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Safinamide has both dopaminergic properties (highly selective and reversible inhibition of
monoamine oxidase-B) and non-dopaminergic properties (selective sodium channel blockade
and calcium channel modulation, with consequent inhibition of excessive glutamate release).
It is added to the use of L-dopa or dopamine agonists. For more information go to Xadago :
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002396/h
uman_med_001847.jsp&mid=WC0b01ac058001d124
The use of L-dopa is limited by wearing off and dyskinesias. The
objective of this study was to investigate the efficacy and safety
of safinamide in L-dopa treated patients who had motor
fluctuations. If no tolerability issues arose by day 14, the starting
dose, 50 mg, was increased to 100 mg. When taking safinamide,
the mean change in daily on time without dyskinesia 2.80 hours.
However, this was not much different from the effect that a
placebo had. The most frequently reported adverse event was
dyskinesia (14%], and as a severe event (2%). These results are
consistent with previous studies in which the increase in "on" time
beyond that of a placebo was only 40 minutes for 50mg
safinamide, and 50 minutes for 100mg safinamide.
Having a service dog can greatly enhance the life of someone living with a chronic disease. They allow patients to regain some of their independence by helping with small everyday tasks like opening and closing doors, fetching meds, acting as a prop or support as their owner stands, switching on lights and attracting attention in cases of emergency. As well as the help they give people with disabilities or illnesses, service dogs make great companions.
However, not everyone is suitable for a service dog. According to theMuscular Dystrophy Association, you need to consider a few things before deciding whether or not a service dog is for you.
Assess your accommodations.
You need to live in a place big enough for a service dog. Other things to take into consideration are whether or not you have a yard and if it’s secure.
Do you have any other pets?
Most service dog providers recommend that the dog is the only pet in the household, so if you already have a dog or a cat, it may be a problem.
Can you take care of the dog?
Having a service dog is a two-way street. You will need to be able to feed, groom, and clean up after your dog or have someone else who can.
Can you afford a service dog?
In addition to the initial cost of the animal, it costs an estimated $1,500 to $2,000 a year to look after a service dog, including food and healthcare. The average service dog stays with an individual or family for around eight years.
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.
A TI stimulation excites an area in the mouse hippocampus, shown in bright green through c-fos labeling. Credit: Nir Grossman, Ph.D., Suhasa B. Kodandaramaiah, Ph.D., and Andrii Rudenko, Ph.D.
Delivering an electrical current to a part of the brain involved in movement control has proven successful in treating many Parkinson's disease patients. This approach, known as deep brain stimulation, requires implanting electrodes in the brain—a complex procedure that carries some risk to the patient.Now, MIT researchers, collaborating with investigators at Beth Israel Deaconess Medical Center (BIDMC) and the IT'IS Foundation, have come up with a way to stimulate regions deep within the brain using electrodes placed on the scalp. This approach could make deep brain stimulation noninvasive, less risky, less expensive, and more accessible to patients.
"Traditional deep brain stimulation requires opening the skull and implanting an electrode, which can have complications. Secondly, only a small number of people can do this kind of neurosurgery," says Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, and the senior author of the study, which appears in the June 1 issue of Cell.
Doctors also use deep brain stimulation to treat some patients with obsessive compulsive disorder, epilepsy, and depression, and are exploring the possibility of using it to treat other conditions such as autism. The new, noninvasive approach could make it easier to adapt deep brain stimulation to treat additional disorders, the researchers say.
"With the ability to stimulate brain structures noninvasively, we hope that we may help discover new targets for treating brain disorders," says the paper's lead author, Nir Grossman, a former Wellcome Trust-MIT postdoc working at MIT and BIDMC, who is now a research fellow at Imperial College London.
Deep locations
Electrodes for treating Parkinson's disease are usually placed in the subthalamic nucleus, a lens-shaped structure located below the thalamus, deep within the brain. For many Parkinson's patients, delivering electrical impulses in this brain region can improve symptoms, but the surgery to implant the electrodes carries risks, including brain hemorrhage and infection.
Other researchers have tried to noninvasively stimulate the brain using techniques such as transcranial magnetic stimulation (TMS), which is FDA-approved for treating depression. Since TMS is noninvasive, it has also been used in normal human subjects to study the basic science of cognition, emotion, sensation, and movement. However, using TMS to stimulate deep brain structures can also result in surface regions being strongly stimulated, resulting in modulation of multiple brain networks.
