# data[].attributes.body
This digital file shows different ways physical activity can affect your brain.

# data[].attributes.headline
Subject Expertise - How Does Exercise Affect the Brain? 

# data[].attributes.subject
Subject Expertise - How Does Exercise Affect the Brain? 

# data[].attributes.body
Physical activity is important to having a healthy lifestyle. Exercising can help boost your mood and reduce stress. Exercise has also been shown to improve mental abilities. As mentioned in the article, "Exercise also induces the release of beneficial proteins in the brain. These nourishing proteins keep brain cells (also known as neurons) healthy, and promote the growth of new neurons."

# data[].attributes.attachment_link.readable_text
Regular physical activity is an important part of a healthy lifestyle. Not only is exercise good for your muscles and bones, but it is also an important part of keeping your brain healthy too.

What counts as "regular exercise?"

According to experts, the recommended amount of exercise to keep your mind sharp is about an hour a day. One of the best ways to get exercise is to play sports. Being on a team can build self-confidence, and regular practice schedules are good for your health. If you don't like sports or competition, that's OK too! Exercise doesn't only mean playing sports, it just means moving your body and being active. A few other examples of exercise are: dancing, walking, biking, swimming, or throwing a Frisbee.

What is happening in the body and brain during exercise?

As your heart rate increases during exercise, blood flow to the brain increases. As blood flow increases, your brain is exposed to more oxygen and nutrients. Exercise also induces the release of beneficial proteins in the brain. These nourishing proteins keep brain cells (also known as neurons) healthy, and promote the growth of new neurons. Neurons are the working building blocks of the brain. As a result, individual neuron health is important to overall brain health.
Exercise boosts your mood and reduces stress
When you exercise, your body releases chemicals such as dopamine (pronounced doh-pa-meen) and endorphins (en-door-fins) in your brain that make you feel happy. Not only is your brain dumping out feel-good chemicals, but exercise also helps your brain get rid of chemicals that make you feel stressed and anxious. People who exercise tend to be happier and less stressed than those who don't exercise. Regular exercise can also help you control your emotions when you do feel angry or upset.
Exercise may improve your grades
That's right! Exercise has been shown to improve mental abilities. On average, children and young adults who exercise tend to have better test scores in math and reading when compared to those who don't. There are a number of mental abilities that are improved with regular exercise:

Physical activity can improve your long-term and short-term memory. Children and young adults who were asked to exercise just a few times a week showed big improvements in their ability to remember what they read.

Being active gives you more energy during the day and helps you sleep better at night. In turn, better sleep improves creativity and brain function.

Being active gives you more energy during the day and helps you sleep better at night. In turn, better sleep improves creativity and brain function.

Exercise is especially important for kids and young adults

As you can see, there are lots of benefits to being active. Creating healthy exercise habits when you're young makes it easier to maintain those routines as you grow older. Consistent exercise through childhood and adulthood keeps brains healthy. Increasing evidence suggests that staying active as an adult can even lower your risk of dementia in old age. It's never too late to start exercising and keep your brain in tiptop shape!

Download this page as a PDF

References

Center for Disease Control and Prevention, Physical activity basics, http://www.cdc.gov/physicalactivity/basics/children/

# data[].attributes.attachment_link.title
How Does Exercise Affect the Brain? | Dana Foundation

# data[].attributes.attachment_link.description
Regular physical activity is an important part of a healthy lifestyle. Not only is exercise good for your muscles and bones, but it is also an important part of keeping your brain healthy too. According to experts, the recommended amount of exercise to keep your mind sharp is about an hour a day.

# data[].attributes.headline
Subject Expertise - The Brain Drain of Inactivity

# data[].attributes.subject
Subject Expertise - The Brain Drain of Inactivity

# data[].attributes.body
Studies are mentioned that regular physical activities improve learning and memory. There was a study that showed middle school students who were in the best physical shape did better on standardized tests and had better grades. There was a report published in 1998 that proved neurogenesis, the growth of new brain cells, occurs in the human brain since scientists didn’t believe we could grow new brain cells. There was also a study that showed an active lifestyle helps preserve gray matter in the brain and slows dementia and Alzheimer’s. The studies provided help get an understanding of the effects of physical activity. As mentioned in the article, "Each of us needs to move our bodies a little bit each day to keep our brains healthy and our minds strong."

# data[].attributes.attachment_link.readable_text
Every week new studies come out reconfirming the benefits of physical activity. In this entry I will highlight some recent studies that link regular physical activity to improved learning and memory. Throughout our lives, regular physical activity stimulates the growth of new neurons through a process called neurogenesis. This entry focuses on how the daily lifestyle choices you make improve the architecture of your mind.

A study published on December 6, 2012 in the Journal of Sports Medicine and Physical Fitness shows that Middle school students who are in the best physical shape outscored their classmates on standardized tests and brought home better report cards. This is the first study linking children's fitness to both improved scores on objective tests and better grades. The results showed the fittest children got the highest test scores and the best grades, regardless of gender or whether they'd yet gone through puberty.

This Michigan State University study is also among the first to examine how academic performance relates to all aspects of physical fitness-including body fat, muscular strength, flexibility and endurance-according to lead researcher Dawn Coe. "We looked at the full range of what's called health-related fitness," said Coe. "Kids aren't really fit if they're doing well in just one of those categories."

The findings suggest that cutting physical education and recess may backfire by undermining students' academic performance and success on the standardized tests that affect school funding and prestige, said co-author James Pivarnik, who advised Coe on the project.

"Look, your fitter kids are the ones who will do better on tests, so that would argue against cutting physical activity from the school day," said Pivarnik, an MSU professor of kinesiology. "That's the exciting thing, is if we can get people to listen and have some impact on public policy." Making fitness a bigger part of children's lives also sets them up for future success," Pivarnik added."Fit kids are more likely to be fit adults," he said. "And now we see that fitness is tied to academic achievement. So hopefully the fitness and the success will both follow."

How does physical activity improve learning and memory?

Until the late 1990s scientists did not believe that we could grow new brain cells. But in 1998, the journal Nature Medicine published a report indicating that neurogenesis (the growth of new brain cells) does indeed occur in humans. As Sharon Begley remarked in her book, Train Your Mind, Change Your Brain, "The discovery overturned generations of conventional wisdom in neuroscience. The human brain is not limited to the neurons it is born with, or even the neurons that fill in after the explosion of brain development in early childhood." Within each of our brains there are neural stem cells which are continually replenished and can regenerate into brain neurons.

