Mapping NMDA Receptors

NEUROSCIENCE NEWSDECEMBER 3, 2016

Summary: Researchers reveal the structures of a portion of the NMDA receptor.

Source: Cold Spring Harbor Laboratory.

This overall view of the NMDA receptor shows its hot air balloon-like shape. Much of the “balloon” portion protrudes from the surface of glutamate neurons. It engages with signals coming from outside the cell. The “basket” portion the at the bottom lies well below the cell membrane, in the cytoplasm. It forms the terminal end of the receptor’s ion channel. NMDA dysfunction is implicated in depression, schizophrenia and Alzheimer’s disease, among others. NeuroscienceNews.com image is credited to Furukawa Lab, CSHL.

Detailed images of NMDA receptors help explain how zinc and a drug affect their function. Drugs precisely targeting portions of this receptor may have applications in Alzheimer’s, depression and schizophrenia.

The difference between mental health and mental illness can turn on changes in brain cells and their connections that are almost incomprehensibly tiny, at least in physical terms. This irony is brought to light by X-ray crystallography, a method that enables neuroscientists to map the structure of brain proteins atom by atom, using high-energy X-rays.

In research appearing today in Neuron, a team at Cold Spring Harbor Laboratory (CSHL) reveals for the first time the structure of a portion of an important brain cell receptor, called the NMDA (N-methyl D-aspartate) receptor. The newly mapped portion of NMDA receptor is responsible for recognizing zinc, an element common throughout the brain that can inhibit a class of NMDA receptors.

Large in size compared with many other proteins, NMDA receptors are shaped like hot air balloons, ones that poke through the surface membrane of neurons in the brain that receive glutamate, the most common excitatory neurotransmitter.

NMDA receptors are activated when a glutamate molecule docks at a site on the receptor, setting in motion a complex series of changes. But that is only part of what is happening. Along with glutamate, some sets of neurons co-release zinc, which can also interact with NMDA receptors, playing an important role in controlling neuronal signaling. The binding of zinc to NMDA receptors is also an important factor in the transmission of the sensation of pain.

The precise structure of the NMDA receptor is critical in current efforts to design new and more effective drugs to treat a host of mental disorders. Overactive NMDA receptors are linked with neurodegenerative illness, such as Alzheimer’s disease. Underactive NMDA receptors may be a factor in schizophrenia. The receptors are also implicated in depression and epilepsy, among other illnesses.

Different sections, called domains, of the giant NMDA protein are involved in these various illnesses, and they are joined together in four major combinations, or subtypes. The subtypes, referred to by the letters A, B, C and D, have specific functions and appear at different times in life and places in the brain. Specific targeting of those subtypes is important in efforts to minimize side effects of new drugs for brain disorders now being tested in labs and clinical trials.

The subtype revealed in the new research, led by CSHL Associate Professor Hiro Furukawa, is the “A” form of the NMDA receptor. The team mapped the amino terminal domain (ATD), one of the four domains of the GluN2A subunit of the receptor. The ATD — the outermost part of the NMDA structure, poking out into extracellular space — is pictured by the team as it forms a complex with zinc.

The team’s high-resolution pictures of the “A” type of the NMDA receptor are the product of 3 years of work by Annabel Romero-Hernandez, a talented graduate student in the Furukawa lab studying at the Watson School of Biological Sciences. “Annabel’s beautiful new pictures are important for a few reasons,” says Furukawa. “They have enabled us to solve two puzzles, both raised by earlier pictures we made of the ‘B’ type of the receptor. First, why does zinc bind so much more readily to the ‘A’ form compared with the ‘B’ form, which is structurally almost identical? And second, why does the important candidate drug ifenprodil bind at a site in the ‘B’ form but not in the ‘A’ form?”

What the new images reveal about zinc binding

Furukawa and Romero-Hernandez were intrigued by the zinc molecule’s interaction with the ‘A’ form of the receptor in part because of discoveries in recent years of zinc’s abundance and important role in the mammalian brain. When a message-transmitting NMDA receptor releases glutamate, it co-releases zinc, which interacts with the receptor at an alternate binding site, called an allosteric site. In the already-mapped ‘B’ form of the receptor, comparatively large amounts of zinc had to be present if binding was to occur; and the binding was found to be physically weak.

The new pictures of the receptor’s ‘A’ form show why much less zinc is needed to achieve binding, and explains why the binding is much more robust. Zinc slips into the pivot point in a clamshell-like assembly in the ATD, and atomic-level resolution reveals that in the ‘A’ form, it is held firmly in place by bonds formed with four surrounding amino acid molecules. In previously obtained views of the ‘B’ form, only two such amino acids lie at the comparable spot in the ATD’s structure. The difference in binding affinity, says Furukawa, “is like the difference between having two hands holding up an object vs. four hands.”

Zinc’s impact on the function of the much larger full NMDA receptor is profound: its binding to the ATD is a regulator of the receptor’ central channel that connects the exterior environment to the cell’s interior. Zinc inhibits the ion channel, encouraging it to close up — much more strongly in the ‘A’ type than the ‘B’ type. “Zinc binding is one of the means by which NMDA receptors regulate themselves,” says Dr. Romero-Hernandez. Such self-regulation is important, she notes, considering that “when you overactivate these receptors the consequence can be neurodegenerative.”

X-ray crystallography by Furukawa and team show how very slight changes in structure between two variants of one of the NMDA receptor’s domains can affect drug binding. On the left, a binding pocket for the drug ifenprodil created in the interface between two subdomains of the receptor, called GluN1b and GluN2B, is shown above in brown, and rendered below as it would appear visually. Tiny structural differences in the latter subdomain, in a variant called GluN2A, collapse the space between the two subdomains and prevent ifenprodil from binding. Drugs generally cause fewer side effects when they are extremely specific in their binding sites. NeuroscienceNews.com image is credited to Furukawa Lab, CSHL.

The receptor’s ion channel flickers open and closed very rapidly — in a tenth to a hundredth of a second — as the brain performs its complex operations. Whether it is being inhibited by zinc or excited by glutamate or other binding partners, the result is profound, considered at the level of entire brain regions.

