Dr. Francis Collins
Posted on by Dr. Francis Collins
As research on Alzheimer’s disease (AD) advances, a desperate need remains for an easy blood test to help diagnose the condition as early as possible. Ideally, such a test could also distinguish AD from other forms of dementia that produce similar symptoms. As published recently in Nature Medicine, an NIH-funded research team has designed a simple blood test that is on course to meet these criteria .
The latest work builds on a large body of work showing that one secret to predicting a person’s cognitive decline and treatment response in AD lies in a protein called tau. Using the powerful, but expensive, approach of PET scan imaging, we know that tau builds up in the brain as Alzheimer’s disease progresses. We also know that some tau spills from the brain into the bloodstream.
The trouble is that the circulating tau protein breaks down far too quickly for a blood test to offer a reliable measure of what’s happening in a person’s brain. A few years ago, researchers discovered a possible solution: test for blood levels of a slightly different and more stable version of the protein called pTau181 . (The “p” in its name comes from the addition of phosphorus in a particular part of the protein’s structure.)
In the latest study, researchers in the lab of Adam Boxer, University of California, San Francisco, followed up further on this compelling lead. Boxer’s team measured pTau181 levels in blood samples from 362 people between the ages of 58 and 70. Those samples included 56 people with an Alzheimer’s diagnosis, along with 47 people with mild cognitive impairment and 69 healthy controls.
The researchers also included another 190 people diagnosed with frontotemporal lobar degeneration (FTLD). It is a relatively rare form of dementia that leads to a gradual decline in behavior, language, and movement, often in connection with a buildup of tau in the brain.
The study found that levels of pTau181 were roughly 3.5-times higher in the blood of people with AD compared to people without AD. Those with mild cognitive impairment due to underlying AD also showed an intermediate increase in blood levels of pTau181.
Importantly, people with FLTD had normal blood levels of pTau181. As a result, the blood test could reliably distinguish between a person with AD and a person with FLTD. That’s important because, while FLTD is a relatively rare condition, its prevalence is similar to AD in people under the age of 65. But both conditions have similar symptoms, making it often challenging to distinguish them.
The findings add to evidence that the new blood test can help in diagnosing AD and in distinguishing it from other neurodegenerative conditions. In fact, it does so with an accuracy that often rivals more expensive PET scans and more invasive cerebrospinal fluid tests, which are now the only reliable ways to measure tau.
There’s still plenty of work to do before this blood test is ready for a doctor’s office. But these initial findings are very promising in helping to simplify the diagnosis of this devastating condition that now affects an estimated 5.5 million Americans .
 Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, Bourakova V, Cobigo Y, Heuer H, Spina S, VandeVrede L, Chai X, Proctor NK, Airey DC, Shcherbinin S, Duggan Evans C, Sims JR, Zetterberg H, Blennow K, Karydas AM, Teunissen CE, Kramer JH, Grinberg LT, Seeley WW, Rosen H, Boeve BF, Miller BL, Rabinovici GD, Dage JL, Rojas JC, Boxer AL; Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators. Nat Med. 2020 Mar 2.
 Plasma phospho-tau181 increases with Alzheimer’s disease clinical severity and is associated with tau- and amyloid-positron emission tomography. Mielke MM, Hagen CE, Xu J, Chai X, Vemuri P, Lowe VJ, Airey DC, Knopman DS, Roberts RO, Machulda MM, Jack CR Jr, Petersen RC, Dage JL. Alzheimers Dement. 2018 Aug;14(8):989-997.
 Alzheimer’s Disease Fact Sheet. National Institute on Aging, May 22, 2019.
Alzheimer’s Disease & Related Dementias (National Institute on Aging/NIH)
Adam Boxer (University of California, San Francisco)
NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
Amid all the headlines and uncertainty surrounding the current COVID-19 pandemic, it’s easy to overlook the important progress that biomedical research is making against other diseases. So, today, I’m pleased to share word of what promises to be the first effective treatment to help young people suffering from the consequences of a painful, often debilitating genetic disorder called neurofibromatosis type 1 (NF1).
