Eye Test Could Predict Alzheimer’s Years Before Symptoms Appear

NEUROSCIENCE NEWS    AUGUST 18, 2017

Summary: Researchers report the retina may provide clues as to those at risk of developing Alzheimer’s disease. A new study reports amyloid plaques have been discovered in peripheral areas of the retina in Alzheimer’s patients. The amount of retinal plaques correlated with the amount of amyoid plaques in specific brain areas.

Source: Cedars Sinai Medical Center.

Cedars-Sinai neuroscience investigators have found that Alzheimer’s disease affects the retina — the back of the eye — similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive eye scan could detect the key signs of Alzheimer’s disease years before patients experience symptoms. Using a high-definition eye scan developed especially for the study, researchers detected the crucial warning signs of Alzheimer’s disease: amyloid-beta deposits, a buildup of toxic proteins. The findings represent a major advancement toward identifying people at high risk for the debilitating condition years sooner. NeuroscienceNews.com image is credited to Cedars-Sinai.

Cedars-Sinai neuroscience investigators have found that Alzheimer’s disease affects the retina — the back of the eye — similarly to the way it affects the brain. The study also revealed that an investigational, noninvasive eye scan could detect the key signs of Alzheimer’s disease years before patients experience symptoms.

Using a high-definition eye scan developed especially for the study, researchers detected the crucial warning signs of Alzheimer’s disease: amyloid-beta deposits, a buildup of toxic proteins. The findings represent a major advancement toward identifying people at high risk for the debilitating condition years sooner.

The study, published today in JCI Insight, comes amid a sharp rise in the number of people affected by the disease. Today, more than 5 million Americans have Alzheimer’s disease. That number is expected to triple by 2050, according to the Alzheimer’s Association.

“The findings suggest that the retina may serve as a reliable source for Alzheimer’s disease diagnosis,” said the study’s senior lead author, Maya Koronyo-Hamaoui, PhD, a principal investigator and associate professor in the departments of Neurosurgery and Biomedical Sciences at Cedars-Sinai. “One of the major advantages of analyzing the retina is the repeatability, which allows us to monitor patients and potentially the progression of their disease.”

Yosef Koronyo, MSc, a research associate in the Department of Neurosurgery and first author on the study, said another key finding from the new study was the discovery of amyloid plaques in previously overlooked peripheral regions of the retina. He noted that the plaque amount in the retina correlated with plaque amount in specific areas of the brain.

“Now we know exactly where to look to find the signs of Alzheimer’s disease as early as possible,” said Koronyo.

Keith L. Black, MD, chair of Cedars-Sinai’s Department of Neurosurgery and director of the Maxine Dunitz Neurosurgical Institute, who co-led the study, said the findings offer hope for early detection when intervention could be most effective.

“Our hope is that eventually the investigational eye scan will be used as a screening device to detect the disease early enough to intervene and change the course of the disorder with medications and lifestyle changes,” said Black.

For decades, the only way to officially diagnose the debilitating condition was to survey and analyze a patient’s brain after the patient died. In recent years, physicians have relied on positron emission tomography (PET) scans of the brains of living people to provide evidence of the disease but the technology is expensive and invasive, requiring the patient to be injected with radioactive tracers.

In an effort to find a more cost-effective and less invasive technique, the Cedars-Sinai research team collaborated with investigators at NeuroVision Imaging, Commonwealth Scientific and Industrial Research Organisation, University of Southern California, and UCLA to translate their noninvasive eye screening approach to humans.

The published results are based on a clinical trial conducted on 16 Alzheimer’s disease patients who drank a solution that includes curcumin, a natural component of the spice turmeric. The curcumin causes amyloid plaque in the retina to “light up” and be detected by the scan. The patients were then compared to a group of younger, cognitively normal individuals.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Investigators who contributed to the study include David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton and Steven R. Verdooner.

Funding: The study was funded by the National Institutes of Health/National Institute on Aging, The Marciano Family Foundation and The Saban Family Foundation.

Source: Anasia Obioha – Cedars Sinai Medical Center

Image Source: NeuroscienceNews.com image is credited to Cedars-Sinai.

Original Research: Full open access research for “Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease” by Yosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, and aya Koronyo-Hamaoui in JCI Insight. Published online August 17 2017 doi:10.1172/jci.insight.93621

Abstract

Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease

BACKGROUND. Noninvasive detection of Alzheimer’s disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits.

METHODS. Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients.

RESULTS. Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson’s r = 0.84–0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031).

CONCLUSION. The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.

FUNDING. National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.

“Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease” by Yosef Koronyo, David Biggs, Ernesto Barron, David S. Boyer, Joel A. Pearlman, William J. Au, Shawn J. Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M. Cole, Carol A. Miller, David R. Hinton, Steven R. Verdooner, Keith L. Black, and aya Koronyo-Hamaoui in JCI Insight. Published online August 17 2017 doi:10.1172/jci.insight.93621

http://neurosciencenews.com/alzheimers-eye-test-7330/

Guist works to give Parkinson’s disease a knockout punch

By Ken Waltz | Aug 18, 2017

'I may have PD, but PD doesn't have me,' Guist said.

