Prion Test Improves Diagnosis For Neurodegenerative Disease

Prion Disease A Spectrum Disease

By the time Kay Schwister got her diagnosis last summer, she couldn’t talk anymore. But she could still scowl, and scowl she did.

After weeks of decline and no clue what was causing it, doctors had told Schwister — a 53-year-old vocational rehab counselor and mother of two from Chicago — that she had an incurable disease called Creutzfeldt-Jakob disease, or CJD.

The disease was shrinking Kay’s brain, and riddling it with holes. She would likely live only a few more weeks, the doctors said.

It was a diagnosis that no one could ever want. But the fact that Schwister was able to get a firm diagnosis while still alive is a relatively new development that represents a step forward in understanding a group of devastating neurological disorders. And, some biochemists say, it could lead to better ways of diagnosing brain diseases that are much more common, including Parkinson’s disease and Alzheimer’s disease.

For Kay Schwister, it all started in the spring of 2016, when she started getting headaches and feeling dizzy all the time. Aging, she told herself, just didn’t feel very good. Over the next few weeks, she got steadily worse.

Kay Schwister and CJD

“She got to the point where she was so nauseous and so dizzy that she stopped driving and working,” says her husband, Tim Schwister.

By the time Kay entered the emergency room last June, her speech had changed. She was enunciating things in a strange way, and finishing each sentence on a really high note.

Doctors drew blood and spinal fluid and tested it for things like multiple sclerosis and mercury poisoning. Those tests came back negative.

Soon, Kay couldn’t talk or walk.

“Not knowing what we were dealing with was probably one of the hardest things to ever go through in life,” says Tim. “We really wanted to know what we were up against, and if there was anything that we could do.”

Ultimately, Kay’s doctors ordered a newly developed test for Creutzfeldt-Jakob disease — a very rare condition that’s thought to kill about 1 in a million people worldwide every year, including about 300 deaths annually in the U.S.

prion disease spectrum

That test came back positive. About a month after Kay entered the hospital, the Schwisters had their answer. It was ugly, but still an answer.

Normal proteins in Kay’s brain had started misfolding, bending themselves into an unnatural shape and coaxing other proteins to do the same, like some kind of malicious origami. These misshapen proteins, known as prions, formed clumps in the brain, causing neurons to die.

“It’s almost as if it starts to turn certain portions of your brain off,” says Tim.

The vast majority of CJD cases worldwide are like Kay’s, popping up for no apparent reason. Other cases seem to be inherited. A very small number of patients have contracted the illness through close contact with material from an infected person’s brain or nervous system — during certain transplant procedures or via contaminated surgical equipment, for example. And another form, variant CJD, is the human version of mad cow disease, and has been linked to eating infected beef.

Prions and Alzheimer's disease

There is no cure or treatment for CJD. All Tim could do for his life partner of 35 years was to try to make her as comfortable as possible. Still, having a diagnosis spurred the many people who loved Kay into action, Tim says. Family and friends flew in from all over the country to visit. She was rarely alone.

“Every day, it was nonstop,” Tim says. “People that were there to visit with her, just to try to keep her spirits up.”

She never went home. Kay Schwister died within seven weeks of entering the hospital.

Until recently, families like the Schwisters wouldn’t have known what their loved one was suffering from until it was all over, when an autopsy might have shown that the brain was smaller than expected. Under a microscope and using a special stain, a pathologist would have seen holes in the brain, along with tangles and clumps of misfolded proteins (prions).

But diagnosis after death is too late — not just for the patient and families, but also for researchers trying to study potential therapies to slow down or stop the progression of the disease. These same diagnostic frustrations apply to some of the most common forms of dementia, including Parkinson’s and Alzheimer’s disease, which are also associated with protein misfolding.

“The trouble with many of these diseases, some of which are incredibly prevalent, is that it can take months or years to diagnose,” says Byron Caughey, a biochemist at Rocky Mountain Laboratories in Hamilton, Mont., a part of the National Institute of Allergy and Infectious Disease.

A previous spinal fluid assay for CJD could identify brain cell injury, but not the cause of that injury. That’s why Caughey recently teamed up with scientists in Italy, Japan and the U.K. to develop a different test. It’s called RT-QuIC, which stands for “real-time quaking-induced conversion.”

The test, developed a few years ago and still available via only a few laboratories, harnesses the bad protein’s ability to induce normal, neighboring proteins to take on its twisted form. The test takes about 90 hours and involves getting a sample of spinal fluid, shaking it up with normal proteins and waiting to see if the normal proteins misfold.