This strategy requires generating two high-frequency electrical currents using electrodes placed outside the brain. These fields are too fast to drive neurons. However, these currents interfere with one another in such a way that where they intersect, deep in the brain, a small region of low-frequency current is generated inside neurons. This low-frequency current can be used to drive neurons' electrical activity, while the high-frequency current passes through surrounding tissue with no effect.
By tuning the frequency of these currents and changing the number and location of the electrodes, the researchers can control the size and location of the brain tissue that receives the low-frequency stimulation. They can target locations deep within the brain without affecting any of the surrounding brain structures. They can also steer the location of stimulation, without moving the electrodes, by altering the currents. In this way, deep targets could be stimulated, both for therapeutic use and basic science investigations.
"You can go for deep targets and spare the overlying neurons, although the spatial resolution is not yet as good as that of deep brain stimulation," says Boyden, who is a member of MIT's Media Lab and McGovern Institute for Brain Research.
Targeted stimulation
Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, and researchers in her lab tested this technique in mice and found that they could stimulate small regions deep within the brain, including the hippocampus. They were also able to shift the site of stimulation, allowing them to activate different parts of the motor cortex and prompt the mice to move their limbs, ears, or whiskers.
"We showed that we can very precisely target a brain region to elicit not just neuronal activation but behavioral responses," says Tsai, who is an author of the paper. "I think it's very exciting because Parkinson's disease and other movement disorders seem to originate from a very particular region of the brain, and if you can target that, you have the potential to reverse it."
Significantly, in the hippocampus experiments, the technique did not activate the neurons in the cortex, the region lying between the electrodes on the skull and the target deep inside the brain. The researchers also found no harmful effects in any part of the brain.
Last year, Tsai showed that using light to visually induce brain waves of a particular frequency could substantially reduce the beta amyloid plaques seen in Alzheimer's disease, in the brains of mice. She now plans to explore whether this type of electrical stimulation could offer a new way to generate the same type of beneficial brain waves.
More information:Cell, Grossman et al.: "Noninvasive deep brain stimulation via delivery of temporally interfering electric fields." DOI: 10.1016/j.cell.2017.05.024 , www.cell.com/cell/fulltext/S0092-8674(17)30584-6
This could be a big deal for Parkinson’s, depression, and epilepsy
Scientists can now move a mouse’s whiskers, ears, and a paw using just electrodes on the outside of the animal’s head. This new method can stimulate deep parts of the brain without surgery and — if it pans out in humans — it could be very helpful for people with neurological conditions like Parkinson’s, depression, or epilepsy.
The brain has surface regions located near the skull and deep regions further inside, such as the motor cortex, the area of the brain that controls movement. Until now, the only real way to stimulate the regions deeper inside the brain was to cut open the skull and directly implant electrodes. (This is called deep-brain stimulation.) But surgery can be dangerous and the electrodes can cause damage inside the brain. In a study published today in the journal Cell, a team of scientists at the Massachusetts Institute of Technology showed a way to sidestep the dangerous surgery and stimulate the motor cortex from the outside.
To do this, the team took advantage of how neurons process electrical signals. Neurons only activate when they receive low-frequency electricity signals. If high-frequency signals are applied to the brain, the brain just ignores them. “It can’t keep up,” says study co-author Ed Boyden, a cognitive scientist at MIT.
But something interesting happens when you send two high-frequency signals that are just a little bit different, like 3000 hertz and 3001 hertz. Most parts of the brain ignore the signals. But when the two frequencies meet at the target site — in this case, the motor cortex — and interfere with each other, the neurons pay attention. They interpret the difference in frequency as if it were a low-frequency wave. This technique, called “temporal interference,” makes it possible to stimulate just one part of the brain and not all the other parts on the way there.
That’s exactly what the team did. After calculating the right frequencies to target the motor cortex, they sent the two frequencies to the mouse brains. In this way, they made the animal wiggle its ears, whiskers, and a paw.
The technique could potentially help humans with certain conditions. In a disease like Parkinson’s, for instance, the motor cortex sends and receives abnormal electrical signals. This causes people to have tremors and their muscles to weaken. With traditional deep-brain stimulation, the electrode implanted in the brain blocks these abnormal signals, which helps control the tremors for up to five years. Ideally, says Boyden, with the new technique one day you could stimulate a human brain from the outside for a brief amount of time, and have the effects last for the rest of the day or the rest of the week.
