Team identifies DNA element that may cause rare movement disorder

 December 11, 2017

A depiction of the double helical structure of DNA. Its four coding units (A, T, C, G) are color-coded in pink, orange, purple and yellow. Credit: NHGRI

A team of Massachusetts General Hospital (MGH) researchers has identified a specific genetic change that may be the cause of a rare but severe neurological disorder called X-linked dystonia parkinsonism (XDP). Occurring only among individuals with ancestry from the Philippines island of Panay, XDP combines features of two common movement disorders, dystonia and Parkinson's disease, in an unusual pattern and significantly shortens the life of affected individuals.

This discovery, which is receiving online publication in PNAS Early Edition, represents the work of the Collaborative Center for X-linked Dystonia Parkinsonism in the MGH Department of Neurology, directed by Nutan Sharma, MD, PhD, and Cristopher Bragg, PhD, who with Laurie Ozelius, PhD, is a co-senior author of the report.

"XDP causes certain nerve cells within the brain to progressively die, and its cause has been difficult to understand," explains Bragg. "Before our study it had been reported that all XDP patients share seven changes in their DNA in an identical pattern known as a haplotype, but it was not known which, if any, of these changes might be responsible for the disease. We have now shown that the pattern in patients is actually not identical and that variation in one of these sequence changes strongly determines the age at which symptoms first appear."

These initial symptoms most often involve dystonia - involuntary muscle contractions that can force body parts into abnormal, sometimes twisted positions. Symptoms appear most commonly around the age of 40 and may affect multiple muscle groups - particularly the head and neck, which can interfere with the ability to speak and swallow. Over time patients also develop Parkinson's-like symptoms, such as slowness of movement and a shuffling gait, and become more disabled as the disease progresses. In many cases, patients die from complications, including infections and pneumonia.

The DNA sequence changes associated with XDP are all located on the X chromosome, clustering around a gene called TAF1, which regulates how genes are expressed within cells. One of these sequence changes is an insertion of a large fragment of DNA known as a retrotransposon, a type of DNA element that can move from one site in the genome to another. While the majority of retrotransposons in the human genome are benign, some are inserted at sites that disrupt the normal function of surrounding genes and cause disease. The team led by Ozelius and Bragg analyzed the sequence of the XDP retrotransposon in 140 patients from the Philippines and North America and discovered significant differences between patients in the length of a segment consisting of repetitive DNA sequences. The number of repeats was correlated with the age at which symptoms first appears - patients with longer repeat tracts developed XDP at earlier ages, while those with shorter repeat lengths did not exhibit symptoms until later in life.

"These are the first data directly linking a DNA sequence in XDP to a clinical disease manifestation, which is the strongest evidence to date that this retrotransposon is the likely cause of this disease," says Bragg.

Ozelius adds, "It further reveals that XDP is another example of what are called DNA repeat expansion diseases, many of which affect the brain such as Huntington's disease and some forms of amyotrophic lateral sclerosis. A major question now is whether therapies being developed for those disorders may have similar benefits for patients with XDP."

Sharma, also a co-author of the PNAS report, explains, "Currently available treatments for XDP are extremely limited, consisting of only a few oral medications, injections of botulinum toxin into affected muscles to relieve painful muscle contractions, and deep brain stimulation, which is a complex neurosurgical procedure. But the vast majority of XDP patients live on Panay, where such treatments are not readily available. Part of the mission of our center, in addition to the research we perform, is to improve delivery of care in those regions, which we are working hard to do in partnership with affiliated organizations in the Philippines."

More information: D. Cristopher Bragg el al., "Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1712526114 

Journal reference: Proceedings of the National Academy of Sciences 

Provided by: Massachusetts General Hospital

https://medicalxpress.com/news/2017-12-team-dna-element-rare-movement.html

FoxFeed Blog: Ask the MD: Constipation and Parkinson's

Posted by  Rachel Dolhun, MD, December 11, 2017

Constipation is a common problem for people both with and without Parkinson's disease (PD). For those with Parkinson's, it can range from a mild nuisance that causes temporary discomfort to a more chronic problem that significantly affects quality of life. In addition to its direct effects, constipation can impact the absorption and effectiveness of Parkinson's medications. Constipation can occur at any time during the course of Parkinson's, sometimes even decades before motor symptoms appear and the disease is diagnosed.