A drug binding pocket that “collapses”

The same mapping of the ATD in the ‘A’ form of the NMDA receptor also solved the question of whether ifenprodil can bind at an allosteric site in the ATD identified clearly in the lab’s prior work on the ‘B’ form.

The new pictures obtained by Furukawa and Romero-Hernandez show clearly that in the ‘A’ form, “the binding pocket, which was so large in the ‘B’ form, has now collapsed into a much smaller space,” says Furukawa. “Now we understand structurally why the drug cannot bind in the ‘A’ form.” This could be crucial to drug developers, since the more specific a drug is, the less likely it will have unwanted side effects.

With recent research demonstrating the almost magical power of the drug ketamine – an NMDA inhibitor — to alleviate the worst forms of non-responsive major depression in some patients, there is great interest in finding mechanisms underlying the illness that do not involve the neurotransmitter serotonin. So-called SSRI antidepressants (drugs in the Prozac class) are taken by tens of millions, many of whom are not helped by it. Furukawa says his work on the NMDA receptoris aimed in part on exploring alternate hypotheses of depression’s causation involving NMDA or glutamate-mediated dysfunctions. His lab is pursuing this work in structural studies as well as by studying signaling pathways inside neurons – activated by the interaction of receptors like the NMDA receptor with the environment beyond the cell membrane.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Funding: The Furukawa lab is supported by the National Institutes of Health and the Stanley Institute of Cognitive Genomics. Annabel Romero-Hernandez is a Ph.D. student at the Watson School of Biological Sciences at CSHL and is supported by the Genentech Foundation Fellowship and the Starr Foundation.

Source: Peter Tarr – Cold Spring Harbor Laboratory

Image Source: NeuroscienceNews.com images are credited to Furukawa Lab, CSHL.

Original Research: Abstract for “Molecular basis for subtype-specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino terminal domain” by Annabel Romero-Hernandez, Noriko Simorowski, Erkan Karakas, and Hiro Furukawa in Neuron. December 1 2016 doi:10.1016/j.neuron.2016.11.006

Abstract

Molecular basis for subtype-specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino terminal domain

Highlights

•Structure of the GluN1-GluN2A ATD heterodimer is obtained for the first time

•The high-affinity zinc-binding site in GluN2A is completely mapped

•Elements for subtype-specific binding of zinc and phenylethanolamine are found

•Inter-lobe interface of ATD controls zinc inhibition and channel open probability

Summary

Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure. Here we show the first crystal structures of the heterodimeric GluN1-GluN2A ATD, which provide the complete map of the high-affinity zinc-binding site and reveal distinctive features from the ATD of the GluN1-GluN2B subtype. Perturbation of hydrogen bond networks at the hinge of the GluN2A bi-lobe structure affects both zinc inhibition and open probability, supporting the general model in which the bi-lobe motion in ATD regulates the channel activity in NMDA receptors.

“Molecular basis for subtype-specificity and high-affinity zinc inhibition in the GluN1-GluN2A NMDA receptor amino terminal domain” by Annabel Romero-Hernandez, Noriko Simorowski, Erkan Karakas, and Hiro Furukawa in Neuron. December 1 2016 doi:10.1016/j.neuron.2016.11.006

http://neurosciencenews.com/nmda-receptor-mapping-5669/

Does Parkinson’s Disease Start in the Gut? Maybe, Scientists Say

DECEMBER 2, 2016  BY JOANA FERNANDES, PHD IN NEWS.

The hallmark of Parkinson’s disease is the formation of aggregates of the protein alpha-synuclein, which are toxic to neurons and promote the loss of brain function. A new animal study suggests these aggregates can form in the gut and, in the course of months, spread to the brain.

These findings were recently discussed at the Society for Neuroscience 2016, in San Diego, in the presentation, “Progression Of Parkinson’s-Like Pathology Following Inoculation Of Alpha-Synuclein Preformed Fibrils In The Gut,” by Collin Challis from Caltech.

Previous studies have suggested that the gut could be involved in Parkinson’s disease. Researchers have found alpha-synuclein aggregates in the gut nerves during autopsies of both patients and individuals with aggregates in the brain but no symptoms. Parkinson’s patients also often report experiencing gastrointestinal problems, such as constipation, about 10 years before the start of movement anomalies, the most typical symptoms of the disease.

This evidence supports the idea that Parkinson’s disease may start in the gut, possibly due to bacteria or toxins.

Challis and his colleagues injected aggregates of alpha-synuclein into the stomach and intestine of mice. The team observed that the aggregates promoted the formation of new aggregates, and that these spread to the base of the brain three weeks later. Two months later, the aggregates had reached deep brain areas responsible for movement control and dopamine production — the neurons that die in people with Parkinson’s. Indeed, the injected mice showed reduced agility, similar to what happens in patients.

It is not yet clear what may trigger the formation of the aggregates in the gut, but previous studies suggest that this may be due to the presence of specific bacteria in Parkinson’s patients. Indeed, some doctors have been trying to see whether antibiotics or fecal transplants may help in preventing the development of Parkinson’s.

“It could be that having the wrong bacteria in your gut triggers inflammation,” Sébastien Paillusson from King’s College London, said in a news release. “We know that inflammation makes synuclein more likely to aggregate.”

Another triggering factor for alpha-synuclein aggregation in the gut may be the exposure to certain chemicals, as some studies have shown that farmers exposed to certain pesticides and people who drink water from possibly contaminated wells are at higher risk of developing Parkinson’s disease. It may be that these chemicals induce damage to the gut and aggregation of alpha-synuclein.

“There are a lot of theories out there,” said Challis, in another news release. “Bacteria may produce compounds called curli that prompt alpha-synuclein to aggregate, a recent study suggests. Pesticides, acid reflux and inflammation are other possible culprits that could somehow increase alpha-synuclein clumps in the gut.”

Although questions remain to be answered, knowing that the gut may be the starting point for the development of Parkinson’s opens the possibility of stopping the disease before the most profound symptoms appear.

http://parkinsonsnewstoday.com/2016/12/02/parkinsons-disease-may-start-in-the-gut-and-travel-to-brain

Researchers ‘Watch’ Protein Aggregation Process That Leads to Parkinson’s Disease

 DECEMBER 1, 2016  BY JOANA FERNANDES, PHD IN NEWS.

