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Friday, November 20, 2015
BY REBECCA HISCOTT
The National Institutes of Health (NIH) announced Wednesday that it will fund two large-scale research projects to study the progression of Alzheimer’s disease (AD) in people with Down syndrome and identify biomarkers that may signal the risk, onset, and progression of the disease.
Patients with Down syndrome are born with an extra copy of chromosome 21, which contains the amyloid precursor protein (APP) gene, according to the NIH.
“The development of AD in Down syndrome is linked to the triplication of the APP gene on chromosome 21. Thus, the Down syndrome population has a very high probability of developing AD dementia,” Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the National Institute on Aging (NIA)’s Division of Neuroscience, told Neurology Today in an email.
Most individuals with Down syndrome develop the pathological hallmarks of AD—amyloid plaques and tau tangles—by their 30s and 40s, and an estimated 50 percent or more develop clinical dementia as they age into their 70s, Dr. Ryan said. Many begin to show symptoms in their 50s and 60s.
Through the NIA and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NIH will be providing an estimated $37 million over five years to support research on AD in patients with Down syndrome.
The studies will be led by Benjamin Handin, PhD, a professor of psychiatry, pediatrics, and psychology and associate professor of instruction and learning (education) in the University of Pittsburgh Department of Psychiatry, and Nicole Schupf, PhD, a professor of epidemiology at Columbia University Medical Center in New York City.
The research teams will use positron emission tomography (PET) and magnetic resonance imaging (MRI) scans to track levels of amyloid and tau in the blood and cerebrospinal fluid and measure brain volume and function; blood tests to look for genetic factors involved in AD risk and identify blood-based biomarkers of AD; and a battery of cognitive and memory tests to measure changes in behavior and cognitive function. The investigators will make their data and samples available to qualified researchers in the field.
“These are the first large-scale efforts to identify the longitudinal progression of clinical, cognitive, imaging, genetic, and biochemical biomarkers of AD in Down syndrome…for use in disease detection, in understanding and monitoring disease progression, and ultimately in assessing treatment response,” Dr. Ryan said.
For more articles about Down syndrome and Alzheimer’s disease, browse our archives here.
Wednesday, November 11, 2015
BY REBECCA HISCOTT
In October, Beth Stevens, PhD, an assistant professor of neurology at Harvard Medical School and the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, was named one of the 24 recipients of the MacArthur Foundation’s prestigious fellowship. The program awards a “no strings attached” grant of $625,000, paid out in quarterly installments over five years, to exceptional individuals in disciplines such as the arts, education, sociology, biology, chemistry, engineering, and neuroscience.
Dr. Stevens’ research on microglial cells has prompted a sea change in the way neurologists and neuroscientists think about these cells. Once thought to serve primarily immunological functions in the brain, Dr. Stevens discovered that microglia are also responsible for pruning synapses during brain development. She and her colleagues also identified immune proteins that “tag” synaptic cells for removal by microglia. Her work has implications for understanding diseases such as autism, schizophrenia, Alzheimer’s, and Huntington’s. Dr. Stevens spoke with Neurology Today about these discoveries, the colleagues who inspired and propelled her research, and her reaction to receiving the prestigious MacArthur “genius” grant.
Listen to a Neurology in the News podcast interview with Dr. Stevens here.
Dr. Stevens was in her office working on a grant application when she received the call about the MacArthur award. “It seemed surreal because it was such a surprise,” she said. “You have no idea you’re being considered for something like this. And then I had to keep it quiet for a few weeks after that, so it was a surreal experience until it was officially announced.”
But she was immensely grateful. She sees the award as a way to push her lab’s current lines of investigation — delving further into the mechanisms of synaptic pruning in normal brain development; understanding the role dysfunction in the pruning pathway might play in autism and schizophrenia; and investigating whether this same pathway becomes reactivated in neurodegenerative diseases — forward into bolder territory.