This news is particularly meaningful to me because, 30 years ago, I led a team that discovered the gene that underlies NF1. About 1 in 3,000 babies are born with NF1. In about half of those affected, a type of tumor called a plexiform neurofibroma arises along nerves in the skin, face, and other parts of the body. While plexiform neurofibromas are not cancerous, they grow steadily and can lead to severe pain and a range of other health problems, including vision and hearing loss, hypertension, and mobility issues.
The good news is the results of a phase II clinical trial involving NF1, just published in the New England Journal of Medicine. The trial was led by Brigitte Widemann and Andrea Gross, researchers in the Center for Cancer Research at NIH’s National Cancer Institute.
The trial’s results confirm that a drug originally developed to treat cancer, called selumetinib, can shrink inoperable tumors in many children with NF1. They also establish that the drug can help affected kids make significant improvements in strength, range of motion, and quality of life. While selumetinib is not a cure, and further studies are still needed to see how well the treatment works in the long term, these results suggest that the first effective treatment for NF1 is at last within our reach.
Selumetinib blocks a protein in human cells called MEK. This protein is involved in a major cellular pathway known as RAS that can become dysregulated and give rise to various cancers. By blocking the MEK protein in animal studies and putting the brakes on the RAS pathway when it malfunctions, selumetinib showed great initial promise as a cancer drug.
Selumetinib was first tested several years ago in people with a variety of other cancers, including ovarian and non-small cell lung cancers. The clinical research looked good at first but eventually stalled, and so did much of the initial enthusiasm for selumetinib.
But the enthusiasm picked up when researchers considered repurposing the drug to treat NF1. The neurofibromas associated with the condition were known to arise from a RAS-activating loss of the NF1 gene. It made sense that blocking the MEK protein might blunt the overactive RAS signal and help to shrink these often-inoperable tumors.
An earlier phase 1 safety trial looked promising, showing for the first time that the drug could, in some cases, shrink large NF1 tumors . This fueled further research, and the latest study now adds significantly to that evidence.
In the study, Widemann and colleagues enrolled 50 children with NF1, ranging in age from 3 to 17. Their tumor-related symptoms greatly affected their wellbeing and ability to thrive, including disfigurement, limited strength and motion, and pain. Children received selumetinib alone orally twice a day and went in for assessments at least every four months.
As of March 2019, 35 of the 50 children in the ongoing study had a confirmed partial response, meaning that their tumors had shrunk by more than 20 percent. Most had maintained that response for a year or more. More importantly, the kids also felt less pain and were more able to enjoy life.
It’s important to note that the treatment didn’t work for everyone. Five children stopped taking the drug due to side effects. Six others progressed while on the drug, though five of them had to reduce their dose because of side effects before progressing. Nevertheless, for kids with NF1 and their families, this is a big step forward.
Drug developer AstraZeneca, working together with the researchers, has submitted a New Drug Application to the Food and Drug Administration (FDA). While they’re eagerly awaiting the FDA’s decision, the work continues.
The researchers want to learn much more about how the drug affects the health and wellbeing of kids who take it over the long term. They’re also curious whether it could help to prevent the growth of large tumors in kids who begin taking it earlier in the course of the disease, and whether it might benefit other features of the disorder. They will continue to look ahead to other potentially promising treatments or treatment combinations that may further help, and perhaps one day even cure, kids with NF1. So, even while we cope with the COVID-19 pandemic, there are reasons to feel encouraged and grateful for continued progress made throughout biomedical research.
 Selumitinib in children with inoperable plexiform neurofibromas. New England Journal of Medicine. Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC. 18 March 2020. N Engl J Med. 2020 Mar 18. [Epub ahead of publication.]
 Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas. Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, Whitcomb P, Martin S, Aschbacher-Smith LE, Rizvi TA, Wu J, Ershler R, Wolters P1, Therrien J, Glod J, Belasco JB, Schorry E, Brofferio A, Starosta AJ, Gillespie A, Doyle AL, Ratner N, Widemann BC. N Engl J Med. 2016 Dec 29;375(26):2550-2560.