Gordon Guist of Camden, right, boxes with personal trainer Steph Williams at the Penobscot Bay YMCA.

CAMDEN — Like so many, Gordon Guist was active during the middle age of adulthood but, seemingly without warning, he was dealt a tough hand from the constantly shuffling deck of cards called life.

The now 67-year old of Camden was nearly 48 when he was first diagnosed with Parkinson's disease, a progressive neurogenic degenerative disorder.

That day, and the weeks, months and years to follow, have profoundly affected Guist — interestingly, perhaps, in negative and positive ways.

Like so many, Guist has to deal with his situation — in his case, Parkinson's — and he does that by exercising as often as possible, including doing his best to give the disease a knockout punch.

While Guist realized he will never knock his situation to the canvas, he knows exercise and continued hard work will help him lead a more productive existence and improve his quality of life.

There was a time Guist played coed softball, wallyball (essentially volleyball inside a racketball court) and volleyball, as well as hiked, camped and sailed.

Then, at age 48, he began to notice subtle changes in his physical abilities. At first, he ignored the changes, thinking they simply were part of the aging process. Then he started having trouble with balance and even catching a ball, something that before was a fairly simple process.

When things persisted, Guist went to the doctor and received the diagnosis he dreaded — he had Parkinson's Disease, and worse, at a fairly young age.

He said it took him about six months to get over the depression of the news, but he slowly, but surely, shook off his feeling sorry for himself news, and simply tried to figure out what would help him move forward with each day of his life.

One of the most famous people to deal with Parkinson's Disease is Michael J. Fox, who was diagnosed with the ailment at age 29 in 1991.

There is no cure for Parkinson's, but medication and therapy are used to help with symptoms.

Guist, who has been married to his wife, Robin, for 45 years (the couple has a 31-year-old son, Geoff, who lives in Swanville), has dealt with the disease for nearly 20 years.

Nerve cell damage in the brain causes dopamine levels to drop, leading to the symptoms of Parkinson's, which often starts with a tremor in one hand. Other symptoms are slow movement, stiffness and loss of balance. Medications can help control the symptoms of Parkinson's.

According to the National Parkinson's Disease Foundation website, symptoms of Parkinson’s disease vary from person to person and change over time. But a Parkinson’s diagnosis will only be considered when two of the following four main motor symptoms are present over a period of time:

• Slowness of movement, also called bradykinesia. This symptom makes it harder to initiate and perform physical actions such as getting out of bed, buttoning a shirt or even speech.

• Involuntary shaking, or tremor at rest. Tremor usually occurs in the hands, but it can also appear in other parts of the body, including the lower lip, jaw or leg. This symptom usually improves when a person starts performing tasks or using the limb in some way.

• Stiffness of the arms, legs or trunk. Muscles feel unusually tight, stiff or achy. This symptom can occur on one side or both sides of the body.

• Trouble with balance and falls, also called postural instability. A person with postural instability will have problems with walking, balance and turning around. Falls may occur without explanation. Postural instability isn’t usually present with diagnosis, but it’s one of the most common and troublesome symptoms that happens later on.

Secondary symptoms of Parkinson’s include: Small, cramped handwriting, called micrographia; Reduced arm swing on the affected side; Slight foot drag on the affected side, resulting in a shuffled walk; Freezing — a term used to describe the phenomenon of being stuck in place when attempting to walk; Loss of facial expression due to rigidity of facial muscles, called hypomimia; Low voice volume or muffled speech, called hypophonia; Tendency to fall backwards, called retropulsion; and Decreased ability in automatic reflexes such as blinking and swallowing.

Parkinson’s disease is generally thought of as a disease that only involves movement. But in addition to so-called motor symptoms such as slowness of movement, tremor and stiffness, most people develop other health problems related to Parkinson's. These symptoms are diverse but are collectively known as the following non-motor symptoms:

• Mood disorders such as depression, anxiety and irritability

• Cognitive changes such as problems with focused attention and planning, slowing of thought, language and memory difficulties, personality changes, dementia.

• Hallucinations and delusions.

• Orthostatic hypotension (a drop in blood pressure when standing, light-headedness).

• Sleep disorders such as insomnia, excessive daytime sleepiness (EDS), rapid eye movement behavior disorder (RBD), vivid dreams, talking and moving during sleep, restless legs syndrome (RLS)/periodic leg movements disorder (PLMD).

• Constipation and early satiety (a feeling of fullness after eating small amounts).

• Pain.

• Fatigue.

• Vision problems.

• Excessive sweating, especially of hands and feet, with no or little exercise.

• Increase in dandruff (seborrhea dermatitis) or oily skin.

• Urinary urgency, frequency and incontinence.

