The behavior of immune cells in the blood is so different in patients with Parkinson's disease that it advocate for a new type of supplementary medicine, which can regulate the immune system and thus inhibit the deterioration of the brain
The behaviour of immune cells in the blood is so different in patients with Parkinson's disease that it advocates for a new type of supplementary medicine, which can regulate the immune system and thus inhibit the deterioration of the brain.
hese are the perspectives in a new study which researchers from the Department of Biomedicine at Aarhus University, Denmark, are behind. The article has just been published in the scientific journal Movement Disorders.
"The research project confirms a growing theory that Parkinson's disease is not only a brain disease, but is also connected with the immune system. Both in the brain and the rest of the body," says Marina Romero-Ramos, associate professor of neuroscience, who leads the team behind the study.
PhD Sara Konstantin Nissen, who is the study's first author adds:
"This knowledge may in the long term lead to the development of supplementary immune-regulating treatment being combined with the current medical treatment with the drug L-dopa, which only has an effect on the brain and the symptoms. We believe such an additional drug might help to slow down the progression of the disease," says PhD Sara Konstantin Nissen.
Parkinson's disease is characterised by the slow degeneration of the neurons in brain due to the abnormal accumulation of a protein called alpha-synuclein. This leads to the patients shaking and then to the slow, stiff movements which many people associate with the disease.
In the new study, researchers have subjected blood samples from 29 Parkinson's patients and 20 control subjects to the protein alpha-synuclein and ascertained that the immune cells in the blood from Parkinson's patients are significantly worse at regulating the immune markers on the cell surface and that they are also less efficient to secrete anti-inflammatory molecules than the controls' cells.
"The immune system functions in a delicate balance. On the one hand, it cleans up invasive microorganisms and accumulations of unwanted proteins, such as alpha-synuclein, and does so by creating an inflammatory condition. But on the other hand, the immune system must also avoid damaging the body's own cells via too much inflammation, and apparently this balance goes awry in the case of Parkinson's disease," says Sara Konstantin Nissen.
She adds that in research circles it is believe that immune cells in the blood, which contain (or express) a certain receptor called CD163 on their surface, migrate into the brains of Parkinson's patients. It has been thought that the cells help to clean up the accumulations of the alpha-synuclein which damages the brain, but with the present study it is now suggested that the cells in question are already incorrectly regulated in the bloodstream -- before they reach the brain.
"This leads us to believe that it might be possible to, at the very least, slow down the degeneration of the neurons in the brain of Parkinson's patients by regulating the immune system with medicine," says Sara Konstantin Nissen.
In addition to paving the way for supplemental medication for patients who have already been diagnosed with Parkinson's, Sara Konstantin Nissen also points out that the study suggests new ways of preventing or delaying the development of Parkinson's disease. This can be achieved by keeping a watchful eye on people who have an increased risk of developing Parkinson's disease, for example those persons diagnosed with REM sleep behaviour disorder (RBD), a disease where patients act vividly their dreams .
"Screening everyone for changes in the blood's immune cells would be pointless. However, we know that more than half of those who suffer from this sleep disorder, RBD, develop Parkinson's disease years later, so this is an obvious place to start. Other studies show that inflammation in the body can be reduced with exercise as a form of treatment, which can therefore reduce the risk of becoming ill at all. However, this requires a change of views among medical doctors and neurologists, because they will have to treat Parkinson's disease as more than just a brain disorder," says Sara Konstantin Nissen.
Behind the study:
Facts about the type of study: A cross-sectional study of 29 Parkinson's patients and 20 healthy control subjects of the same age and gender distribution. Immune cells from the blood (PBMCs) were purified and stimulated in culture with fibrils of alpha-synuclein. Markers were subsequently measured on the cell surface using flow cytometry and on secreted cytokines using ELISA and Mesoscale. The study cohort was collected by the Hertie Biobank in Germany.
Partners from Denmark and abroad include: Professor Daniel Otzen (Interdisciplinary Nanoscience Centre (iNANO)) and MD and Professor Holger Jon Møller (Aarhus University Hospital) together with a team of neurologists from the University of Tübingen in collaboration with Hertie Biobank.
