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Traumatic Brain Injury And Parkinson’s Disease

Conflict Of Interest Statement

Traumatic Brain Injury Vlog – Episode 75

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer SAH and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.

Chronic Tbi Induces Depression

To examine anxiety-like behavior and locomotor function, mice subjected to chronic TBI were compared to sham mice at 1, 7, 14, and 30 days on several behavioral tests, including the open field test, EPM, and Barnes maze. Mice were tested in the EPM at all time points, TBI mice spent notably less time in the open arms as compared to sham animals . The anxiety-like phenotype induced by the lesion was confirmed in the open field test . Chronic TBI mice showed a pronounced increase in thigmotaxis, seen as the tendency to remain close to the wall , when compared to sham mice, as specified by less time spent in the center of the open field and shorter distance covered in the center of the open field . Spatial learning and memory were assessed in TBI mice using the Barnes maze. In this test, sham mice quickly learned to escape the open field and reach the black escape box, as revealed by the rapid decline in escape latency. In contrast, there was a statistically significant decrease in spatial learning induced by TBI for all time points, with an increase in escape latency and mean number of errors F = 12 at 1 days, F = 2.583 at 3 days, F = 7 at 7 days, F = 1.714 at 30 days): Figure C1) F = 1 at 1 days, F = 1 at 3 days, F = 2.333 at 7 days, F = 4 at 30 days).

Tbi And Neurological Disease Findings

After looking at the data, researchers uncovered:

  • There was no statistically significant link between a TBI with LOC and an increased risk of dementia or Alzheimers development.
  • There was, however, a strong link between TBI with LOC and the eventual development of Parkinsons Disease.

The results of this study suggest that some individuals with a history of TBI are at risk for late-life neurodegeneration, but not Alzheimers disease, said researcher Kristen Dams-OConnor. We want to identify and treat post-TBI neurodegeneration while people are still alive, but to do this, we need to first understand the disease. Prospective TBI brain donation studies can help us characterize post-TBI neurodegeneration, identify risk factors, and develop effective treatments.

Dams-OConnor said the ultimate goal is to develop a better understanding of the mechanisms behind a TBI with LOC and why it leads to Parkinsons Disease so we can come up with earlier interventions and treatment programs to reduce to progression of the disease.

These results suggest that greater attention should be given to the long-term risk of Parkinsons after traumatic brain injury, said study author David A. Hovda.

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Just One Concussion Could Raise Parkinson’s Risk

HealthDay Reporter

WEDNESDAY, April 18, 2018 — If you’ve ever had a mild concussion, your risk of developing Parkinson’s disease goes up by 56 percent, a new study of more than 300,000 U.S. veterans suggests.

“Upwards of 40 percent of adults have had a traumatic brain injury , so these findings are definitely concerning,” said study author Dr. Raquel Gardner. She is an assistant professor of neurology at the University of California, San Francisco, and the San Francisco VA Medical Center.

But Gardner stressed that the findings don’t mean everyone who has ever had a concussion is doomed to develop the degenerative neurological disorder that affects coordination of movement.

“Even in this study, the vast majority of veterans with traumatic brain injury did not develop Parkinson’s,” she said.

Dr. Rachel Dolhun, vice president of medical communications for the Michael J. Fox Foundation for Parkinson’s Research, pointed out the lifetime risk of Parkinson’s is probably about 1 to 2 percent, so a greater than 50 percent increase in that risk isn’t as alarming as it sounds.

“Having a TBI doesn’t definitively equate with getting Parkinson’s disease. The risk is still pretty small,” Dolhun said.

But these findings do lend credence to the idea that some professional athletes have developed Parkinson’s disease as a result of their athletic careers. The most famous is probably boxer Muhammad Ali.

Study volunteers were aged 31 to 65, and were followed for up to 12 years.

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What Does The Research Say

During agitationor a concussion the brain makes contact with the skull ...

One study that examined PD and TBI in twins that is, people who would have the same genetic risk factors found that mild TBI increased the risk of PD, even if the injury occurred decades before PD developed. The researchers found that people with TBI developed PD earlier, and the risk of PD was higher in people with more than one head injury.