What Is Constipation?

Constipation occurs when bowel movements, or "stools," become less frequent and/or more difficult to pass. Some define constipation as less than three bowel movements per week, but what constitutes constipation typically varies from person to person because our usual bathroom patterns differ. Some people go every day, while others may go only three or four times per week. 

What Causes Constipation? 

There are many possible causes of constipation. In Parkinson's, constipation may be part of the underlying disease process. PD can affect the autonomic nervous system, a network of nerves that directs bodily functions we don't consciously control, such as blood pressure and digestion. When digestive tract movement slows in PD, constipation can result. Constipation can be a side effect of Parkinson's drugs, as well. It's a common problem, for example, with Artane (trihexiphenidyl), a drug sometimes used to target tremor. 

Other prescription and over-the-counter medications, including narcotic painkillers, antacids that contain calcium (Tums) or aluminum (Mylanta), or iron supplements, can contribute to constipation too. Limited physical activity and inadequate water and fiber intake also can play a role.

The diagnosis of constipation is typically based on your medical history. If constipation is particularly severe or you have a family history of colon cancer, your doctor may perform certain tests, such as a colonscopy or abdominal x-ray, to exclude other medical conditions.

How Is Constipation Treated? 

In some people, the treatment of constipation can be complex. Most, however, will notice substantial improvement with diet adjustments and increased exercise. 

Dietary recommendations for constipation include:

• Drink at least six 8-ounce glasses of water per day. 
  Water increases flow through the digestive tract, allowing the system to function more effectively. Higher amounts may be necessary for some people, especially in hot weather, but start with at least six glasses per day. Keep in mind that caffeine and alcohol can cause dehydration, which will worsen constipation. And consider drinking warm liquid in the mornings, as this can sometimes stimulate a bowel movement.

• Add more fiber. 
  Fiber helps drive waste through the intestine. Gradually increasing the amount of fiber in your diet can be helpful for constipation. Vegetables, berries, fruits with skin (e.g., pears, apples) and whole grains are good sources.

• Eat smaller meals throughout the day instead of fewer larger meals. 
  Some people notice this helps with constipation as it allows more time for digestion.

Exercise is another key element of constipation management. Abdominal muscle movement helps to activate the digestive system. Steady, moderately strenuous exercise, such as gentle walking, swimming or light weightlifting, is one of the best ways to accomplish this.

When diet and exercise are not enough, both over-the-counter and prescription medications, including stool softeners, laxatives, suppositories or enemas, may be necessary.

• Stool softeners, such as docusate (Colace) can be used if stools are very hard. These can be taken short-term on a daily basis and should be used in conjunction with dietary modifications and exercise.

• Laxatives work in different ways. Some, such as polyethylene glycol (Miralax), pull water into the colon to ease constipation. These are fairly gentle and very popular. "Stimulant" laxatives, such as bisacodyl (Dulcolax) or senna (Senokot), promote muscle contractions in the digestive tract. As a general rule, these aren't recommended for daily use as they can be more harsh and associated with dependency.

• Enemas are sometimes used for significant constipation, but these should be used cautiously and under the advice of your health care provider. 

Although there are no prescription drugs specifically for Parkinson's-related constipation, the U.S. Food and Drug Administration (FDA) has relatively recently approved three drugs for "chronic idiopathic constipation" -- constipation not due to a known medical cause or medication. These drugs -- linaclotide (Linzess), lubiprostone (Amitiza) and plecanatide (Trulance) -- may be considered in certain cases after diet changes, exercise and the above over-the-counter therapies have failed. However, they can be expensive.

As with all Parkinson's symptoms, you should discuss the treatment of constipation with your personal physician so you can work together to find a regimen that fits your needs.

What Research Is Ongoing?

