Posted on by Lawrence Tabak, D.D.S., Ph.D.
As we get older, unfortunately our chances of having a stroke rise. While there’s obviously no way to turn back the clock on our age, fortunately there are ways to lower our risk of a stroke and that includes staying physically active. Take walks, ride a bike, play a favorite sport. According to our current exercise guidelines for American adults, the goal is to get in at least two and a half hours each week of moderate-intensity physical activity as well as two days of muscle-strengthening activity .
But a new study, published in the journal JAMA Network Open, shows that reducing the chances of a stroke as we get older doesn’t necessarily require heavy aerobic exercise or a sweat suit . For those who are less mobile or less interested in getting out to exercise, the researchers discovered that just spending time doing light-intensity physical activity—such as tending to household chores—“significantly” protects against stroke.
The study also found you don’t have to dedicate whole afternoons to tidying up around the house to protect your health. It helps to just get up out of your chair for five or 10 minutes at a time throughout the day to straighten up a room, sweep the floor, fold the laundry, step outside to water the garden, or just take a leisurely stroll.
That may sound simple, but consider that the average American adult now spends on average six and a half hours per day just sitting . That comes to nearly two days per week on average, much to the detriment of our health and wellbeing. Indeed, the study found that middle-aged and older people who were sedentary for 13 hours or more hours per day had a 44 percent increased risk of stroke.
These latest findings come from Steven Hooker, San Diego State University, CA, and his colleagues on the NIH-supported Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Launched in 2003, REGARDS continues to follow over time more than 30,000 Black and white participants aged 45 and older.
Hooker and colleagues wanted to know more about the amount and intensity of exercise required to prevent a stroke. Interestingly, the existing data were relatively weak, in part because prior studies looking at the associations between physical activity and stroke risk relied on self-reported data, which don’t allow for precise measures. What’s more, the relationship between time spent sitting and stroke risk also remained unknown.
To get answers, Hooker and team focused on 7,607 adults enrolled in the REGARDS study. Rather than relying on self-reported physical activity data, team members asked participants to wear a hip-mounted accelerometer—a device that records how fast people move—during waking hours for seven days between May 2009 and January 2013.
The average age of participants was 63. Men and women were represented about equally in the study, while about 70 percent of participants were white and 30 percent were Black.
Over the more than seven years of the study, 286 participants suffered a stroke. The researchers then analyzed all the accelerometer data, including the amount and intensity of their physical activity over the course of a normal week. They then related those data to their risk of having a stroke over the course of the study.
The researchers found, as anticipated, that adults who spent the most time doing moderate-to-vigorous intensity physical activity were less likely to have a stroke than those who spent the least time physically active. But those who spent the most time sitting also were at greater stroke risk, whether they got their weekly exercise in or not.
Those who regularly sat still for longer periods—17 minutes or more at a time—had a 54 percent increase in stroke risk compared to those who more often sat still for less than eight minutes. After adjusting for the time participants spent sitting, those who more often had shorter periods of moderate-to-vigorous activity—less than 10 minutes at a time—still had significantly lower stroke risk. But, once the amount of time spent sitting was taken into account, longer periods of more vigorous activity didn’t make a difference.
While high blood pressure, diabetes, and myriad other factors also contribute to a person’s cumulative risk of stroke, the highlighted paper does bring some good actionable news. For each hour spent doing light-intensity physical activity instead of sitting, a person can reduce his or her stroke risk.
The bad news, of course, is that each extra hour spent sitting per day comes with an increased risk for stroke. This bad news shouldn’t be taken lightly. In the U.S., almost 800,000 people have a stroke each year. That’s one person every 40 seconds with, on average, one death every four minutes. Globally, stroke is the second most common cause of death and third most common cause of disability in people, killing more than 6.5 million each year.
If you’re already meeting the current exercise guidelines for adults, keep up the good work. If not, this paper shows you can still do something to lower your stroke risk. Make a habit throughout the day of getting up out of your chair for a mere five or 10 minutes to straighten up a room, sweep the floor, fold the laundry, step outside to water the garden, or take a leisurely stroll. It could make a big difference to your health as you age.
 How much physical activity do adults need? Centers for Disease Control and Prevention. June 2, 2022.
