Concussions in the NFL lead to Depression

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Professional football players who suffer from a concussion are more likely to develop long-term mental health episodes such as depression.

 

The prevalence of concussions in football has significant mental health ramifications. One concussion occurs every 2.44 NFL games. A study published in the American Journal of Sports Medicine looked at correlations between concussion incidences and depression (Nine-Year Risk of Depression Diagnosis Increases With Increasing Self-Reported Concussions in Retired Professional Football Players, 2012. Zachary Y. Kerr, et al.).

The study used a 2001 General Health Survey sent to the 3,729 members of the NFL Retired Players Association. A second General Health Survey was sent nine years later in 2010. The surveys asked questions regarding the respondents physical and mental health as well as the number of concussions suffered during their professional careers. Those exhibiting depression in the first survey were not used in the study.

Of the players who reported never having a concussion, only 3.0% were diagnosed with depression. Of those who reported suffering from 10 or more concussions, 26.8% were found to suffer from depression. The relationship between number of self-reported concussions and likelihood of suffering from depression was a linear relationship. Those who reported suffering from 3 or more concussions were twice as likely to suffer from depression as those reporting 1-2 concussions over their career and three times more likely than retired professional football players who did not suffer any concussions over their professional career.

Work on depression in US soldiers in Iraq has suggested there may be a link between tauopathies, tau protein deposits in the brain, and depression. Repeated head impacts elevate tau protein levels causing neural breakdown. The physical blow to the head could directly cause neuron death or breakage of neuron connections. Lesions in neural tissue could release harmful biochemical agents.

Concussions often go unreported, especially at the amateur level. This study highlights the importance of monitoring the accumulation of concussions. Other studies have found that concussions can lead to negative personality and cognitive changes. Although the dangers of concussions cannot be underscored enough, with regards to this study on concussions in former NFL players there are several limitations. Most significantly, it is likely that there are many lurking variables that this study could not account for. For example, risky behavior that leads to concussions may be favored in those prone to depression. Career-ending concussion accumulation may lead to depression. Nonetheless, the number of concussions suffered is a significant predictor of depression later in life.

Most likely, a positive relationship between concussions and depression would apply across sports, competition levels as well as to the military and other non-athletic instances.

Brain Plasticity through Resistance Training

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A study finds that resistance training generates memory gains in mice greater than those seen in resistance-free endurance training. The biochemical pathway appears to be a neurotrophic factor, BDNF.

 

 

In a recent post on Exercisemed.org, the effects of endurance training on memory was discussed. That paper, released in the spring of 2012, discussed the impact that brain derived neurotrophic factor (BDNF) had on memory in middle aged mice (Running throughout Middle-Age Improves Memory function, Hippocampal Neurogenesis, and BDNF Levels in Female C57BI/6J Mice, 2012; Michael W. Marlatt, et al.). The study found that the release of BDNF through endurance exercise improved the memory of middle-aged, female mice. The mechanism is likely brain plasticity, the ability of neurons to form new connections and pathways. A Japanese study published this month found that mice participating in a high-load resistance training program had an even stronger improvement in memory (Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling, 2012. Min Chul Lee, et al.).

The study used running wheels to exercise the mice. The mice were assigned to three groups: a sedentary control group (Sed), voluntary wheel running with no resistance (WR) and voluntary wheel running with increasing resistance.  The mice were maintained with these controls for 30 days. As the figure below shows, the mice with resistance-free running wheels ran a greater distance than their counterparts with resistance running wheels. However, the work performed was higher in the resistance wheel group. Resistance is given as a percentage of body weight.

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The mice were tested for memory capacity and general cognitive function with a water maze. The water maze has a hidden platform that the mice must find.  The mice were placed in the maze four days in a row.  On average, the mice became more efficient at finding the hidden platform each day. As the figure below demonstrates, the mice with running wheels performed better than the sedentary mice (Sed) regardless of whether or not they had resistance (RWR) or no resistance (WR) on their running wheels. The mice that did resistance training spent more time in the target quadrant, quadrant P (graph C).

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Like other studies, the neurotropic factor BDNF was found to be higher in the wheel running groups. In addition, the protein p-CREB was found to be higher in the wheel running groups and significantly higher in the resistance wheel running group. BDNF and p-CREB have both been implicated by previous studies in brain plasticity and memory. The authors speculated that the gains in resistance training were observed because the training was voluntary. Thus, the negative affects of stress on the brain did not occur. This is the first study to suggest that quality over quantity is the rule for brain plasticity.