New research helps to explain how alpha-synuclein — the defective protein causing Parkinson’s disease — achieves its structure in neurons. These findings may help understand how aggregates of alpha-synuclein form in the brain of a Parkinson’s patient.

The study, “Structural Basis For The Dissociation Of Α-Synuclein Fibrils Triggered By Pressure Perturbation Of The Hydrophobic Core,” published in the journal Scientific Reports, was conducted by Jerson Silva with the Federal University of Rio de Janeiro, Brazil, and colleagues.

Parkinson’s disease develops when alpha-synuclein abnormally aggregates in neurons. Normally, this protein contributes to the exchange of chemical signals between neurons and regulates dopamine transport. In Parkinson’s, however, alpha-synuclein aggregates into structures known as Lewy bodies, which disrupt dopamine signaling and promote motor deficiencies.

Current efforts to treat Parkinson’s symptoms include stabilizing alpha-synuclein in its original form, to prevent several protein units from binding together and forming the toxic aggregates. But exactly how alpha-synuclein forms these aggregates remains elusive.

Researchers used high hydrostatic pressure (HHP) — a process also used to preserve and sterilize food by applying high-pressure water pumps — as a tool to dismantle alpha-synuclein aggregates and release the protein units back to their original “single” form. The HHP technique did this by forcing water into the core of the alpha-synuclein aggregates, causing the units to separate.

In the meantime, researchers could follow this “unfolding” of the proteins using a technique called nuclear magnetic resonance (NMR) spectroscopy. NMR gave the team access to the folding and unfolding process so members could analyze these alpha-synuclein units, looking for signs of what goes wrong with the protein to cause aggregate formation and, consequently, Parkinson’s disease.

Team members believe that uncovering this process helps them to understand what happens to alpha-synuclein in a disease state, which may lead to ways to avoid that state.

“Understanding the molecular forces behind the formation of pathogenic [aggregates] uncovered by pressure perturbation will aid in the development of new therapeutics against Parkinson’s disease,” the authors concluded.

http://parkinsonsnewstoday.com/2016/12/01/researchers-find-way-to-watch-protein-aggregation-process-in-parkinsons

Dolly scientist Professor Sir Ian Wilmut predicts new drugs for Parkinson's and motor neurone disease

December 3, 2016

Professor Ian Wilmut. Photo credit: Gordon Terris.

THE creator of Dolly the Sheep has predicted the cloning of the mammal will lead to new drug treatments for inherited conditions such as Parkinson’s and motor neurone disease.

Professor Sir Ian Wilmut said researchers now were using the information gained from the cloning process to “search hard” for possible treatments for degenerative illnesses.

The scientist, who led the team at the Roslin Institute in Edinburgh which created the world’s first cloned mammal from an adult cell, said this would be a major advance – but cautioned it would be unlikely to be widely available for at least a decade.

Wilmut will be one of the keynote speakers at a major conference being held in London on Wednesday by the Progress Educational Trust (PET), which will gather leading experts in science, medicine, policy and ethics to discuss the latest developments in embryo research and genome editing.

Speaking to the Sunday Herald ahead of the event, he said that while cloning itself had only had limited application, the success of Dolly’s creation had altered the way biologists think “radically and swiftly”.

Until then it had been thought that once a cell had become specialised for a particular function – such as skin - it could not be changed.

But the birth of Dolly 20 years ago demonstrated it was possible to “turn the clock back” and make a “differentiated” cell behave as if it was a recently fertilised egg.

This knowledge was used by researchers in Japan to create the equivalent of embryonic stem cells – called “induced pluripotent stem cells” – from skin cells.

Wilmut, who is Professor Emeritus of Edinburgh University’s Centre for Regenerative Medicine, said these could be key to finding treatments for inherited conditions for which there is currently no effective treatment, such as motor neurone and Parkinson’s diseases.

He said: “You could turn the pluripotent cells into the nerve cells which are damaged in the disease.

“You could compare those [damaged] cells with the equivalent cells from the healthy person and perhaps for the first time be able to understand what has gone wrong in the patient.

“That information can then be used to look for drugs which prevent the abnormal change.”

He added: “This is going on - people are searching hard at the present time in relation to those two diseases.

“One day they will come up with drugs – it is not a cure for the disease, it just stops or slows down the rate of degeneration.

“But even so, there is no really effective treatment for either motor neurone disease or Parkinson’s at the present time, so is potentially a major advance.

“The disappointing thing for anyone who has the disease it that is probably a decade or more away, partly because of the amount of testing that has to be done.”

One of the main issues which will be discussed at the conference include the current 14-day rule, which means human embryos can only be developed in the laboratory up to 13 days after they were created.

In the UK this legislation has been in place since 1990 - however scientists had never managed to develop embryos beyond seven days.

But the issue is now in the spotlight after Cambridge University scientist Professor Magdalena Zernicka-Goetz developed human embryos for 13 days, the longest ever achieved.

http://www.heraldscotland.com/news/health/14945171.How_Dolly_the_sheep_could_lead_to_major_advances_in_drug_treatment/

Psychosis affects half the patients of Parkinson's disease

December 4, 2016

But now there is a new drug to treat it.

One night without warning, Jay Sagen leapt from his bed and grabbed the quilt, then ran downstairs and threw it out onto the street. He was certain there was a large black snake in it. His startled wife Diane hurried after him and tried to explain that nothing was there. “But he wasn’t listening to me trying to talk sense into him.”

Then Jay began seeing black cats everywhere in the house. He believed there were groups of people on the property at night too, and that a creature called Big Boy was in their bed with them. Sometimes, he believed he’d whiled away whole afternoons talking to his brother in the living room of their cosy California home south of Los Angeles.

He simply didn’t understand when Diane told him his brother was never there.