Neurofibromatosis Fact Sheet (National Institute of Neurological Disorders and Stroke/NIH)
Brigitte Widemann (National Cancer Institute/NIH)
Andrea Gross (National Cancer Institute/NIH)
NIH Support: National Cancer Institute
Posted on by Dr. Francis Collins
Note to my blog readers: the whole world is now facing a major threat from the COVID-19 pandemic. We at NIH are doing everything we can to apply the best and most powerful science to the development of diagnostics, therapeutics, and vaccines, while also implementing public health measures to protect our staff and the patients in our hospital. This crisis is expected to span many weeks, and I will occasionally report on COVID-19 in this blog format. Meanwhile, science continues to progress on many other fronts—and so I will continue to try to bring you stories across a wide range of topics. Perhaps everyone can use a little break now and then from the coronavirus news? Today’s blog takes you into the intricacies of memory.
When recalling the name of an acquaintance, you might replay an earlier introduction, trying to remember the correct combination of first and last names. (Was it Scott James? Or James Scott?) Now, neuroscientists have found that in the split second before you come up with the right answer, your brain’s neurons fire in the same order as when you first learned the information .
This new insight into memory retrieval comes from recording the electrical activity of thousands of neurons in the brains of six people during memory tests of random word pairs, such as “jeep” and “crow.” While similar firing patterns had been described before in mice, the new study is the first to confirm that the human brain stores memories in specific sequences of neural activity that can be replayed again and again.
The new study, published in the journal Science, is the latest insight from neurosurgeon and researcher Kareem Zaghloul at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Zaghloul’s team has for years been involved in an NIH Clinical Center study for patients with drug-resistant epilepsy whose seizures cannot be controlled with drugs.
As part of this work, his surgical team often temporarily places a 4 millimeter-by-4 millimeter array of tiny electrodes on the surface of the brains of the study’s participants. They do this in an effort to pinpoint brain tissues that may be the source of their seizures before performing surgery to remove them. With a patient’s informed consent to take part in additional research, the procedure also has led to a series of insights into what happens in the human brain when we make and later retrieve new memories.
Here’s how it works: The researchers record electrical currents as participants are asked to learn random word pairs presented to them on a computer screen, such as “cake” and “fox,” or “lime” and “camel.” After a period of rest, their brain activity is again recorded as they are given a word and asked to recall the matching word.
Last year, the researchers reported that the split second before a person got the right answer, tiny ripples of electrical activity appeared in two specific areas of the brain . The team also had shown that, when a person correctly recalled a word pair, the brain showed patterns of activity that corresponded to those formed when he or she first learned to make a word association.
The new work takes this a step further. As study participants learned a word pair, the researchers noticed not only the initial rippling wave of electricity, but also that particular neurons in the brain’s cerebral cortex fired repeatedly in a sequential order. In fact, with each new word pair, the researchers observed unique firing patterns among the active neurons.
If the order of neuronal firing was essential for storing new memories, the researchers reasoned that the same would be true for correctly retrieving the information. And, indeed, that’s what they were able to show. For example, when individuals were shown “cake” for a second time, they replayed a very similar firing pattern to the one recorded initially for this word just milliseconds before correctly recalling the paired word “fox.”
The researchers then calculated the average sequence similarity between the firing patterns of learning and retrieval. They found that as a person recalled a word, those patterns gradually became more similar. Just before a correct answer was given, the recorded neurons locked onto the right firing sequence. That didn’t happen when a person gave an incorrect answer.
Further analysis confirmed that the exact order of neural firing was specific to each word pair. The findings show that our memories are encoded as unique sequences that must be replayed for accurate retrieval, though we still don’t understand the molecular mechanisms that undergird this.
Zaghloul reports that there’s still more to learn about how these processes are influenced by other factors such as our attention. It’s not yet known whether the brain replays sequences similarly when retrieving longer-term memories. Along with these intriguing insights into normal learning and memory, the researchers think this line of research will yield important clues as to what changes in people who suffer from memory disorders, with potentially important implications for developing the next generation of treatments.
 Replay of cortical spiking sequences during human memory retrieval. Vaz AP, Wittig JH Jr, Inati SK, Zaghloul KA. Science. 2020 Mar 6;367(6482):1131-1134.
 Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Vaz AP, Inati SK, Brunel N, Zaghloul KA. Science. 2019 Mar 1;363(6430):975-978.
Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)
Brain Basics (NINDS)
Zaghloul Lab (NINDS)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute of General Medical Sciences