Humans are born with an excess of synapses in the brain — roughly twice as many as are needed for optimal brain function, she explained. But early in development, these synapses are trimmed away. The important synaptic connections are strengthened, while weak or unwanted synapses are eliminated, resulting in a brain where only the most efficient neuronal connections remain.
Until recently, microglia — the brain’s immune cells — were not thought to play a role in this pruning process. But Dr. Stevens’ research has shown that, in fact, these cells engulf or “eat” extra synapses that have been tagged for elimination.
The 2015 MacArthur grantee has worked with glial cell types for nearly her entire scientific career, beginning with her stint as a research assistant in the lab of R. Douglas Fields, PhD, at the National Institutes of Health (NIH), after undergraduate school.
“Compared with neurons, there was much less known about the functions and roles of glia,” she said, “both in the normal brain and in disease.” She found herself particularly fascinated by the role of glia during brain development, “when the brain is wiring up.”
After obtaining her PhD from the University of Maryland in 2003, Dr. Stevens moved to the lab of Ben A. Barres, MD, PhD, a professor of neurobiology, developmental biology, neurology, and ophthalmology at Stanford. There, the researchers made a discovery that would pave the way for Dr. Stevens’ later work. They found that C1q, the initiating protein in the classical complement cascade, which “tags” cells or debris for engulfment or removal by immune cells, is expressed in postnatal neurons, binding to synapses in the developing visual system. This suggested to the researchers that C1q might be doing the same thing in the brain as it does in the immune system, tagging unwanted synapses for removal.
Using mouse models, they showed that removing C1q or the downstream complement protein C3 would result in defects in synapse elimination in the central nervous system. Furthermore, they found that in a mouse model of glaucoma, this complement protein became up-regulated in the adult retina early in the disease, suggesting that this process of synapse elimination might become aberrantly reactivated in neurodegenerative disease.
When Dr. Stevens started her own lab at Harvard and Boston Children’s Hospital in 2008, she resolved to investigate this crucial process of synaptic pruning further. That led her to microglia. “In the immune system, [complement] molecules are basically ‘eat me’ signals,” she explained. Given microglia’s immunological function in the brain, working to reduce inflammation and eliminate debris, Dr. Stevens wondered whether these cells could be working with complement to engage in synaptic pruning.
A postdoctoral fellow in Dr. Stevens’ lab, Dorothy Schafer, PhD, set about designing experiments by which they could test this hypothesis. Using the mouse visual system as their model, they labeled synapses with one color of fluorescent dye and microglia with another. They were able to observe, using high-resolution imaging and three-dimensional reconstruction, that microglia were, indeed, engulfing or “eating” extra synapses during brain development. That work, published in Neuron in May 2012, was widely praised in the neuroscience community for bringing about an entirely new understanding of the role of microglia.
The next step, Dr. Stevens said, is to further understand how and why certain synapses are tagged and targeted for elimination.
Look for the full article in the December 3 issue of Neurology Today, and listen to a podcast interview with Dr. Stevens here.
Thursday, October 22, 2015
BY REBECCA HISCOTT
The thalamus (green) and primary motor cortex (blue). Image courtesy of University of Birmingham/Dr. Davinia Fernández-Espejo.
Researchers have identified a possible biomarker for patients in a vegetative state who retain some level of conscious awareness, despite being unable to move or speak.
The findings, published online October 19 in JAMA Neurology, suggest that structural damage to the fibers connecting the thalamus and the primary motor cortex impede the translation of thought into action.
For years, physicians assumed that all patients in a vegetative state — unable to move or speak — were alike. But more recent research has shown that some patients in a vegetative state retain some level of awareness, showing signs of neural activity on neuroimaging in response to certain commands (being asked to imagine hitting a tennis ball, for example) despite remaining behaviorally unresponsive.
The investigators said that damage to the pathways that physically connect the thalamus — “one of the hubs of consciousness,” said study author Davinia Fernández-Espejo, PhD, in a news release — and the motor cortex may explain why a patient who retains so-called “covert awareness” remains incapable of intentional movement.