Jay, a 77-year-old artist, taught for decades at local community colleges. He was diagnosed with Parkinson’s disease in 2009 after a neurologist observed his tremors and other physical symptoms, including stiffness. Diane, a therapist now aged 73, was not scared: “We’ll deal with it, if that’s what it is,” she thought.

Preparing for the tough adjustment to life as the primary caregiver to a person with a neurodegenerative illness, Diane knew the disease was associated with health problems ranging from difficulty sleeping to tremors and slowing of movement. She also expected that it would take a toll on her time and energy as she assisted Jay with his physical impairments.

What she didn’t know – and what few people even within the medical and caring professions realise – is that over the course of their illness at least half of all people diagnosed with Parkinson’s disease will develop another set of symptoms known as Parkinson’s disease psychosis (PDP). The impact on the patient and their family – often because they don’t know what is happening – can be devastating.

Jay’s PDP symptoms began as frustrating, annoying behaviours. He would insist Diane was stealing from the family finances, for example, or accuse her of being unfaithful after 50-odd years of marriage. Eventually, the manifestations became more serious. He was increasingly seeing things and people that weren’t there. He was frightened. On one occasion Diane returned from work to learn Jay was in hospital. He’d fallen badly while charging out of the house because he had become convinced he was late for a party. “When I think back, that was disturbing,” she says. “I would think: ‘How bad is this going to get?’”

There was no answer to her question. PDP brings with it a number of serious related issues, such as a higher risk of premature death. To make matters worse, drugs for treating psychosis can heighten the physical symptoms of Parkinson’s disease. In recent months, however, a new drug has become available. It is the first of its kind and specifically treats psychosis without affecting other symptoms – but for people like Jay and Diane, questions about who the drug might help, who can get access to it, and how much it costs now loom large.

The drug paradox

“Parkinson’s is pretty easily recognised. People are slowed down, they’re bent over, they have a tremor and we think of it as a motor disorder – which it is,” explains Dr Jeffrey Cummings, Director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas and a leading authority on Parkinson’s and PDP. “But people aren’t often familiar with the non-motor components of Parkinson’s disease, including depression [and] psychosis.”

Between 7 and 10 million people are estimated to have Parkinson’s disease worldwide – 1m in the USA and more than 100,000 in the UK. This means several million people will also develop PDP and experience sometimes debilitating delusions and hallucinations. Yet while experts acknowledge that general awareness of the motor symptoms of Parkinson’s is high (certainly in the USA, where the launch of a foundation by actor Michael J Fox after his diagnosis propelled it into the limelight), PDP remains largely hidden, misunderstood and undertreated.

Dr Rachel Dolhun, Vice-president of Medical Communications at the Michael J Fox Foundation, points out that it can be difficult for people to make the connection between PDP symptoms and Parkinson’s, and to talk openly about it. “I think the difficulty is that PDP has symptoms that people don’t recognise, that they don’t bring up to their doctors and to their caregivers because they don’t realise it’s a problem… they’re afraid they’re going crazy or they think there’s not a treatment for it. Even the fact that it is defined as psychosis is a scary thing.”

Reassuring people that it is part of the disease is a big issue, she adds. “It can happen and there are things that we can do – but we can’t do anything if you don’t tell us about it.”

It isn’t clear exactly what causes it, but the psychosis can stem from either the underlying Parkinson’s disease (mostly among those who have lived with it for a long time) or the medication used to treat it. Drugs prescribed to alleviate the motor symptoms of Parkinson’s work by replenishing dopamine, the brain chemical that is diminished in people with the disease. The problem is that while this can reduce motor symptoms, increasing dopamine can overstimulate other parts of the brain and cause psychosis.

Meanwhile the medications used to date to treat psychosis symptoms – drugs such as clozapine – act by blocking the dopamine system, which tends to worsen motor problems as well as run the risk of serious side-effects.

Cummings sums it up this way: “The great paradox is that the drugs that improve psychosis make Parkinson’s worse. And so we just have not had a good alternative for our patients in terms of controlling psychosis.”

The hallucinations and depression

Diane Sagen perches on the sofa in the living room of her house in a tranquil cul-de-sac near Newport Beach. She has a stack of notes in her hands – pages from a diary she’s kept to chronicle the progression of Jay’s illness. By her side, propped up on a cushion, is a screen with live video streaming from the bedroom so she can keep an eye on her husband while he rests.

“[I’m] always being vigilant in case he falls, which he does a lot,” she says. “I’m very hypervigilant. Every now and again you can’t take it any more and you’ll turn [the vigilance] off and then something will happen.”

Diane has had intermittent support for Jay, such as care assistants, without which she says she would struggle to cope. While we are talking, she takes an unexpected call from a healthcare worker who confirms the couple have quaHallucinations and depressionlified for some new respite care through Medicare, the federal health insurance programme for retired people. Putting down the phone she takes a long, deep breath and says to herself: “Oh that’s great.”

Without this kind of help what would she do? “I don’t know. Go out of my mind. I would just be totally worn out.”

Diane says online groups have helped her to support others in similar circumstances – especially on the worst days – and to receive support in return. She is active in carers’ groups and puts herself forward for interviews like this one to raise people’s awareness. But even with her resolve to make the most of things, and given that from time to time there are glimpses of the Jay she fell in love with, she confesses it has been getting tougher as time has gone on. Physical exhaustion is one repercussion of assisting Jay day in, day out with his mobility.

But in the absence of unlimited funds to pay for help full-time, she says, it’s a mounting effort. Loneliness is a particularly challenging aspect of the caregiving role too. “You just want to escape, basically. It really is 24 hours a day of caring. And if you don’t get away occasionally, you know, you suddenly wake up and realise you are under water.

“That’s the big thing with this. It’s that feeling of isolation you get,” she says. “Nobody understands. They don’t know how hard it is. If you’ve had enough sleep you can separate yourself and say, ‘OK, it’s the disease.’ If you’re not feeling rested, you’re like, ‘Oh my god, I’m gonna kill this man.’”

Coming back downstairs at one point after checking on Jay, Diane explains why she has been speaking out about PDP. “This is what was handed to me. I guess I feel a responsibility. I’m glad to have that voice.”