“This technique has potential to be an extremely useful tool to both probe and potentially change the functioning of brain regions and brain circuits that are very important to a lot of human illnesses,” says Ben Greenberg, associate director of Providence VA Hospital’s Center for Neurorestoration and Neurotechnology, who was not involved in the study. But he notes that it’s simply “too soon to say” how this stacks against deep-brain stimulation, which has been researched since the 1980s.
There are many questions that need to be answered. We don’t know yet how precise this new method can be; for now, we just know it’s nowhere near as precise as implantable devices. Safety is another concern: early tests showed that this type of stimulation didn’t harm the animals, but more research needs to be done, according to Boyden.
And, of course, the big question is how useful this could be in humans. For one, the human skull is thicker than a mouse’s, which will change the types of frequencies needed. Plus, different people might respond to frequencies differently, says Greenberg. “Even in the mice, there were differences in how responsive their cells were.”
Boyden’s team is already doing more safety experiments with animals, and early studies with human volunteers. “We want to be as careful as possible, of course,” Boyden says, “but the good news is that since we’re building from decades of research on electric fields, so it’s not like we’re starting from scratch.”
An accurate diagnosis for Parkinson's disease is often complicated and delayed by an array of symptoms resembling other conditions, according to a new survey from Health Union.
The survey involved more than 1,100 individuals currently living with Parkinson's disease and was released through Health Union's newest online community, ParkinsonsDisease.net. It finds patients are frustrated in coping with and treating a complex condition that encompasses many diverse symptoms.
As many as one million Americans are living with Parkinson's disease, a chronic disorder of the central nervous system that slowly worsens over time. Nerve cells in the brain die or become damaged, affecting levels of dopamine. It manifests with motor symptoms; such as diminished ability to move, tremors at rest, limb stiffness, and impaired balance. Non-motor symptoms may also be present, including reduced ability to smell, difficulty swallowing, pain, depression, and cognitive problems.
Survey respondents reported experiencing a variety of symptoms prior to diagnosis. Tremor or shaking was the most common at 72 percent. Other reported symptoms include: changes in walking or difficulty walking (42 percent), changes in handwriting called micrographia (40 percent), fatigue (37 percent), and reduced ability to smell (31 percent). Many of the symptoms, including tremor, can be present in other conditions, which can lead to misdiagnosis. About one-third of respondents initially received an improper diagnosis, including essential tremor (31 percent), depression/anxiety (27 percent), and benign essential tremor (15 percent).
"I was officially diagnosed at age 32, but I had begun to see symptoms at 29," said ParkinsonsDisease.net patient advocate Allison Smith. "I had difficulty getting a Parkinson's diagnosis because I was so young. When something was wrong, I was told I had injured myself or that I had overworked myself in graduate school. This is a frustrating time and you almost feel like you are losing your mind because the doctors can't figure out an accurate diagnosis."
On top of the difficulties they present for diagnosis, Parkinson's symptoms can make life extremely challenging; 80 percent of survey respondents saying they felt scared about their future. In addition, respondents had painful spasms or muscle cramps (59 percent), felt depressed (59 percent), had trouble concentrating (58 percent), and had trouble getting around outside their home (46 percent).
Parkinson's disease can take a physical and emotional toll on the patient. As well, Parkinson's disease can be overwhelming for caregivers or other family members, and they may not know where to turn for help.
ParkinsonsDisease.net caregiver contributor Angela Robb notes that "frustration can happen on many levels. For example, with facial masking, the lack of facial expression due to Parkinson's makes it extremely hard for caregivers, families, and loved ones to communicate effectively. One can literally think a loved one with Parkinson's is angry or sad because they cannot move their facial muscles or not hear them because of low speech volume."
"The results of this survey underscore the reasons Health Union launched ParkinsonsDisease.net earlier this year," said Tim Armand, President and co-founder of Health Union. "It is a privilege to provide a place where patients can get information and support for dealing with this life altering condition. In addition to meeting needs for patient support, ParkinsonsDisease.net provides specific resources for caregivers and family members."