Story Source:
Materials provided by Aarhus University. Note: Content may be edited for style and length.
Journal Reference:
Sara Konstantin Nissen, Kalpana Shrivastava, Claudia Schulte, Daniel Erik Otzen, David Goldeck, Daniela Berg, Holger Jon Møller, Walter Maetzler, Marina Romero‐Ramos. Alterations in Blood Monocyte Functions in Parkinson's Disease. Movement Disorders, 2019; DOI: 10.1002/mds.27815
James Parkinson changed the course of medical history when he first described the “Shaking Palsy” in 1817, at a time when little was known about neurological and degenerative diseases.
I decided to delve into the history of the disease to see how it might relate to modern medical practices. I wondered how James Parkinson’s research made current treatments possible for my dad.
Did Parkinson’s disease look like it does today? What might we learn from the man whose work has resonated throughout modern medical history?
Medical thinking during Parkinson’s time seems bizarre by today’s standards. Mere decades before Parkinson published his seminal essay, Scottish physician John Brown brought forth his “excitability” theory, categorizing illnesses as sthenic (strong) and asthenic (weak). According to the Encyclopedia Britannica, treatments were either sedatives or stimulants.
While characteristics of Parkinson’s disease were recorded in early clinical documents, James Parkinson was the first doctor to attempt to understand the disease in its entirety. He was way ahead of his time in terms of research and diagnosis.
Who was James Parkinson?
James Parkinson was born in London in 1755, the son of an apothecary and surgeon. He followed in the footsteps of his father, studying at the London Hospital Medical College, before qualifying as a surgeon in 1784.
As a political activist, he challenged the political system of the time. He also advocated for social reform and universal suffrage, later adopting humanitarian causes.
Parkinson began to study the condition, which was later given his name, hoping to alleviate the suffering of his patients. His motivation for becoming a doctor was apparent in a pamphlet he wrote about the requirements of a medical education. In the document, he describes “a sympathetic concern, and a tender interest for the sufferings of others [that] ought to characterize all those who engage themselves in a profession, the object of which should be to mitigate, or remove, one great portion of the calamities to which humanity is subject.”
An essay on the ‘Shaking Palsy’
In 1817, Parkinson published a 66-page document describing symptoms that he believed to be fundamental to diagnosis of the disease.
He defined the “Shaking Palsy (paralysis agitans)” as follows: “Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the sense and intellects being uninjured.”
In a recent column, I described Dad’s approach to handling muscular changes as Parkinson’s progresses. Nearly 200 years ago, James Parkinson identified “lessened muscular power” as one of the key elements of the disease.
While observing the first signs of the disease, Parkinson noted: “So slight and nearly imperceptible are the first inroads of this malady, and so extremely slow its progress, that it rarely happens, that the patient can form any recollection of the precise period of its commencement. The first symptoms perceived are, a slight sense of weakness, with a proneness to trembling in some particular part; sometimes in the head, but most commonly in one of the hands and arms. These symptoms gradually increase in the part first affected; and at an uncertain period, but seldom in less than twelvemonths or more, the morbid influence is felt in some other part.”
The text goes on to evaluate six case studies, observing the differences and similarities in Parkinson’s patients and their disease progression.
It seems strange to me to think that Parkinson could predict how my dad’s journey with the disease would unfold. Dad noticed a slight tremor in his right foot, which led to his diagnosis in 2013. Over the last six years, the tremor has spread to his other limbs.
Parkinson’s work paved the way for future medical research by linking the symptoms that are unique to the disease.
Research toward a cure
Much of Parkinson’s research is still relevant today. His observations enabled researchers and neurologists to take the next steps in fighting Parkinson’s disease. Parkinson’s Lifenotes that the biggest difference between Parkinson’s observations and modern understanding of the disease is the current recognition of dementia on the spectrum of Parkinsonism symptoms.
His research was aimed at a cure and finding a solution that would slow the progress of the disease. When he died in 1824, he left a legacy that changed how Parkinson’s disease was understood in the future.
