Posts Tagged ‘Parkinson’s disease’


Illustration by Paweł Jońca

by Helen Thomson

In March 2015, Li-Huei Tsai set up a tiny disco for some of the mice in her laboratory. For an hour each day, she placed them in a box lit only by a flickering strobe. The mice — which had been engineered to produce plaques of the peptide amyloid-β in the brain, a hallmark of Alzheimer’s disease — crawled about curiously. When Tsai later dissected them, those that had been to the mini dance parties had significantly lower levels of plaque than mice that had spent the same time in the dark.

Tsai, a neuroscientist at Massachusetts Institute of Technology (MIT) in Cambridge, says she checked the result; then checked it again. “For the longest time, I didn’t believe it,” she says. Her team had managed to clear amyloid from part of the brain with a flickering light. The strobe was tuned to 40 hertz and was designed to manipulate the rodents’ brainwaves, triggering a host of biological effects that eliminated the plaque-forming proteins. Although promising findings in mouse models of Alzheimer’s disease have been notoriously difficult to replicate in humans, the experiment offered some tantalizing possibilities. “The result was so mind-boggling and so robust, it took a while for the idea to sink in, but we knew we needed to work out a way of trying out the same thing in humans,” Tsai says.

Scientists identified the waves of electrical activity that constantly ripple through the brain almost 100 years ago, but they have struggled to assign these oscillations a definitive role in behaviour or brain function. Studies have strongly linked brainwaves to memory consolidation during sleep, and implicated them in processing sensory inputs and even coordinating consciousness. Yet not everyone is convinced that brainwaves are all that meaningful. “Right now we really don’t know what they do,” says Michael Shadlen, a neuroscientist at Columbia University in New York City.

Now, a growing body of evidence, including Tsai’s findings, hint at a meaningful connection to neurological disorders such as Alzheimer’s and Parkinson’s diseases. The work offers the possibility of forestalling or even reversing the damage caused by such conditions without using a drug. More than two dozen clinical trials are aiming to modulate brainwaves in some way — some with flickering lights or rhythmic sounds, but most through the direct application of electrical currents to the brain or scalp. They aim to treat everything from insomnia to schizophrenia and premenstrual dysphoric disorder.

Tsai’s study was the first glimpse of a cellular response to brainwave manipulation. “Her results were a really big surprise,” says Walter Koroshetz, director of the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “It’s a novel observation that would be really interesting to pursue.”


A powerful wave

Brainwaves were first noticed by German psychiatrist Hans Berger. In 1929, he published a paper describing the repeating waves of current he observed when he placed electrodes on people’s scalps. It was the world’s first electroencephalogram (EEG) recording — but nobody took much notice. Berger was a controversial figure who had spent much of his career trying to identify the physiological basis of psychic phenomena. It was only after his colleagues began to confirm the results several years later that Berger’s invention was recognized as a window into brain activity.

Neurons communicate using electrical impulses created by the flow of ions into and out of each cell. Although a single firing neuron cannot be picked up through the electrodes of an EEG, when a group of neurons fires again and again in synchrony, it shows up as oscillating electrical ripples that sweep through the brain.

Those of the highest frequency are gamma waves, which range from 25 to 140 hertz. People often show a lot of this kind of activity when they are at peak concentration. At the other end of the scale are delta waves, which have the lowest frequency — around 0.5 to 4 hertz. These tend to occur in deep sleep (see ‘Rhythms of the mind’).

At any point in time, one type of brainwave tends to dominate, although other bands are always present to some extent. Scientists have long wondered what purpose, if any, this hum of activity serves, and some clues have emerged over the past three decades. For instance, in 1994, discoveries in mice indicated that the distinct patterns of oscillatory activity during sleep mirrored those during a previous learning exercise. Scientists suggested that these waves could be helping to solidify memories.

Brainwaves also seem to influence conscious perception. Randolph Helfrich at the University of California, Berkeley, and his colleagues devised a way to enhance or reduce gamma oscillations of around 40 hertz using a non-invasive technique called transcranial alternating current stimulation (tACS). By tweaking these oscillations, they were able to influence whether a person perceived a video of moving dots as travelling vertically or horizontally.