The process of neurogenesis is controlled by specific gene codes which triggers the production of a protein called, Brain-Derived Neurotrophic Factor (BDNF). BDNF plays a key role in creating new neurons. The gene that turns on BDNF is activated by a variety of factors, including physical exercise. Lab rats that exercise have been shown to produce far more BDNF in their brains when compared to sedentary animals. And, there is a direct relationship between elevation of BDNF levels in these animals and their ability to learn and remember.

Researchers in a report in the Journal of the American Medical Association, entitled "Effect of Physical Activity in Cognitive Function in Older Adults at Risk for Alzheimer's Disease," found that elderly individuals who engaged in regular physical exercise for a 24-week period had an improvement of an astounding 1,800 percent on measures of memory, language ability, attention and other important cognitive functions compared to an age-matched group not involved in the exercise program.

The mechanism by which exercise enhances brain performance is described in these and other studies as being directly linked with increased production of BDNF.

Neurogenesis in the Hippocampus

Researchers in 2010 found an association between physical fitness levels and the hippocampus size of 9 and 10-year-old children. The children who were more fit had a larger hippocampus and performed better on a test of memory than their less-fit peers. The hippocampus is a structure tucked deep in the brain, which is known to be important in learning and memory.

"This is the first study I know of that has used MRI measures to look at differences in brain between kids who are fit and kids who aren't fit," said University of Illinois psychology professor and Beckman Institute director Art Kramer, who led the study with doctoral student Laura Chaddock and kinesiology and community health professor Charles Hillman. "Beyond that, it relates those measures of brain structure to cognition."

When they analyzed the MRI data, the researchers found that the physically fit children tended to have bigger hippocampal volume - about 12 percent bigger relative to total brain size - than their out-of-shape peers. The children who were in better physical condition also did better on tests of relational memory - the ability to remember and integrate various types of information - than their less-fit peers.

Other studies in older adults and in animals have also shown that exercise can increase the size of the hippocampus. A larger hippocampus is associated with better performance on spatial reasoning and other cognitive tasks. "In animal studies, exercise has been shown to specifically affect the hippocampus, significantly increasing the growth of new neurons and cell survival, enhancing memory and learning, and increasing molecules that are involved in the plasticity of the brain," Chaddock said.

An active lifestyle preserves gray matter and slows Alzheimer's

According to a study presented on November 26, 2012 an active lifestyle helps preserve gray matter in the brains of older adults and could reduce the burden of dementia and Alzheimer's disease. Alzheimer's disease currently has no cure and is the most common cause of dementia. More than 35 million people worldwide live with dementia, according to the World Health Organization, and the prevalence is expected to double by 2030.

Cyrus Raji, M.D., Ph.D., radiology resident at the University of California in Los Angeles, and colleagues recently examined how an active lifestyle can influence brain structure in 876 adults, with an average age of 78 years. The patients' conditions ranged from normal cognition to Alzheimer's dementia. "We had 20 years of clinical data on this group, including body mass index and lifestyle habits," Dr. Raji said. "We drew our patients from four sites across the country, and we were able to assess energy output in the form of kilocalories per week."

The lifestyle factors examined included recreational sports, gardening and yard work, bicycling, dancing and riding an exercise cycle. The researchers used magnetic resonance imaging (MRI) and a technique called voxel-based morphometry to model the relationships between energy output and gray matter volume.

Dr. Raji said, "Gray matter volume is a key marker of brain health. Larger gray matter volume means a healthier brain. Shrinking volume is seen in Alzheimer's disease. Gray matter includes neurons that function in cognition and higher order cognitive processes. The areas of the brain that benefited from an active lifestyle are the ones that consume the most energy and are very sensitive to damage."
The researchers found a strong association between energy output and gray matter volumes in areas of the brain crucial for cognitive function.

Greater caloric expenditure was related to larger gray matter volumes in the frontal, temporal and parietal lobes, including the hippocampus, posterior cingulate and basal ganglia. There was a strong association between high energy output and greater gray matter volume in patients with mild cognitive impairment and Alzheimer's disease.

A key aspect of the study was its focus on having a variety in lifestyle choices, Dr. Raji noted. "What struck me most about the study results is that it is not one but a combination of lifestyle choices and activities that benefit the brain," he said. "Virtually all of the physical activities examined in this study are some variation of aerobic physical activity, which we know from other work can improve cerebral blood flow and strengthen neuronal connections," he said. "Additional work needs to be done," Dr. Raji added. "However, our initial results show that brain aging can be alleviated through an active lifestyle."
Conclusion
Homo Sapiens evolved for millenia to be physically active from childhood into our senior years. Our current sedentary lifestyle is causing our collective waist-lines to swell and our brain cells to shrink. Each of us needs to move our bodies a little bit each day to keep our brains healthy and our minds strong. The Greeks had it right: " A Sound Mind in a Sound Body." I'm much less concerned about the "Body Mass Index" of Americans than the "Brain Mass Index" that is atrophying due to inactivitiy.

People talk a lot about the skyrocketing health care costs linked to unhealthy lifestyle choices and obesity. But what will the trickle down of the 'Brain Drain' caused by inactivity be on American ingenuity, innovation, entrepreneurship, trademarks, patents, etc? How much does our collective lack of physical activity stunt creative thinking and new ideas en masse? How much does inactivity impact our Gross Domestic Product? Can we remain a "Super Power" if our citizens remain sedentary? These are questions Americans from all walks of life should be asking ourselves as we approach the fiscal cliff.

Regardless of any altruistic motives, business and government leaders need to focus on ways to inspire and facilitate Americans of all generations to stay active throughout their lifetimes. As a nation we are only as strong as our weakest link. Inactivity and obesity could sink the U.S.A. in a global economy.

# data[].attributes.attachment_link.description
This entry focuses on how the lifestyle choices you make improve the architecture and function of your mind. Two new studies out this week reconfirm that physical activity improves learning and memory. Regular physical activity stimulates the growth of new brain cells and stops "brain drain.'' Regular exercise makes you smarter and gives you the competitive advantage.