Several therapies to treat Parkinson's constipation are currently in clinical trials. MJFF is funding trials to test a novel drug as well as a fiber supplement (a prebiotic) that acts as a fertilizer for "good" gut bacteria. Other ongoing work is testing additional medications and a gentle hands-on treatment that reduces tension and improves joint mobility ("osteopathic manipulative medicine"). Sign up for Fox Trial Finder to learn more and see if you're eligible. 

In addition to developing treatments, researchers are working toward a better understanding of the link between the gut and brain and Parkinson's. The MJFF-sponsored Systemic Synuclein Sampling Study (S4) measures the protein alpha-synuclein in the gut (and other fluids and tissues), which may help develop tests to diagnose and track PD and assess new therapies. And, in a partnership between MJFF and genetics testing company 23andMe, investigators are analyzing gut bacteria (the microbiome) to see if and how this differs in Parkinson's and among people with PD who have different symptoms (tremor vs. gait-dominant problems, for example). 

https://www.michaeljfox.org/foundation/news-detail.php?ask-the-md-constipation-and-parkinson

Virtual House Calls Are Feasible for Patients With Parkinson’s Disease

Neurology Reviews. 2017 December;25(12):33

Participants prefer virtual visits with a remote specialist to their standard in-person clinician.

Christopher A. Beck, PhD

Providing remote neurologic care directly into the homes of patients with Parkinson’s disease is feasible and is neither more nor less efficacious than usual in-person care, according to research published in the September 12 issue ofNeurology. Virtual house calls are also efficient, eliminating approximately 35,000 miles of travel, and reducing the need for parking lots, waiting rooms, and clinic space.

“The [virtual] visits provide most patients the care that they prefer, the convenience that they need, and the comfort that they value,” said lead author Christopher A. Beck, PhD, Associate Professor of Biostatistics and Orthopedics at the University of Rochester in New York, and colleagues.

Virtual house calls are becoming increasingly common for episodic conditions, but limited evidence supports their use for chronic conditions, according to the researchers. Approximately 40% of patients with Parkinson’s disease never receive care from a neurologist. These patients are more likely to have increased morbidity, to lose independence, and to die prematurely, they said.

Standard Care Versus Virtual House Calls

To determine whether providing virtual house calls is feasible, valuable, and beneficial, Dr. Beck and colleagues conducted a one-year randomized controlled study. Eligible participants had a clinical diagnosis of Parkinson’s disease; had a private, Internet-enabled device; and lived in a state where a site investigator was licensed to practice. Patients currently hospitalized, who had a condition that would preclude study participation in the judgment of the site investigator, or who were currently enrolled in another telemedicine study were excluded.

Investigators compared usual care to usual care supplemented with four virtual visits via video conferencing from a remote specialist into patients’ homes. Primary outcome measures were feasibility, measured by the proportion of participants who completed at least one virtual visit and the proportion of virtual visits completed on time, and efficacy, measured by change in the Parkinson’s Disease Questionnaire-39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.

Most Participants Were Satisfied With Virtual Visits

A total of 927 patients indicated interest in the study. Of these, 732 were excluded because they did not meet eligibility requirements, did not consent, or withdrew prior to randomization. A total of 210 patients were enrolled, and 195 were randomized. In all, 73% of participants had recently visited a specialist, 73% were college-educated, and 96% were white. The mean age of participants was 66. Ninety-eight percent of participants randomized to the intervention arm completed at least one virtual visit; 91% of 388 virtual visits were completed.

Quality of life did not improve for patients who received virtual house calls, nor did quality of care or caregiver burden. However, each virtual house call saved patients a median of 88 minutes per visit and 38 miles per visit. Ninety-seven percent of patients and 86% of physicians were satisfied or very satisfied with virtual visits.

One limitation of this study was that the majority of participants were white, well educated, and more familiar with the Internet than the general population. 

“Dedicated outreach to underserved populations, including those with advanced disease and from underserved demographic groups, especially women, rural residents, minorities, the homebound, or those in assisted living facilities, will help determine if the results are more generalizable and whether the benefits are potentially greater for those with historically less access to care,” said Dr. Beck and colleagues.