The oscillations also provide a potential mechanism for how the brain creates a coherent experience from the chaotic symphony of stimuli hitting the senses at any one time, a puzzle known as the ‘binding problem’. By synchronizing the firing rates of neurons responding to the same event, brainwaves might ensure that the all of the relevant information relating to one object arrives at the correct area of the brain at exactly the right time. Coordinating these signals is the key to perception, says Robert Knight, a cognitive neuroscientist at the University of California, Berkeley, “You can’t just pray that they will self-organize.”


Healthy oscillations

But these oscillations can become disrupted in certain disorders. In Parkinson’s disease, for example, the brain generally starts to show an increase in beta waves in the motor regions as body movement becomes impaired. In a healthy brain, beta waves are suppressed just before a body movement. But in Parkinson’s disease, neurons seem to get stuck in a synchronized pattern of activity. This leads to rigidity and movement difficulties. Peter Brown, who studies Parkinson’s disease at the University of Oxford, UK, says that current treatments for the symptoms of the disease — deep-brain stimulation and the drug levodopa — might work by reducing beta waves.

People with Alzheimer’s disease show a reduction in gamma oscillations5. So Tsai and others wondered whether gamma-wave activity could be restored, and whether this would have any effect on the disease.

They started by using optogenetics, in which brain cells are engineered to respond directly to a flash of light. In 2009, Tsai’s team, in collaboration with Christopher Moore, also at MIT at the time, demonstrated for the first time that it is possible to use the technique to drive gamma oscillations in a specific part of the mouse brain6.

Tsai and her colleagues subsequently found that tinkering with the oscillations sets in motion a host of biological events. It initiates changes in gene expression that cause microglia — immune cells in the brain — to change shape. The cells essentially go into scavenger mode, enabling them to better dispose of harmful clutter in the brain, such as amyloid-β. Koroshetz says that the link to neuroimmunity is new and striking. “The role of immune cells like microglia in the brain is incredibly important and poorly understood, and is one of the hottest areas for research now,” he says.

If the technique was to have any therapeutic relevance, however, Tsai and her colleagues had to find a less-invasive way of manipulating brainwaves. Flashing lights at specific frequencies has been shown to influence oscillations in some parts of the brain, so the researchers turned to strobe lights. They started by exposing young mice with a propensity for amyloid build-up to flickering LED lights for one hour. This created a drop in free-floating amyloid, but it was temporary, lasting less than 24 hours, and restricted to the visual cortex.

To achieve a longer-lasting effect on animals with amyloid plaques, they repeated the experiment for an hour a day over the course of a week, this time using older mice in which plaques had begun to form. Twenty-four hours after the end of the experiment, these animals showed a 67% reduction in plaque in the visual cortex compared with controls. The team also found that the technique reduced tau protein, another hallmark of Alzheimer’s disease.

Alzheimer’s plaques tend to have their earliest negative impacts on the hippocampus, however, not the visual cortex. To elicit oscillations where they are needed, Tsai and her colleagues are investigating other techniques. Playing rodents a 40-hertz noise, for example, seems to cause a decrease in amyloid in the hippocampus — perhaps because the hippo-campus sits closer to the auditory cortex than to the visual cortex.

Tsai and her colleague Ed Boyden, a neuro-scientist at MIT, have now formed a company, Cognito Therapeutics in Cambridge, to test similar treatments in humans. Last year, they started a safety trial, which involves testing a flickering light device, worn like a pair of glasses, on 12 people with Alzheimer’s.

Caveats abound. The mouse model of Alzheimer’s disease is not a perfect reflection of the disorder, and many therapies that have shown promise in rodents have failed in humans. “I used to tell people — if you’re going to get Alzheimer’s, first become a mouse,” says Thomas Insel, a neuroscientist and psychiatrist who led the US National Institute of Mental Health in Bethesda, Maryland, from 2002 until 2015.

Others are also looking to test how manipulating brainwaves might help people with Alzheimer’s disease. “We thought Tsai’s study was outstanding,” says Emiliano Santarnecchi at Harvard Medical School in Boston, Massachusetts. His team had already been using tACS to stimulate the brain, and he wondered whether it might elicit stronger effects than a flashing strobe. “This kind of stimulation can target areas of the brain more specifically than sensory stimulation can — after seeing Tsai’s results, it was a no-brainer that we should try it in Alzheimer’s patients.”