• Loss of sense of smell.

• Sexual problems.

• Weight loss or weight gain.

• Impulsive control disorders such as binge eating, excessive shopping or gambling, usually a side effect of medications.

Guist was diagnosed with Parkinson's disease  in 1998, just before his 48th birthday. "But, I had symptoms for at least three years before my formal diagnosis," he said. "These included loss of my sense of smell, my eyes stopped blinking, my left arm stopped swinging when I walked and I developed a tremor on my left hand.

"After my diagnosis, I felt anger and denial — why me? I had been quite active — riding my bike to work (20 miles roundtrip) nearly every day in the spring, summer and fall; I played coed softball, I sailed, I played volleyball and walleyball. I hiked. Because of PD, I had to give up all these. An example of how PD affected me, I could no longer catch a ball."

Guist said that, fortunately, he had been active. "This slowed the progression of PD. I worked for FMC in Rockland since 1974. After my diagnosis, I continued to work for five more years. In 2003, I felt I couldn't do my job safely, so I left work on disability."

He did continue to exercise with the help of Carol Witham, who developed a program for people with PD. 

"I also worked with Carol as my personal trainer," Guist said. "Carol moved to New Mexico a couple of years ago, so I was in the market for a new trainer. That is when Stephanie Williams came onto the scene. Steph and I have been working on my balance, flexibility and strength. We tried boxing exercises because of the success of programs such as Rock Steady. Steph has been an inspiration to me. She has made a difference."

While Guist's overall physical abilities have deteriorated over the years, he maintains as best as he can with consistent exercise, much of that now centered around the Penboscot Bay YMCA and the work with certified trainer Williams.

Williams, health and wellness director at the Rockland Harbor YMCA in Rockland, said she is inspired by Guist, and others with daily health challenges.

Guist boxes (wearing gloves and hitting pads held by Williams) to improve hand-eye coordination, stamina and agility and also works hard at strength and balance exercises, as well as stretching and other movements.

"Gordie is an inspiration not only to me but the people he is around while we work out," Williams said. "His attitude and perseverance are greatly admired. He comes in every Wednesday morning with a smile on his face, and lots of pep in his step.

"We start our sessions with a mile walk, and some boxing. He loves to box. Rock Steady boxing has been proven to greatly help Parkinson's symptoms. Focusing on cross body movements, and combinations with jabs, crosses, hooks and upper cuts. He is very enthusiastic when he straps up his gloves, I worry that he just likes to hit me! Pay back for making him work hard I guess."

Guist deals with all the symptoms of Parkinson's disease, including shakes, stability, stiffness and general overall health.

There is no cure for Parkinson’s, but it is well documented that exercise may slow the progression of the disease and improve the quality of life for those with Parkinson's. Any type of exercise will do — walking, jogging, swimming and bicycling, to mention a few. Recently, boxing has proved effective for treating the symptoms of Parkinson’s. Not the "mano-o-mano-type" of boxing, but working on the basic skills and technique, Guist said.

"Rock Steady Boxing" is one program for those with Parkinson's that has been leading the way. He said 60,000 people worldwide are diagnosed with Parkinson’s each year. There are 395 Rock Steady Boxing venues throughout the world, and more than 19,000 people with Parkinson's participate in this non-contact fitness course. Exercises are developed from boxing drills with emphasize on hand-eye coordination, speed, agility, balance, footwork, and midline crossover. All are intended to challenge the participant to overcome deficiencies caused by Parkinson’s.

Guist continues to be involved with a Parkinson's disease support group at Anderson Inn at Quarry Hill in Camden.

He continues to volunteer at the Camden food pantry, at the Penobscot Pet Pantry, and occasionally at P.A.W.S.  He is an advocate for Parkinson's disease research through the Parkinson's Disease Foundation.

"I may have PD, but PD doesn't have me," Guist said.

"I couldn't be more proud and honored to train Gordon," Williams said. "He is well-known throughout the community and is the kind of person you just want to be around. His laugh is contagious."

https://youtu.be/epig3ehmjZU

Gordon Guist, who deals with Parkinson's Disease, works out with Steph Williams at the Penobscot Bay YMCA. (Video by: Ken Waltz and Holly Vanorse Spicer)

https://knox.villagesoup.com/p/guist-works-to-give-parkinson-s-disease-a-knockout-punch/1673229

Bio-inspired materials give boost to regenerative medicine

August 18, 2017

In a new study in Nature Communications, Stephanopoulos and his colleague Ronit Freeman successfully demonstrated the ability to dynamically control the environment around stem cells, to guide their behavior in new and powerful ways. Credit: Northwestern University

What if one day, we could teach our bodies to self-heal like a lizard's tail, and make severe injury or disease no more threatening than a paper cut?

Or heal tissues by coaxing cells to multiply, repair or replace damaged regions in loved ones whose lives have been ravaged by stroke, Alzheimer's or Parkinson's disease?