“Virtual house calls generated great interest and provided substantial convenience,” the researchers said. “Future efforts must address the digital divide and policy barriers to ensure that this new care model can address inequities in access to care.”

—Erica Tricarico

http://www.mdedge.com/neurologyreviews/article/151852/parkinsons-disease/virtual-house-calls-are-feasible-patients

Bidirectional Gut-Brain Axis Can Perpetuate a Vicious Cycle

December 11, 2017 By Christopher Bergland, The Athletes Way

Brain injury can cause intestinal damage, which exacerbates brain inflammation.

In recent years, it’s become increasingly apparent that there is a bidirectional feedback loop commonly referred to as the “gut-brain axis” (or microbiome–gut–brain axis) that facilitates two-way communication between the gastrointestinal tract and the brain.

Gut-brain communication relies on afferent and efferent pathways of the vagus nerve and other mechanisms to send signals from "gut-to-brain" and "brain-to-gut." Bidirectional gut-brain interactions help to regulate homeostasis, immune responses, and inflammation. 

It's important to emphasize that the human gut-brain axis is far from being fully understood. Disruptions of the gut-brain axis are associated with a diverse spectrum of maladies that include Parkinson’s disease, anxiety disorders, depression, and irritable bowel syndrome (IBS). However, the vast majority of research to date on the gut-brain axis has been conducted on animal models and much more human research is needed.

That being said, this week, the University of Maryland School of Medicine (UMSOM) announced that a research team led by Alan Faden has discovered a two-way correlation between traumatic brain injury (TBI) and intestinal changes in mice that are influenced by bidirectional gut-brain interactions. These findings were recently published in the journal Brain, Behavior, and Immunity.

This study is the first to identify that TBI in mice can trigger a vicious cycle in which a traumatic brain injury causes gut dysfunction. These gut disruptions exacerbate the original brain injury by causing inflammation, which further worsens gut dysfunction. And so on, and so on...This vicious cycle has the potential to snowball out of control.

More specifically, the UMSOM scientists found that TBI in mice caused changes in the GI tract that made the colon more permeable. This permeability increased the odds of harmful microbes migrating from the GI tract to other parts of the body and causing infection. Bacterial infections emanating from the GI system increased brain inflammation and were linked to neuron loss in the hippocampus.

The authors point out that human patients are 12 times more likely to die from blood poisoning (which is generally caused by bacteria) after TBI. Additionally, patients with TBI are 2.5 times more likely to die of a digestive system problem, compared with those without traumatic brain injury.

For years, researchers have known that TBI influences the gastrointestinal tract. But, until now, scientists were unaware that brain trauma in mammals can make the colon more permeable. Unfortunately, it remains unclear exactly how and why traumatic brain injury causes these specific changes in the gut.

As part of their bidirectional gut-brain axis research, the UMSOM scientists also focused on how extreme gut dysfunction may worsen brain inflammation. To pinpoint gut-to-brain directional influences, Faden et al. infected mice with the rodent equivalent of E. coli, which is called "Citrobacter rodentium.” Notably, when mice were infected with a potent gut bacteria, brain inflammation worsened.

The authors sum up their findings in the study abstract: “These experimental studies demonstrate chronic and bidirectional brain-gut interactions after TBI, which may negatively impact late outcomes after brain injury.”

The senior researcher of this study, Alan Faden, is a professor in the departments of Anesthesiology, Anatomy & Neurobiology, Psychiatry, Neurology, and Neurosurgery at UMSOM, and director of the Center for Shock, Trauma and Anesthesiology Research.  In a statement, Faden concluded:

“These results indicate strong two-way interactions between the brain and the gut that may help explain the increased incidence of systemic infections after brain trauma and allow new treatment approaches. These results really underscore the importance of bi-directional gut-brain communication on the long-term effects of traumatic brain injury.”