His team has begun an early clinical trial in which ten people with Alzheimer’s disease receive tACS for one hour daily for two weeks. A second trial, in collaboration with Boyden and Tsai, will look for signals of activated microglia and levels of tau protein. Results are expected from both trials by the end of the year.

Knight says that Tsai’s animal studies clearly show that oscillations have an effect on cellular metabolism — but whether the same effect will be seen in humans is another matter. “In the end, it’s data that will win out,” he says.

The studies may reveal risks, too. Gamma oscillations are the type most likely to induce seizures in people with photosensitive epilepsy, says Dora Hermes, a neuroscientist at Stanford University in California. She recalls a famous episode of a Japanese cartoon that featured flickering red and blue lights, which induced seizures in some viewers. “So many people watched that episode that there were almost 700 extra visits to the emergency department that day.”

A brain boost

Nevertheless, there is clearly a growing excitement around treating neurological diseases using neuromodulation, rather than pharmaceuticals. “There’s pretty good evidence that by changing neural-circuit activity we can get improvements in Parkinson’s, chronic pain, obsessive–compulsive disorder and depression,” says Insel. This is important, he says, because so far, pharmaceutical treatments for neurological disease have suffered from a lack of specificity. Koroshetz adds that funding institutes are eager for treatments that are innovative, non-invasive and quickly translatable to people.

Since publishing their mouse paper, Boyden says, he has had a deluge of requests from researchers wanting to use the same technique to treat other conditions. But there are a lot of details to work out. “We need to figure out what is the most effective, non-invasive way of manipulating oscillations in different parts of the brain,” he says. “Perhaps it is using light, but maybe it’s a smart pillow or a headband that could target these oscillations using electricity or sound.” One of the simplest methods that scientists have found is neurofeedback, which has shown some success in treating a range of conditions, including anxiety, depression and attention-deficit hyperactivity disorder. People who use this technique are taught to control their brainwaves by measuring them with an EEG and getting feedback in the form of visual or audio cues.

Phyllis Zee, a neurologist at Northwestern University in Chicago, Illinois, and her colleagues delivered pulses of ‘pink noise’ — audio frequencies that together sound a bit like a waterfall — to healthy older adults while they slept. They were particularly interested in eliciting the delta oscillations that characterize deep sleep. This aspect of sleep decreases with age, and is associated with a decreased ability to consolidate memories.

So far, her team has found that stimulation increased the amplitude of the slow waves, and was associated with a 25–30% improvement in recall of word pairs learnt the night before, compared with a fake treatment7. Her team is midway through a clinical trial to see whether longer-term acoustic stimulation might help people with mild cognitive impairment.

Although relatively safe, these kinds of technologies do have limitations. Neurofeedback is easy to learn, for instance, but it can take time to have an effect, and the results are often short-lived. In experiments that use magnetic or acoustic stimulation, it is difficult to know precisely what area of the brain is being affected. “The field of external brain stimulation is a little weak at the moment,” says Knight. Many approaches, he says, are open loop, meaning that they don’t track the effect of the modulation using an EEG. Closed loop, he says, would be more practical. Some experiments, such as Zee’s and those involving neuro-feedback, already do this. “I think the field is turning a corner,” Knight says. “It’s attracting some serious research.”

In addition to potentially leading to treatments, these studies could break open the field of neural oscillations in general, helping to link them more firmly to behaviour and how the brain works as a whole.

Shadlen says he is open to the idea that oscillations play a part in human behaviour and consciousness. But for now, he remains unconvinced that they are directly responsible for these phenomena — referring to the many roles people ascribe to them as “magical incantations”. He says he fully accepts that these brain rhythms are signatures of important brain processes, “but to posit the idea that synchronous spikes of activity are meaningful, that by suddenly wiggling inputs at a specific frequency, it suddenly elevates activity onto our conscious awareness? That requires more explanation.”

Whatever their role, Tsai mostly wants to discipline brainwaves and harness them against disease. Cognito Therapeutics has just received approval for a second, larger trial, which will look at whether the therapy has any effect on Alzheimer’s disease symptoms. Meanwhile, Tsai’s team is focusing on understanding more about the downstream biological effects and how to better target the hippocampus with non-invasive technologies.