Such is the vision, promise and excitement in the burgeoning field of regenerative medicine, now a major ASU initiative to boost 21st-century medical research discoveries.

ASU Biodesign Institute researcher Nick Stephanopoulos is one of several rising stars in regenerative medicine. In 2015, Stephanopoulos, along with Alex Green and Jeremy Mills, were recruited to the Biodesign Institute's Center for Molecular Design and Biomimetics (CMDB), directed by Hao Yan, a world-recognized leader in nanotechnology.

"One of the things that that attracted me most to the ASU and the Biodesign CMDB was Hao's vision to build a group of researchers that use biological molecules and design principles to make new materials that can mimic, and one day surpass, the most complex functions of biology," Stephanopoulos said. 

"I have always been fascinated by using biological building blocks like proteins, peptides and DNA to construct self-assembled structures, devices and materials, and the interdisciplinary and highly collaborative team in the CMDB is the ideal place to put this vision into practice."

Yan's research center uses DNA and other basic building blocks to build their nanotechnology structures—only at a scale 1,000 times smaller than the width of a human hair.

They've already used nanotechnology to build containers to specially deliver drugs to tissues, build robots to navigate a maze or nanowires for electronics.

To build a manufacturing industry at that tiny scale, their bricks and mortar use a colorful assortment of molecular Legos. Just combine the ingredients, and these building blocks can self-assemble in a seemingly infinite number of ways only limited by the laws of chemistry and physics—and the creative imaginations of these budding nano-architects.

Learning from nature

"The goal of the Center for Molecular Design and Biomimetics is to use nature's design rules as an inspiration in advancing biomedical, energy and electronics innovation through self-assembling molecules to create intelligent materials for better component control and for synthesis into higher-order systems," said Yan, who also holds the Milton Glick Chair in Chemistry and Biochemistry.

Prior to joining ASU, Stephanopoulos trained with experts in biological nanomaterials, obtaining his doctorate with the University of California Berkeley's Matthew Francis, and completed postdoctoral studies with Samuel Stupp at Northwestern University. At Northwestern, he was part of a team that developed a new category of quilt-like, self-assembling peptide and peptide-DNA biomaterials for regenerative medicine, with an emphasis in neural tissue engineering.

"We've learned from nature many of the rules behind materials that can self-assemble. Some of the most elegant complex and adaptable examples of self-assembly are found in biological systems," Stephanopoulos said.

Because they are built from the ground-up using molecules found in nature, these materials are also biocompatible and biodegradable, opening up brand-new vistas for regenerative medicine.

Stephanopoulos' tool kit includes using proteins, peptides, lipids and nucleic acids like DNA that have a rich biological lexicon of self-assembly.

"DNA possesses great potential for the construction of self-assembled biomaterials due to its highly programmable nature; any two strands of DNA can be coaxed to assemble to make nanoscale constructs and devices with exquisite precision and complexity," Stephanopoulos said.

Proof all in the design

During his time at Northwestern, Stephanopoulos worked on a number of projects and developed proof-of-concept technologies for spinal cord injury, bone regeneration and nanomaterials to guide stem cell differentiation. 

Now, more recently, in a new study in Nature Communications, Stephanopoulos and his colleague Ronit Freeman in the Stupp laboratory successfully demonstrated the ability to dynamically control the environment around stem cells, to guide their behavior in new and powerful ways.

In the new technology, materials are first chemically decorated with different strands of DNA, each with a unique code for a different signal to cells.

To activate signals within the cells, soluble molecules containing complementary DNA strands are coupled to short protein fragments, called peptides, and added to the material to create DNA double helices displaying the signal.

Hao Yan’s research center uses DNA and other basic building blocks to build their nanotechnology structures — only at a scale 1,000 times smaller than the width of a human hair. As demonstrated in a cover article in Science, they’ve already used nanotechnology to build containers to specially deliver drugs to tissues, robots to navigate a maze or nanowires for electronics. Credit: Arizona State University

By adding a few drops of the DNA-peptide mixture, the material effectively gives a green light to stem cells to reproduce and generate more cells. In order to dynamically tune the signal presentation, the surface is exposed to a soluble single-stranded DNA molecule designed to "grab" the signal-containing strand of the duplex and form a new DNA double helix, displacing the old signal from the surface.

This new duplex can then be washed away, turning the signal "off." To turn the signal back on, all that is needed is to now introduce a new copy of single-stranded DNA bearing a signal that will reattach to the material's surface.

One of the findings of this work is the possibility of using the synthetic material to signal neural stem cells to proliferate, then at a specific time selected by the scientist, trigger their differentiation into neurons for a while, before returning the stem cells to a proliferative state on demand.

One potential use of the new technology to manipulate cells could help cure a patient with neurodegenerative conditions like Parkinson's disease.

The patient's own skin cells could be converted to stem cells using existing techniques. The new technology could help expand the newly converted stem cells back in the lab—and then direct their growth into specific dopamine-producing neurons before transplantation back to the patient.