# data[].attributes.body
In this TEDTalk, Wendy Suzuki mentioned how exercise puts her in a better mood. After learning that being physically active can help with your mood and stress levels I've been exercising almost everyday. After my workout routine I feel like I'm in a better mood and more energized.

# data[].attributes.attachment_link.title
Wendy Suzuki: The brain-changing benefits of exercise | TED

# data[].attributes.headline
Essay 4 - Physical Activity  and the Brain

# data[].attributes.subject
Essay 4 - Physical Activity  and the Brain

# data[].attributes.body
Physical Activity and the Brain
Does physical activity and inactivity have an impact on our brain?
Being physically active or inactive can have some contributions to your brain health whether you are a kid, teen, adult, or elderly. There are multiple studies that show the effects of physical activity and inactivity has on the brain such as studies on rats, middle school kids, and elderlies. Physical activity affects our brain in ways we may not know about such as our mood, how we learn, and risks of brain disorders.

# data[].attributes.headline
Subject Expertise: Academic Journal Article - Physical Activity, Cognitive Function, and Brain Health

# data[].attributes.subject
Subject Expertise: Academic Journal Article - Physical Activity, Cognitive Function, and Brain Health

# data[].attributes.body
Studies on animals and humans were conducted to show the effects physical activity has on cognitive function. Physical activity promotes brain health and improve cognitive function. As mentioned in the article, “These collective findings indicate that physical activity may improve or reverse age- and stress-related impairment in hippocampal-related cognitive tasks.”

# data[].attributes.attachment_link.readable_text
Your access to the NCBI website at www.ncbi.nlm.nih.gov has been temporarily blocked due to a possible misuse/abuse situation involving your site. This is not an indication of a security issue such as a virus or attack. It could be something as simple as a run away script or learning how to better use E-utilities, http://www.ncbi.nlm.nih.gov/books/NBK25497/, for more efficient work such that your work does not impact the ability of other researchers to also use our site. To restore access and understand how to better interact with our site to avoid this in the future, please have your system administrator contact info@ncbi.nlm.nih.gov.

# data[].attributes.attachment_link.description
Your access to the NCBI website at www.ncbi.nlm.nih.gov has been temporarily blocked due to a possible misuse/abuse situation involving your site. This is not an indication of a security issue such as a virus or attack.

# data[].attributes.headline
Subject Expertise: Academic Journal Article - Total daily physical activity, brain pathologies, and parkinsonism in older adults

# data[].attributes.subject
Subject Expertise: Academic Journal Article - Total daily physical activity, brain pathologies, and parkinsonism in older adults

# data[].attributes.body
The Rush Memory and Aging Project studies adults 65 years old and older who agree to clinical assessments and organ donation at death. Their total activity daily was analyzed. Higher levels of physical activity in older adults showed less severe Parkinsonism. As said in the article, "Together, these prior studies show that both physical activity and brain pathologies are related to the severity of parkinsonism.”

# data[].attributes.attachment_link.readable_text
Shahram Oveisgharan,

Robert J. Dawe,

Sue E. Leurgans,

Lei Yu,

Julie A. Schneider,

David A. Bennett,

Aron S. Buchman

Subject Areas

For more information about PLOS Subject Areas, click here.

We want your feedback. Do these Subject Areas make sense for this article? Click the target next to the incorrect Subject Area and let us know. Thanks for your help!

Abstract

Objective

We examined the association of physical activity, postmortem brain pathologies, and parkinsonism proximate to death in older adults.

Methods

We studied the brains of 447 older decedents participating in a clinical-autopsy cohort study. We deployed a wrist worn activity monitor to record total daily physical activity during everyday living in the community-setting. Parkinsonism was assessed with 26 items of a modified motor portion of Unified Parkinson's Disease Rating Scale (UPDRS). We used linear regression models, controlling for age and sex, to examine the association of physical activity with parkinsonism with and without indices of Alzheimer's disease and related disorders (ADRD) pathologies. In separate models, we added interaction terms to examine if physical activity modified the associations of brain pathologies with parkinsonism.

Results

Mean age at death was 90.9 (SD, 6.2), mean severity of parkinsonism was 14.1 (SD, 9.2, Range 0-59.4), and 350 (77%) had evidence of more than one ADRD pathologies. Higher total daily physical activity was associated with less severe parkinsonism (Estimate, -0.315, S.E., 0.052, p<0.001). The association of more physical activity with less severe parkinsonism persisted after adding terms for ten brain pathologies (Estimate, -0.283, S.E., 0.052, p<0.001). The associations of brain pathologies with more severe parkinsonism did not vary with the level of physical activity.

Conclusion

The association of higher physical activity with less severe parkinsonism may be independent of the presence of ADRD brain pathologies. Further work is needed to identify mechanisms through which physical activity may maintain motor function in older adults.

Citation: Oveisgharan S, Dawe RJ, Leurgans SE, Yu L, Schneider JA, Bennett DA, et al. (2020) Total daily physical activity, brain pathologies, and parkinsonism in older adults. PLoS ONE 15(4): e0232404. https://doi.org/10.1371/journal.pone.0232404

Editor: Diane K. Ehlers, University of Nebraska Medical Center, UNITED STATES

Received: October 5, 2019; Accepted: April 14, 2020; Published: April 29, 2020

Copyright: © 2020 Oveisgharan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data included in these analyses are available via the Rush Alzheimer's Disease Center Research Resource Sharing Hub, which can be found at www.radc.rush.edu. It has descriptions of the studies and available data. Any qualified investigator can create an account and submit requests for deidentified data.

Funding: This work was supported by National Institute of Health grants: A.S.B.: R01AG47679; R01AG056352; R01AG059732 D.A.B.: P30AG10161; R01AG017917; R01AG15819; R01AG043379 The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Parkinsonism, a complex aging phenotype, includes impaired gait and balance, bradykinesia, rigidity, and tremor and may affect 50% or more of adults 85 years or older[ 1]. The presence of clinical parkinsonism is associated with an increased risk of disabilities[ 2], mild cognitive impairment[ 3], and dementia[ 4]. Given the magnitude of the personal and social consequences of parkinsonism, modifiable risk factors like physical activity are being intensely studied for their potential efficacy to maintain or reduce the severity of parkinsonism in older adults[ 5]. The neurobiology underlying the potential efficacy of a higher level of physical activity to reduce the severity of parkinsonism is unknown.