For Tsai, the work is personal. Her grandmother, who raised her, was affected by dementia. “Her confused face made a deep imprint in my mind,” Tsai says. “This is the biggest challenge of our lifetime, and I will give it all I have.”

https://www.nature.com/articles/d41586-018-02391-6

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After being stung by a parasitic wasp, the American cockroach loses control of its behavior, becoming host to the wasp’s egg. Days later, the hatchling consumes the cockroach alive. While this is a gruesome process for the cockroach, scientists now report in ACS’ journal Biochemistry the discovery of a new family of peptides in the wasp’s venom that could be key to controlling roach minds, and might even help researchers develop better Parkinson’s disease treatments.

Scientists have long studied venoms, such as that of the wasp, seeking out novel and potent molecules to treat disease, among other applications. In the case of the enigmatic wasp Ampulex compressa, it uses its venom in a two-pronged approach against the cockroach, with an initial sting to the thorax to paralyze the front legs and a subsequent sting directly to the brain. This second sting causes the roach first to vigorously groom itself, then to fall into a state of lethargy, allowing the wasp to do whatever it wants. This immobile state resembles symptoms of Parkinson’s disease, and both may be related to dysfunction in the dopamine pathway. In this study, Michael E. Adams and colleagues wanted to identify the ingredients in wasp venom that dictate this behavior.

The researchers milked wasps for their venom and then analyzed the components using liquid chromatography and mass spectrometry. They identified a new family of alpha-helical peptides and named them ampulexins. To test their function, the team injected the most abundant venom peptide into cockroaches. Afterward, the bugs needed, on average, a 13-volt electric shock to the foot to get them moving, while an average of 9 volts sufficed prior to the injection, suggesting the peptides help the wasp immobilize its prey. Future work will focus on identifying cellular targets of ampulexins, and potentially generating a useful animal model for the study of Parkinson’s disease treatments.

The authors acknowledge funding from the United States-Israel Binational Science Foundation, the University of California, Riverside Office of Research and Economic Development and the University of California Agricultural Experiment Station.

https://www.acs.org/content/acs/en/pressroom/presspacs/2018/acs-presspac-february-7-2018/mind-controlling-molecules-from-wasp-venom-could-someday-help-parkinsons-patients.html

By Bradley J. Fikes

A diabetes drug developed by a San Diego biotech company from a venomous lizard’s saliva reduces Parkinson’s disease symptoms, according to a study published Thursday.

The placebo-controlled study of 62 patients found the drug, exenatide, provided statistically significant effectiveness in preserving motor control. It may actually slow down disease progression, although this has to be confirmed with more research.

For Parkinson’s patients, the trial represents stronger grounds to expect more effective treatments. For San Diego’s life science community, it represents another example of the benefits of original research and innovation.

The study was published in The Lancet by researchers led by Thomas Foltynie and Dilan Athauda, both of University College London in London, England. While the study wasn’t particularly large, with 62 patients, it was placebo-controlled, and is in line with a previous clinical study published in 2014.

Exenatide was found in Gila monster saliva by Dr. John Eng, an endocrinologist at Bronx Veterans Affairs Medical Center in New York. The venomous lizard, native to the Southwestern United States and northwestern Mexico, delivers excruciating pain with its bite.

San Diego’s Amylin Pharmaceuticals licensed the discovery in 1996. Further development yielded exenatide, sold under the brand name Byetta.

The drug became a hit, providing a major reason for Amylin’s 2012 purchase for $7 billion by Bristol-Myers Squibb. As for Amylin, the company was disbanded and no longer exists.

Exenatide/Byetta reduces insulin resistance in Type 2 diabetes, allowing for better control of blood glucose. There’s evidence that Parkinson’s disease is also related to problems with insulin signaling.

The new clinical study improves on the previous study because it is placebo-controlled, according to an accompanying commentary in The Lancet. But the study has limitations that prevent it from being considered definitive.

“Whether exenatide acts as a novel symptomatic agent or has neuroprotective effects on the underlying Parkinson’s disease pathology remains unclear, but Athauda and colleagues’ study opens up a new therapeutic avenue in treatment of Parkinson’s disease,” the commentary stated.