Pressure on marriages and other relationships are recurring characteristics of living with PDP, not least because paranoia about infidelity features so highly. Dr Jim Beck, Vice-president of Scientific Affairs at the Parkinson’s Disease Foundation in the USA, says the “ripple effect” on the wider family and loved ones is significant. “The psychosis, as it gets more severe, can be really disruptive for relationships and for caregivers. That’s the number one reason people with Parkinson’s enter nursing homes. It’s because of psychosis.”

And because the symptoms are so complex and challenging to manage, once someone experiencing psychosis is placed in a nursing home, they are highly likely to remain there permanently. A drug that treats the symptoms of psychosis without making the physical symptoms of Parkinson’s worse is something that medical professionals and those affected by PDP have long hoped for. They know it would have a massive impact on the quality of life of people with Parkinson’s and their carers.

Elaine Casavant is a longstanding advocate on behalf of people with PDP and their families. A former nurse, she is a member of the People with Parkinson’s Advisory Council, which guides the work of the Parkinson’s Disease Foundation and speaks all across the USA on the subject. She says the difficulties of living with and treating PDP should be much more visible and a higher priority for policymakers, researchers and medics.

Elaine’s husband Len was diagnosed with Parkinson’s in the early 1990s when he was in his mid-40s. His psychosis symptoms, initially wrongly diagnosed as dementia, have waned at times as some medications and interventions, such as deep brain stimulation, have produced temporary relief. But on the whole, she says, the accusations of infidelity and the delusions and hallucinations have taken their toll. “They’re odd, they’re hurtful, they’re frightening,” she says.

One night, Len got up thinking children were playing in his room. Elaine heard him shouting in the night and ran into the room. But Len had strung an extension cord across the doorway. As she tripped and fell, he started yelling: “Elaine, Elaine, I’ve got one!”

Watching her husband suffer has at times felt relentless. “Sometimes I feel like I’m a prisoner in my own household. No matter how many times you correct or fix or clean up, tomorrow is going to be the same if not worse.”

Over the years Elaine has heard the same frustrations from people in similar circumstances, and that the strain is often unbearable. She has also been highlighting through her personal experience and activism the glaring absence of any effective treatment to target PDP. But that absence may soon be over.

The game changer?

On 29 April 2016, the US Food and Drug Administration (FDA) approved the first ever drug to specifically treat delusions and hallucinations associated with PDP. Trials showed the medication – brand name Nuplazid and from the compound pimavanserin – eased the symptoms of the condition without the same negative effects on motor symptoms as other antipsychotic drugs. This is because the new drug, from the San Diego-based pharmaceutical firm Acadia, doesn’t act on dopamine in the brain.

In fact, it is the first example of a class of drugs called selective serotonin inverse agonists, and is being touted by Acadia as a “breakthrough therapy”. “It does not work on the dopamine receptors. It works on the serotonin pathways,” explains Rachel Dolhun. “So it has this new mechanism of action.”

Jeffrey Cummings, a lead researcher on the trial, says that after a long time spent searching for a compound that would relieve symptoms of hallucinations and delusions in people with Parkinson’s, the new drug is a game changer. “It’s a breakthrough compound because not only have we not had any treatment for psychosis in Parkinson’s disease, we haven’t had treatment for psychosis in any neurological disease.”

The arrival of Nuplazid is “a big deal” for people with PDP as well as for their loved ones if the burden of care can be reduced, says Jim Beck: “Having a drug which doesn’t interfere with motor symptoms or other aspects of Parkinson’s yet has the potential to really address the psychosis – it’s really important.” 

Testing Nuplazid

Ruth Ketcham was one of the people who took part in the trial. Her hallucinations had begun one year after her diagnosis with Parkinson’s. At first, her daughter Jody Wade explains, it was a belief that animals were in the house at night. “I believed her. I said, ‘What kind of animals?’” An exterminator confirmed there were none.

The alarm bells began ringing louder when Ruth started repeating a “kind of entertaining” story about the neighbours doing T’ai Chi in the garden every morning at daybreak. “Again, I believed it,” says Jody. “She described people in amazing detail and the detail never changed.” Only after Jody stayed overnight at the house did she realise it was an elaborate hallucination.

After being made aware by her specialist of the phase III trial of pimavanserin, Ruth agreed to take part. “I have to say – and I didn’t say this to my mother – I really wasn’t that hopeful,” Jody admits. “She had a 50/50 shot of getting the placebo. But you know what? It was worth a shot. There was nothing else that was going to help her.”

More than five years later, and now 93, Ruth is still taking the drug and the outcome has been dramatic for the whole family. “I remember going back to the doctor with my mother and just being absolutely elated,” says Jody, welling up. She told the doctor that her mother had obviously got the real drug. “The doctor said: ‘You don’t know that.’ But I said: ‘Yeah. But I do know that.’” Within weeks, the hallucinations had drastically reduced, and while there are some mild symptoms now and again, they are nothing like before.

“I ask my mother: ‘What does this mean to you? What do you take away from this?’ And she says: ‘It gave me a normal life back.’ Five years later I still cry talking about it. It gave us years with my mother that we wouldn’t have had.”

Like any drug, Nuplazid has various possible side-effects. Adverse reactions recorded in the trials included a small number of participants experiencing nausea, constipation and confusion – luckily, Ruth has experienced none of them.

Elaine Casavant cautions that drugs don’t work in the same way for everyone, but also that people aren’t always able to access medication when it has been approved, for example if health insurance doesn’t cover it, or if they are poor. Drugs don’t come cheap in the USA, especially branded ones.

“Most people dealing with this are exactly like me, living on a fixed income and already paying for medications,” she says. “I’m in the process of negotiating the insurance [for a Nuplazid prescription]. It’s a matter of negotiating a rate we can afford. But again, I’d be willing to pay out of pocket to get this drug as soon as I can get it.”

In early September, a few weeks into Jay Sagen’s first prescription of Nuplazid, Diane noted some positive signs in her diary. “It’s sort of sporadic,” she confirmed. “He’ll have a couple of days with no delusions, then a day with lots of them. I notice a difference though. He’ll point to what he thinks is a man (usually in the mirror) and say something about him. All it takes is for me to say, ‘There’s no man,’ and he’ll say, ‘Oh,’ and drop it. So he’s easier to bring around to reality than he was.”