Alzheimer's disease diagnosis

Caughey and some Italian scientists have even figured out how to avoid the spinal tap; they can make the test work with a sample of cells taken from deep inside a patient’s nostril, from a spot that is separated from the brain by just a bony partition.

“So, we now have the ability to collect a little bit of spinal fluid or nasal brushing from patients while they’re still alive, and with quite a high degree of certainty, tell whether or not they have a prion disease,” says Caughey. In several studies now, he says, the RT-QuIC test has sensitively and specifically identified CJD prions in symptomatic patients; the test has since been distributed to CJD surveillance centers in multiple countries.

“Technologically, it’s a major new paradigm for testing protein misfolding,” says Dr. Jiri Safar, director of the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland and one of Caughey’s collaborators. Since the center started using the assay in April 2015, it has tested more than 5,000 samples from patients referred by doctors scattered around the U.S., Canada and Mexico. And within that group, Safar says, about 500 people tested positive for CJD. The assay costs about $50 to run.

“It’s a major game changer,” says Safar, who hopes wider use of the test in suspected cases will help to completely eliminate the possibility of transmitting CJD through infected blood, bodily fluids or organs.

Caughey, Safar and colleagues reported in late November in the journal Annals of Neurology that a second-generation version of their test was just as effective in diagnosing the disease as an autopsy or biopsy of a living brain (which is another diagnostic option, but a risky, invasive one).

Alison Green, a biochemist at the University of Edinburgh in the U.K., is now working on a modified version of the test that has been shown capable of detecting Parkinson’s disease and Lewy body dementia.

“It’s very important, because there is no other diagnostic test for Parkinson’s disease,” Green says. “It’s purely a clinical diagnosis at present.”

Parkinson’s is a chronic and progressive movement disorder that eventually includes symptoms of dementia in an estimated 50 to 80 percent of cases. Diagnosing it sometimes requires years of observation, at which point a patient has already lost a lot of neurons.

In a small study published last summer, Green used a version of RT-QuIC that looks for alpha-synuclein (a protein that’s associated with Parkinson’s) on 20 people who had a Parkinson’s diagnosis, and 15 people in a control group.

“And you can get a nice, clear-cut positive result after 120 hours,” she says. Nineteen out of 20 patients with Parkinson’s were correctly identified, and there were no false positives. Green is now replicating the study with 110 subjects.

If the test proves to be as reliable as it was in her first study, Green says, it could become an important diagnostic tool for doctors to rapidly identify a patient’s ailment and start therapies as soon as possible, when they might still make a difference.

“A lot of these drugs or therapies are being introduced way too late because patients aren’t diagnosed early enough,” Green explains. “And they may be effective treatments if you give them earlier.”

She’s also applied for funding to develop a test that would look for abnormal beta-amyloid peptides, possible indicators of Alzheimer’s disease.

The ultimate goal, says Green, is to have a whole bank of RT-QuIC assays so that patients with any kind of undiagnosed dementia can get answers.

Knowing the prognosis earlier, she says, could give some patients and families more choices.

“If you have early onset dementia, do you really want to spend the last few years of your life working, or do you want to take early retirement?” says Green.

And even for diseases that have no option of being slowed or reversed, she says, a firm and accurate diagnosis can still offer something essential to families — a spur to move beyond tests and treatments.

“We really, truly wanted to know if there was something that we could do for her,” says Tim Schwister of his wife, Kay. The diagnosis let him and his sons know that chasing further treatment at that point wouldn’t help, and that the best they could do was to turn their attention to making Kay comfortable, and spending time with her.

The diagnosis also helped the Schwisters connect with other families who’d gone through the same experience.

In a time of such great loss, Tim says, “it’s nice to know that you’re not alone.”

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Crossbow Communications specializes in issue management and public affairs. Alzheimer’s disease, Creutzfeldt-Jakob disease, chronic wasting disease and the prion disease epidemic is an area of special expertise. Please contact Gary Chandler to join our coalition for reform

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Key Proteins Found In Early Phases Of Alzheimer’s Disease

Tau, Amyloid Detection Could Improve Diagnostic Capabilities

Researchers from Aberdeen have identified changes in the brains of those suffering early signs of Alzheimer’s disease.

A University of Aberdeen study confirmed for the first time that two proteins, assumed to contribute to the disease process, are both present at very early stages of Alzheimer’s disease. Both are present in an area of the brain that is involved in memory formation and information processing–the hippocampus.

Alzheimer's disease and caregivers

The Alzheimer’s Research UK funded the research, which will have implications for the development of new drugs, but may also provide important information for diagnosis of the disease. 