Christian Weyer, M.D., a former Amylin executive, said one of the most interesting parts of the study was exenatide’s potential for modifying the course of Parkinson’s disease. Weyer is now president of Chula Vista’s ProSciento, a clinical services provider.

Patients were measured on motor skills after getting 48 weeks of injections, either with exenatide or placebo. The treated group showed an advantage of 4 points on a 132-scale test, which was statistically significant.

Exenatide mimics the action of a hormone, and such drugs often show disease-modifying properties, said Weyer, who was Amylin’s Senior Vice President of Research and Development.

“It’s not conclusive that exenatide has the potential for disease-modification, but I was impressed by the fact that the endpoint of the test was in the off-medication period, so you actually assess whether there’s an effect even after the treatment had been stopped,” Weyer said.

Amylin had performed early preclinical research on exenatide for Parkinsons’ disease, Weyer said. The research was funded by a small grant from the Michael J. Fox Foundation.

In chronic diseases such as Type 2 diabetes and Parkinson’s, finding disease-modifying therapies is the “Holy Grail,” Weyer said.

“These are life-long diseases, and anything you can do to either delay or prevent the onset of the disease, or to slow its progression over a long period of time” has great benefit, Weyer said.

Insulin has many biological roles in the body, so it’s not surprising that an abnormal response to insulin could play a role in Parkinson’s disease as well as diabetes, Weyer said.

http://www.sandiegouniontribune.com/business/biotech/sd-me-exenatide-parkinsons-20170803-story.html

New findings indicate that phosphorylated LRRK2 (leucine-rich repeat kinase 2) protein levels in urine are elevated in patients diagnosed with idiopathic Parkinson Disease (PD), and that urinary phosphorylated LRRK2 levels correlate with the presence and severity of symptoms such as cognitive impairment in individuals with PD. Researchers affiliated with the University of Alabama at Birmingham published their findings in Neurology and in Movement Disorders (1,2).

The etiology of PD is currently unknown and mechanisms of action are still not completely clarified. It is well established, however, that aging is the single most important risk factor. PD is the second most frequent age-related neurodegenerative disorder, and one of the key pathogenic features is slow and progressive neuronal death that is concomitant with cognitive dysfunction. Current therapeutic modalities are inadequate and clinical need is significant. More than 6 million individuals worldwide are diagnosed with PD.

To date, several common genetic variants, or single nucleotide polymorphisms (SNPs), have been identified that influence the risk for disease. For example, polymorphic variants in LRRK2 gene have previously been validated as genetic factors that confer susceptibility to PD.

Although the gene remains poorly characterized, five different mutations in the gene encoding LRRK2 are considered a common cause of inherited PD (3). One of the five mutations that are causal is the G2019S mutation in the LRRK2 kinase domain, a mutation that significantly increases phosphorylation activity (1,3).

“There are currently no known ways to predict which G2019S mutation carriers will develop PD,” the authors wrote in the Neurology publication. Investigators purified LRRK2 protein from urinary exosomes collected from a total of 76 men. (Exosomes are membrane vesicles of endosomal origin that are secreted by most cells in culture, and are present in most biological fluids such as urine, blood, and saliva.) Then, they compared the ratio of phosphorylated LRRK2 to total LRRK2 in urine exosomes. Results show that “elevated … phosphorylated LRRK2 predicted the risk” for onset of PD in LRRK2 G2019S mutation carriers (1).

In their follow-up study, which was published in Movement Disorders, investigators compared phosphorylated LRRK2 levels in urine samples of 79 individuals diagnosed with PD to those of 79 healthy control participants. Results show that phosphorylated LRRK2 levels were significantly elevated in patients with PD when compared to those of controls. Also, phosphorylated LRRK2 levels correlated with the severity of cognitive impairment in patients with PD (2).

“Because few viable biomarkers for PD exist … phosphorylated LRRK2 levels may be a promising candidate for further exploration,” the authors concluded in their publication.