"It's extremely important for caregivers and other loved ones to acknowledge that they need help," Robb added. Caregivers need to care for themselves. Joining an online community like ParkinsonsDisease.net is a great way to share your experiences and learn from others about coping with the stress of caring for someone living with Parkinson's."
An infographic series depicting the survey results is also available. Go to:
TheParkinson's In America 2017 survey was conducted online between January 19 and March 13, 2017.More details about the survey are available upon request.
About Health Union, LLC and ParkinsonsDisease.net
Health Union inspires people to live better with challenging health conditions - combining new, original content every day with digital, social and mobile technologies to cultivate active online health communities. Health Union platforms are unique ecosystems dedicated to illuminating the voices and experiences of people with type migraine, rheumatoid arthritis, type 2 diabetes, hepatitis C, and more. Its services and offerings foster open and honest interactions about these health conditions between and among patients, caregivers, professionals, providers and industry partners to help all stakeholders make more informed decisions about healthcare. ParkinsonsDisease.net is Health Union's online community dedicated to people living with Parkinson's, where patients and supporters of people living with this condition can connect, share experiences, and learn about managing the condition.
Researchers at the Karolinska Institute in Sweden have identified the underlying neural mechanisms responsible for the reduced sense of touch and smell which Parkinson’s patients experience in early stages of the disease. A better understanding of these processes can help in the development of new early diagnostic methods.
The primary recognized symptoms of Parkinson’s disease are muscular stiffness, poor balance, and uncontrollable trembling. Although there is no cure yet for Parkinson’s, many efforts have been made to reduce or delay these motor symptoms to improve patients’ quality of life.
In many cases the early signs of this disease are related not only to motor skills, but to sensory capacities, such as touch, smell, and vision impairments.
The motor symptoms of Parkinson’s have been related to the death of neurons and the loss of signals triggered by the neurotransmitter dopamine in a brain region called the striatum. But the cellular and neurological processes causing these sensory deficits were unclear to investigators.
Making use of mouse models and a new tool called an optopatcher, researchers were able to record the striatum cells’ sensory response after they sent a light puff of air to either the right or left whiskers of mice. These sensory tests were performed in both normal mice and in mice lacking dopamine, which mimics the neurological networks found in Parkinson’s patients.
This approach allowed researchers to identify a specific neuronal network responsible for recognizing sensory signals in the striatum. This network was impaired in dopamine-deficient mice, which weren’t able to distinguish between left and right puffs of air to their whiskers. Those with normal dopamine levels presented an earlier and larger neurological response to the stimulation.
“By studying neuronal activity in the striatum, we found that the neurons in dopamine-depleted mice did not properly signal if it was the right or left whiskers that were being stimulated,” Gilad Silberberg, associate professor at Karolinska Institute’s Department of Neuroscience and senior author of the study, said in a press release.
The researchers were able to overcome the observed sensory deficits by treating the animals lacking dopamine with Levodopa (L-DOPA), one of the most commonly used drugs to treat Parkinson’s patients. The Levodopa treatments caused the mice to recover the ability to recognize left from right stimuli by restoring some of the features of the neuronal network.
This study not only highlights the involvement of this brain region in decoding sensory signals, it also described new processes involved in sensory impairments seen in Parkinson’s patients.
Using the same medicine(s) to treat everyone with a given disease is the mainstay of modern medicine. Nonetheless, this "one-size-fits-all" approach doesn't always lead to outcomes patients want, as people often respond differently to the same medicine, and some may not respond at all. Researchers are working to address this challenge through "precision medicine."
Precision medicine involves tailoring therapies for individuals based on their genes, environment and/or lifestyle. You may be familiar with this approach for cancer -- unlike chemotherapy that kills cancer (and healthy) cells, successful personalized drugs instead target genetic mutations. But how might precision medicine be used to treat Parkinson's disease (PD)?
Parkinson's is a heterogeneous disorder, meaning no two individuals have the same symptoms, disease course or treatment response. If we could better understand what drives these differences, we could, in theory, develop better medicine.
As in cancer, some Parkinson's scientists believe genetic mutations may be the basis for tailored treatments. Even though known mutations account for fewer than 10 percent of total PD cases, a greater understanding of Parkinson's genetics already has led to critical discoveries believed to be applicable to all individuals with the disease. "Finding a common mechanism behind different suspected causes of Parkinson's suggests that there might also be a common means to treat or cure it," says Marco Baptista, PhD, director of research programs at The Michael J. Fox Foundation (MJFF).
