Mild TBI May Elevate Parkinson’s Disease Risk


Military veterans diagnosed with mild traumatic brain injury (mTBI) have a 56% increased risk of developing Parkinson’s disease (PD), a large, retrospective cohort study shows.

Investigators also found those with traumatic brain injury (TBI) of any severity had a 71% increased risk for PD and those with mild-to-moderate TBI had an 83% increased risk.

“Our study adds to the mounting evidence that even mild TBI is a risk factor for several neurodegenerative diseases of aging, including both dementia and Parkinson’s disease,” first author, Raquel C. Gardner, MD, San Francisco Veterans Affairs Medical Center and assistant adjunct professor of neurology at the University of California San Francisco Weill Institute for Neurosciences, told Medscape Medical News.

“I would encourage clinicians to counsel their TBI-exposed veterans to engage in brain healthy activities such as a heart-healthy diet, increased physical activity, cessation of activities that may harm the brain or vasculature, and optimized management of any chronic medical conditions.

“I would also apply fall-prevention strategies to those patients at high risk for falls and would be on the lookout for symptoms of parkinsonism that may further increase fall risk and risk for repeat injury,” Gardner said.

The study was published online April 18 in Neurology.

Paucity of Data on mTBI

Prior studies have shown a strong association between moderate-to-severe TBI and risk for neurodegenerative disorders such as PD. However, the research on mTBI has been inconclusive, with only one case-controlled study focused on military veterans (Ann Neurol. 2006;60:65-72).

“Our research looked at a very large population of US veterans who had experienced either mild, moderate or severe traumatic brain injury in an effort to find an answer to whether mild traumatic brain injury can put someone at risk,” senior author, Kristine Yaffe, MD, said in a release.

The study, which is part of the Chronic Effects of Neurotrauma Consortium research, included 325,870 veterans from three US Veterans Health Administration databases.

Participants were aged 31 to 65 years and had no dementia or PD diagnosis at baseline.

Investigators defined mTBI as loss of consciousness for 0 to 30 minutes, alteration of consciousness for a moment to 24 hours, or amnesia for 0 to 24 hours.

They defined moderate-to-severe TBI as a loss of consciousness for more than 30 minutes, alteration of consciousness of more than 24 hours, or amnesia exceeding 24 hours.

TBI exposure and severity were determined via detailed clinical assessments or International Classification of Diseases, Ninth Revision (ICD-9) codes using Department of Defense and Defense and Veterans Brain Injury Center criteria.

Approximately 50% of the cohort had TBI. At an average follow-up of 4.6 years, 1462 veterans had a PD diagnosis. Of these, 949 had prior TBI and 513 had no TBI history.

Investigators reported that of the veterans with TBI of any severity, 949 (0.58%) developed PD vs 513 (0.31%) of those with no TBI.

Results also showed that 360 of 76,297 veterans with mTBI, or 0.47%, developed the disease and 543 of 72,592 with moderate-to-severe TBI, or 0.75%, developed PD.

After adjustment for age, sex, race, education, diabetes, hypertension, and other health conditions, any kind of TBI was associated with a 71% increased risk for PD.

In addition, those with mTBI had a 56% increased risk and those with moderate-to-severe TBI had an 83% increased risk.

Researchers also found that those with any type of TBI were diagnosed with PD an average of 2 years earlier than those without TBI.

Gardner said the current research is “the first nationwide cohort study to establish an association between mild TBI and Parkinson’s disease, and the first cohort study in veterans.”

“Based on evidence from prior small case-control studies as well as our prior California-wide cohort study [of civilians] published in Annals of Neurology, [2015;77:987-995] I was not surprised by our result,” Gardner said.

“I am, however, very concerned by our result as our study now confirms, via the highest level of epidemiological evidence that a single study can achieve, that this association is not spurious.”

The use of physician-diagnosed TBI and PD, the longitudinal cohort design, and the large sample size are strengths of the study, the researchers note.

However, use of ICD-9 codes may have limited the inclusion of all cases of TBI and PD. The investigators attempted to correct for this limitation by including inpatient and outpatient data and by conducting a sensitivity analysis requiring at least three separate healthcare encounters with a PD diagnosis.