A month later, in a further update, she explained that things were continuing to improve: “The Nuplazid is working really well now. He only sees the occasional phantom person now.” 

For now, Nuplazid is only available in the USA. While Acadia pushes for wider distribution and informs medical professionals on developments, plus makes moves to have it approved in other markets such as Europe, millions of people with PDP will have to wait to see if this potentially transformative compound will work for them.

Still understanding Parkinson’s

So what’s next? That a new therapy has been approved is understandably welcome, but it is far from the end of the suffering, not least because the causes of Parkinson’s disease are still not well understood and a cure is nowhere on the horizon.

However, Rachel Dolhun says that for the first time a variety of “really exciting” therapies could be on course to offer relief for people with Parkinson’s in general, and also for those with PDP. Some might even be available in less than two years. Most of these potential new therapies are in the early stages of trials but, she says, the possibilities are nonetheless significant: “Knowing that there’s research going on into understanding Parkinson’s better, developing better and newer treatments, and finding a cure is certainly reason for optimism.”

Jeffrey Cummings too is hopeful. He thinks the step forward with pimavanserin could blaze a trail for others like it and says he’s already being approached by drug companies interested in further research following the trials that brought Nuplazid to market.

“This is a paradigm shift in terms of opening up the field. To say: ‘Yes, we are beginning to know enough about the underlying biology of these symptoms that we can intervene more effectively.’ And it won’t be just Parkinson’s. This is a gateway to more effective neuropsychiatric interventions.”

In the meantime, caregivers like Jody Wade, Elaine Casavant and Diane Sagen understand what it’s like to be on the frontline of PDP. They would all like a cure for their loved ones, of course, but in its absence they say better support, such as more respite for patients and caregivers to help navigate the condition’s unique challenges, is vital. Raising awareness is crucial too, not only so that people are diagnosed and treated, but also because research funding may follow.

According to Jim Beck, educating the wider population about PDP is paramount. “I think this really speaks to the heart of the matter – that this is something that is just not spoken about.”

“You would not believe the people living in isolation with this,” concludes Elaine. “They have no backup, they have no support.” Jody agrees: “Too many people suffer in silence.”

http://scroll.in/pulse/823219/psychosis-affects-half-the-patients-of-parkinsons-disease

Woman combats debilitating disease by staying active

December 2, 2016   Kathy Aney

East Oregonian

Carol Clupny and the Energizer Bunny have much in common. 

Like the bunny, Clupny keeps up a steady pace. The bunny, however, doesn’t have Parkinson’s disease, a progressive neurological disorder that affects movement, speech and cognition.

The Hermiston woman resolved to keep moving after her diagnosis eight years ago, shortly after her 50th birthday. The final wake-up call came during a kayaking weekend in the San Juan Islands when she started feeling weak and shaky and had trouble paddling. 

After the diagnosis, she realized that exercise helped beat back the symptoms. She shot free throws at lunchtime. Three times, she walked sections of the Camino de Santiago, a web of trails that converge on the Spanish town of Santiago de Compostela from starting points in France, Portugal and Spain. Using carbon trekking poles for balance, she walked over the steep Pyrenees Mountains. Twice, she and husband Charlie pedaled across the rolling hills of Iowa for The Register’s Annual Great Bicycle Ride Across Iowa, billed as the oldest, largest and longest recreational bicycle touring event in the world. She kayaks with a group of female friends and rides her family’s two Tennessee walking horses. A punching bag hangs in her garage.

“I’ve just got to keep moving,” Clupny said. 

After the diagnosis, she found an advocate in Charlie.

“Rather than treating Parkinson’s as a death sentence and sitting down and waiting for it to happen, we realized there was a lot of life to live,” he said. “We started making plans.”

She eventually resigned her job as head of the speech and hearing program of the InterMountain Education Services District, where she had worked for three decades, to focus on living with Parkinson’s. 

The cycling started in earnest after she read a research study reporting that people with Parkinson’s benefited from hopping on a bike. The study showed that riding at a certain rate for 40 minutes three times a week saw a 35 percent improvement in their symptoms. Tremors eased and the sense of smell often returned in those who had lost it. 

She and Charlie borrowed a tandem bike they dubbed the Yellow Mosquito Eater and rode across Iowa. Later, they bought their own bike. They often pedal the Umatilla County backroads with Carol occasionally yelling “faster, faster,” to her husband when traveling downhill. 

Her quest to stay active got a boost this spring when she underwent a procedure called deep brain stimulation at the Oregon Health & Science University. Clupny’s surgeon drilled two nickel-sized holes in her skull and implanted tiny electrodes. The electrodes connect to a battery-powered neurostimulator implanted under her left collarbone. The pacemaker-like device delivers continuous low-voltage current to the brain.

Clupny shared her feelings in a blog just before the surgery.

“I will somehow be different when I begin deep brain stimulation therapy at the end of April,” she wrote. “After I am healed up from the two procedures to surgically implant the devices, there will be three programming sessions. Then, we will know how changed I will be.”

A specialist fine-tuned the devices with on-the-spot feedback from Clupny. Since the surgery, tremors have subsided. She has increased control over her voice, moves more freely and needs less medication. She blogged after her first programming session.

“All I can say is ‘Oh, my.’ I think it will be like peeling an onion – more layers and layers will be revealed as this device is tweaked and I discover what I have forgotten I was able to do.”

Recently, the former softball player noticed two men tossing a softball back and forth in a park. She asked if she could play catch, too, to test out her increased mobility. When she threw, the ball hit the glove with a satisfying smack.

“It was just like it was yesterday,” she said. 

Though the surgery dialed down the disease, it didn’t wipe it away, but the difference was still remarkable. Charlie, a retired educator, described the before and after. 

“Before the surgery, she was unable to hold numbers in her head and do addition. Her cognition was starting to wane,” he said. 

Medications wore off faster. 

“We’d be having a conversation and her whole body started to weave,” Charlie said. “Her toes started to cross.”