In a previous study, we found that a higher level of total daily physical activity in older adults is associated with less severe parkinsonism [ 6]. In several other studies, we have also shown that postmortem indices of brain pathology such as macroinfarcts are related to more severe parkinsonism[ 7, 8], and to less total daily physical activity[ 9]. Together, these prior studies show that both physical activity and brain pathologies are related to the severity of parkinsonism. As illustrated in Fig 1, these reports provide the scientific framework and support for testing the hypothesis that brain pathologies link (mediates) physical activity with parkinsonism in older adults. If we do not find evidence for mediation, this would suggest that physical activity and brain pathologies are independently associated with parkinsonism in older adults. Thus, testing this hypothesis would provide novel data about a potential mechanism underlying the motor benefits of physical activity in older adults. In turn this would provide novel targets for interventions to maintain motor function in old age.

Our prior work has shown that a higher level of physical activity is related to less severe parkinsonism ( A [ 6]), physical activity and brain pathologies are related ( B [ 9]), and brain pathologies are related to the severity of parkinsonism ( C [ 7, 8, 10]). Based on these findings, this study tested the hypothesis that brain pathology links (mediates) the association of physical activity with parkinsonism. If the hypothesized sequence of events shown in D is correct, then adding the term for brain pathology to the model would attenuate the association of physical activity with parkinsonism, which would no longer be significant. If brain pathology does not mediate this association, both physical activity and brain pathology would be independently associated with parkinsonism.

Prior investigators did not test this mediation hypothesis since it is uncommon to obtain postmortem indices from large numbers of well-characterized older adults prior to death. To test the hypothesis that brain pathologies link physical activity with the severity of parkinsonism, we used novel data from 447 deceased participants from the Rush Memory and Aging Project[ 11].

Methods

Participants

The Rush Memory and Aging Project (MAP) is an ongoing cohort study of community-dwelling healthy older adults 65 years older or older who agree to annual clinical assessments and organ donation at the time of death. The study was approved by an Institutional Review Board of Rush University Medical Center. Written informed consent was obtained from all study participants as was an Anatomical Gift Act for organ donation. Participants are recruited from retirement facilities, subsidized housings, and individual homes across Chicago Metropolitan area. While the study's recruitment started in 1997, multi-day physical activity recordings started in 2005.

This study focuses on the associations between total daily physical activity metrics extracted from multiday activity recordings obtained in the community setting, brain indices of ADRD obtained at autopsy, and the severity of clinical parkinsonism based on the United Parkinson's Disease Rating Scale (UPDRS). As such, inclusion was limited to decedents with completed brain autopsy with valid measures of quantitative physical activity metrics and clinical parkinsonism assessment proximate to death. Since 2005, 613 participants with physical activity metrics died and 537 of them underwent autopsy (88% autopsy rate). Of these, 519 (97%) had completed autopsy results at the time of these analyses, 72 had missing clinical data (e.g. parkinsonism) which left 447 for these analyses. Comparison of participants included in the current analyses with participants excluded ( S1 Table) showed that the two groups were not different in age, education, vascular risk factors and diseases, and levels of physical activity, but were different in the percentage of women and neuroleptic medication consumption ( S1 Table).

Assessment of parkinsonism

Trained nurse clinicians assessed parkinsonism annually using 26 items of a modified version of UPDRS[ 12, 13]. This assessment has high inter-rater reliability and short-term stability among nurses and compared with a movement disorders specialist[ 12, 13].

This testing assessed four common parkinsonian signs: parkinsonian gait, bradykinesia, rigidity, and tremor. Each of the 26 items was scored on a similar 0-4 scale, with 0 indicating no impairment and 4 indicating very severe impairment. We summarized scores for each of the four parkinsonian signs and the scores for these four signs were then averaged together to form a summary global parkinsonism score for the overall severity of parkinsonism as previously described. This measure was the primary outcome measure in our analyses[ 12, 13].

Assessment of total daily physical activity

Each participant wore an activity monitor (Actical; Philips Healthcare, Andover, MA) over the non-dominant hand 24 hours/day for up to 10 days. The Actical is an omni-directional accelerometer which generates a signal proportional to the magnitude of all movements it registers. The device digitizes the signal and expresses the average activity for each recording epoch as activity counts (15s in this study; 5760 epochs/day). More physical activity is reflected in higher activity counts.

In prior work we constructed and validated two measures which summarize the mean total daily physical activity based on multiday recording[ 6, 14]. In this study, we analyzed total daily activity for all days with complete 24 hours recordings. Total daily physical activity is the mean sum of all activity counts for up to 10 days of complete recordings. Since the benefits of physical activity may be related to the intensity of activity, we constructed a second measure. Intensity of daily physical activity was calculated by dividing the total daily activity counts by the total duration of non-zero 15 second epochs to yield a metric of the intensity of activity counts per hour of activity. These two metrics were validated in prior studies predicting adverse health outcomes and are independently associated with these outcomes when controlling for self-reported physical activity[ 6, 14].

Movement during sleep and non-rest periods may make different contributions to parkinsonism. Sleep diaries are not available in this cohort and many participants nap extensively during the daytime making it difficult to filter out movements related to periods of sleep/rest. In prior studies, we developed and validated a sleep fragmentation metric k RA, from actigraphic recordings [ 15]. K RA captures the temporal organization of human rest-activity patterns in terms of transition probabilities between periods of rest (when recorded activity is zero) to recording epochs in which movement (non-zero activity) is recorded. Conceptually, k RA is a measure of the tendency to fragment sustained rest periods by physical activity. A higher value of k RA represents more fragmented rest, and a lower value represents a more consolidated rest. Since most rest periods are recorded during sleep, a higher k RA is associated with more frequent movement during sleep. K RA is weakly related to total daily physical activity (Spearman correlation coefficient = 0.15, p = 0.003), suggesting that they measure different constructs.

These continuous multiday recordings were obtained during routine living in the community-setting and captured all movements including both exercise and habitual physical activity. While these inform on total levels of physical activity, the particular device employed cannot be used to quantify the contributions of specific activities. Thus, these metrics quantify total daily physical activity which shows how active an individual's lifestyle was during these multiday recordings.