Gardner noted it is “critical” for future research to examine whether there are specific high-yield risk factors that can be modified to prevent or delay onset of post-TBI PD.

“Simultaneously,” she added, “it is critical to unravel the biological mechanisms and neuropathology of these cases of post-TBI Parkinson’s disease, as well as early biomarkers to guide screening and early treatment trials.”

Controversial Association

Commenting on the findings for Medscape Medical News, Rahul Raj, MD, PhD, adjunct professor of experimental neurosurgery and a neurosurgery resident at the HYKS NeuroCenter in Helsinki, Finland, said, “The epidemiological association between TBI and Parkinson’s disease is still somewhat controversial, and at least two nationwide register studies did not find any association between TBI and Parkinson’s disease” (BMJ. 2008;337:a2494; PLoS Med. 2017;14:e1002316).

“This might, in part, be due to the fact that the authors used the Veteran Health Administration database, including only US veterans, whose risk-profile might somewhat differ from the [general] population,” Raj said.

Also commenting on the findings, Kristen Dams-O’Connor, PhD, associate professor of rehabilitation medicine and associate professor of neurology at the Icahn School of Medicine at Mount Sinai in New York City, noted that TBI history may not have been fully captured because it “isn’t always recorded in the health record and many veterans receive care outside of the VA. This would actually bias findings toward the null, and still they still found significantly increased risk for Parkinson’s disease.”

“This study suggests that mTBI is associated with 56% increased risk of PD, while more severe TBI is associated with greater risk for PD. These findings are consistent with what our group reported previously. We found an even greater risk for Parkinson’s disease associated with TBI with loss of consciousness longer than 1 hour,” Dams-O’Connor added (JAMA. 2016;73:1062-1069).

“Not all people who serve get care at a VA,” agreed Paul Crane, MD, MPH, professor of medicine at the University of Washington in Seattle. “The authors are unable to quantify the extent of care received outside the VA system. They may be under-counting their Parkinson’s disease outcomes.”

“Likewise, capture of Parkinson’s disease from ICD-9 codes as opposed to research-based criteria by trained research personnel is susceptible to incomplete capture,” he added.

“Parkinson’s disease is a highly age-dependent condition, with rates that go higher with advancing age. The mean age of the cohort is only about 48 years, and they cover only about 5 years on average in follow-up. So the middle of the distribution is not at high risk for Parkinson’s disease,” Crane said.

“I suspect…the magnitude of effect may be somewhat stronger than the magnitude Gardner et al report in their interesting and carefully conducted study,” he added.

Raj noted that “although the relative risk reported in hazard ratios by the authors seems high, the absolute PD risk is still very small — 0.2% to 0.3% increase between non-TBI and TBI.”

His point was supported by Dams-O’Connor, who noted that “for people living with a history of mTBI, I do think it’s important to bear in mind that the absolute risk for developing PD, even after a TBI, is quite small.”

Advertisements

PET/CT neuroimaging reveals pituitary abnormalities in veterans with PTSD


Hybrid neuroimaging of the pituitary region of the brain could help distinguish military veterans with posttraumatic stress disorder from those with mild traumatic brain injury, according to research presented at the annual meeting of the Radiological Society of North America.

Besides the utility of PET/CT in differential diagnosis, the findings support the notion that pituitary gland damage from blast injuries are causing hormonal irregularities affecting veterans diagnosed with posttraumatic stress disorder(PTSD).

“It’s important that providers as well as patients are aware of what might be causing these PTSD-like symptoms and that there are therapeutics that can help them if current therapies, such as antidepressants, anxiolytics and group therapy, aren’t helping,” Thomas M. Malone, a research associate at Saint Louis University School of Medicine, told Endocrine Today.

Malone and colleagues focused on 18F-fluorodeoxyglucose (18F-FDG) PET/CT, which measures uptake of the radiopharmaceutical FDG to show metabolism, in a retrospective review of 159 brain exam records; all PET images were obtained in the morning and adhered to standard brain PET/CT protocol. MRI scans of the brain were subsequently taken and given a structurally normal interpretation by a fellowship-trained neuroradiologist.

Cases were divided into three groups — normal control, traumatic brain injury(TBI) and TBI+PTSD — matched for age and sex. Based on criteria from the 2009 Department of Defense and Department of Veterans Affairs consensus definition of TBI, patients were further stratified by severity.