"People would love to have cell therapies that utilize stem cells derived from their own bodies to regenerate tissue," Stupp said. "In principle, this will eventually be possible, but one needs procedures that are effective at expanding and differentiating cells in order to do so. Our technology does that."

In the future, it might be possible to perform this process entirely within the body. The stem cells would be implanted in the clinic, encapsulated in the type of material described in the new work, and injected into a particular spot. Then the soluble peptide-DNA molecules would be given to the patient to bind to the material and manipulate the proliferation and differentiation of transplanted cells.

Scaling the barriers

One of the future challenges in this area will be to develop materials that can respond better to external stimuli and reconfigure their physical or chemical properties accordingly.

"Biological systems are complex, and treating injury or disease will in many cases necessitate a material that can mimic the complex spatiotemporal dynamics of the tissues they are used to treat," Stephanopoulos said. 

It is likely that hybrid systems that combine multiple chemical elements will be necessary; some components may provide structure, others biological signaling and yet others a switchable element to imbue dynamic ability to the material.

A second challenge, and opportunity, for regenerative medicine lies in creating nanostructures that can organize material across multiple length scales. Biological systems themselves are hierarchically organized: from molecules to cells to tissues, and up to entire organisms.

Consider that for all of us, life starts simple, with just a single cell. By the time we reach adulthood, every adult human body is its own universe of cells, with recent estimates of 37 trillion or so. The human brain alone has 100 billion cells or about the same number of cells as stars in the Milky Way galaxy.

But over the course of a life, or by disease, whole constellations of cells are lost due to the ravages of time or the genetic blueprints going awry.

Collaborative DNA

To overcome these obstacles, much more research funding and recruitment of additional talent to ASU will be needed to build the necessary regenerative medicine workforce.

Last year, Stephanopoulos' research received a boost with funding from the U.S. Air Force's Young Investigator Research Program (YIP).

"The Air Force Office of Scientific Research YIP award will facilitate Nick's research agenda in this direction, and is a significant recognition of his creativity and track record at the early stage of his careers," Yan said.

They'll need this and more to meet the ultimate challenge in the development of self-assembled biomaterials and translation to clinical applications.

Buoyed by the funding, during the next research steps, Stephanopoulos wants to further expand horizons with collaborations from other ASU colleagues to take his research team's efforts one step closer to the clinic. 

"ASU and the Biodesign Institute also offer world-class researchers in engineering, physics and biology for collaborations, not to mention close ties with the Mayo Clinic or a number of Phoenix-area institutes so we can translate our materials to medically relevant applications," Stephanopoulos said.

There is growing recognition that regenerative medicine in the Valley could be a win-win for the area, in delivering new cures to patients and building, person by person, a brand-new medicinal manufacturing industry.

More information: Ronit Freeman et al. Instructing cells with programmable peptide DNA hybrids, Nature Communications (2017). DOI: 10.1038/ncomms15982 

Journal reference: Nature Communications

Provided by: Arizona State University 

https://medicalxpress.com/news/2017-08-bio-inspired-materials-boost-regenerative-medicine.html

Study of nervous system cells can help to understand degenerative diseases

August 18, 2017 by Peter Moon

Research highlights differences between human and murine microglia used in studies of Alzheimer's and other diseases Credit: Suely Nagahashi Marie and Thais Galatro, University of São Paulo Medical School

The results of a new study show that many of the genes expressed by microglia differ between humans and mice, which are frequently used as animal models in research on Alzheimer's disease and other neurodegenerative disorders.

Microglia are the primary immune cells of the central nervous system, with functions similar to those of white blood cells, especially in actively defending the brain and spinal cord. The collaborative research by Brazilian and Dutch scientists on the main genes expressed by human microglia were published in Nature Neuroscience. It also shows that human microglial cells age differently from those of mice. The research was supported by the São Paulo Research Foundation (FAPESP).

"The findings are important for studies of the gene expression profiles of normal microglia during human aging. They can serve as a basis for comparisons designed to detect changes in microglia as part of several neurodegenerative diseases," said Suely Nagahashi Marie, who heads the Molecular & Cellular Biology Laboratory at the University of São Paulo's Medical School (FM-USP).

Microglia terminate on neurons and inspect their surroundings in search of external agents to fight off, dead synapses to remove, and neurons that are dying and require elimination. When they detect a problem, they move swiftly to phagocytize the inflammation-causing agent. Given the role of microglia in the central nervous system's immune responses, these cells are also a focus for research on neurodegenerative diseases such as Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Alzheimer's.

"In order to understand the role of microglia in neurodegenerative diseases, we first have to know which genes in human microglia are expressed at the highest levels in a healthy nervous system," said biomedical scientist Thais Fernanda de Almeida Galatro, another author of the research project. "This has never been investigated. Our idea was to establish a gene expression profile of human microglia." 