Assessment of postmortem brain pathologies

Structured brain autopsies were performed by staff blinded to clinical data. Following brain removal, tissue preparation and sectioning, gross inspection, and tissue blocks were obtained from pre-specified brain regions as previously described[ 16].

Alzheimer's disease pathology.

A modified Bielschowsky silver stain was used to visualize diffuse plaques, neuritic plaques, and neurofibrillary tangles, the AD pathological indices, in the frontal, temporal, parietal, entorhinal and hippocampal cortical areas[ 16]. Each of the three AD pathological indices was counted in each of the brain regions. For each AD pathological index, we created a summary measure by counting the index in each brain region and standardizing the count followed by making an average of the standardized scores across the 5 brain regions. Then, we constructed the global AD pathology score by averaging the summary measures of the three AD pathologic indices. We previously showed that each regional standardized score, e.g. neuritic plaques in the frontal cortex, was correlated with the other standardized AD indices' regional scores (r range: 0.47-0.73, median r = 0.67) and the Cronbach α coefficient was 0.90, indicating high internal consistency and supporting use of the global AD pathology score[ 17].

Nigral neuronal loss.

Dissection of the diagnostic blocks included a hemisection of the midbrain containing subtantia nigra. Nigral neuronal loss was assessed in the substantia nigra at the level of the 3 rd nerve exit using H&E staining. We used a semi-quantitative scale (none, mild to severe) for the assessment of nigral neuronal loss, as described previously[ 8].

Other clinical covariates

Sex and years of education were recorded at study entry. Age was calculated from date of birth to date of physical activity assessment. Chronic health conditions included the sum of three self-reported vascular risk factors (hypertension, diabetes mellitus, and smoking) and sum of four self-reported vascular diseases (myocardial infarction, congestive heart failure, stroke, and claudication). Self-reported marital status was assessed and classified into five categories: never married, married, widowed, divorced, and separated. All clinical data used in these analyses were obtained from the same visit proximate to death.

As done in prior studies, a diagnosis of Parkinson disease (PD) was based on self-reported medical history of a clinical diagnosis of PD for which the participants had received levodopa or dopamine agonists[ 20]. At each visit, study personnel reviewed and recorded all medications including neuroleptics taken by the study participants.

Statistical analysis

The global parkinsonism scores were positively skewed, and these scores were square root transformed for these analyses [ 6, 20]. As illustrated in Fig 1, we employed a series of multivariable linear regressions, adjusted for age at death and sex, to assess whether indices of brain pathologies link (mediate) the association of physical activity with the severity of parkinsonism proximate to death ( Fig 1 and 1D). First, in a model without postmortem indices, we replicated the finding that physical activity was related to the severity of parkinsonism ( Fig 1 and 1A). Second, we examined the association of total daily physical activity with ADRD pathology indices ( Fig 1 and 1B). Third, we examined the association of postmortem indices with the severity of parkinsonism in a model without total daily physical activity (Fig 1 and 1C). Fourth, we examined a model that included both physical activity and brain pathologies together ( Fig 1 and 1D). If the association of physical activity with parkinsonism is attenuated in model D, it would suggest that brain pathologies may link (mediate) the association of total daily physical activity with the severity of parkinsonism. In contrast, if the association of physical activity with the severity of parkinsonism does not change in the presence of brain pathology indices it will suggest that physical activity and brain pathologies are independently associated with the severity of parkinsonism. To examine potential collinearity among pathology indices, we calculated their variance inflation factor (VIF). VIF greater than 10 strongly suggests collinearity[ 21]. Since other health conditions and covariates may affect parkinsonism and physical activity, in further analyses we controlled for possible confounding effects of education, marital status, vascular risk factors and diseases, and use of neuroleptic medications. Finally, we repeated the models after exclusion of decedents with a clinical diagnosis of PD or decedents receiving neuroleptic medications that can affect the severity of parkinsonism.

Next, we repeated these analyses, but replaced total daily physical activity with the intensity of total daily physical activity, a second metric that captures aspects of daily physical activity that may be important for the benefit of physical activity. As the association of parkinsonism with sleep related movement may be different compared to movement during wake periods, we repeated the analyses by further adjustment for k RA [ 15], which is the probability of sleep disruption by movement.

Multiple mechanisms may account for the motor benefits of higher levels of physical activity. Prior studies have reported that life style factors are associated with less cognitive and motor impairment through modifying association of ADRD pathologies with cognitive and motor outcomes [ 22- 25]. Therefore, in secondary analyses, we added interaction terms between physical activity and brain pathologies in model D to determine if the motor benefit of physical activity was due to modification of the association between brain pathologies and parkinsonism. The analyses were done using SAS version 9.4.

Results

Characteristics of study participants

Clinical Characteristics: There were 447 participants and their clinical and postmortem indices are summarized in Table 1. On average total daily physical activity was measured 2.1 (SD = 2.0) years prior to death, and the average length of recording was for 9.4 (SD = 1.8) days.

Total daily physical activity, brain pathologies, and parkinsonism

First, we replicated prior findings that a higher level of total daily physical activity proximate to death was associated with less severe parkinsonism ( Fig 1A; Table 2, Model 1-TDPA). Second, we replicated prior findings that a higher level of physical activity was associated with lower odds of nigral neuronal loss and macroinfarcts ( Fig 1B; S2 Table).

Third, we found that a higher burden of nigral neuronal loss and atherosclerosis were associated with more severe parkinsonism proximate to death ( Fig 1C; Table 2, Model 2-Path). The VIFs in this model were less than 1.5 indicating that collinearity did not exist among the examined pathology indices [ 21].

Fourth, we examined the association of total physical activity with the severity of parkinsonism in a model which also included terms for brain pathologies. In this model, the association of total daily physical activity with parkinsonism was not attenuated by the presence of brain pathologies ( Fig 1D; Table 2, Model 3-TDPA+Path). In the Model 3-TDPA-Path model, total daily physical activity was independently associated with parkinsonism accounting for an additional 5.7% of the variance of parkinsonism as compared to 8.3% contributed by age, sex and brain pathologies.