Exercise’s effect on brain plasticity is a very “hot” research subject right now.  However, no research has been done on the biochemical affects of exercise in human subjects. While other studies have been focused on endurance training’s effect on brain plasticity, this is the first to look at how shorter resistance training affects the brain.

Memory Loss, Anxiety Reduction in Middle-Aged Running Mice

 

Running is shown by one study to increase memory, reduce anxiety, raise stability via increased brains levels of neurotrophic factor BDNF.

 

Running has been shown by several studies to increase neurogenesis (proliferation of new neurons) in the brain, specifically the dentate gyrus in the hippocampus. A decrease in neurogenesis later in life has been linked with memory loss.

A recent study looked at the affects of 6 months of running on neurogenesis and chemistry of brain sections as well as behaviors dependent on brain function (Running throughout Middle-Age Improves Memory function, Hippocampal Neurogenesis, and BDNF Levels in Female C57BI/6J Mice, 2012; Michael W. Marlatt, et al.).

The mice were tested for behavioral changes after one month and six months of voluntary running-wheel training. Many behavioral changes were significant only after six months of training. For example, the running mice were significantly better at the Morris water maze after six months of training, but not after one month of training. How does the water maze work?  Mice were placed in a water bath with a target. After finding the target they were placed back in the water bath at a later date. The mice were tracked with a video camera and the amount of time in the target quadrant was recorded. After six months of training the running mice showed significantly more preference for the target quadrant. This suggests that these middle aged running mice had a greater memory retention.

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Time spent in quadrants in the Morris water maze. Only the 6 month running mice spent significantly more time in the target quadrant.

To test for anxiety, mice were placed in an open field an observed. The ratio of time spent in the center of the field to the periphery of the wall was calculated.  Mice that spent more time in the center of the field would be expected to have less anxiety, while mice that spent time hiding along the wall would have more anxiety. The running mice were found to spend more time in the center of the field than their control counterparts at both one month and six months of voluntary exercise training. This supports previous studies showing that running reduces stress and anxiety.

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Falls on a rotarod after 15 seconds in running mice (dark grey) and resting mice (light grey).

The running mice were found to be stronger and better balanced. This was tested with a rotarod. Mice spent 15 seconds on the rotarod and the number of falls were recorded. The running mice fell about a fifth as much as the control mice as the figure above demonstrates.

The researchers then looked at brain sections of the hippocampus to explain the behavioral differences. BrdU (an agent that gets incorporated into the DNA of new nuclei) was used to look for new neurons. Running mice had significantly higher levels of BrdU in the dentate gyrus of the hippocampus. In addition, DCX, a neural marker, was found to be slightly higher after 6 months of voluntary exercise training.  Finally, neurotrophin factor BDNF was measured. BDNF aids in keeping neurons healthy. The running mice had significantly higher levels of BDNF.

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The dentate gyrus with DCX and DAPI immunochemistry.

 

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A: Running mice showed increased levels of neurogenesis marker BrdU B: BrdU co-localized with NeuN neural marker C: DCX in type D neurons D: DCX in type C neurons

In conclusion, this study found that six months of voluntary running raised memory retention, decreased anxiety and increased stability in middle aged mice. The hippocampus was found to have increased levels of neurogenesis, BDNF and DCX.

Retaining Muscle Function in ALS Patients

 

ALS patients lose significant muscle mitochondrion causing muscle degradation and muscular atrophy. However, as the figure to the right demonstrates, treatment with PGC-1alpha reduces muscle degradation suggesting a therapy for improving quality of life, but not survival, for ALS patients.

 

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a progressive, fatal, adult-onset neurodegenerative disorder characterized by loss of motor neurons and degeneration of skeletal muscle.  Approximately 300,000 people are affected by ALS worldwide. Although scientists have not found a cure for the disease, a team of researchers from San Diego, California have found a possible lead for a way to alleviate the muscle degeneration that makes the end of life for ALS patients so painful.

The study, Elevated PGC-1alpha Activity Sustains Mitochondrial Biogenesis and Muscle Function Without Extending Survival in a Mouse Model of Inherited ALS (Sandrine Da Cruz, Philippe A. Parone, et al., May 2012), looked at the effects of increased transcriptional coactivator PGC-1alpha on SOD1 mutant mice.  PGC-1alpha exerts control over cellular metabolism, specifically mitochondria angiogenesis and biogenesis. The SOD1 mutation causes mitochondrion toxicity that models ALS. The researchers found that by increasing levels of PGC-alpha1, muscle degradation was reduced.