References
1. Fraser KB, Moehle MS, Alcalay RN, et al. Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers. Neurology. 2016;86:994-999.
2. Fraser KB, Rawlins AB, Clar RG, et al. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov Disord. 2016. doi: 10.1002/mds.26686.
3. Greggio E, Cookson MR. Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro. 2009;1:e00002.

http://www.psychiatryadvisor.com/neurocognitive-disorders/urinary-biomarker-of-parkinson-disease-identified/article/508195/?DCMP=EMC-PA_Update_RD&cpn=psych_md,psych_all&hmSubId=&hmEmail=5JIkN8Id_eWz7RlW__D9F5p_RUD7HzdI0&NID=1710903786&dl=0&spMailingID=14919209&spUserID=MTQ4MTYyNjcyNzk2S0&spJobID=820575619&spReportId=ODIwNTc1NjE5S0

Coffee lovers may live longer than those who don’t imbibe — with lower risks of early death from heart disease and neurological conditions such as Parkinson’s disease, a large U.S. study finds.

Researchers said the study, published online Nov. 16 in Circulation, adds to a large body of evidence on the good side of coffee.

People often think of coffee-drinking as a bad habit that they need to break, said study leader Dr. Frank Hu, a professor of nutrition and epidemiology at Harvard School of Public Health in Boston.

But, Hu said, many studies have linked moderate coffee intake to lower risks of developing various diseases — from heart disease and diabetes, to liver cancer, to neurological diseases such as Parkinson’s, multiple sclerosis and Alzheimer’s.

His team’s study, funded by the U.S. National Institutes of Health, adds another layer of evidence. It found that coffee drinkers were not only less likely to develop certain diseases — they also tended to live longer.

Over 30 years, nonsmokers who drank three to five cups of coffee a day were 15 percent less likely to die of any cause, versus nondrinkers. Specifically, they had lower rates of death from heart disease, stroke, neurological conditions and suicide.

Both regular coffee and decaf were linked to longer survival, the study found.

None of that proves coffee, itself, extends people’s lives or directly protects against certain diseases, Hu said. Other factors might explain the connection.

But, Hu added, his team did account for many of those factors. And the coffee benefit remained.

The findings are based on more than 200,000 U.S. doctors, nurses and other health professionals who were surveyed repeatedly over almost three decades. During that time, almost 32,000 study participants died.

It turned out that people who drank one to five cups of coffee at the outset had lower odds of dying during the study period when other lifestyle habits and certain health problems, such as high blood pressure and diabetes, were taken into account.

The relationship grew stronger when the researchers looked only at nonsmokers: Those who drank three to five cups of coffee a day were 15 percent less likely to die during the study period, compared with adults who didn’t drink coffee. Lower risks were even seen among the heaviest coffee drinkers (more than five cups a day), who had a 12 percent lower death risk than nondrinkers.

“The body of evidence does suggest coffee can fit into a healthy lifestyle,” Hu said.

That evidence, Hu noted, has already been incorporated into the latest U.S. dietary guidelines, which say that a healthy diet can include up to three to five cups of coffee a day.

But overall lifestyle is key, Hu said. That is, there’s a difference between a person who gets little sleep, then uses coffee to function during the day, and a person who sleeps well, exercises, and eats a balanced diet that includes some coffee.

Alice Lichtenstein, a spokesperson for the American Heart Association, agreed.

“This doesn’t mean you should start drinking coffee in the hopes of getting health benefits,” said Lichtenstein, who is also a professor of nutrition science and policy at Tufts University in Boston.

But, she added, the new findings build on years of evidence that coffee is not the bad guy many believe it is. “There’s this lingering idea that coffee must be bad for you because it’s enjoyable,” Lichtenstein said. “It’s almost like we’ve been trying to find something wrong with it.”

There are caveats, though. “You do need to be careful about what you’re putting in your coffee,” Lichtenstein pointed out. Some milk is fine, she said, but watch the sugar and heavy cream.

And why would coffee be related to health benefits? It’s not clear from this study, Hu said, but other research has suggested that compounds in coffee can reduce inflammation, act as antioxidants, and improve blood sugar regulation, among other things.

Also, when it comes to some neurological conditions, such as Parkinson’s disease, Hu said, there’s evidence that caffeine offers benefits.