Galatro learned a technique for sampling cortical microglia from the team working under Bart Eggen, a professor in Gronigen's Department of Neuroscience. The collaboration included a visit by a member of Eggen's team to the laboratory headed by Nagahashi Marie. The cortical samples used in the research were collected from autopsies performed in the Netherlands and by São Paulo City's Death Certification Service (SVOC), which donated them to the Human Brain Bank of FM-USP's Cerebral Aging Study Group.

Thirty-nine of 81 samples were selected from individuals without a history of cerebral pathology. "This is so we could be sure the microglia used in the study were from healthy brains," Galatro said. The selected samples were from men and women aged between 34 and 102 years. This wide age range was deliberately chosen, because the researchers wanted to understand how aging affects microglial gene expression.

The microglia obtained from the cortical samples were submitted to transcriptome (RNA) sequencing. "Next-generation sequencing is used to assess the level of expression of all genes encoded in the sample analyzed. In our study, we used a technique called ribosomal RNA depletion. Ribosomal RNA accounts for about 80 percent of total microglial RNA," Nagahashi Marie said.

This approach enabled the researchers to perform an accurate count of protein-encoding messenger RNAs. They detected between 17,000 and 19,000 human microglial genes. "We compared "these large sets of genes between two groups—microglia in isolation versus total brain tissue," she explained.

Microglia represent a specific cellular compartment of brain tissue. In the comparison between microglia and total brain tissue, the 17,000 to 19,000 genes were ranked according to their abundance in each of the compartments. As a result, the researchers were able to identify the 1,297 genes that were most abundantly expressed in human microglia.

"This group of genes was considered the molecular signature of human microglia," Nagahashi Marie said.

Having isolated the 1,297 most highly expressed genes in human microglia, the researchers compared these genes with murine microglial genes. Most research on microglia uses a murine model.

"We found that the most expressed microglial genes in humans and mice are similar to those most expressed in general terms," Galatro said. In both humans and mice, these genes relate mainly to the functions of motility (microglial cells move through nerve tissue) and defense (phagocytosis of pathological agents).

However, a small number of the most highly expressed human microglial genes are unique to our species and are not found in mice. "We discovered that these few exclusively human genes play an important role in the immune response. In other words, they're important to the host organism's defense against infections," Galatro said.

Comparison with primates

According to Nagahashi Marie, the main outcome of the research project was the demonstration of this key difference despite the large overlap between human and murine microglial genes. "The implication is that the results of experiments in murine models of neurodegeneration, including models of Alzheimer's, must be interpreted with caution," she said. "Our results for the expression of human microglia during the aging process differ from those described hitherto for the murine model of aging."

The next step for the group is to analyze the functions of the genes identified in order to discover what roles they play in the normal physiology of the brain and to understand the changes that take place in neurodegenerative diseases. Having compared human and murine genes, the researchers are naturally interested in comparisons with the microglia of animals that are closer to humans in evolutionary terms.

"The sequencing of primate microglia is underway in our lab," Nagahashi Marie said. "When we have the primate transcriptome, we'll be able to compare the evolution of human microglial gene expression with that of microglia in other primates, mice and zebrafish."

The researchers have also sequenced microglia isolated from seven brain regions in autopsied individuals without cognitive dysfunction, and they are analyzing the samples using bioinformatics. "The new study will enable us to see whether there are differences between microglia in different parts of the brain," she said. "Our hypothesis is that there are, and that microglia are relevant to the pathology of neurodegenerative diseases. We're therefore including in our analysis the brain regions most compromised in the progression of Alzheimer's."

More information: Thais F Galatro et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes, Nature Neuroscience (2017). DOI: 10.1038/nn.4597 

Journal reference: Nature Neuroscience

Provided by: FAPESP 

https://medicalxpress.com/news/2017-08-nervous-cells-degenerative-diseases.html

Mirapex: A Miracle Treatment with Troubling Effects for Some

AUGUST 17, 2017   BY SHERRI WOODBRIDGE

Mirapex (pramipexole), a common treatment for Parkinson’s disease, is believed to work by boosting the action of whatever dopamine is available, which is low in people with Parkinson’s. It is a dopamine agonist that directly stimulates nerves in the brain that are not naturally being stimulated by dopamine.

Several years ago, my doctor diagnosed me with Parkinson’s. Immediately, he placed me on Mirapex (pramipexole dihydrochloride). I can’t say that I’ve had a problem with this particular medication, except that sometimes I felt as if I could lie down right where I was and have a glorious nap about half an hour after taking it.

Although I haven’t had many side effects, others have. Just as PD affects each individual differently, so do the medications.

My reactions were mild, and yet at each checkup, my doctor did not fail to ask if I had started having addictive behaviors with gambling, shopping, or sex. Fortunately, I was able to answer no to his questions, but that is not the case with three people I became acquainted with through a PD support group I belong to through Facebook. I am going to call them Cora, Jim, and Carl.