In a series of sensitivity analyses, we examined the association of total daily physical activity with parkinsonism severity in models adjusting for education, marital status, vascular risk factors and diseases, and consumption of neuroleptic medications as possible confounding variables. Adjustment for these covariates did not affect the finding that higher levels of total daily physical activity was associated with less severe parkinsonism independent of brain pathology indices ( S3 Table). Participants with a clinical diagnosis of PD (N = 17) or those taking neuroleptics (N = 86) might have more severe parkinsonism. After excluding these participants, our results were unchanged ( S4 Table).

Other physical activity metrics, brain pathologies, and parkinsonism

In a series of similar models, we replaced total daily physical activity with the intensity of daily activity. Controlled for age and sex, more intense physical activity was associated with less severe parkinsonism (estimate = -4.406, SE 0.671, p < 0.001), and the association was unaffected by the presence of the terms of brain pathologies ( Table 2, Model 4-Intensity+Path).

The association of parkinsonism with sleep related movement may be different compared to movement during wake periods. To quantify sleep-related movement, we used k RA [ 15], which is the probability of sleep disruption by movement. We examined if adding a term for k RA to model A confounded the association between total daily physical activity and parkinsonism. In this model, a higher level of total daily physical activity remained associated with less severe parkinsonism, while a higher level of k RA was associated with more severe parkinsonism ( S5 Table). These finding suggest that a higher level of physical activity is associated with less severe parkinsonism and increased sleep fragmentation, due to more frequent movement during sleep, is associated with more severe parkinsonism. These associations persisted in the presence of brain pathologies ( S5 Table).

Total daily physical activity and modification of the association between brain pathologies and parkinsonism

Physical activity might also be associated with less severe parkinsonism through a second mechanism by modifying the untoward contribution of brain pathologies to the severity of parkinsonism. Therefore, we examined if there was evidence to support this mechanism by addition of interaction terms for total daily physical activity and brain pathologies to Model D ( Fig 1). The association of the pathology indices with the parkinsonism did not vary with the level of total daily physical activity (nigral neuronal loss × total daily physical activity [estimate = -0.323, SE 0.233, p = 0.166]; and atherosclerosis × total daily physical activity [estimate = -0.216, SE 0.114, p = 0.060]). These additional analyses suggest that the association of a higher level of physical activity with less severe parkinsonism was not due to physical activity modifying the association of ADRD pathologies with the severity of parkinsonism.

Discussion

Using novel data from almost 450 community-dwelling older participants, a higher level of total daily physical activity proximate to death was associated with less severe parkinsonism. Postmortem indices of ADRD pathologies did not mediate the association of physical activity with parkinsonism. Rather, we found that both physical activity and ADRD pathologies were independently associated with the level of parkinsonism proximate to death. These findings were robust and did not change when controlling for a wide range of clinical and health covariates. Further analyses did not show evidence for an interaction between physical activity and brain pathology in their association with the severity of parkinsonism, and hence, the interaction does not underlie the motor benefits of physical activity. Together, these findings highlight the need for further studies to elucidate the biology underlying the motor benefits of a more active lifestyle in older adults.

While the health benefits of higher levels of physical activity are well-known, the mechanisms underlying its potential benefits to reduce the severity of parkinsonism is unknown. Prior mouse studies suggest that higher levels of physical activity were associated with less amyloid and phosphorylated tau deposition, higher levels of markers of neurogenesis, and better spatial memory [ 26, 27]. However, due to limited brain tissues available in well-characterized older adults, few studies have examined the association of physical activity and ADRD pathologies in older adults, and extant amyloid brain imaging studies have shown conflicting results [ 28].

Our prior studies have shown that a higher level of physical activity at study baseline in this cohort is associated with a slower progression of parkinsonism as well as a decreased incident of parkinsonism during an average of four years of follow-up. Additional studies have shown indices of brain pathology are associated with lower levels of total daily physical activity and more severe parkinsonism [ 9, 10]. Together, these studies provided the scientific framework of the current study suggesting the possibility that brain pathologies may link (mediate) the association of higher levels of physical activity with less severe parkinsonism.

The current study replicated previous findings showing that a higher level of physical activity is associated with less severe parkinsonism [ 6]. While this association was significant, total daily physical activity explained only 7.2% of the variance of parkinsonism. This finding is similar with a previous study which reported that total daily physical activity was mildly correlated with a different motor phenotype which summarized several motor abilities, including gait speed, grip strength, and finger tapping and explained 9% of its variance [ 29].

Total daily physical activity and motor phenotypes may be weakly correlated as they assess different facets of motor function, a complex multidimensional phenotype. It has been suggested that total daily physical activity measures the quantity of volitional activity that occurs during the day. In contrast, other motor phenotypes may assess innate motor abilities. A person with poor motor abilities might nonetheless be very active and, conversely, an individual with good motor abilities might voluntarily elect not to move.

Similar to prior studies, in the current study brain pathologies were related to parkinsonism, but only accounted for a minority of its variance [ 30]. The accumulation of ADRD pathologies in motor regions outside the brain that were not measured in this study [ 31] may account for the small amount of the variance of parkinsonism explained by brain ADRD pathologies. In addition, while the amount of parkinsonism variance explained by the physical activity or ADRD pathologies is small at the individual level their effect at the public health level is not inconsequential. Given the extent of motor impairment in old age, even the modest effect sizes observed in the current study are likely to be very important.

The current analyses did not find evidence that ADRD pathologies link physical activity with the severity of parkinsonism. Rather, we found that both ADRD pathologies and physical activity were independently associated with parkinsonism. Recent studies have suggested that some clinical covariates may modify indices of brain pathology and mitigate its untoward clinical effects [ 22- 25]. The current study did not find evidence that the motor benefits of physical activity are due the interaction and modification of indices of ADRD brain pathologies with the severity of parkinsonism in older adults.

The current results with parkinsonism are similar to a prior study, in this cohort, in which we found that a higher level of total daily physical activity in older adults was associated with better cognition and this association was also independent of the presence of brain ADRD pathologies [ 29]. Thus, both the potential cognitive and motor benefits of a higher level of physical activity in older adults were unrelated to the presence of indices of brain pathologies, and there was also no evidence that physical activity modify the association of brain pathologies with parkinsonism or cognition.