In 1997, a mutation in the alpha-synuclein gene was first linked to a family with Parkinson's. Though the mutation is extremely rare, alpha-synuclein protein clumps (Lewy bodies) are seen in the brains of nearly everyone with Parkinson's, and offer a potential target for slowing or stopping disease progression.
To date, five anti-alpha-synuclein therapies have advanced through drug development to arrive in clinical (human) testing. Other genetic mutations also are leading to treatments. LRRK2, although fairly uncommon, is the greatest known genetic contributor to PD and has inspired the development of LRRK2 inhibitor drugs expected to enter clinical trials within 18 months. Additionally, medications targeting GBA, the most common of the currently known PD genetic mutations, have made it into clinical testing. These are all examples of precision medicine.
"We will only get to true cures if we can move away from historical clinical disease definitions to one more nuanced and linked to underlying biology, genetics and pathology," said MJFF CEO Todd Sherer, PhD and co-authors in Personalized Medicine. "Truly transforming PD treatment into a precision approach will require tackling key research and regulatory challenges and the coordinated effort of the entire PD community."
Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease. Credit: Wikipedia
Scientists have discovered a new enzyme that will make a drug used to treat Parkinson's disease cheaper and quicker to produce.
Researchers at the Universities of Manchester and York found the enzyme in Aspergillus oryzae, a kind of fungus used for making soy sauce. The discovery, 'A reductive aminase from Aspergillus oryzae' was published in Nature Chemistry.
The enzyme's greatest impact could be in a class of medications called monoamine oxidase (MAO) inhibitors. One such example of this kind of drug is Rasagiline. Rasagiline helps Parkinson sufferers by increasing a substance in the brain that affects motor function.
These substances help reduce the involuntary tremors that are associated with the condition. The medicine works in both early and advanced Parkinson's, and is especially useful in dealing with non-motor symptoms of the condition, like fatigue.
The team, led by Professor Nick Turner, Professor of Chemical Biology from the Manchester Institute of Biotechnology (MIB), have identified a new biocatalyst (RedAm) that accelerates a process called reductive amination.
Reductive amination is one of the most important methods for the synthesis of chiral amines, which are important chemical building blocks in the production of pharmaceutical products.
The discovery of RedAms means more efficient routes for chiral amine synthesis, including medications such as Rasagiline. The application of RedAms will result in a dramatic reduction in time required for synthesis which will also have a positive impact on the costings and manpower needed to produce chiral amines.
A recent analysis of drugs approved by America's Food and Drug Administration (FDA) found that approximately 40 percent of new chemical entities (NCEs) contain one or more chiral amine building blocks. This means this new enzyme could also be key to improving the manufacture of numerous other medications on the market treating multiple conditions.
There is currently no cure for Parkinson's, but there are a range of treatments to control the symptoms. However, medication such as Rasagiline is the main treatment for Parkinson's. Every hour, someone in the UK is told they have Parkinson's. One person in every 500 has Parkinson's. That's about 127,000 people in the UK.
Professor Nick Turner said: 'This is a very exciting discovery from both a chemistry and pharmaceutical perspective. It is the first enzyme of its kind that has these properties and has the potential to improve the production of this and other important drugs.'
More information: Godwin A. Aleku et al. A reductive aminase from Aspergillus oryzae, Nature Chemistry (2017). DOI: 10.1038/nchem.2782
Salk and UC San Diego scientists conducted a vast survey of microglia (pictured here), revealing links to neurodegenerative diseases and psychiatric illnesses. Credit: Nicole Coufal
Scientists have, for the first time, characterized the molecular markers that make the brain's front lines of immune defense—cells called microglia—unique. In the process, they discovered further evidence that microglia may play roles in a variety of neurodegenerative and psychiatric illnesses, including Alzheimer's, Parkinson's and Huntington's diseases as well as schizophrenia, autism and depression.
"Microglia are the immune cells of the brain, but how they function in the human brain is not well understood," says Rusty Gage, professor in Salk's Laboratory of Genetics, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, and a senior author of the new work. "Our work not only provides links to diseases but offers a jumping off point to better understand the basic biology of these cells."