Cora’s father is a PD patient and has taken Mirapex for two years. During this time, he developed serious gambling problems, delusions, and hallucinations.

Meanwhile, Jim had been taking Mirapex for restless leg syndrome (RLS), often a complication of PD. He read up on some undesirable side effects that included compulsive gambling, excessive spending, and compulsive, excessive sexual behavior.

What disturbed Jim most was that patients taking Mirapex often are unaware that a change is occurring. Jim began engaging in several of these atypical behaviors. He was unaware that they were actually becoming addictive behaviors. Fortunately for Jim, his doctor recognized that Mirapex was causing the addictions. Jim thought he was the only one with these side effects until his doctor put him in touch with Carl.

Carl first noticed his bowel movements had changed and constipation was regular. He gained 40 pounds in the first five months and couldn’t sleep. He understood it was the medication but had another issue: He was embarrassed by the things he couldn’t seem to quit doing. He never read the informational insert inside the drug box. He was just following the doctor’s orders.

Carl began to lose control sexually, and his internet use became an outlet for improper behavior. He was ashamed and felt isolated in his problem. He went to see a new neurologist and discovered he wasn’t alone. Several other PD patients who were prescribed Mirapex were dealing with similar issues. [Such extreme side effects in Mirapex users are considered unusual, but are known and reported. Here’s the Mayo Clinic’s list of common and uncommon reactions; here’s a similar one on Drugs.com. The possibility of “unusual urges” — gambling, compulsive eating, compulsive buying, and increased sex drive —  is also noted on Mirapex’s online information page.]

Carl’s neurologist diagnosed the problem and he stopped the drug. Sheryl, however, lost everything to gambling before learning the likely cause of her problem. After her house, savings, retirement, husband and children were gone, and she found herself taking money from the church offering, she sought help. Her doctor, too, took her off Mirapex, and her gambling urges ceased.

I also came to know a woman I’ll call Becky. Her story isn’t as devastating, unless you count Becky’s painting the outside of her house 17 times in one year.

While the incidence of such behavior is low — psychiatric effects are estimated to involve 0.1% to 1% of all PD and RLS Mirapex users — it is troubling. So why do physicians continue to prescribe such a drug?

According to the website CanadianMedsUSA, “Mirapex eases the symptoms of Parkinson’s disease, a progressive disorder marked by muscle rigidity, weakness, shaking, tremor, and eventually difficulty with walking and talking. Parkinson’s disease results from a shortage of the chemical messenger dopamine in certain areas of the brain. Mirapex is believed to work by boosting the action of whatever dopamine is available.”

With relief like that, it’s hard to not want to take it. It also is a miracle drug of sorts for RLS, providing relief almost instantaneously.

Chances are that your doctor will prescribe Mirapex if your diagnosis is PD or RLS, and most likely you will experience some sort of side effect while you’re on it. It is extremely important to keep the communication open between you and your doctor and to make sure you’re checking in regularly.

Each case is different. Don’t hesitate to seek help if you begin to notice changes or to feel different. You may be fine. It may be nothing. Nevertheless, your health is ultimately your responsibility and hesitation could be costly. Be proactive in your care. It could be what saves your family, your job, and your life.

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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. 

https://parkinsonsnewstoday.com/2017/08/17/parkinsons-disease-mirapex-miracle-drug-with-some-strange-possible-side-effects/

Box breathing for anxiety: Techniques and tips

August 17, 2017  By Zawn Villines

Practicing breathing techniques, such as box breahting, may help to ease anxiety and manage panic attacks

Box breathing, sometimes called square breathing, is a simple tool for managing anxiety.

A racing heart, rapid breathing, and dizziness can make people with anxiety feel out of control. Controlled, slow breaths can support a regained sense of control, offering relief from anxiety and panic attacks.

What is box breathing?

Like the four corners of a square, box breathing requires only four steps, each of which requires participants to count to four.

To try box breathing, a person should get into a comfortable position that makes it easy to breathe freely. They should then follow these steps:

1. Breathe in through the nose while counting to four. Continue inhaling for the entire 4 seconds. The breath should be slow and steady.
2. Hold the breath in the lungs for another count of four.
3. Exhale through the mouth while counting to four. As with the inhale, the exhale should be slow and steady.
4. Continue repeating this pattern for 4 minutes.

People with a history of fainting, who feel dizzy during deep breathing, or who have cardiovascular health problems should talk to a doctor before trying any breathing technique.

Tips and techniques for box breathing

When practicing box breathing, it is important to relax the body and find a comfortable position. This may be a sitting position, or lying down.

Breathing is something that everyone does naturally, but people with anxiety sometimes develop unhealthy breathing habits, during stressful or anxiety-provoking situations.

To get the most out of box breathing, people should practice mindful breathing, remaining conscious of each breath and how it feels.

Some strategies to increase the effectiveness of box breathing include the following:

Practice diaphragmatic breathing

Deep breathing uses the diaphragm, the muscle that helps the lungs pull in oxygen. This technique is also called diaphragmatic breathing.