As discussed below, these cross-sectional findings derive from observational data and conclusive causal inferences require further interventional studies. Yet, the current study's findings together with prior longitudinal studies which show that higher levels of baseline physical activity are associated with slower progressive parkinsonism[ 6] and cognitive decline[ 14] may lend support for interim public health strategies until more conclusive data is available. Currently, there are no treatments for AD and other degenerative brain pathologies. Findings that the potential clinical benefits of physical activity are unrelated to indices of brain pathology lend support public health efforts to increase the level of physical activity as a means to maintain both physical and cognitive function in older adults, even in the absence of efficacious treatments for ADRD pathologies.

If the results of the current study are replicated what potential mechanisms might underlie the motor benefits of physical activity? Most prior studies about the beneficial effects of life style factors have examined their association with cognition, not motor function. Like physical activity, varied factors such as education[ 32, 33], late-life cognitive[ 34] and physical activities[ 29], and psychological factors like purpose in life[ 23] and social networks[ 35] were associated with slower cognitive decline independent of AD pathology. These data like the current data highlight that physical activity and other lifestyle factors may be linked with cognition via unidentified mechanisms which lack a known "pathologic footprint". Results of some human brain imaging studies suggest that increased physical activity may lead to better memory through vascular and structural brain changes [ 36]. Recently, system biology and network-based approaches have been exploited to leverage transcriptome data to identify genes and proteins i.e. molecular brain mechanisms that may drive cognition [ 37]. For example, higher levels of inositol 1, 3, 4-triphosphate 5/6-kinase (ITPK1) was associated with slower cognitive decline, but its association with cognition was independent of the presence of ADRD pathologies [ 38]. A similar approach may be useful to elucidate novel molecular mechanisms that underlie the potential motor and cognitive benefits of a more active lifestyle in older adults.

The biology underlying the association of life style factors with motor function is unclear. Two prior studies have suggested that education and physical activity modify the association of white matter hyperintensities with motor function [ 24, 39]. These studies examined brain imaging indices in living adults, but did not examine indices of ADRD pathologies. While the current study found that physical activity did not modify the association of ADRD with motor function, this study did not examine brain imaging indices. Therefore, further studies will need to examine brain imaging together with ADRD pathologies indices. In examining the underlying mechanisms of the association between life style factors and motor function, it is also important to consider the widespread distribution of motor-related CNS regions. In contrast to cognition, the motor system extends beyond the brain to influence spinal cord structures which via the peripheral nervous system regulate muscle structure, the final effector of all movement. Damage to any portion of this distributed motor system can impair motor function. Recent work has shown that indices of ADRD extend beyond the brain and brainstem to reach the spinal cord and are related to the severity of parkinsonism in older adults [ 31]. Further work is needed to extend the collection of indices of ADRD pathologies in postmortem studies to outside of the brain and also include brainstem and spinal cord motor structures. Finally, no prior work has examined the role of motor unit structures (spinal motor neuron, peripheral nerve and muscle) in linking ADRD phenotypes with parkinsonism in older adults [ 40]. These motor tissues will also be need to be examined to identify genes and proteins that may underlie the motor benefits of physical activity without manifesting a pathologic footprint.

Another question raised by the current study is the extent to which the association of higher levels of physical activity with better cognition and motor function derive from similar or distinct central nervous system (CNS) loci or mechanisms. For example recent work suggests that physical activity may cause muscle to release a hormone-like factor, irisin, that may reach cognitive brain regions via systemic circulation to protect cognition[ 40, 41]. Finally, recent work suggests that molecular brain mechanisms without a known "pathologic" footprint may drive both cognitive and motor function[ 38, 42].

Our study has several strengths. We analyzed quantitative metrics of physical activity derived from multiday continuous recordings obtained during everyday living in the community-setting. Structured and validated methods were employed to assess parkinsonism and brain autopsies. The combination of antemortem measures of physical activity and parkinsonism with neuropathological indices only available postmortem is especially challenging from a logistics perspective and adds to the strength of this work.

Our study has important limitations. The study was composed of highly educated Caucasians limiting generalizability of the study findings. However, the frequency of ADRD pathologies is this cohort is similar to other clinical-pathological longitudinal studies of aging ( S6 Table) [ 43]. Another limitation is the cross sectional design of this study limiting causal inferences, as we cannot rule out reverse causality i.e., that reduced parkinsonism might lead to reduced physical activity. However, a prior longitudinal study in this same cohort showed that higher baseline total daily physical activity was associated with slower rate of progressive parkinsonism over time lending support for the potential beneficial effect of physical activity on the severity of parkinsonism [ 6]. Future longitudinal physical activity interventional studies employing repeated imaging of brain pathologies together with clinical data might be needed and might identify links between physical activity and parkinsonism not observed in the current study.

Moreover, prior data about how active the individuals in the current study were over the course of their lifespan was not available. Therefore, it is unclear if the benefit of a more active lifestyle is due to lifestyle choices over many years or due to choices during this study. Brain imaging indices were not examined in these analyses. Since the motor system extends beyond the brain, further work is needed to determine if ADRD pathologies in motor tissues outside the brain might mediate the association of total daily physical activity with the severity of parkinsonism [ 41, 44]. Finally, the activity monitors employed in this study do not differentiate between different physical activities, and further studies are needed to determine whether the specific types of movements associated with less severe parkinsonism. In addition, removal of the device employed in the current study cannot always be distinguished from periods of no activity.

Despite its limitations, accumulating more than 450 autopsies from well-characterized older adults with both quantitative multi-day activity metrics as well as assessments of parkinsonism proximate to death provides novel data which has potential to inform on the design of both clinical and interventional studies of physical activity in older adults. Further studies are needed to elucidate the knowledge gaps about the mechanisms underlying the benefits of physical activity. This is crucial to facilitate interventions that modify lifestyles as a means to maintain physical and cognitive function in our aging population.

Acknowledgments

We thank participants of the Rush Memory and Aging project. Also, we appreciate staff of the Rush Alzheimer's Disease Center.

