be to develop and validate the skin prion tests for clinical use.

Said the researcher, "Since the skin is readily accessible and skin biopsy is minimally invasive, detection of skin prions will be very useful for monitoring disease progression and assessing therapeutic efficacy during clinical trials or treatments when prion therapy becomes available in the future."

 The researchers were recently awarded a $2.9 million grant to validate the test methods using human skin samples. They will determine if skin prions could serve as a diagnostic biomarker for CJD or a source of prion transmission.

The researchers believe the methods may also be adapted for diagnosis of other diseases involving misfolded proteins. "Sensitive, minimally invasive detection of various misfolded proteins in skin, such as tau in Alzheimer's disease and alpha-synuclein in Parkinson's disease, could be highly valuable for disease diagnosis and monitoring of disease progression and efficacy of treatments," the researcher said. "It's possible that the skin will ultimately serve as a mirror for us to monitor these misfolded proteins that accumulate and damage the brain in patients with these conditions." 
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Deadly brain disease spreads from gut !

Offering hope for early detection of prion disease, a difficult to detect deadly brain condition in humans and farm animals, researchers have found how the proteins that cause the disorder spread from our gut.

Until now, it was not known the proteins – called prions – spread from the gut to the brain after consuming contaminated meat.

“We need a greater understanding of what factors enhance our susceptibility to prion diseases so that we can put in place safeguards to prevent these conditions from spreading in people and farmed animals,” said lead researcher.

It is important to spot the detection early as many people could be carrying infectious prions without showing any symptoms of disease.

For the study, the researchers studied the course of prion infection in mice.
They found that prions must first build up in specialised structures in the lining of the small intestine before they are able to spread throughout the body to the brain.

The structures – called Peyer’s patches – are part of the body’s immune system and form the first line of defence against contaminated food.

Prions hijack Peyer’s patches to cause infection, the findings showed.

Prions did not build up in similar patches in the large intestine until a later stage of infection, the team found. At this stage, prions were also detected in the spleen and lymph nodes.

When prions get into the brain, they destroy nerve cells. This can lead to major neurological symptoms including memory impairment, personality changes, and difficulties with movement.

However, in people, the disease remains very rare – 229 people have died from it since it was first identified almost 20 years ago, the study noted.

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Alzheimer's breakthrough hailed as 'turning point'

The discovery of the first chemical to prevent the death of brain tissue in a neurodegenerative disease has been hailed as the "turning point" in the fight against Alzheimer's disease.

More work is needed to develop a drug that could be taken by patients.

But scientists say a resulting medicine could treat Alzheimer's, Parkinson's, Huntington's and other diseases.

In tests on mice,it showed all brain cell death from prion disease could be prevented.

Researcher said: "This finding, I suspect, will be judged by history as a turning point in the search for medicines to control and prevent Alzheimer's disease."

He told the BBC a cure for Alzheimer's was not imminent but: "I'm very excited, it's the first proof in any living animal that you can delay neurodegeneration.

"The world won't change tomorrow, but this is a landmark study."

Cells starve

The team  focused on the natural defence mechanisms built into brain cells.

When a virus hijacks a brain cell it leads to a build-up of viral proteins. Cells respond by shutting down nearly all protein production in order to halt the virus's spread.

However, many neurodegenerative diseases involve the production of faulty or "misfolded" proteins. These activate the same defences, but with more severe consequences.

The misfolded proteins linger and the brain cells shut down protein production for so long that they eventually starve themselves to death.

This process, repeated in neurons throughout the brain, can destroy movement or memory or even kill, depending on the disease.

This process is thought to take place in many forms of neurodegeneration, so safely disrupting it could treat a wide range of diseases.

The researchers used a compound which prevented those defence mechanisms kicking in and in turn halted neurodegeneration.

The study,  showed mice with prion disease developed severe memory and movement problems. They died within 12 weeks.

However, those given the compound showed no sign of brain tissue wasting away.

Lead researcher told : "They were absolutely fine, it was extraordinary.

"What's really exciting is a compound has completely prevented neurodegeneration and that's a first.

"This isn't the compound you would use in people, but it means we can do it and it's a start."

She said the compound offered a "new pathway that may well give protective drugs" and the next step was for drug companies to develop a medicine for use in humans.

'Very dramatic'

The lab is also testing the compound on other forms of neurodegeneration in mice but the results have not yet been published.

Side effects are an issue. The compound also acted on the pancreas, meaning the mice developed a mild form of diabetes and lost weight.

Any human drug would need to act only on the brain. However, this gives scientists and drug companies a starting point.

A professor of neuroscience described the results as "very dramatic and highly encouraging" but cautioned that more research was needed to see how the findings would apply to diseases such as Alzheimer's and Parkinson's.

The director of research  said: "Targeting a mechanism relevant to a number of neurodegenerative diseases could yield a single drug with wide-reaching benefits, but this compound is still at an early stage.

"It will be important for these findings to be repeated and tested in models of other neurodegenerative diseases, including Alzheimer's disease."

Neurodegeneration

• A neurodegenerative disease is one in which the cells of the brain and spinal cord are lost
• The functions of these cells include decision making and control of movements
• These cells are not easily regenerated, so the effects of diseases can be devastating
• Neurodegenerative diseases include Alzheimer's, Parkinson's, multiple sclerosis and Huntington's

It is rare to get cautious scientists keen to describe a study in mice as a turning point in treating Alzheimer's.

It is early science, a lot can go wrong between a drug for mice and a drug for humans and the only published data is for prion disease, not even Alzheimer's.

So why the excitement?

It is the first time that any form of neurodegeneration has been completely halted, so it is a significant landmark. It shows that the process being targeted has serious potential.

If this can be successfully developed, which is not guaranteed, the prize would be huge.

In Parkinson's the alpha-synuclein protein goes wrong, in Alzheimer's it's amyloid and tau, in Huntington's it's the Huntingtin protein.

But the errant protein is irrelevant here as the researchers are targeting the way a cell deals with any misfolded protein.

It means one drug could cure many diseases and that really would be something to get excited about.

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