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Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.
When I think of a victim, I think of someone who has had something bad happen to them. A victim could be someone who has been tricked or fooled in some way. Maybe the person has been harmed, or even killed.
Or it could be someone who has been affected by an illness.
Enter Parkinson’s disease
A diagnosis of Parkinson’s disease (PD) is a life sentence. It is an incurable, chronic illness destined to be your companion for the rest of your days. And a not so pleasant companion at that.
But must we take on the role of victim? Because we have been told that we must live with this disease we often loathe, must we live defeated? Must we live as if we have lost the fight against something that begs for control over our body? Give in and give up, throwing to the wind whatever hope we had left?
Enter the winner
A winner perseveres in the game, whether it is soccer, parkour, Monopoly, boxing, or cards. Winners are the champions of their games. A winner wins. They defeat their opponent with ability, strategy, and hard work.
We are playing a game with Parkinson’s disease. It is a never-ending game, and we must work hard and play strategically, giving it our all. Our life depends on it.
How to play the game
As with any game, if you don’t play to win, you most likely will lose. If you don’t play to win at Parkinson’s, you most likely are playing without hope.
Playing without hope is nothing short of a death sentence. It is as if we are deciding that there is nothing better. As if we think we know what the future holds.
Instead of allowing dark clouds to hover above our heads, we should be playing this game of PD with unfettered hope. A hope that says and believes that someone is out there fighting with and for us. A hope that doesn’t give up.
The Michael J. Fox Foundation mission statement says, “Here. Until Parkinson’s isn’t. We went into business to go out of business. We act with urgency, focus and determination, and won’t stop until a cure is found.”
I don’t know about you, but that gives me hope.
***
Note: Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Parkinson’s News Today or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to Parkinson’s disease.
Researchers have found a compound that can rescue dopaminergic neurons from cell death and improve locomotor activity in fly models of Parkinson’s disease.
The identification of reliable molecular biomarkers that can distinguish Parkinson’s from other conditions, monitor disease progression, or provide insight about a patient’s response to a given therapeutic intervention would be groundbreaking in the field of Parkinson’s research.
Evidence indicates that dysfunctional mitochondria — i.e. the powerhouses of cells — may be a causative mechanism behind this neurodegenerative disorder. When mitochondria are dysfunctional, the body eliminates them through a process called mitophagy, whereby mitochondria are sent to cellular compartments called lysosomes, the cell’s so-called “recycling center.”
A series of proteins direct damaged mitochondria to lysosomes. For mitochondria to be recycled, these same proteins must remove Miro1, a protein found on the outer membrane of mitochondria that attaches them to the cells’ cytoskeleton. Miro1 has been linked to multiple Parkinson’s-causing genes.
Like the skeletal system, the cytoskeleton offers structural support, helps cells move around, and enables the transport of molecules and organelles, including mitochondria, inside cells.
In Parkinson’s, cells are not able to remove Miro1 from mitochondria, which then don’t get to be recycled and end up becoming toxic and eventually killing the cell — contributing to neurodegeneration.
Stanford University researchers investigated the clinical utility of Miro1 for detecting Parkinson’s and its potential in developing treatment strategies.
Results revealed 94% of Parkinson’s fibroblasts could not remove Miro1 from mitochondria, but cells from the controls and patients with other movement disorders had no trouble doing so. This Miro1 defect was also observed in all of the at-risk subjects.
“We’ve identified a molecular marker that could allow doctors to diagnose Parkinson’s accurately, early and in a clinically practical way,” Xinnan Wang, MD, PhD, associate professor of neurosurgery and lead author of the study, said in a news release.
“This marker could be used to assess drug candidates’ capacity to counter the defect and stall the disease’s progression,” Wang added.
Using artificial intelligence, the scientists screened 6,835,320 commercialized small molecules, all of which were able to bind in some way to the Miro1 protein. Their analysis showed four of these molecules were non-toxic, orally available, able to cross the blood-brain barrier, and would significantly reduce Miro1 levels in fruit flies by facilitating its separation from mitochondria.