In the current study, the researchers identified one such patient — Patient 1 — who fulfilled all the clinical criteria for a vegetative state but consistently showed evidence of covert awareness on multiple MRI and EEG assessments. The patient had sustained a severe traumatic brain injury (TBI) and had been in a vegetative state for more than 12 years.
This patient was compared with a second TBI patient — Patient 2 — with similar clinical variables, but who was able to produce some intentional movements (moving her right upper limb to reach for different objects, for example). The study also enrolled 15 healthy volunteers as controls.
The researchers used functional magnetic resonance imaging (fMRI) to compare brain regions involved in voluntary motor imagery (imagining a movement) to motor execution (carrying out a movement). They asked the control participants to either imagine hitting a tennis ball or to actually hit a tennis ball, then looked at the brain regions that became activated in each task.
They discovered that excitatory outputs from the thalamus to the primary motor cortex were activated when the participants performed the action, but not when they only thought about doing it, suggesting that this circuit played a critical role in producing voluntary movements.
Based on these findings, the researchers then used diffusion tensor imaging (DTI) tractography to evaluate the structural integrity of the fibers connecting the thalamus and the primary motor cortex in the two TBI patients. They discovered that these fibers were damaged in Patient 1 (fractional anistrophy, 0.294; p=0.047), but not in Patient 2 (fractional anistrophy, 0.413; p=0.35).
“To our knowledge, this study provides the first direct neural correlate for the absence of intentional movement in a covertly aware, but clinically vegetative, patient,” the study authors wrote.
“The ultimate aim is to use this information in targeted therapies that can drastically improve the quality of life of patients,” Dr. Fernández-Espejo said. “For example, with the advances being made in assistive technology, if we can help a patient to regain even limited movement in one finger, it opens up so many possibilities for communication and control of their environment.”
For more articles on research in vegetative state patients, browse our archives here.
Friday, October 16, 2015
BY REBECCA HISCOTT
A stressful job may increase a person’s risk for stroke, according to a new study published in the October 14 online edition of Neurology. The risk appears to be highest for ischemic stroke and in women, the researchers said.
Chinese researchers conducted a meta-analysis of studies on job strain and stroke risk. They identified six studies involving a total of 138,782 participants who ranged in age from 18 to 75 and were followed for three to 17 years.
The studies assessed the demands of different job types according to psychological job demand and job control. Variables included stressors such as deadlines, workplace conflicts, and mental load (for psychological job demand), and the ability to problem-solve, learn new skills, and make authoritative decisions in the workplace (for job control). Based on these variables, they classified the jobs as low strain (low demand and high control), passive (low demand and low control), high strain (high demand and low control), or active (high demand and high control).
Passive jobs included janitors, miners, and other manual labors; low strain jobs included natural scientists and architects; high strain jobs included service industry occupations like servers and nurses aids; and active jobs include doctors, teachers, and engineers.
Those with high strain jobs had a 22 percent higher risk of stroke than those with low strain jobs, the researchers reported (relative risk [RR] 1.22, 95% confidence interval [CI], 1.01-1.47). Having a passive or active job was not associated with stroke risk, they said.
In a subanalysis including five studies with data for 126,459 women and three studies with data for 12,323 men, stroke risk was found to be significant for women—33 percent higher for those with high strain jobs than those with low strain jobs (RR 1.33, 95% CI, 1.04-1.69)—but not for men. However, the difference between men and women was not significant, possibly because of the limited number of studies, the researchers noted.
In another subanalysis of three studies of ischemic stroke in 76,000 participants and two studies of hemorrhagic stroke in 54,495 participants, high strain jobs significantly increased the risk for ischemic stroke—by 58 percent (RR 1.58, 95% CI, 1.04-1.69)—but not hemorrhagic stroke.