After the surgery, he said she was more alert and quick-witted. The tremors abated and her toes no longer crossed. Her messy handwriting again became legible.

Dr. Matthew Brodsky, medical director for OHSU’s deep brain stimulation program, said DBS works best for Parkinson’s patients who are experiencing excessive involuntary movements and for whom medication is losing its effectiveness.

“There are perturbations of signaling that occur in the brains of people with Parkinson’s,” Brodsky said. “Deep brain stimulation helps to reset or normalize this signaling within the brain.”

The procedure isn’t a cure, he said. The disease will continue to progress, albeit with the suppression of some of the symptoms. 

In her quest to live well with a degenerative disease, Clupny draws encouragement from her many friends, some who have Parkinson’s and some who don’t. One of them, a Seattle resident named Nan Little, is something of a mentor for Clupny. Little, who schooled Clupny in cycling, has climbed Kilimanjaro and is the author of “If I Can Climb Mt. Kilimanjaro, why can’t I brush my teeth?”

Clupny also gets comfort and camaraderie from a Facebook group of Parkinson’s patients and members of a Parkinson’s support group she and Charlie started several years ago. The group meets at noon, the first Monday of every month at Desert Lanes bowling alley. She also spends time with her guitar, sometimes jamming with a bluegrass group that meets weekly at the Great Pacific in Pendleton. 

A life with Parkinson’s is challenging every day, even with the neurostimulator in her chest. Clupny said she tries to dwell on the positive, because “being irritated and upset is a waste of personal energy.” Instead she hops on her bike or “grabs a couple spoonfuls of Cherry Garcia.”

“You have to make a choice,” Clupny said. “And you have to choose it every day.”

Clupny is in the process of turning her blog into a book.

http://www.eastoregonian.com/eo/local-news/20161202/woman-combats-debilitating-disease-by-staying-active

Acupuncture Slows Parkinson’s Progression, Provides Relief

02 DECEMBER 2016

Acupuncture benefits patients with Parkinson’s disease. Researchers discovered that acupuncture helps improve cognitive abilities, emotional stability, and daily living activity scores for patients with Parkinson’s disease. By combining scalp acupuncture with standard pharmaceutical medications, patients had significant reductions in post-treatment complications due to adverse effects associated with medication therapy. The researchers confirm that acupuncture combined with conventional medication therapy significantly prevents degradation of cognitive abilities and improves mental and emotional health.

The research team compared two groups in their investigation. Both groups received identical drug therapies commonly used for Parkinson’s disease patients. One group received the addition of scalp acupuncture with electrostimulation delivered with an electroacupuncture device. The group receiving only drug therapy had a 73.3% total treatment effective rate. The group receiving drug therapy plus acupuncture had an 87% total treatment effective rate. The research team of Gu et al. reported the results of the investigation in the Shanghai Journal of Acupuncture and Moxibustion in the research paper entitled Clinical Observations on Combined Treatment of Parkinson's Disease Using Acupuncture and Medicine. 

The researchers used mild reinforcing and reducing manual acupuncture techniques to achieve the clinical results. The primary acupoints administered during the study were the following:

• GB20
• LI11
• LI4
• LV3
• KD3
• GB34
• Motor Line (scalp acupuncture)

The researchers add that the Traditional Chinese Medicine (TCM) diagnosis of liver and kidney yin deficiency is common among Parkinson’s disease patients. They note that the addition of acupuncture to standard drug therapy significantly improved the quality of life for the patients. Moreover, the progress of the disease was slowed by the application of acupuncture.

Both groups in the study received the medication Madopar. This has the active ingredients of benserazide and levodopa. For patients receiving acupuncture, deqi was stimulated manually at the acupoints. Bilaterally, the motor line was stimulated with a G6805-2 electroacupuncture device. A continuous wave at 2 Hz was set to patient tolerance levels. Total treatment duration time was 20 minutes per acupuncture session. Treatments were administered weekly for a total of 36 acupuncture sessions per patient.

This confirms the findings of Iseki et al. (Fukushima Medical University), whose case findings determine that acupuncture reduces Parkinson’s disease related pain, anxiety, depression, hot flashes, and abnormal sweating. The researchers used Seirin brand acupuncture needles at the following acupoints, using manual stimulation:

• LV3
• LI4
• KD5
• KD7
• SP6
• GB34
• BL18
• BL15
• GB20

Electroacupuncture was applied to relax muscle tension and rigidity with a 1 Hz frequency for 7 minutes at the following acupoints:

• KD10
• LV9
• BL23
• BL25

In the case study, depression and anxiety scores improved significantly. Also, the patient “steps became larger” and bradykinesia was greatly reduced. Bradykinesia is a slowness of movement characteristic of Parkinson’s disease.

In the USA, University of Arizona researchers confirm that acupuncture improves the balance and gait for patients with Parkinson’s disease. Published in Neurology (the journal of the American Academy of Neurology), Lei et al. confirm that acupuncture improves balance by 31%, gait speed by 10%, and stride length by 5%. The study used rigorous sham controls and determined that only true acupuncture delivers the clinical results. This eliminated any concerns that a placebo effect may have influenced the results. The doctors from the surgery and neurology departments at the University of Arizona conclude that “EA (electroacupuncture) is an effective therapy in improving certain aspects of balance and gait disorders in PD (Parkinson’s disease).”

Researchers from the Research Group of Pain and Neuroscience at Kyung Hee University (Seoul, Republic of Korea) have discovered how acupuncture benefits brain chemistry for patients with Parkinson’s disease. The application of two acupuncture points (LV3, GB34) inhibits decreases of tyrosine hydroxylase in nigrostriatal dopaminergic neurons. Tyrosine hydroxylase is a brain protecting enzyme that assists in the creation of L-DOPA, which is an important dopamine precursor. The researchers determined that LV3 and GB34 prevent decreases of L-DOPA in the thalamic portions of the brain. This helps in the protection of motor functions in Parkinson’s disease patients.