One of these four tested compounds, which scientists called a “Miro1 reducer,” was then used to treat fibroblasts from a patient with Parkinson’s of unknown cause (also known as idiopathic). The compound improved Miro1 “detachment” in damaged mitochondria within these cells.
Three distinct fruit-fly strains modelling Parkinson’s-like symptoms were fed the Miro1 reducer for their entire life span (around 90 days). The compound showed no toxicity towards the animals’ physiology, prevented dopaminergic neuronal death in all fly models, and rescued locomotor deficits in two of these models.
“Our hope,” Wang said, “is that if this compound or a similar one proves nontoxic and efficacious and we can give it, like a statin drug, to people who’ve tested positive for the Miro-removal defect but don’t yet have Parkinson’s symptoms, they’ll never get it.”
Stanford’s Office of Technology Licensing has filed a provisional patent for the use of the Miro1 reducer in Parkinson’s and other neurodegenerative diseases. Wang has formed a company called CuraX to speed up the molecule’s development.
“Our results indicate that tracking this Miro1 marker and engaging in Miro1-based therapies could open new avenues to personalized medicine,” the researchers said.
OCTOBER 2, 2019 BY JOSE MARQUES LOPES, PHD IN NEWS.
Although it may be protective against infections, a specific mutation in the LRRK2 gene — the gene linked to most inheritable mutations that can cause Parkinson’s disease — may increase Parkinson’s risk by promoting inflammation in the brain, according to new research.
Mutations in the LRRK2 gene are found in about 2% of people with Parkinson’s, with different studies reporting a greater frequency in women. But a mutated LRRK2 also has been associated with greater risk for two other disorders in which inflammation is a key component: Crohn’s disease (CD), which targets the gut, and leprosy, which affects the peripheral nervous system.
LRRK2 is highly expressed in several types of immune cells, including macrophages and natural killer cells. This suggests it plays a role in innate immunity — nonspecific defense mechanisms prompted by any given microbe.
To test this hypothesis, a team from Canada assessed LRRK2 expression in human white blood cells and tissues during inflammation, and studied viral and bacterial infections in Lrrk2 mutant animals.
First, the team found that neutrophils — immune cells that travel to the site of an infection — were the cell type with the highest expression of LRRK2 in healthy participants. Immune–related tissues, such as the bone marrow and lymph nodes, showed abundant RNA levels of LRRK2. RNA is the genetic template that gives origin to proteins.
Then, the investigators found significant protein production in gut samples of patients with Crohn’s disease, and in brain tissue of people infected by HIV, rabies virus, or virally infected peripheral nerve roots. All of these are characterized by inflammation.
Taking this data together with findings in Parkinson’s patients, which showed strong LRRK2 production in brain white blood cells, the team “concluded that LRRK2 appears to be abundant in infiltrating leukocytes of human tissues during acute or chronic inflammation.”
In mice, the researchers used a sepsis model — inoculation with Salmonella typhimurium— and an encephalitis model, induced by infection with reovirus, to assess the role of LRRK2 in acute bacterial and viral infection.
They found that, in both models, normal (wild-type) Lrrk2 expression was protective compared with complete Lrrk2 absence or production from only one gene copy. Female mice lacking Lrrk2 showed a stronger inflammatory response than male animals that lacked the gene, the researchers noted.
Then, the scientists studied the p.G2019S mutation — the most common mutation in LRRK2 — which increases the activity of the LRRK2 protein. Carrying this mutation enhanced inflammation and boosted the protective effect of normal Lrrk2, with reduced bacterial growth and longer survival during sepsis. This greater protection was mediated by the higher number of myeloid cells — monocytes, macrophages and neutrophils — in the spleen.
In mice with sepsis and with the Lrrk2 mutation, the scientists also observed increased oxidative damage in the spleen and the brain.
“When mice with the Parkinson’s-linked mutation were infected with Salmonella bacteria, we saw very high levels of oxidative stress in the brain, almost twice as high as in normal mice,” Bojan Shutinoski, PhD, the study’s first author, said in a press release. “This was particularly surprising because the bacteria never even entered their nervous system!”