Another group of researchers looking at the connection between TBI and PD published a meta-analysis of 22 different research studies including nearly 100,000 participants. The researchers found that people with a history of TBI were more than 1.5 times as likely to develop PD than people with no history of TBI.

A more recent study examined the risk of PD in people who experienced head injuries later in life, at age 55 years or older. Five to seven years after the head injury, older adults with TBI were almost 1.5 times more likely to develop PD than their peers without TBI. This study also found that moderate to severe TBI and repeated TBI were associated with a greater increase in PD risk.

Finally, a study of PD in military veterans aged 18 and older revealed that TBI significantly increased the risk of developing PD by 71 percent. Using data from more than 300,000 people, the studys researchers found that mild TBI increased the risk of PD by 56 percent, and moderate to severe TBI increased the risk of PD by 83 percent. The researchers also saw a higher rate of comorbidities in people with TBI compared to those without TBI.

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New Evidence Links Traumatic Brain Injury With Parkinsons

A new study finds that traumatic brain injury from a blow to the head, with loss of consciousness, may increase a persons risk of developing Parkinsons disease later in life. The results appear in the July 11 online edition of JAMA Neurology. The researchers did not find an association between head injury and Alzheimer’s disease.

The neurological effects of head injuries are much in the news, with worry over repeated, relatively mild, concussions among athletes, and with the recent death of boxing great Muhammad Ali, who lived with Parkinson’s disease. This new study, however, focused narrowly on the long-term effects of even one instance of trauma to the head especially injuries involving loss of consciousness among older people more representative of the general population.

Researchers led by Paul K. Crane, M.D., M.P.H., at the University of Washington in Seattle, analyzed self-reported data, collected between 1994 and 2014, from 7,130 people who had enrolled in other studies that gathered data on memory, cognition and aging. On average, study participants were 80 years old at the time of this report, and did not have dementia, PD, or Alzheimers disease when they enrolled in the original studies. Forty percent were men. Brain tissue was examined on autopsy for 1,589 participants, to search for signs of PD and Alzheimers disease.

Results

What Does It Mean?

Traumatic Brain Injuries And The Risk For Parkinsons

Parkinsons disease is associated with genetic and environmental risk factors. Among these factors, the most common nongenetic risk factor for PD is traumatic brain injury .

TBI is damage to the brain caused by head injuries such as:

  • Falling and hitting your head
  • Being hit in the head during sports
  • Penetrating trauma, such as from a gunshot wound
  • Injuries that cause a skull fracture
  • Blast injuries seen in combat

TBI can occur without significant signs of external injury. Symptoms of TBI such as loss of consciousness, confusion, blurred vision, difficulties with memory or concentration can begin immediately after injury or days or weeks later. TBI is classified as mild, moderate, or severe based on symptoms caused by the injury. The more severe the injury is, the more severe the symptoms will be.

Numerous studies have found a significantly increased risk of PD after TBI.

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Brain Injury And Parkinsons Disease

Head injuries can increase a persons risk of developingParkinsons Disease and other forms of parkinsonism.

However, even with the increased risk, it is still a rareside effect of brain injury. Only about 1% of TBI patients will experienceparkinsonism.

If you do end up diagnosed with post-traumatic parkinsonism, treatment will most likely involve a combination of physical therapy and medication.

Changes Of Pd Markers In The Snc After Chronic Tbi

Symptoms of CTE

To examine if chronic TBI can modify PD-like markers, brain sections from control and TBI mice 30 days after surgery were stained with dopaminergic-specific markers and -syn. Midbrain expression of TH-positive neurons and DAT was significantly decreased 30 days after TBI . Western blot analysis confirmed a significant reduction of TH and DAT protein expression . In contrast, chronic TBI resulted in a visible increase in -syn staining compared to control group and protein as shown by Western blot analysis .