The team, led by Dr Koss and Professor Bettina Platt, used human brain samples provided by the Brains for Dementia Research platform to investigate changes in the brain at different stages of the disease. The researchers developed novel ways to study two proteins (tau and amyloid), both associated with Alzheimer’s disease, and determined how each one contributed to the onset, progression and symptoms of the disease.

“The entire research community is in agreement that it’s important to diagnose Alzheimer’s disease early,” said Dr. Koss. “Our findings will go some way to help achieve this. These early-stage changes in the brains of people with Alzheimer’s disease highlight key biochemical processes that may not only enable improved diagnostic procedures but may also inform drug development.”

Early diagnosis also can help protect caregivers and others from the transmission of Alzheimer’s disease. It’s likely spreading through the bodily fluids of victims. Items exposed, including drinking glasses, utensils are impossible to sterilize.

“There is now real evidence of the potential transmissibility of Alzheimer’s,” says Thomas Wiesniewski M.D. a prion and Alzheimer’s researcher at New York University School of Medicine. “In fact, this ability to transmit an abnormal conformation is probably a universal property of amyloid-forming proteins.”

Prions and Alzheimer's disease

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Microcephaly One Of Many Symptoms Caused By Zika Virus

Zika Virus A Byproduct Of Infectious Waste

Published In MedScape

Zika infection can have devastating effects on the central nervous system of people of all ages. The infection can cause a wide range of brain abnormalities, including paralysis and death in adults, according to two new studies from Brazil.

Infection with mosquito-borne Zika virus is a cause of the neurological disorder Guillain-Barre Syndrome (GBS), in addition to microcephaly and other congenital brain abnormalities, according to a systematic review published in PLOS Medicine by Nicola Low of the University of Bern, Switzerland, and colleagues in the World Health Organization (WHO) Zika Causality Working Group.

“All radiologists must know about these typical symptoms because sometimes you don’t see the symptoms of Zika virus in the pregnant mother,” said Bianca Guedes Ribeiro, MD, from the Clínica de Diagnóstico por Imagem in Rio de Janeiro.

“If the microcephaly and calcifications don’t show until the third trimester, it’s late,” she said.

microcephaly and Zika virus

Microcephaly is a nonspecific term used to describe a small head circumference, and can be caused by maternal exposure to HIV, alcohol, radiation, or TORCH pathogens (Toxoplasma gondii, other, rubella virus, cytomegalovirus, and herpes simplex virus).

Most of these pathogens and toxins are found in the modern sewage stream, which is being dumped on crops, parks, golf courses and beyond. It is therefore important that radiologists know what to look for when it comes to “Zika.”

Dr. Guedes Ribeiro presented results from one of the studies here at the Radiological Society of North America 2016 Annual Meeting. She and her colleagues looked at pre- and postnatal images of the central nervous system in pregnant women exposed to the Zika virus. In their perinatal MRI and CT scans, they saw brain abnormalities presenting as multiple calcifications, both cortically and subcortically, and microcephaly. They diagnosed pachygyria, corpus callosum dysgenesis, and small anterior fontanel with premature closure of cranial sutures in their cohort.

microcephaly and Zika virus

During her presentation, Dr Guedes Ribeiro described one case in which a 27-year-old pregnant woman presented with fever, a telltale sign of Zika, and a rash at 12 weeks of gestation. In that case, the fetus did not show microcephaly or calcifications until 32 weeks. “In a case like this, the mother might only know she got the infection at the final ultrasound scanning,” Dr Guedes Ribeiro explained.

Now that Zika is showing up in many other countries around the world, radiologists in the United States should consider the Zika virus when they see these typical central nervous system findings, as they do now in Brazil, even when a pregnant woman has no clinical history of Zika, said Dr Guedes Ribeiro. “When you see these findings, think about Zika,” she advised.

“It’s important to look deep inside the brain because you will get the detailed information about brain malformations that you can’t get with clinical observations,” said Fernanda Tovar-Moll, MD, PhD, from the D’Or Institute for Research and Education in Rio de Janeiro.

Dr Tovar-Moll was involved in a recent study that showed that a number of brain abnormalities, beyond microcephaly, can affect fetuses exposed to intrauterine Zika virus infection. Radiologists need to be aware of these abnormalities so they can guide diagnoses and appropriate counseling for patients and their caregivers, the researchers explain.

All the babies she and her colleagues examined showed calcifications in the brain, “particularly between the grey and white matter junction,” Dr Tovar-Moll told Medscape Medical News. “This is not the same or common in any other congenital infection.”