Mouse pups with encephalitis and no Lrrk2 had increased mortality — especially females — and increased activation of microglia, the resident immune cells of the brain. Animals with the p.G2019S mutation showed reduced survival despite lower viral levels. These mice also exhibited greater brain infiltration of white blood cells, and higher concentrations of the alpha-synuclein protein — the main component of Parkinson’s hallmark Lewy bodies.
The higher mortality in mice with the p.G2019S mutation was likely due to increased enzymatic activity of Lrrk2, as animals with a mutation (p.D1994S) that suppresses this activity showed greater survival.
“Our findings support a growing body of evidence that the LRRK2 protein functions in immune cells both within the brain … and the periphery,” the investigators said.
“Everyone thought that LRRK2’s primary role was in the brain, because of its association with Parkinson’s disease. But our research shows for the first time that its primary role is probably in the immune system,” said Michael Schlossmacher, MD, the study’s senior author and a neurologist at The Ottawa Hospital.
“Our research suggests that certain mutations in LRRK2 enhance inflammation and help the body to defend itself better against viruses and bacteria, but this enhanced inflammation could also increase the risk of Parkinson’s and other brain diseases,” added Schlossmacher, also a professor at the University of Ottawa Brain and Mind Research Institute.
“If this theory about LRRK2 is correct, it could open the door for the monitoring of infections as a key risk element for prediction, early detection and prevention of Parkinson’s, and importantly, for new treatment approaches in general,” Schlossmacher said.
The results also may have implications for the clinical development of therapies that block LRRK2 activity.
“Our research suggests that these drugs may well succeed in safely reducing excessive inflammation,” Shutinoski said. “However, we should be careful not to abolish LRRK2 function altogether, as this could make people more susceptible to infections, in particular when being treated potentially for years.”
Dogs around the world are successfully detecting cancer, malaria, Parkinson’s disease and other health issues to help scientists better protect humans.
While humans have around 6 million olfactory receptors, dogs can have up to 300 million, giving them a nose up in scent detection.Doctor Dogs
Twice a week, a rescue dog named Shugga has a very important job. Dressed in her signature tutu, the little Pomeranian barks with excitement for her turn to play her favorite game: detecting Parkinson’s disease. Inside a training room, four canisters conceal T-shirts worn overnight by four different people — three healthy, and one with Parkinson’s disease.
“She kind of just barrels through the room and goes right to the canister most times, and smacks it,” her owner, Amber Chenoweth, told TODAY. “It’s winning the game that gives her so much confidence and makes her so happy.”
Shugga is one of 21 dogs of various sizes and breeds training to detect Parkinson’s disease, a nervous system disorder that affects movement, withPads for Parkinson’s, a nonprofit based on San Juan Island in Washington state. The goal is for researchers to be able to identify which molecules allow the canines to detect the disease, and then develop early-detection methods and possibly a cure.
Chenoweth, a 47-year-old photographer, recently lost a friend to Parkinson’s disease, so she’s incredibly grateful for the chance to volunteer the services of her spunky dog. Over the past year of training, she’s also been impressed by Shugga’s aptitude for the work, as well as the skills of the other detection dogs, which include diverse breeds like the Jack Russell terrier, vizsla, Australian shepherd, miniature schnauzer, Labrador retriever, standard poodle, golden retriever, dachshund and Nova Scotia duck tolling retriever.
“I’ve learned every dog sees the world through scent and odor in a way that we can’t understand because we, as humans, don’t have the ability,” she said. “And I know that any rescue dog sitting in a shelter could have this potential of doing this work if they were given a chance.”
While researching the book, Goodavage met medical detection dogs across the United States and Canada as well as Japan, the Netherlands, Italy, Hungary, Croatia, China and the United Kingdom.
The dogs Goodavage observed were all trained with positive reinforcement techniques rather than punishment. The reward for a successful find is typically food or a toy, depending on each dog’s preference.
“I wish that most people could love their job as much as these working dogs — these medical dogs — love theirs,” she told TODAY.