Other authors from UMSOM involved in this research include first author Elise Ma, a doctoral student; Terez Shea-Donahue, professor of radiation oncology; Bogdan A. Stoica, associate professor of anesthesiology; and David J. Loane, associate professor of anesthesiology.

References

Ma, Elise L., Allen D. Smith, Neemesh Desai, Lumei Cheung, Marie Hanscom, Bogdan A. Stoica, David J. Loane, Terez Shea-Donohue, Alan I. Faden. "Bidirectional Brain-Gut Interactions and Chronic Pathological Changes After Traumatic Brain Injury in Mice." Brain, Behavior, and Immunity. (Published: November 2017) DOI: 10.1016/j.bbi.2017.06.018

Powell, Nick, Marjorie M. Walker, and Nicholas J. Talley. "The Mucosal Immune System: Master Regulator of Bidirectional Gut-Brain Communications." Nature Reviews Gastroenterology & Hepatology (Published online: January 18, 2017) DOI: 10.1038/nrgastro.2016.191 

https://www.psychologytoday.com/blog/the-athletes-way/201712/bidirectional-gut-brain-axis-can-perpetuate-vicious-cycle

Brain Inflammation Caused by Sleep Disorder May Lead to Parkinson’s Disease, Study Shows

DECEMBER 11, 2017  BY ALICE MELÃO 

Patients with rapid eye movement sleep behavior disorder, or RBD, have a form of inflammation in the brain that puts them at risk of developing Parkinson’s disease or dementia, according to researchers at Aarhus University in Denmark.

The study, “Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study,” appeared in The Lancet Neurology.

RBD is a sleeping disorder that affects men more frequently than women, and is commonly diagnosed in people ages 50 to 70. It is characterized by abnormal movements and dream-enacting behaviors during the stage of sleep were dreams take place.

While healthy people stay still and relax during sleep, people with RBD can be quite active, responding vividly with kicks and shouts to the dream they are having.

Previous studies have related RBD with Parkinson’s and dementia, however, little has been known about the link between these diseases.

To address this, researchers analyzed the brains of 20 individuals with RDB and 19 healthy participants enrolled in sleep centers in Barcelona, Spain, and at Aarhus.

They found that RDB patients had more active microglial cells – the brain’s resident immune cells – in the substantia nigra region and reduced levels of dopamine – a neurotransmitter – in the putamen region than healthy individuals. This is important because the substantia nigra and the putamen are the brain regions that are mostly affected in Parkinson’s disease.

“These patients have an inflammation of the brain in the area where the dopamine-producing nerve cells are found,” Morten Gersel Stokholm, MD, a PhD student at Aarhus University and lead author of the study, said in a news release.

Overall, the results show that the underlying features of RBD in the brain are very similar to those seen in Parkinson’s disease and dementia. This suggests that these individuals may be at risk of developing Parkinson’s or dementia in the future.

This is the first time that this type of brain inflammation has been seen as an early risk factor for the development of Parkinson’s disease.

“With this study, we have gained new knowledge about the disease processes in the brain in the early initial stages of the disease development,” Stokholm said.

“The idea is for this knowledge to be used to determine which patients with the sleep disorder will later develop Parkinson’s disease. At the same time, this is also knowledge that can help to develop drugs which can stop or slow the development of the diseases,” he added.

This study was supported by the Independent Research Fund Denmark.

https://parkinsonsnewstoday.com/2017/12/11/brain-inflammation-caused-by-sleep-disorder-may-lead-to-parkinsons-disease/

High-intensity exercise delays Parkinson's progression

December 11, 2017

High-intensity exercise three times a week is safe for individuals with early-stage Parkinson's disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by Northwestern Medicine and University of Denver scientists.

This is the first time scientists have tested the effects of high-intensity exerciseon patients with Parkinson's disease, the second most common neurodegenerative disorder and the most common movement disorder, affecting more than a million people in the United States.

It previously had been thought high-intensity exercise was too physically stressful for individuals with Parkinson's disease.

The paper will be published in JAMA Neurology Dec. 11, 2017.