Genes that have previously been linked to neurological diseases are turned on at higher levels in microglia compared to other brain cells, the team reported in Science on May 25, 2017. While the link between microglia and a number of disorders has been explored in the past, the new study offers a molecular basis for this connection.
"These studies represent the first systematic effort to molecularly decode microglia," says Christopher Glass, a Professor of Cellular and Molecular Medicine and Professor of Medicine at University of California San Diego, also senior author of the paper. "Our findings provide the foundations for understanding the underlying mechanisms that determine beneficial or pathological functions of these cells."
Microglia are a type of macrophage, white blood cells found throughout the body that can destroy pathogens or other foreign materials. They're known to be highly responsive to their surroundings and respond to changes in the brain by releasing pro-inflammatory or anti-inflammatory signals. They also prune back the connections between neurons when cells are damaged or diseased. But microglia are notoriously hard to study. They can't be easily grown in a culture dish and quickly die outside of a living brain.
Nicole Coufal, a pediatric critical care doctor at UC San Diego, who also works in the Gage lab at Salk, wanted to make microglia from stem cells. But she realized there wasn't any way to identify whether the resulting cells were truly microglia.
"There was not a unique marker that differentiated microglia from circulating macrophages in the rest of the body," she says.
David Gosselin and Dylan Skola in the Glass lab, together with Coufal and their collaborators, set out to characterize the molecular characteristics of microglia. They worked with neurosurgeons at UC San Diego to collect brain tissue from 19 patients, all of who were having brain surgery for epilepsy, a brain tumor or a stroke. They isolated microglia from areas of tissue that were unaffected by disease, as well as from mouse brains, and then set out to study the cells. The work was made possible by a multidisciplinary collaboration between bench scientists, bioinformaticians and clinicians.
The team used a variety of molecular and biochemical tests—performed within hours of the cells being collected—to characterize which genes are turned on and off in microglia, how the DNA is marked up by regulatory molecules, and how these patterns change when the cells are cultured.
Microglia, they found, have hundreds of genes that are more highly expressed than other types of macrophages, as well as distinct patterns of gene expression compared to other types of brain cells. After the cells were cultured, however, the gene patterns of the microglia began to change. Within just six hours, more than 2,000 genes had their expression turned down by at least fourfold. The results underscore how dependent microglia are on their surroundings in the brain, and why researchers have struggled to culture them.
Next, the researchers analyzed whether any of the genes that were upregulated in microglia compared to other cells had been previously implicated in disease. Genes linked to a variety of neurodegenerative and psychiatric diseases, they found, were highly expressed in microglia.
"A really high proportion of genes linked to multiple sclerosis, Parkinson's and schizophrenia are much more highly expressed in microglia than the rest of the brain," says Coufal. "That suggests there's some kind of link between microglia and the diseases."
For Alzheimer's, more than half of the genes known to affect a person's risk of developing the disease were expressed more highly in microglia than other brain cells.
In mice, however, many of the disease genes weren't as highly expressed in microglia. "That tells us that maybe mice aren't the best model organisms for some of these diseases," Coufal says.
More work is needed to understand exactly how microglia may be altered in people with diseases, but the new molecular profile of microglia offers a way for researchers to begin trying to better culture the cells, or coax stem cells to develop into microglia for future studies.
More information: David Gosselin et al. An environment-dependent transcriptional network specifies human microglia identity, Science (2017). DOI: 10.1126/science.aal3222
Summary: Stimulating microglial cells could delay the onset of some neurodegenerative diseases, researchers report.
Source: LMU.
The precise impact of the microglia in neurodegenerative diseases such as Alzheimer’s and Parkinson’s remains unclear. In the brain, microglial cells migrate to sites of neural damage in response to neuro-inflammatory signals, and dispose of dying cells and insoluble cell debris by engulfing and enzymatically digesting them. NeuroscienceNews.com image is adapted from the LMU news release.
The role of microglial cells in neurodegenerative disease is not fully understood. But new results from researchers in Munich and Basel suggest that stimulation of this arm of the immune system might well delay the onset of such disorders.
The precise impact of the microglia in neurodegenerative diseases such as Alzheimer’s and Parkinson’s remains unclear. In the brain, microglial cells migrate to sites of neural damage in response to neuro-inflammatory signals, and dispose of dying cells and insoluble cell debris by engulfing and enzymatically digesting them. The microglia therefore perform essentially the same role as that carried out by the immune cells known as macrophages in other tissues.