Goodavage noted that while humans have around 6 million olfactory receptors, dogs can have up to 300 million, giving them a nose up in scent detection
A Labrador retriever in a prostate cancer study walks around a scent carousel at Medical Detection Dogs in England.Maria Goodavage / Doctor Dogs
“They’re detecting these diseases that until recently we didn’t even realize had a scent,” she said. “They can pick up many things around the world, like different kinds of cancers. So far, they’ve detected breast, ovarian, lung, bladder, stomach, liver, prostate and skin — a bunch.”
In some cases, the dogs don’t detect cancer from tissue samples but from blood, saliva or even breath. The dog trainers collaborate with scientists who hope to develop “inexpensive, rapid early-detection devices available to people around the world,” according to Goodavage.
“I wish that most people could love their job as much as these working dogs — these medical dogs — love theirs."
Medical detection dogs are also working to detect dangerous pathogens like Clostridium difficile, aka C. diff, a highly contagious bacterium that can lead to life-threatening conditions. In Vancouver, British Columbia, Goodavage met a dog named Angus who checks Vancouver General Hospital for C. diff, alerting teams to stations that need cleaning. Unsurprisingly, incidences of C. diff there have declined.
Angus, an English springer spaniel, enjoys his work sniffing out Clostridium difficile, a highly contagious bacterium that can lead to life-threatening conditions, in a hospital in Vancouver, British Columbia.Maria Goodavage / Doctor Dogs
In England, detection dogs are able to sniff the socks of children — submitted by health care workers in Gambia — and largely determine which former wearers have malaria. The preliminary findings could lead not only to helping more quickly detect malaria in local communities and ideally eradicate it, but also stop its spread around the world.
“This could mean they could stop the spread of malaria at checkpoints like airports,” she said. “If a dog alerts, someone would need a further test before being admitted to a country that has pretty much eliminated malaria so it doesn’t spread there again.”
Author Maria Goodavage greets Stewie, an Australian shepherd trained to detect ovarian cancer in laboratory samples.Photo courtesy of Maria Goodavage
Some medical detection dogs are trained as service dogs for their handlers. For instance, autism-assistance dogs can apply calming pressure to a child who is becoming overstimulated, and service dogs trained in post-traumatic stress disorder can lead a veteran out of a crowd at the onset of a panic attack. Diabetic-alert dogs alert handlers to blood sugar changes.
Diabetic alert dogs, like these Labrador retrievers trained by California-based nonprofit Canine Hope for Diabetics, can alert their handlers to blood sugar fluctuations.Maria Goodavage / Doctor Dogs
In England, Goodavage met with a young woman with unexplained fainting spells; her service dog alerts her when she’s about to pass out so she can sit or lie down. The dog started pawing at her during a group meeting with Queen Elizabeth II, so the woman went to the back of the room to lie down.
“She didn’t have to faint in front of the queen,” Goodavage said. “Then the queen met with her afterward and the woman’s dog sort of 'snortled' into the queen’s purse and it was a grand affair.”
Daisy, a psychiatric service dog for post-traumatic stress disorder, cuddles future PTSD service dog Oprah.Judy McDonald / Doctor Dogs
A Labrador retriever named Hank provides a special service to a teen with severe schizophrenia and bipolar disorder. He seems to know when she’s about to have a hallucination and provides calming pressure; the girl has also realized that if her dog doesn’t acknowledge scary people screaming at her that she should kill herself, then they aren't real.
However, when people partner with the right service dog, she said that “it can be a life-changing experience.” In fact, she’s inspired by all the dogs doing cutting-edge medical work.
“Dogs are offering us so much hope to detect so many things that we thought there wasn’t a lot of hope for,” Goodavage said. “I love that we are finally realizing their potential. It just makes them even more our best friends.”
Dogs are man’s best friend and, sometimes, his most faithful colleague. From dogs who jump out of planes with anti-terrorism forces to rescue pups who travel through snow and water to save lives, take a look at some of the ways our four-legged friends contribute to society while on the job.