In 10 percent of cases, Dr Tovar-Moll and her colleagues found that the baby’s head was a normal size at birth. However, she reported, “the brain inside was very abnormal. The MRI and ultrasound showed that they already had severe malformations — even more severe than those with a smaller head size at birth.”

It is incredibly important to look inside the brain because microcephaly is just one of the clinical signs for diagnosis, she added.

“Zika also causes neurologic damage that leads to paralysis in adults,” said Emerson de Melo Casagrande, MD, from the Federal Fluminense University in Niterói, Brazil.

“There are adults affected — who aren’t in the focus of the media — who were healthy people but aren’t now. Some of them will never recover,” he reported.

biosolids land application sewage sludge

Dr de Melo Casagrande presented results from a study that looked at adults, pregnant women, and newborns. He explained that the study got its start when the hospital began sending patients to radiology to rule out common diseases because serologic testing for Zika was not available.

The researchers were surprised by the effect the virus could have in adults. Of the 16 adults with acute neurologic syndromes sent to their lab, many presented with evidence of Guillain-Barré syndrome, its Miller Fisher variant, and Bickerstaff encephalitis. All three of the patients who presented with encephalomyelitis are now paralyzed.

“They were healthy and now they can’t move their arms or legs — that’s from Zika,” Dr de Melo Casagrande explained. Some patients recovered from the infection and others have sequelae in the face — they can work “and they have a life — but three people remain in the hospital.”

They don’t have the virus anymore, he pointed out, but it is still destroying their body as an autoimmune disease triggered by the infection. A previous infection could have had something to do with the strong reaction.

“We don’t know what makes it more severe in those patients, but we know we need to move the Zika conversation away from microcephaly alone,” said Dr de Melo Casagrande.

The problem in Brazil right now is that many hospitals cannot diagnose Zika because testing is not available. “They have a fast test for dengue because people can die from dengue,” he explained. “But if it’s not dengue, then you have to go home.”

Dr de Melo Casagrande said that his team expects to continue to use radiology to exclude other infections. All people should be wary of Zika, not just pregnant women. “It can be devastating for anyone,” he warned.

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Urine Test Can Diagnose Creutzfeldt-Jakob Disease

Prions Fueling A Public Health Disaster

Urine can be used to test for Creutzfeldt-Jakob disease. Unfortunately, it also is a pathway that spreads prion disease among mammals.

infectious waste and food contamination

The Medical Research Council team is working on a simple test. They claim that their prototype test still needs honing before it could be used routinely. Currently there is no easy test available for this rare but fatal brain condition. Instead, doctors have to take a sample of spinal fluid or brain tissue, or wait for a post-mortem after death. What they look for is tell-tale deposits of abnormal proteins called prions, which cause the brain damage.

Building on earlier US work, Dr. Graham Jackson and colleagues, from University College London, have now found it is also possible to detect prions in urine. This might offer a way to diagnose CJD rapidly and earlier, they say, although there is no cure.

CJD is a rare, but fatal degenerative brain disorder caused by abnormal proteins called prions that damage brain cells. In the 1990s it became clear that a brain disease could be passed from cows to humans (it can also be passed from humans to other mammals). Since then, officials have kept a close check on how many people have become sick or died from CJD. There is no known cure.

Prions and Alzheimer's disease

The study looked at urine samples from 162 people. Of these:

  • 91 were healthy controls
  • 34 had neurological disease that was not thought to be caused by CJD
  • 37 had a diagnosis of CJD (20 of these were sporadic CJD)

The urine test gave no “false-positive” results – meaning it did not falsely suggest there was CJD in any of the patients known not to have the disease. But it was less reliable when it came to detecting actual cases. It accurately detected just under half of the sporadic CJD patients and even fewer of the vCJD patients. The researchers hope they will be able to improve the test further so it can reliably detect all types of CJD.

“Although there is currently no cure for this disease, an accurate and early diagnosis is extremely important for patients and their families, said Dr. Jackson. “In the future, as trials of potential therapies become available, the earlier a patient can be diagnosed the more effective any treatment is likely to be. This test could be a critical step forward.”

Editor’s Note: Prion disease is a spectrum disease that includes Alzheimer’s disease, Creutzfeldt-Jakob disease, Parkinson’s disease, Huntington’s disease, mad cow disease, chronic wasting disease and is likely a contributing factor in the global rise in autism. Victims are infectious long before they exhibit symptoms. Misinformation and mismanagement of sewage and wastewater are contributing to the global epidemic in neurodegenerative disease. As more people get the disease, the waste stream becomes even deadler. It’s time to regulate wastewater streams, including biosolids, as infectious waste and it’s time to enforce the Bioterrorism Preparedness and Response Act of 2002.

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