However, neuro-inflammatory responses may also contribute to the pathogenesis of neurodegeneration, as microglia are known to be activated in virtually all types of dementia. This may simply relate to their role as phagocytic cells in the degradation of the extracellular protein deposits (amyloid plaques) that are a hallmark of Alzheimer’s. But it is also possible that activated microglia promote disease progression by secreting molecular signals that exacerbate inflammatory responses which are ultimately deleterious to healthy nerve cells.
The new study was carried out by an interdisciplinary German-Swiss team of cell biologists, radiologists and neuropathologists led by Professor Christian Haass, who holds the Chair of Metabolic Biochemistry at LMU and is Speaker of the German Center for Neurodegenerative Diseases (DZNE) in Munich. To clarify whether the microglia are the good guys or the bad guys, the researchers focused on the function of the gene TREM2. In the brain, this gene is expressed predominantly in microglia. Furthermore, mutations that impair its expression or the function of its protein product are associated with increased risk for neurodegenerative conditions such as Alzheimer’s, Parkinson’s and frontotemporal dementia (FTD).
A minimal change in the TREM2 gene results in a marked reduction in the phagocytic activity of microglial cells in the brain of mutant mice (green, on the right) relative to the control (yellow and red, on the left). Source: Haass Lab. Credit: Ludwig Maximilian University of Munich
With the aid of the CRISPR/Cas9 gene-editing system, Haass and his colleagues altered a single subunit (base-pair) in the coding sequence of the TREM2 gene of mice, which directs the synthesis of the TREM2 protein. In humans, this same mutation is associated with increased risk for a form of FTD. In earlier studies, it had been demonstrated that the normal TREM2 protein is transported to the cell membrane in order to perform its biological function. The mutation introduced by the CRISPR system disrupts this process, such that very little of the protein is expressed on the surface of microglial cells. In mice, this genetic alteration leads to a drastic impairment of microglial function, as evidenced by a variety of tests.
For example, the mutant strain no longer activates its microglial cells in response to neuronal loss in the brain. As a result, the cells fail to migrate to sites of cell damage – and dead cells, insoluble debris and plaques cannot be disposed of. In addition, the mutation has catastrophic consequences for energy metabolism. The normal brain is totally dependent on glucose as an energy source, but loss of the TREM2 function leads to a significant fall in glucose consumption in the mutant brain. Moreover, the blood supply to the brain in a whole is markedly curtailed. Similar phenomena are observed in patients who carry loss-of-function mutations in the TREM2 gene. Taken together, these observations argue that microglial activation is indispensable for normal brain function.
Christian Haass summarizes the wider implications of the study as follows: “Our findings underline the significance of microglia for homeostasis in the brain, and they imply that these cells have an immunoprotective function, at least in the early stages of the pathogenesis of neurodegenerative diseases. We believe that our data provide the rationale for a new approach to the development of effective therapies, based on boosting the defense response of the microglia. If we succeed in enhancing this function, either by pharmacological or other means, it might be possible to delay the onset of dementias.”
Image Source: NeuroscienceNews.com image is adapted from the LMU news release.
Original Research:Abstractfor “The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism” by Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez‐Calvet, argol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger,and Christian Haass in EMBO Journal. Published online May 30 2017 doi:10.15252/embj.201796516
Abstract
The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer’s disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD‐like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock‐in mouse model for the disease‐associated Trem2 p.T66M mutation. Consistent with a loss‐of‐function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation. Trem2 p.T66M knock‐in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity. Immunohistochemistry together with in vivo TSPO small animal positron emission tomography (μPET) demonstrates an age‐dependent reduction in microglial activity. Surprisingly, perfusion magnetic resonance imaging and FDG‐μPET imaging reveal a significant reduction in cerebral blood flow and brain glucose metabolism. Thus, we demonstrate that a TREM2 loss‐of‐function mutation causes brain‐wide metabolic alterations pointing toward a possible function of microglia in regulating brain glucose metabolism.
“The FTD‐like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism” by Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez‐Calvet, argol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger,and Christian Haass in EMBO Journal. Published online May 30 2017 doi:10.15252/embj.201796516