Parkinson's symptoms include progressive loss of muscle control, trembling, stiffness, slowness and impaired balance. As the disease progresses, it may become difficult to walk, talk and complete simple tasks. Most people who develop Parkinson's are 60 and older.

"If you have Parkinson's disease and you want to delay the progression of your symptoms, you should exercise three times a week with your heart rate between 80 to 85 percent maximum. It is that simple," said co-lead author Daniel Corcos, professor of physical therapy and human movement sciences at Northwestern University Feinberg School of Medicine.

Because medications for Parkinson's have adverse side effects and reduced effectiveness over time, new treatments are needed.

The randomized clinical trial included 128 participants ages 40 to 80 years old from Northwestern University, Rush University Medical Center, the University of Colorado and the University of Pittsburgh.

Participants enrolled in the Study in Parkinson Disease of Exercise (SPARX) were at an early stage of the disease and not taking Parkinson's medication, ensuring the results of the study were related to the exercise and not affected by medication.

"The earlier in the disease you intervene, the more likely it is you can prevent the progression of the disease," Corcos said. "We delayed worsening of symptoms for six months; whether we can prevent progression any longer than six months will require further study."

Scientists examined the safety and effects of exercise three times weekly for six months at high intensity, 80 to 85 percent of maximum heart rate, and moderate intensity, 60 to 65 percent of maximum heart rate. They compared the results to a control group who did not exercise.

After six months, participants were rated by clinicians on a Parkinson's disease scale ranging from 0 to 108. The higher the number, the more severe the symptoms.

Participants in the study had a score of about 20 before exercise. Those in the high intensity group stayed at 20. The group with moderate exercise got worse by 1.5 points. The group that did not exercise worsened by three points. Three points out of a score of 20 points is a 15 percent change in the primary signs of the disease and considered clinically important to patients. It makes a difference in their quality of life.

"We are stopping people from getting worse, which is significant, particularly if we catch them early in the disease," Corcos said.

What sets this study apart from others is the high number of participants, and that they exercised for a relatively long period of time. Most exercise studies are 12 weeks, Corcos said.

"We gave them a proper workout," Corcos said. "This is not mild stretching. This is high intensity. It's part of the idea that exercise is medicine."

Corcos and colleagues confirmed it was safe for the participants to do high-intensity exercise by giving them a cardiologist-supervised graded exercise test to evaluate the heart's response to exercise.

Previous studies in humans suggest high-intensity exercise improves motor symptoms, but the evidence wasn't sufficient to determine whether exercise intensity modifies symptoms or disease progression. In addition, most studies have not precisely measured or controlled exercise intensity and none have been conducted at 80 to 85 percent maximum heart rate.

"Several lines of evidence point to a beneficial effect of exercise in Parkinson's disease," said Dr. Codrin Lungu, program director at the National Institute of Neurological Disorders and Stroke. "Nevertheless, it's not clear which kind of exercise is most effective. The SPARX trial tries to rigorously address this issue. The results are interesting and warrant further exploration of the optimal exercise regimes for Parkinson's."

Journal reference: Archives of Neurology

Provided by: Northwestern University 

https://medicalxpress.com/news/2017-12-high-intensity-parkinson.html

Updated brain cell map connects various brain diseases to specific cell types

 December 11, 2017

Researchers have developed new single-cell sequencing methods that could be used to map the cell origins of various brain disorders, including Alzheimer's, Parkinson's, schizophrenia and bipolar disorder.

By analyzing individual nuclei of cells from adult human brains, researchers at the University of California San Diego, Harvard Medical School and Sanford Burnham Prebys Medical Discovery Institute have identified 35 different subtypes of neurons and glial cells and discovered which of these subtypes are most susceptible to common risk factors for different brain diseases.

"There are multiple theories regarding the roots of various brain diseases. Our findings enable us to narrow down and rank which types of cells in the brain carry the most genetic risk for developing these diseases, which can help drug developers pick better targets in the future," said Kun Zhang, a professor of bioengineering at the UC San Diego Jacobs School of Engineering and co-senior author of the study.