Dr. Xibin Liang, PhD combined efforts with Wang et al. in research entitled The Antioxidative Effect of Electro-Acupuncture in a Mouse Model of Parkinson’s Disease and determined that acupuncture protects the brain by creating antioxidative and antiapoptosis effects. Dr. Liang received his postdoctoral training at UCLA (Los Angeles, California) and Johns Hopkins University (Baltimore, Maryland). He is currently working at the Steinberg Lab at Stanford University (Stanford, California) investigating neural stem cell treatments for stroke injuries to the brain.

The discovery by the researchers that acupuncture stimulates homeostatic antioxidative and antiapoptosis effects demonstrates that acupuncture provides neuroprotection, especially in the substantia nigra. This is the area of the brain that supplies the basal ganglia (which controls motor actions) with dopamine. As a result, the research indicates that Parkinson’s disease patients are well served by the neuroprotective effects of acupuncture.

Yeo et al. used fMRIs to confirm that acupuncture re-activates brain centers suffering from excess deactivation in Parkinson’s disease patients. In a controlled experiment, it was shown that needling acupoint GB34 “may be helpful in the treatment of symptoms involving PD (Parkinson’s Disease).” Application of needling to GB34 re-activated several areas of the brain: substantia nigra, caudate, thalamus, putamen.

Qiu et al. confirm that acupuncture benefits Parkinson’s patients in a meta-analysis. The works of Zhou Sha and Yuan Yin et al. were included in the comprehensive review. Both investigations examined the Lu Di Seven Point Combination. This combined three bilateral acupoints with one singular point:

• GV15
• GB20
• SI4
• ST25

Both investigations reveal that acupuncture improves physical, behavioral, and mental indices for patients with Parkinson’s disease. Ren Xiaoming et al. demonstrated improvements by needling the following acupoints:

• BL18
• BL23
• GB20
• LI11
• LI4
• GB34
• KD3
• LV3

Yao Xiaoping conducted a comparison of patients receiving only levodopa with patients receiving levodopa and acupuncture. Using only levodopa, patients had a 66.7% total effective rate. However, the combination of levodopa with acupuncture produced a 93.3% total effective rate. Improvements were seen across many clinical variables including facial expressions, posture, linguistic abilities, pace, dyskinesia, shaking, and rigidity.

In the meta-analysis, Deng Xianbin et al. demonstrated that moxibustion is useful for the relief of myotonia, which is the lack of ability to relax voluntary muscles after effort. The primary acupoints receiving moxibustion included the following:

• CV12
• CV6
• CV4
• BL19
• BL17
• DU4

Traditional Chinese Medicine (TCM) includes acupuncture, qi gong, tai ji quan, moxibustion, herbal medicine, and more. Researchers find herbal medicine effective for the alleviation of Parkinson’s disease complications. In research published in Progress in Neuro-Psychopharmacology and Biological Psychiatry(Shiman School of Medicine), it was found that the herbal formula Yi Gan San provides neuroprotection in an induced Parkinsonian mouse model. The study concludes that “in the mouse Parkinson's disease model, treatment with Yi-Gan San also significantly improved motor functioning and prevented dopaminergic loss.”

The evidence across multiple studies suggests that patients with Parkinson’s disease are best served with integrative medicine including acupuncture and other TCM modalities. Acupuncture demonstrates the ability to reduce adverse effects associated with medications. In addition, acupuncture and TCM modalities demonstrate the ability to improve motor abilities and cognitive function.

References:

Gu K, Liu K, Lu ZY, Fan XP & Zong L. (2013). Clinical Observations on Combined Treatment of Parkinson's Disease Using Acupuncture and Medicine. Shanghai Journal of Acupuncture and Moxibustion. 32(12).

Wang S, Zhou ZK, Hu BC et al. (2003). Scalp electroacupuncture with acupoints penetration therapy in treating Parkinson’s disease. China Journal of Acupuncture. 23(6): 129-131.

He, Tian, Wen Zhu, Si-Qi Du, Jing-Wen Yang, Fang Li, Bo-Feng Yang, Guang-Xia Shi, and Cun-Zhi Liu. "Neural mechanisms of acupuncture as revealed by fMRI studies." Autonomic Neuroscience (2015).

Iseki, Chifumi, Taiga Furuta, Masao Suzuki, Shingo Koyama, Keiji Suzuki, Tomoko Suzuki, Akiyo Kaneko, and Tadamichi Mitsuma. "Acupuncture Alleviated the Nonmotor Symptoms of Parkinson’s Disease including Pain, Depression, and Autonomic Symptoms." Case Reports in Neurological Medicine 2014 (2014).

Lei, Hong, Nima Toosizadeh, Michael Schwenk, Scott Sherman, Stephen Karp, Saman Parvaneh, Esther Esternberg, and Bijan Najafi. "Objective Assessment of Electro-acupuncture Benefit for Improving Balance and Gait in Patients with Parkinson’s Disease (P3. 074)." Neurology 82, no. 10 Supplement (2014): P3-074.

Gene. 9 December 2012. Neuroprotective Changes of Thalamic Degeneration-Related Gene Expression by Acupuncture in an MPTP Mouse Model of Parkinsonism: Microarray Analysis. Sujung Yeo, Yeong-Gon Choi, Yeon-Mi Hong, Sabina Lim. Kyung Hee University (Seoul, Korea).

Wang H, Pan Y, Xue B, Wang X, Zhao F, et al. (2011) The Antioxidative Effect of Electro-Acupuncture in a Mouse Model of Parkinson’s Disease.

Yeo, S., Lim, S., Choe, I.-H., Choi, Y.-G., Chung, K.-C., Jahng, G.-H. and Kim, S.-H. (2012), Acupuncture Stimulation on GB34 Activates Neural Responses Associated with Parkinson's Disease. CNS Neuroscience & Therapeutics, 18: 781–790. doi: 10.1111/j.1755-5949.2012.00363.x. Kyung Hee University, Seoul, Korea.

Qiu Congsheng, Wang Xuhui, Development of acupuncture treatment for Parkinson’s disease, Hunan Journal of Traditional Chinese Medicine, 2015 (31).

http://www.healthcmi.com/Acupuncture-Continuing-Education-News/1692-acupuncture-slow-parkinson