Effect of chronic TBI on Parkinsonian markers. Midbrain was stained with antibodies against tyrosine hydroxylase , dopamine transporter and synuclein . Immunohistochemical analysis of midbrain obtained from mice subjected to TBI revealed a positive staining for TH, DAT, and -syn compared with sham-operated mice . Data are expressed as a percentage of total tissue area and are means ± SE of 5 mice/group. **P< 0.005 vs. Sham *P< 0.05 vs. sham . Western blot analysis confirmed our data . Each data are expressed as Mean ± SEM from N = 5 mice/group. *P< 0.01 vs. sham, **P< 0.005 vs. sham.

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Pathology Overlap Between Tbi And Pd

TBI sequalae can be divided in to 3 phases: acute , post-acute , and chronic . During the acute period cell necrosis from direct transfer of force to the brain tissue occurs, followed by secondary cell death from axonal pathology, and inflammation. The post-acute period can be characterized by neuronal remodeling, decreased inflammation, and an increase in chronic pathology . Chronic pathology of most interest here includes, neurodegeneration, protein misfolding , and persistent inflammation. Chronic TBI pathology can vary, with some patients recovering completely while others suffer physical and cognitive decline, and eventually develop neurodegenerative diseases , most notably Parkinsons Disease .

PD as well as TBI brains are characterized by neuronal degeneration, compromised blood brain barrier, infiltration and expansion of resident microglia into the affected areas, and infiltration of phagocytic cells from the periphery . In both PD and following a TBI this histological presentation is accompanied by inflammation, metabolic disturbances, and protein aggregation, making them essential factors to consider when studying the mechanisms connecting these two disorders.

Figure 1

Inflammation

Metabolism

Protein aggregation

Chronic Tbi Induces A Significant Neuroinflammatory Response Regulated By Nf

To investigate the cellular substrate that link PD with chronic TBI, Western blot analysis was assessed in midbrain tissue 30 days post-TBI, using IB- and NF-B- specific antibodies. There was a basal expression of IB in sham mice , while IB expression was considerably reduced in mice subjected to chronic TBI . Moreover, p65 subunit translocation was increased in nuclear brain homogenates after TBI, compared with sham . Translocation of NF-B is a critical phase in the coupling of extracellular stimuli to the transcriptional stimulation of specific pro-inflammatory target genes such as iNOS and COX-2. To evaluate the role of nitric oxide in TBI, iNOS expression was evaluated by Western blot analysis. At 30 days post-TBI there was a significant increase in iNOS expression in midbrain of TBI mice . COX-2 expression was also stimulated by TBI compared to sham .

Figure 5. Effects of chronic TBI on Nuclear factor B pathway and pro-inflammatory enzymes. Degradation of IB was significantly increased 30 days after TBI . Also, chronic TBI resulted in enhancednuclear translocation of p65 . A significant increase in inducible nitric oxide synthase and cyclooxygenase -2 was observed in the midbrain from TBI mice compared with the Sham mice . Data show one representative blot from three independent experiments with similar results. Data are expressed as Mean ± SEM from N = 5 mice/group. * P< 0.01 vs. sham, **P< 0.005 vs. sham,***P< 0.005 vs. sham. .

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Traumatic Brain Injury And Ambient Paraquat Exposure

Cases and controls provided information on demographics, detailed lifetime residential, workplace address, and medical histories, and behavioral risk factors in interviews. As part of the medical history interview, participants reported ever having experienced a head injury with loss of consciousness for over 5 minutes, their age at the time of the event, and whether they had been hospitalized. We defined TBI as having reported a head injury with loss of consciousness for more than 5 minutes.

Definition Of Tbi Exposure And Severity

Severe head injury linked to Parkinson

TBI exposure was defined either by having a diagnosis of TBI after a comprehensive neurologic assessment or by having at least one inpatient or outpatient TBI diagnosis from a comprehensive list of ICD-9 codes used by the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Branch for TBI surveillance.15 ICD-9 codes were used as these were available during the study period ending in 2014.