 Association of accelerometer-measured sedentary time and physical activity with risk of stroke among US adults. Hooker SP, Diaz KM, Blair SN, Colabianchi N, Hutto B, McDonnell MN, Vena JE, Howard VJ. JAMA Netw Open. 2022 Jun 1;5(6):e2215385.
 Trends in sedentary behavior among the US population, 2001-2016. Yang L, Cao C, Kantor ED, Nguyen LH, Zheng X, Park Y, Giovannucci EL, Matthews CE, Colditz GA, Cao Y. JAMA. 2019 Apr 23;321(16):1587-1597.
Stroke (National Institute of Neurological Disorders and Stroke/NIH)
REGARDS Study (University of Alabama at Birmingham)
NIH Support: National Institute of Neurological Disorders and Stroke; National Institute on Aging
Posted on by Dr. Francis Collins
The primary motor cortex is the part of the brain that enables most of our skilled movements, whether it’s walking, texting on our phones, strumming a guitar, or even spiking a volleyball. The region remains a major research focus, and that’s why NIH’s Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative – Cell Census Network (BICCN) has just unveiled two groundbreaking resources: a complete census of cell types present in the mammalian primary motor cortex, along with the first detailed atlas of the region, located along the back of the frontal lobe in humans (purple stripe above).
This remarkably comprehensive work, detailed in a flagship paper and more than a dozen associated articles published in the journal Nature, promises to vastly expand our understanding of the primary motor cortex and how it works to keep us moving . The papers also represent the collaborative efforts of more than 250 BICCN scientists from around the world, teaming up over many years.
Started in 2013, the BRAIN Initiative is an ambitious project with a range of groundbreaking goals, including the creation of an open-access reference atlas that catalogues all of the brain’s many billions of cells. The primary motor cortex was one of the best places to get started on assembling an atlas because it is known to be well conserved across mammalian species, from mouse to human. There’s also a rich body of work to aid understanding of more precise cell-type information.
Taking advantage of recent technological advances in single-cell analysis, the researchers categorized into different types the millions of neurons and other cells in this brain region. They did so on the basis of morphology, or shape, of the cells, as well as their locations and connections to other cells. The researchers went even further to characterize and sort cells based on: their complex patterns of gene expression, the presence or absence of chemical (or epigenetic) marks on their DNA, the way their chromosomes are packaged into chromatin, and their electrical properties.
The new data and analyses offer compelling evidence that neural cells do indeed fall into distinct types, with a high degree of correspondence across their molecular genetic, anatomical, and physiological features. These findings support the notion that neural cells can be classified into molecularly defined types that are also highly conserved or shared across mammalian species.
So, how many cell types are there? While that’s an obvious question, it doesn’t have an easy answer. The number varies depending upon the method used for sorting them. The researchers report that they have identified about 25 classes of cells, including 16 different neuronal classes and nine non-neuronal classes, each composed of multiple subtypes of cells.
These 25 classes were determined by their genetic profiles, their locations, and other characteristics. They also showed up consistently across species and using different experimental approaches, suggesting that they have important roles in the neural circuitry and function of the motor cortex in mammals.
Still, many precise features of the cells don’t fall neatly into these categories. In fact, by focusing on gene expression within single cells of the motor cortex, the researchers identified more potentially important cell subtypes, which fall into roughly 100 different clusters, or distinct groups. As scientists continue to examine this brain region and others using the latest new methods and approaches, it’s likely that the precise number of recognized cell types will continue to grow and evolve a bit.
This resource will now serve as a springboard for future research into the structure and function of the brain, both within and across species. The datasets already have been organized and made publicly available for scientists around the world.
The atlas also now provides a foundation for more in-depth study of cell types in other parts of the mammalian brain. The BICCN is already engaged in an effort to generate a brain-wide cell atlas in the mouse, and is working to expand coverage in the atlas for other parts of the human brain.
The cell census and atlas of the primary motor cortex are important scientific advances with major implications for medicine. Strokes commonly affect this region of the brain, leading to partial or complete paralysis of the opposite side of the body.
By considering how well cell census information aligns across species, scientists also can make more informed choices about the best models to use for deepening our understanding of brain disorders. Ultimately, these efforts and others underway will help to enable precise targeting of specific cell types and to treat a wide range of brain disorders that affect thinking, memory, mood, and movement.
 A multimodal cell census and atlas of the mammalian primary motor cortex. BRAIN Initiative Cell Census Network (BICCN). Nature. Oct 6, 2021.