To master diaphragmatic breathing, a person needs to practice expanding their abdomen when inhaling and contracting it when exhaling.

Diaphragmatic breathing does not always feel natural to people who are used to chest breathing, which is a shallower form of breathing where it is the chest muscles that move mostly, during inhalation and exhalation.

People with anxiety should practice diaphragmatic breathing, as frequently as possible. Taking 5-10 deep breaths throughout the day can supplement box breathing. It also helps the body "remember" how to breathe correctly during a box breathing session.

Choose a comfortable position

Bad posture can make it harder to take deep breaths. Being slumped over reduces the amount of oxygen the lungs can take in. It also makes it more difficult to breathe into the abdomen.

People should choose a comfortable position, but not one that means they slump over. A comfortable chair with a sturdy back is an ideal location to try box breathing. Lying flat on the back also works well.

Relax the body

Some people with anxiety unconsciously tense up their muscles. This can cause muscle pain, make it more difficult to breathe, and make anxiety worse. Before or after a box breathing session, people should try a simple strategy called progressive muscle relaxation.

Beginning with the toes, slowly and steadily tense and then relax each muscle in the body. This exercise supports awareness of muscle tension and, similarly to controlled breathing, can help people with anxiety regain a sense of control over their bodies.

Try visualization

Just as box breathing can help people with anxiety slow their breaths, visualization exercises can help slow a flood of anxious thoughts.

Try visualizing a relaxing and peaceful scene. It can be an imaginary place or a place that has always felt safe. Beaches, mountains, and quiet rooms are popular places to visualize.

People who have lots of overwhelming thoughts while breathing can find visualization particularly helpful because it gives the brain something else on which to focus.

Know that practice makes perfect

Box breathing is a skill just like throwing a ball or typing. It takes time to perfect. At first, it can feel uncomfortable. Some people even get dizzy because they are not used to slow, deliberate breathing.

It is important to understand that the effects of breathing techniques tend to get better with practice. Try several sessions each day to perfect the technique.

Remembering the steps during an anxiety attack

It is hard to think clearly during an anxiety attack, especially when the mind is flooded with anxious thoughts. Practicing box breathing during times of calm can make the process easier and more familiar when anxiety strikes.

Some people may also find that visualizing a physical box helps. This makes it more difficult for the mind to jump from one anxious thought to another and serves as a cue for the breathing technique.

How box breathing can treat anxiety

                         

Other methods for treating anxiety include group therapy, medication, and psychotherapy.

Anxiety is more than just an emotion. It is a physical experience, as well.

People experiencing panic attacks may hyperventilate or take only shallow, quick breaths. Some even hold their breaths without realizing that is what they are doing. This lack of oxygen can make anxiety worse, creating a vicious cycle of oxygen deprivation and anxiety.

When there is less oxygen in the blood, the brain gets less oxygen. That makes it hard to think clearly and may even affect vision. As a result, people experiencing intense anxiety can benefit from simple techniques that are easy to remember.

Box breathing does not require special skills or equipment, and its emphasis on four steps and four counts makes it easy to remember, even in the middle of a panic attack.

Breathing techniques, including box breathing, do not treat the underlying cause of anxiety. Breathing techniques can, however, give people with anxiety a greater sense of control over their anxiety and help them manage their situation with less difficulty.

Anxious people often fear having an anxiety attack. Knowing that a simple technique can reduce their anxiety may help them to feel more secure.

Someone with an anxiety disorder, such as post-traumatic stress disorder (PTSD), or panic disorder may need other treatments to get relief. Those treatments include:

• Psychotherapy - therapy can address the causes of anxiety, including trauma. CBT, or cognitive behavioral therapy, which helps people understand and control automatic thoughts, is particularly helpful.
• Medication - a wide range of medications can help with anxiety. Anti-anxiety drugs such as Xanax and Klonopin work on an "as needed" basis. Some people with anxiety also use anti-depressants. These drugs can take several days or weeks to work and must be taken each day.
• Self-help groups - support groups offer people with anxiety the chance to discuss their feelings and learn from the experiences of others, facing similar difficulties.
• Lifestyle remedies - a range of lifestyle remedies can help, including dietary changes such as avoiding caffeine. Some people with anxiety find that their symptoms improve with regular exercise.
• Managing stress - stress reduction, self-care strategies to manage times of stress, support from friends, and positive self-talk can help with anxiety.
• Clinical trials - some people with anxiety cannot find relief with traditional methods. Clinical drug trials offer the possibility of relief from experimental drugs. Some clinical trials also use new therapeutic techniques or lifestyle remedies to tackle anxiety.

Outlook

Practicing box breathing helps people get better at it and to know when to try using it. This means that, over time, box breathing may more quickly reduce anxiety symptoms. As a result, it is possible to see improvements in anxiety over time by using this technique.

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