Veterans with more than one TBI-related encounter were classified based on the most severe injury reported during the index year. TBI frequency could not be assessed in this study of nationwide inpatient and outpatient data because multiple TBI-related encounters in the VHA databases may pertain to a single prior TBI event and therefore do not necessarily indicate repeated TBI events. Veterans with undetermined TBI severity were included in the any TBI analysis but were not included in the TBI severity analysis.

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Chronic Tbi Reduces Neurotrophic Factor Expression Levels

To test whether chronic TBI modulates PD via regulation of neurotrophic factors, we used immunohistochemistry to examine BDNF, GDNF, and NT-3 levels in the midbrain. Thirty days post-trauma there was a reduction in immunostaining for all three neurotrophic proteins in comparison to sham animals. Moreover, Western blot analysis confirmed these observations .

Figure 6. Effect of chronic TBI on Neurotrophic factors. By immunohistochemical analysis, a basal level of BDNF GDNF and NT-3 positive staining was detected in midbrain samples from sham-operated mice . BDNF and GDNF and NT-3 expression was significantly reduced in midbrain samples from TBI mice . Data are expressed as a percentage of total tissue area and are means ± SE of 5 mice/group. **P< 0.005 vs. Sham *P< 0.05 vs. sham . Western blot analysis confirmed our data showing a significant decrease of neurotrophic factor following TBI . Each data are expressed as Mean ± SEM from N = 5 mice/group. **P< 0.005 vs. sham *P< 0.05 vs. sham .

Assessment Of Movement Preparation Initiation And Execution

Visual simple and four choice reaction time tasks were completed, as well as the Purdue pegboard and index finger tapping. On all these tests our patient performed worse than an age matched healthy normal subject and similar to previously published data for elderly patients with Parkinsons disease. For both the SRT and CRT tasks his initiation times were slightly slower and his movement times considerably slower with the right hand compared with the left. Movement related cortical potentials in our patient were compared with a normal age matched subject, and the amplitude of all components was reduced. The MRCPs before left hand movements had a smaller amplitude and more delayed onset, with the early Bereitschaft Potential component possibly being absent, suggesting bilateral deficits in MRCPs.

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Microglia But Not Astrocytes In The Snc Regulate

To evaluate microglia involvement and its correlation with PD markers, the midbrain was double-stained with antibodies against Iba1 and -syn . Microglial cells visibly expressed -syn-positive staining in chronic TBI tissue compared to sham. Further, there was a clear co-localization of -syn and Iba1 in the TBI samples .

Figure 3. Effect of chronic TBI on -synuclein expression in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein positive cells. Midbrain sections wer double-stained with antibodies against Iba1 or GFAP and -syn . The red spots indicate the co-localizations indicated by yellow arrows. There were increased microglia cells in TBI mice as compared to the control group . -syn positive neurons were significantly increased in microglia after chronic TBI . Considerable astrogliosis was present in TBI panels . -syn positive neurons did not show any significant immunoreactivity in astrocytes after TBI . Scale bar = 50 and 20 m . Each data are expressed as Mean ± SEM from N = 5 mice/group. Counting of colocalized cell confirmed our data. The co-localization of image was analyzed with image J software. *P< 0.05.

How Does Tbi Increase Risk Of Pd

Is CTE a brain injury or brain disease?

TBI is a risk factor for several neurodegenerative diseases, including PD, Alzheimers disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy. The link between TBI and the risk of developing PD is clear: TBI affects the brain in some of the same ways as PD and other neurodegenerative diseases, causing the same types of damage to brain cells.

TBI causes metabolic disturbances, inflammation, and protein aggregation in the brain cells, effects that can all cause immediate or long-term damage to the brain. All of these effects caused by TBI are also part of the disease processes seen in people with PD and certain other neurodegenerative diseases.

TBI can cause damage to the blood-brain barrier , the layer of cells in blood vessels in the brain that controls what substances can cross from the bloodstream into brain tissue. Damage to the BBB results in an inflammatory immune response and also disrupts normal metabolism in brain cells, causing long-term damage and cell death.

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