SOURCES: Frank Hu, M.D., Ph.D., professor, nutrition and epidemiology, Harvard School of Public Health, Boston; Alice Lichtenstein, D.Sc., professor, nutrition science and policy, Tufts University, Boston; Nov. 16, 2015, Circulation, online

Read more at http://www.philly.com/philly/health/HealthDay705311_20151116_Coffee_Drinkers_May_Live_Longer.html#rPogcDb2tVXwEFwz.99

by Jon Hamilton

A drug that’s already approved for treating leukemia appears to dramatically reduce symptoms in people who have Parkinson’s disease with dementia, or a related condition called Lewy body dementia.

A pilot study of 12 patients given small doses of nilotinib found that movement and mental function improved in all of the 11 people who completed the six-month trial, researchers reported Saturday at the Society for Neuroscience meeting in Chicago.

And for several patients the improvements were dramatic, says Fernando Pagan, an author of the study and director of the Movement Disorders Program at Georgetown University Medical Center. One woman regained the ability to feed herself, one man was able to stop using a walker, and three previously nonverbal patients began speaking again, Pagan says.

“After 25 years in Parkinson’s disease research, this is the most excited I’ve ever been,” Pagan says.

If the drug’s effectiveness is confirmed in larger, placebo-controlled studies, nilotinib could become the first treatment to interrupt a process that kills brain cells in Parkinson’s and other neurodegenerative diseases, including Alzheimer’s.

One of the patients in the pilot study was Alan Hoffman, 74, who lives with his wife, Nancy, in Northern Virginia.

Hoffman was diagnosed with Parkinson’s in 1997. At first, he had trouble moving his arms. Over time, walking became more difficult and his speech became slurred. And by 2007, the disease had begun to affect his thinking.

“I knew I’d dropped off in my ability to read,” Hoffman says. “People would keep giving me books and I’d have read the first chapter of about 10 of them. I had no ability to focus on it.”

“He had more and more difficulty making sense,” Nancy Hoffman says. He also became less active, less able to have conversations, and eventually stopped doing even household chores, she says.

But after a few weeks on nilotinib, Hoffman “improved in every way,” his wife says. “He began loading the dishwasher, loading the clothes in the dryer, things he had not done in a long time.”

Even more surprising, Hoffman’s scores on cognitive tests began to improve. At home, Nancy Hoffman says her husband was making sense again and regained his ability to focus. “He actually read the David McCullough book on the Wright Brothers and started reading the paper from beginning to end,” she says.

The idea of using nilotinib to treat people like Alan Hoffman came from Charbel Moussa, an assistant professor of neurology at Georgetown University and an author of the study.

Moussa knew that in people who have Parkinson’s disease with dementia or a related condition called Lewy body dementia, toxic proteins build up in certain brain cells, eventually killing them. Moussa thought nilotinib might be able to reverse this process.

His reasoning was that nilotinib activates a system in cells that works like a garbage disposal — it clears out unwanted proteins. Also, Moussa had shown that while cancer cells tend to die when exposed to nilotinib, brain cells actually become healthier.

So Moussa had his lab try the drug on brain cells in a Petri dish. “And we found that, surprisingly, with a very little amount of the drug we can clear all these proteins that are supposed to be neurotoxic,” he says.

Next, Moussa had his team give the drug to transgenic mice that were almost completely paralyzed from Parkinson’s disease. The treatment “rescued” the animals, he says, allowing them to move almost as well as healthy mice.

Moussa’s mice got the attention of Pagan from Georgetown’s Movement Disorders Program. “When Dr. Moussa showed them to me,” Pagan says, “it looked like, hey, this is type of drug that we’ve been looking for because it goes to the root of the problem.”

The pilot study was designed to determine whether nilotinib was safe for Parkinson’s patients and to determine how much drug from the capsules they were taking was reaching their brains. “But we also saw efficacy, which is really unheard of in a safety study,” Pagan says.

The study found that levels of toxic proteins in blood and spinal fluid decreased once patients began taking nilotinib. Also, tests showed that the symptoms of Parkinson’s including tremor and “freezing” decreased. And during the study patients were able to use lower doses of Parkinson’s drugs, suggesting that the brain cells that produce dopamine were working better.

But there are some caveats, Pagan says. For one thing, the study was small, not designed to measure effectiveness, and included no patients taking a placebo.

Also, nilotinib is very expensive. The cost of providing it to leukemia patients is thousands of dollars a month.