NIH Support: National Institute of Mental Health; National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
It’s a race against time when someone suffers a stroke caused by a blockage of a blood vessel supplying the brain. Unless clot-busting treatment is given within a few hours after symptoms appear, vast numbers of the brain’s neurons die, often leading to paralysis or other disabilities. It would be great to have a way to replace those lost neurons. Thanks to gene therapy, some encouraging strides are now being made.
In a recent study in Molecular Therapy, researchers reported that, in their mouse and rat models of ischemic stroke, gene therapy could actually convert the brain’s support cells into new, fully functional neurons . Even better, after gaining the new neurons, the animals had improved motor and memory skills.
For the team led by Gong Chen, Penn State, University Park, the quest to replace lost neurons in the brain began about a decade ago. While searching for the right approach, Chen noticed other groups had learned to reprogram fibroblasts into stem cells and make replacement neural cells.
As innovative as this work was at the time, it was performed mostly in lab Petri dishes. Chen and his colleagues thought, why not reprogram cells already in the brain?
They turned their attention to the brain’s billions of supportive glial cells. Unlike neurons, glial cells divide and replicate. They also are known to survive and activate following a brain injury, remaining at the wound and ultimately forming a scar. This same process had also been observed in the brain following many types of injury, including stroke and neurodegenerative conditions such as Alzheimer’s disease.
To Chen’s NIH-supported team, it looked like glial cells might be a perfect target for gene therapies to replace lost neurons. As reported about five years ago, the researchers were on the right track .
The Chen team showed it was possible to reprogram glial cells in the brain into functional neurons. They succeeded using a genetically engineered retrovirus that delivered a single protein called NeuroD1. It’s a neural transcription factor that switches genes on and off in neural cells and helps to determine their cell fate. The newly generated neurons were also capable of integrating into brain circuits to repair damaged tissue.
There was one major hitch: the NeuroD1 retroviral vector only reprogrammed actively dividing glial cells. That suggested their strategy likely couldn’t generate the large numbers of new cells needed to repair damaged brain tissue following a stroke.
Fast-forward a couple of years, and improved adeno-associated viral vectors (AAV) have emerged as a major alternative to retroviruses for gene therapy applications. This was exactly the breakthrough that the Chen team needed. The AAVs can reprogram glial cells whether they are dividing or not.
In the new study, Chen’s team, led by post-doc Yu-Chen Chen, put this new gene therapy system to work, and the results are quite remarkable. In a mouse model of ischemic stroke, the researchers showed the treatment could regenerate about a third of the total lost neurons by preferentially targeting reactive, scar-forming glial cells. The conversion of those reactive glial cells into neurons also protected another third of the neurons from injury.
Studies in brain slices showed that the replacement neurons were fully functional and appeared to have made the needed neural connections in the brain. Importantly, their studies also showed that the NeuroD1 gene therapy led to marked improvements in the functional recovery of the mice after a stroke.
In fact, several tests of their ability to make fine movements with their forelimbs showed about a 60 percent improvement within 20 to 60 days of receiving the NeuroD1 therapy. Together with study collaborator and NIH grantee Gregory Quirk, University of Puerto Rico, San Juan, they went on to show similar improvements in the ability of rats to recover from stroke-related deficits in memory.
While further study is needed, the findings in rodents offer encouraging evidence that treatments to repair the brain after a stroke or other injury may be on the horizon. In the meantime, the best strategy for limiting the number of neurons lost due to stroke is to recognize the signs and get to a well-equipped hospital or call 911 right away if you or a loved one experience them. Those signs include: sudden numbness or weakness of one side of the body; confusion; difficulty speaking, seeing, or walking; and a sudden, severe headache with unknown causes. Getting treatment for this kind of “brain attack” within four hours of the onset of symptoms can make all the difference in recovery.
 A NeuroD1 AAV-Based gene therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Chen Y-C et al. Molecular Therapy. Published online September 6, 2019.
 In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. Cell Stem Cell. 2014 Feb 6;14(2):188-202.
Stroke (National Heart, Lung, and Blood Institute/NIH)
Gene Therapy (National Human Genome Research Institute/NIH)
Chen Lab (Penn State, University Park)
NIH Support: National Institute on Aging; National Institute of Mental Health