# data[].attributes.attachment_link.title
Total daily physical activity, brain pathologies, and parkinsonism in older adults

# data[].attributes.attachment_link.description
Objective We examined the association of physical activity, postmortem brain pathologies, and parkinsonism proximate to death in older adults. Methods We studied the brains of 447 older decedents participating in a clinical-autopsy cohort study. We deployed a wrist worn activity monitor to record total daily physical activity during everyday living in the community-setting.

# data[].attributes.headline
Subject Expertise - The Brain: The Story of You by David Eagleman

# data[].attributes.subject
Subject Expertise - The Brain: The Story of You by David Eagleman

# data[].attributes.body
Our brain is capable of many things that we may not be aware of. How our brain changes, how it works is just so complex. Eagleman has mentioned, "Throughout our childhoods, our local environments refine our brain, taking the jungle of possibilities and shaping it back to correspond to what we're exposed to."

# data[].attributes.attachment_link.readable_text
This is a very subjective question. Meaning it always depends on who you're asking. Because none of this has yet to be "proven" people will argue for This is a very subjective question. Meaning it always depends on who you're asking. Because none of this has yet to be "proven" people will argue for whoever's research and theories they agree with. I can give you some of my own personal (and I try really hard to be objective and steer clear of opinions, but that will always have a role so that's just my warning label of sorts, ha) but because this is such a big topic today it'd help if you were more specific... do you mean subconscious mind just basically like how we make decisions, fears, etc or do you want to go deeper meaning the abnormal subconscious mind and/or subconscious mind of trauma, etc. there are so many good out there. If you want recs let me know, but another good way to find is to do a bit of research online and/or going to a book store and looking at several books that deal with your specific questions... I hope this helps! ...more (less)

# data[].attributes.attachment_link.description
This is a very subjective question. Meaning it always depends on who you're asking. Because none of this has yet to be "proven" people will argue for This is a very subjective question. Meaning it always depends on who you're asking.

# data[].attributes.headline
Societal Position - The NY Times: How Inactivity Changes the Brain

# data[].attributes.subject
Societal Position - The NY Times: How Inactivity Changes the Brain

# data[].attributes.body
A study on rats showed how inactivity changes the shape of neurons in the brain. That rats that were kept from any physical activity showed that their neurons had sprouted far more branches. This shows how being inactive can contribute to the health of your brain. As stated in the article, "The results underscore that inactivity can change the structure and functioning of the brain, just as activity does."

# data[].attributes.attachment_link.readable_text
A number of studies have shown that exercise can remodel the brain by prompting the creation of new brain cells and inducing other changes. Now it appears that inactivity, too, can remodel the brain, according to a notable new report.

The study, which was conducted in rats but likely has implications for people too, the researchers say, found that being sedentary changes the shape of certain neurons in ways that significantly affect not just the brain but the heart as well. The findings may help to explain, in part, why a sedentary lifestyle is so bad for us.

Until about 20 years ago, most scientists believed that the brain's structure was fixed by adulthood, that you couldn't create new brain cells, alter the shape of those that existed or in any other way change your mind physically after adolescence.

But in the years since, neurological studies have established that the brain retains plasticity, or the capacity to be reshaped, throughout our lifetimes. Exercise appears to be particularly adept at remodeling the brain, studies showed.

But little has been known about whether inactivity likewise alters the structure of the brain and, if so, what the consequences might be.

So for a study recently published in The Journal of Comparative Neurology, scientists at Wayne State University School of Medicine and other institutions gathered a dozen rats. They settled half of them in cages with running wheels and let the animals run at will. Rats like running, and these animals were soon covering about three miles a day on their wheels.

The other rats were housed in cages without wheels and remained sedentary.

After almost three months of resting or running, the animals were injected with a special dye that colors certain neurons in the brain. In this case, the scientists wanted to mark neurons in the animals' rostral ventrolateral medulla, an obscure portion of the brain that controls breathing and other unconscious activities central to our existence.

The rostral ventrolateral medulla commands the body's sympathetic nervous system, which among other things controls blood pressure on a minute-by-minute basis by altering blood-vessel constriction. Although most of the science related to the rostral ventrolateral medulla has been completed using animals, imaging studies in people suggest that we have the same brain region and it functions similarly.

A well-regulated sympathetic nervous system correctly directs blood vessels to widen or contract as needed and blood to flow, so that you can, say, scurry away from a predator or rise from your office chair without fainting. But an overly responsive sympathetic nervous system is problematic, said Patrick Mueller, an associate professor of physiology at Wayne State University who oversaw the new study. Recent science shows that "overactivity of the sympathetic nervous system contributes to cardiovascular disease," he said, by stimulating blood vessels to constrict too much, too little or too often, leading to high blood pressure and cardiovascular damage.

The sympathetic nervous system will respond erratically and dangerously, scientists theorize, if it is receiving too many and possibly garbled messages from neurons in the rostral ventrolateral medulla.

And, as it turned out, when the scientists looked inside the brains of their rats after the animals had been active or sedentary for about 12 weeks, they found noticeable differences between the two groups in the shape of some of the neurons in that region of the brain.

Using a computerized digitizing program to recreate the inside of the animals' brains, the scientists established that the neurons in the brains of the running rats were still shaped much as they had been at the start of the study and were functioning normally.

But many of the neurons in the brains of the sedentary rats had sprouted far more new tentacle-like arms known as branches. Branches connect healthy neurons into the nervous system. But these neurons now had more branches than normal neurons would have, making them more sensitive to stimuli and apt to zap scattershot messages into the nervous system.

In effect, these neurons had changed in ways that made them likely to overstimulate the sympathetic nervous system, potentially increasing blood pressure and contributing to the development of heart disease.

This finding is important because it adds to our understanding of how, at a cellular level, inactivity increases the risk of heart disease, Dr. Mueller said. But even more intriguing, the results underscore that inactivity can change the structure and functioning of the brain, just as activity does.

Of course, rats are not people, and this is a small, short-term study. But already one takeaway is that not moving has wide-ranging physiological effects. In upcoming presentations, Dr. Mueller said, he plans to show slides of the different rat neurons and, echoing the old anti-drug message, point out that "'this is your brain.' And this is your brain on the couch."

# data[].attributes.attachment_link.description
A number of studies have shown that exercise can remodel the brain by prompting the creation of new brain cells and inducing other changes. Now it appears that inactivity, too, can remodel the brain, according to a notable new report.