And finally, Parkinson’s and dementia patients would have to keep taking nilotinib indefinitely or their symptoms would continue to get worse.

Alan Hoffman was okay for about three weeks after the study ended and he stopped taking the drug. Since then, “There’s (been) a pretty big change,” his wife says. “He does have more problems with his speech, and he has more problems with cognition and more problems with mobility.”

The Hoffmans hope to get more nilotinib from the drug’s maker, Novartis, through a special program for people who improve during experiments like this one.

Meanwhile, the Georgetown team plans to try nilotinib in patients with another brain disease that involves toxic proteins: Alzheimer’s.

http://www.npr.org/sections/health-shots/2015/10/17/448323916/can-a-cancer-drug-reverse-parkinsons-disease-and-dementia

Why do some people remain healthy into their 80s and beyond, while others age faster and suffer serious diseases decades earlier? New research led by UCLA life scientists may produce a new way to answer that question—and an approach that could help delay declines in health.

Specifically, the study suggests that analyzing intestinal bacteria could be a promising way to predict health outcomes as we age.

The researchers discovered changes within intestinal microbes that precede and predict the death of fruit flies. The findings were published in the open-source journal Cell Reports.

“Age-onset decline is very tightly linked to changes within the community of gut microbes,” said David Walker, a UCLA professor of integrative biology and physiology, and senior author of the research. “With age, the number of bacterial cells increase substantially and the composition of bacterial groups changes.”

The study used fruit flies in part because although their typical life span is just eight weeks, some live to the age equivalent of humans’ 80s and 90s, while others age and die much younger. In addition, scientists have identified all of the fruit fly’s genes and know how to switch individual ones on and off.

In a previous study, the UCLA researchers discovered that five or six days before flies died, their intestinal tracts became more permeable and started leaking.

In the latest research, which analyzed more than 10,000 female flies, the scientists found that they were able to detect bacterial changes in the intestine before the leaking began. As part of the study, some fruit flies were given antibiotics that significantly reduce bacterial levels in the intestine; the study found that the antibiotics prevented the age-related increase in bacteria levels and improved intestinal function during aging.

The biologists also showed that reducing bacterial levels in old flies can significantly prolong their life span.

“When we prevented the changes in the intestinal microbiota that were linked to the flies’ imminent death by feeding them antibiotics, we dramatically extended their lives and improved their health,” Walker said. (Microbiota are the bacteria and other microorganisms that are abundant in humans, other mammals, fruit flies and many other animals.)

Flies with leaky intestines that were given antibiotics lived an average of 20 days after the leaking began—a substantial part of the animal’s life span. On average, flies with leaky intestines that did not receive antibiotics died within a week.

The intestine acts as a barrier to protect our organs and tissue from environmental damage.

“The health of the intestine—in particular the maintenance of the barrier protecting the rest of the body from the contents of the gut—is very important and might break down with aging,” said Rebecca Clark, the study’s lead author. Clark was a UCLA postdoctoral scholar when the research was conducted and is now a lecturer at England’s Durham University.

The biologists collaborated with William Ja, an assistant professor at Florida’s Scripps Research Institute, and Ryuichi Yamada, a postdoctoral research associate in Ja’s laboratory, to produce an additional group of flies that were completely germ-free, with no intestinal microbes. Those flies showed a very dramatic delay in intestinal damage, and they lived for about 80 days, approximately one-and-a-half times as long as the animal’s typical life span.

Scientists have recently begun to connect a wide variety of diseases, including diabetes and Parkinson’s, among many others, to changes in the microbiota, but they do not yet know exactly what healthy microbiota look like.

“One of the big questions in the biology of aging relates to the large variation in how we age and how long we live,” said Walker, who added that scientific interest in intestinal microbes has exploded in the last five years.

When a fruit fly’s intestine begins to leak, its immune response increases substantially and chronically throughout its body. Chronic immune activation is linked with age-related diseases in people as well, Walker said.

Walker said that the study could lead to realistic ways for scientists to intervene in the aging process and delay the onset of Parkinson’s disease, Alzheimer’s disease, cancer, stroke, cardiovascular disease, diabetes and other diseases of aging—although such progress could take many years, he said.