Mitochondrion density is significantly reduced by ALS, however as the picture above demonstrates, comparing SOD1-mutant mice saw significant increases in skeletal muscle mitochondrion density when treated with PGC-1alpha.Vascular endothelial growth factor (VEGF) levels were also raised by the PGC-1alpha.  The alleviation of muscle degradation resulted in the increased endurance and voluntary physical activity (distance covered in an open field) in the PGC-1alpha treated mice. The results can be seen below.

 

The figure above demonstrates that survival duration was not increased in PGC-1alpha treated/SOD1-mutant mice (blue) compared to SOD1-mutant mice (red).

PPG-1alpha does not alter the pathogenesis of ALS, it simply reduces the effect of mitochondrion toxics that are released in ALS patients.  Unfortunately then, raising PGC-1aplha levels in SOD1-mutant mice did not prevent the motor neurons from being degraded. Thus, PGC-1alpha worked on preventing degradation to the muscular system, but not the terminal nervous system degradation. As the figure below demonstrates, survival duration was not increased by the PGC-1alpha.

This study is significant because it introduces PGC-1alpha as a potential therapy for increasing the quality of life for ALS patients by maintaining muscle function. Unfortunately, PGC-1alpha does not prevent neuron degradation or increase survival duration after onset of ALS. However, it means that Lou Gehrig could have continued playing baseball for a few more months.

Controlling Alzheimer’s Risk

elderly coupleOne study shows that physical activity and diet health exert some control over Alzheimer’s risk. Scientists have found possible mechanisms between physical activity and Alzheimer’s risk.

 

 

 

 

Alzheimer’s disease is a brain disease that causes loss of memory and cognitive function. The disease is caused by the build up of toxins in the brain leading to deterioration of brain tissue. The hippocampus, our brain’s memory center, deteriorates as the disease progresses. The National Institute of Health estimates that 5.1 million Americans suffer from Alzheimer’s.

In 2009 a study found negative correlations between the risk of developing Alzheimer’s disease and physical activity and diet health (Physical Activity, Diet, and Risk of Alzheimer Disease, 2009, Nikolaos Scarmeas, et al.). The study looked at 1880 elderly individuals from New York City over an average period of 5.4 years.  Individuals diet score and physical activity score was collected. The study participants were screened to ensure that they were not suffering from dementia before participating in the study. Those reporting significant physical activity had a 37-50% lower risk of developing Alzheimer’s disease. Those in the highest Mediterranean-style diet adherence tertile had a 32-40% reduced risk of developing Alzheimer’s disease.

Good physical activity and a healthy diet were both found to independently reduce risk of developing Alzheimer’s disease. The Godin leisure time questionnaire was administered to determine physical activity. The questionnaire looked at physical activity over a two-week interval. Diet was determine with the 61-item version of the Willett Semiquantitative Food Frequency Questionnaire to determine adherence to a mediterean-type diet (points for fruits, vegetables, fish, grains and lost for meats, dairy, fats). Subsequent questionnaires were administered every 1.5 years to ensure the validity of the initial questionnaire.

Alzheimer Disease (AD) Incidence by High or Low Physical Activity Levels and Mediterranean-Type Diet Adherence Scores

 

The participants were all 77+/-1 years old; as is the case with elderly populations  physically activity was not prevalent in the study participants.  Therefore, the high physical activity corresponded to 1.3 hours of vigorous physical activity, 2.4 hours of moderate physical activity or 4 hours of light physical activity. This demonstrates that even a small amount of physical activity can lead to significant benefits in reducing Alzheimer’s.

How does exercise protect the brain?

The mechanism that exercise influences Alzheimer’s Disease risk may be through various toxins and neuro-factors. Research has shown that brain-derived neurotrophic factor (BDNF) protects against synapse deterioration and may be able to treat Alzheimer’s. Moderate to vigorous physical activity increases BDNF. Low levels of Nerve Growth Factor (NGF) has been shown to be a risk factor for Alzheimer’s. Like BDNF, exercise increases the brain’s NGF. Reactive oxygen species in the brain may be another risk factor for Alzheimer’s. Exercise takes care of reactive oxygen species via two pathways: exercise reduces their production and exercise raises antioxidant levels, which detoxify reactive oxygen species. Exercise has been shown in mice models to reduce expression of several genes that have been found to correlate with Alzheimer risk.

Another mechanism exercise may influence Alzheimer’s risk is through cerebral blood flow and metabolism. Both cerebral blood flow and metabolism decrease with the onset of Alzheimer’s. Exercise significantly increases both. Exercise increases vascular endothelial growth factor (VEGF) in the brain. VEGF spurs the development of nigral microvessels, countering the decrease in nigral micro vessel density, an effect of aging. Exercise, especially high intensity exercise, at a young age has been shown to have a tremendous impact on the the promotion of VEGF.