This work builds off of a previous study published in Science, which Zhang also co-led, in which researchers identified 16 subtypes of neurons in the cerebral cortex. That study was the first large-scale mapping of gene activity in the human brain and provided a basis for understanding the diversity of individual brain cells.

"Our ultimate goal is to produce a complete cell atlas of the human brain," Zhang said. "Here, we've created a fuller and more detailed map than what we've done in our previous work."

In the new study, researchers developed a new generation of single-cell sequencing methods that enabled them to identify additional neuronal subtypes in the cerebral cortex as well as the cerebellum, and even further divide previously identified neuronal subtypes into different classes. The new methods also enabled researchers to identify different subtypes of glial cells, which wasn't possible in the previous study due to the smaller size of glial cells.

The advance was made possible by combining next-generation RNA sequencing with chromatin mapping—mapping of DNA and proteins in the nucleus that combine to form chromosomes—for more than 60,000 individual neurons and glial cells. The work was published Dec. 11 in Nature Biotechnology.

Using the information from RNA sequencing and chromatin mapping methods, researchers were able to map which cell types in the brain were affected by common risk alleles—snippets in DNA that occur more often in people with common genetic diseases. Researchers could then rank which subtypes of neurons or glial cells are more genetically susceptible to different brain diseases. For example, they found that two subtypes of glial cells, microglia and oligodendrocytes, were the first and second most at risk, respectively, for Alzheimer's disease. They also identified microglia as most at risk for bipolar disorder, and a subtype of excitatory neurons as most at risk for schizophrenia.

"Now we can locate where the disease likely starts," Zhang said. "However, we are only mapping the genetic risk. We don't know the precise mechanism of how these specific cells actually trigger the disease."

One caveat of this study, explained Zhang, is that it primarily analyzed data from adult brains (ages 20 to 50), so the findings do not represent younger or older populations. In order to better understand brain disorders that manifest early on, for example in infants, like autism spectrum disorder, the study would need to analyze cells from younger brains, he said.

The team also plans to expand their studies to map additional regions of the brain.

More information: Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain, Nature Biotechnology (2017). nature.com/articles/doi:10.1038/nbt.4038 

Journal reference: Nature Biotechnology 

Provided by: University of California - San Diego

https://medicalxpress.com/news/2017-12-brain-cell-diseases-specific.html

All you need to know about akinesia

Sun 10 December 2017 - By Rachel Nall, RN, BSN, CCRN


Akinesia is a disease symptom that causes a person to lose the ability to move their muscles on their own. Sometimes a person's body feels as if it is "frozen" in time.

Doctors commonly associate akinesia with Parkinson's disease, which causes someone to lose control of their movements. However, there are other medical causes connected with akinesia.

Babies in the womb can experience akinesia, which in turn impacts their development. Movement is an important part of fetal development, and akinesia can affect growth and maturation in the womb.

Fast facts on akinesia:

• Akinesia is a condition that can occur at any age.
• It is sometimes referred to as "freezing."
• In Parkinson's disease, akinesia is usually a symptom of later stages.

What are the symptoms?

Some of the symptoms associated with akinesia include:

• Difficulty when a person starts out to walk somewhere.
• Muscle rigidity, usually beginning in the neck and legs. Muscles in the face can become rigid, similar to a mask.
• Sudden inability to move the feet properly, especially when turning or approaching a destination.

Not all people with Parkinson's disease have the same symptoms. Doctors often use the acronym TRAP to describe the symptoms of Parkinson's disease. These stand for:

• Tremor at rest
• Rigidity
• Akinesia
• Postural instability

A person with Parkinson's may display some or all of these symptoms. However, according to a study in the Journal of Neurology, Neurosurgery & Psychiatry, 47 percent of more than 6,600 people with Parkinson's disease who responded to a questionnaire reported akinesia or freezing as a symptom.

It is also possible that a person can experience akinesia on its own with no underlying signs of Parkinson's disease.