It’s not clear why those with high strain jobs have a higher stroke risk, the researchers said. “It’s possible that high stress jobs lead to more unhealthy behaviors, such as poor eating habits, smoking, and a lack of exercise,” study author Dingli Xu, MD, a researcher in the department of cardiology at Southern Medical University in Guangzhou, China, said in a news release. Lifestyle modifications may therefore reduce the risk, the researchers said.
Work stress is also associated with cardiovascular risk factors such as metabolic syndrome, high body mass index, impaired glucose metabolism, and dyslipidemia, the researchers noted, and may lead to neuroendocrine disturbances like over-activation of the sympathetic nervous system. “Further studies are needed to evaluate whether job strain directly increases the risk of stroke or whether other concurrent risk factors are responsible for the increased risk observed,” they concluded.
The results suggest that giving workers more job control might also help reduce their risk of stroke, wrote Jennifer J. Majersik, MD, an associate professor of medicine at the University of Utah in Salt Lake City, in an accompanying editorial. Making sure employees have access to psychological resources or therapy and allowing for more flexible work arrangements like telecommuting may also help.
For more articles about stroke and stroke risk factors, browse our archives here.
Image via John Bastoen on Flickr.
Thursday, October 15, 2015
BY REBECCA HISCOTT
Minor infections like a cold or the flu may temporarily increase stroke risk in vulnerable children, according to a study published in the September 30 online edition of Neurology. But vaccination might reduce that risk, the study authors said.
Pediatric stroke is rare, affecting about 2.4 per 100,000 children in the US each year, the researchers noted. But the study suggests that simple interventions like encouraging regular, thorough hand-washing and vaccinating children can lower this risk further.
As part of the Vascular Effects of Infection in Pediatric Stroke study, researchers from 37 children’s hospitals in nine countries (the US, Canada, Australia, the UK, France, China, Chile, Serbia, and the Philippines) reviewed medical records of 355 children under age 18 with a confirmed stroke diagnosis between January 2010 and March 2014, along with 354 age-matched healthy children. They also interviewed the children’s parents.
Eighteen percent of children who experienced an arterial ischemic stroke were found to have had an infection in previous week, compared with 3 percent of healthy children. Children with stroke were 6.3 times more likely to have had an infection in the previous week than those who were stroke-free (odds ratio [OR] 6.3, 95% confidence interval [CI], 3.3-12; p<0.0001). There was no association between infections that occurred one month or six months earlier and stroke incidence, the researchers noted.
Children who were poorly vaccinated — meaning their parents reported they received some, few, or none of their routine vaccinations — were 7.3 times more likely to experience a stroke than children who received all or most of their vaccines (p=0.0002). Among the children with stroke, 8 percent were poorly vaccinated, compared with 1 percent of the healthy children.
It is unclear why vaccination might be linked to a lower risk of stroke, or whether one particular vaccine was more effective at lowering the risk than another, the researchers said.
The association remained after adjustments for age, sex, season, and socioeconomic status. Other independent risk factors for stroke were black race (compared to white; OR 1.9, p=0.009) and rural residence (compared to urban; OR 3.0; p=0.0003).
“If our results hold up in further studies, controlling infections like colds and [the] flu through hand-washing and vaccines may be a strategy for preventing stroke in children,” said study author Heather J. Fullerton, MD, a pediatric vascular neurologist at the University of California, San Francisco Benioff Children’s Hospital, in a news release.
However, “parents should be reassured that while the risk was increased, the overall risk of stroke among children is still extremely low,” said José Biller, MD, FAAN, professor and chair of the neurology department at Loyola University Stritch School of Medicine in Chicago, who wrote an editorial accompanying the study.
“It is possible that changes in the body as a result of these infections, such as inflammation and dehydration, could tip the balance in a child who is already at a higher risk for stroke” for other reasons, such as a genetic predisposition, he said.
The study authors agreed, writing that “infection likely acts as a stroke trigger in a child who is otherwise predisposed, and explains why the stroke happened at that particular point in that child’s life.”
For more articles about pediatric stroke, browse our archives here.
Image via woodleywonderworks on Flickr.