For more information about the biological mechanisms behind exercises reduction in Alzheimer’s risk read Exercise Plays a Preventive Role Against Alzheimer’s Disease (Z. Radak, et al., 2010).

In summary, physical activity and diet exert significant influence on Alzheimer’s Disease risk. Although the mechanism is not exactly known, researchers speculate that it may be through neuro-factors, toxins, cerebral blood flow and cerebral metabolism, all of which are controlled by some extend through exercise. Please share your thoughts!

Exercise Reduces Parkinson’s Disease Morbidity

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Two studies suggest exercise may reduce risk of Parkinson’s Disease and reduce the behavioral effects after onset.

 

 

Parkinson’s disease affects over a million Americans is the second most prevalent neurodegenerative disease following Alzheimers disease.  Parkinson’s disease is a dopaminergic brain disorder that leads to slow movements (bradykinesia), rigidity, tremor and postural instability. Parkinsons patients often develop problems with speech, memory, general cognition and smell. As a result of these symptoms, Parkinson’s disease is a dehibilating disease burdening life for both patient and family. However, patients can remain functional with treatment for over 30 years after diagnosis, it is a slowly progressing disease unlike some other neurodegenerative diseases. Parkinson’s disease results from a loss of dopaminergic neurons in the substantia nigra (a region in the midbrain of the brainstem). An etiology is not known, although several genes have been implicated including alpha-synuclein (which forms lewy bodies in neurons, a pathologic characteristic of Parkinsons) and DJ1 (related to mitochondria function). Reactive oxygen species, calcium signaling, proteinaupathy, and viruses have all been discussed as possible etiologies. Several different treatments are available to mask the symptoms, but there is currently no cure. These treatments include dopamine (prescribed as Levodopa), dopamine agonists (Mirapex) and deep brain stimulation (DBS).

In 2010, a study was published finding that adults who participated in physical activity had a reduced risk of developing parkinson’s disease in the next four to ten years (Physical Activities and Future Risk of Parkinson Disease, 2010, Q. Xu, Y. Park, et al.). This study looked at the physical activity of 200,000 plus participants in a NIH-AARP study. Doctor diagnosed Parkinson’s disease rates were collected ten years later. Those who were diagnosed with Parkinson’s in the four years immediately following the initial physical activity survey were left out of the statistical analysis. The study found that adults who reported participating in physical activity over each of the two survey periods had a 40% lower risk of being diagnosed with Parkinson’s disease ten years later. Interestingly, the study found that physical activity at early ages had no link to risk of developing Parkinson’s. Exactly why physical activity is correlated with a reduced risk of developing Parkinson’s is not exactly known. Most likely, exercise was delaying onset of symptoms and progression of disease, rather than fully preventing diagnosis. However, several studies provide some light on possible explanations.

A study published in 2003 found that mice forced to run on a treadmill after being injected with a dopamine toxin, 6-hydroxydopamine, showed less loss of motor control and better retention of neurochemicals that play a role in the dopamine pathway (Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson’s disease, 2003, J.L. Tillerson, et al.).

The study looked at the levels of DAT, VMAT2 (vesicular monamine transporter) and TH (tyrosine hydoxalase). DAT is responsible for dopamine re-uptake in the synapse.  VMAT2 is responsible for the vesicle that transports dopamine between the synapses. TH is the rate-limiting enzyme in the synthesis of dopamine. Studies have shown that people with Parkinson’s have reduced levels of VMAT2. When mice were treated with the toxin MPTP significant decreases in VMAT2, DAT and TH were observed.  However, as figure A shows, mice forced to run on a treadmill showed a reduced drop in DAT, VMAT2 and TH.

Figure A. Mice treated with MPTP had significant losses of neurochemicals DAT, VMAT2 and TH relative to the control. However, mice treated with MPTP and forced to run on a treadmill showed less loss of all three measured neurochemicals.

In addition, motor function was measured in the neurotoxin-treated mice using a forepaw test. Parkinsons-model mice running on a treadmill showed significantly better performance in motor function than sedentary mice. This suggests that exercise could be used to reduce the behavioral consequences of Parkinson’s disease.

In summary, a large human study demonstrated exercise reduces risk of being diagnosed with Parkinson’s disease over the next ten years. In addition, a study of mice treated with a parkinsons-inducing neurotoxin found that exercise reduced dopamine neurochemical drop and motor function. Researchers will find a cure for parkinson’s disease, but in the meantime exercise may be the only option for delaying the progression.