One such instance of akinesia is known as "pure" akinesia with so-called gait-freezing. This symptom does not have the other accompanying Parkinson's symptoms of resting tremors, generalized slower movements, or rigidity.

What is fetal akinesia deformation sequence?

Fetal akinesia deformation sequence (FADS) involves a type of akinesia that causes a combination of abnormalities in the womb when a baby is developing.

Examples of these symptoms include:

• joint contractures
• facial anomalies
• intrauterine growth restriction (IUGR)
• underdeveloped lungs

According to the National Center for Advancing Translational Sciences, an estimated 30 percent of those with FADS are stillborn.

Others may not survive for long outside of the womb due to problems associated with their underdeveloped lungs.

Difference between akinesia and dyskinesia

Akinesia and dyskinesia are both symptoms that describe disorders in movement.

Akinesia is the absence of movement. A person with akinesia cannot move their muscles, even if they try.

A person with dyskinesia or difficulty in movement has muscles that move involuntarily and unexpectedly. Examples can include tremors or shaking or spastic movements, which can appear like sudden jerking movements.

Both symptoms can occur when a person has Parkinson's disease.

Risk factors for akinesia

In adults, some of the causes associated with akinesia include:

• Parkinson's disease: This results in reduced amounts of dopamine produced in the brain, affecting a person's ability to control their muscles.
• Medication-induced Parkinson's-like symptoms: Where a person takes too much of a medication that inhibits dopamine.
• Progressive supranuclear palsy (PSP): A gradual brain-damaging condition that usually first affects balance while walking.
• Hormone levels: Hypothyroidism or severely low levels of the thyroid hormone can result in akinesia.

In people with Parkinson's disease, men are more likely to have akinesia than women. Those who have a resting tremor as the predominant symptom of their Parkinson's disease are less likely to have akinesia than others.

Other risk factors include:

• history of bradykinesia or slowed muscle movements
• having Parkinson's disease for a long time
• postural instability
• problems with muscle rigidity

Potential causes of FADS include:

• abnormalities in nervous system development
• connective tissue disorders, such as chondrodysplasias
• fetal edema
• a history of maternal illness or drug use

Any changes or alterations in the womb that cause insufficient blood flow and oxygen levels to reach the developing fetus can result in fetal akinesia.

Genetic causes

Doctors have also isolated two gene mutations that are associated with increased risks for fetal akinesia.

If a person has a history of family members or babies with the condition, they may wish to see a genetic specialist. By doing so, they can be tested for the gene mutations DOK7 and RAPSN that are associated with akinesia.

Treatments

Treatment depends on what is causing the akinesis symptoms in someone. For example, medication-related akinesia can be treated by stopping taking the medication that is causing the problem.

Treatments for Parkinson's disease-related akinesia can be more complicated. Doctors will often prescribe medications that increase the amount of the neurotransmitter dopamine in the body or the activity it causes. These can help, as reduced levels of dopamine cause the neuromuscular symptoms that are associated with Parkinson's disease.

Examples of these medicines include levodopa and carbidopa, as well as MAO-B inhibitors and dopamine agonists.

When to see a doctor

Seeking treatment for akinesia is necessary as having the symptoms increases the likelihood of a person falling. This can lead to bone breakages and other injuries.

People with Parkinson's disease or other disorders may wish to see a physical therapist, who can help them learn to work past "freezing" episodes and try to continue moving in a safer way whenever possible.

Currently, there are no treatments for PSP or fetal akinesia other than supportive care. However, support could include help with breathing for babies born with akinesia whose lungs are not well developed or working fully.

Takeaway

Akinesia is a difficult symptom to experience for anyone whatever their age. Losing the ability to engage in controlled movements can be devastating for a person with Parkinson's disease or another underlying disorder that causes this to happen.

If a person starts displaying akinesia or any other related symptoms, they should talk to their doctor. Sometimes a person with Parkinson's disease can have acute episodes of akinesia that can be treated for a short time to reduce sudden attacks.

In others cases, akinesia can represent the progression to more severe Parkinson's disease forms or pure akinesia from something other than Parkinson's disease.

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