Two board certified nuclear medicine physicians masked to the groups read the PET/CT scans.

Maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) of the pituitary gland and the hypothalamus were log-recorded. With approximately normal distributions and sufficiently large sample sizes, parametric tests were performed.

The SUVmax from the hypothalamus was lower in patients with TBI only vs. normal controls (5.78 vs. 6.46; P=.04). With TBI stratified by severity and limited to military veterans, the SUVmean from the pituitary was higher among patients with mild TBI+PTSD compared with those with mild TBI only (3.08 vs. 2.54; P=.04).

The higher FDG uptake demonstrated in the pituitary glands of patients with PTSD points to the possibility that some PTSD cases may actually be hypopituitarism masked, according to the researchers, in which case screening and treatment could help.

“I really hope it helps remove the stigma that many soldiers feel is attached to a PTSD diagnosis,” Malone said. “Being able to see that there is a physical, neurological injury caused by blast or a car accident should help remove any moral judgment about someone feeling depressed, anxious or continuing to experience fatigue or cognitive difficulties after a [TBI].” – by Allegra Tiver

PET/CT neuroimaging reveals pituitary abnormalities in veterans with PTSD


Hybrid neuroimaging of the pituitary region of the brain could help distinguish military veterans with posttraumatic stress disorder from those with mild traumatic brain injury, according to research presented at the annual meeting of the Radiological Society of North America.

Besides the utility of PET/CT in differential diagnosis, the findings support the notion that pituitary gland damage from blast injuries are causing hormonal irregularities affecting veterans diagnosed with posttraumatic stress disorder(PTSD).

“It’s important that providers as well as patients are aware of what might be causing these PTSD-like symptoms and that there are therapeutics that can help them if current therapies, such as antidepressants, anxiolytics and group therapy, aren’t helping,” Thomas M. Malone, a research associate at Saint Louis University School of Medicine, told Endocrine Today.

Malone and colleagues focused on 18F-fluorodeoxyglucose (18F-FDG) PET/CT, which measures uptake of the radiopharmaceutical FDG to show metabolism, in a retrospective review of 159 brain exam records; all PET images were obtained in the morning and adhered to standard brain PET/CT protocol. MRI scans of the brain were subsequently taken and given a structurally normal interpretation by a fellowship-trained neuroradiologist.

Cases were divided into three groups — normal control, traumatic brain injury(TBI) and TBI+PTSD — matched for age and sex. Based on criteria from the 2009 Department of Defense and Department of Veterans Affairs consensus definition of TBI, patients were further stratified by severity.

Two board certified nuclear medicine physicians masked to the groups read the PET/CT scans.

Maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) of the pituitary gland and the hypothalamus were log-recorded. With approximately normal distributions and sufficiently large sample sizes, parametric tests were performed.

The SUVmax from the hypothalamus was lower in patients with TBI only vs. normal controls (5.78 vs. 6.46; P=.04). With TBI stratified by severity and limited to military veterans, the SUVmean from the pituitary was higher among patients with mild TBI+PTSD compared with those with mild TBI only (3.08 vs. 2.54; P=.04).

The higher FDG uptake demonstrated in the pituitary glands of patients with PTSD points to the possibility that some PTSD cases may actually be hypopituitarism masked, according to the researchers, in which case screening and treatment could help.

“I really hope it helps remove the stigma that many soldiers feel is attached to a PTSD diagnosis,” Malone said. “Being able to see that there is a physical, neurological injury caused by blast or a car accident should help remove any moral judgment about someone feeling depressed, anxious or continuing to experience fatigue or cognitive difficulties after a [TBI].” – by Allegra Tiver

Pituitary May Link Brain Injury and PTSD


Metabolic activity in the pituitary gland may help doctors differentiate between patients who are exhibiting signs of mild traumatic brain injury alone and those who are also suffering from post traumatic stress disorder (PTSD), researchers suggested here.

Metabolic activity in the pituitary gland — as measured by PET/CT scans — was significantly higher in the mild traumatic brain injury plus PTSD patient group who averaged an SUVmean (standardized uptake value) score of 3.08, compared with a score of 2.54 for patients whose condition was limited to mild traumatic brain injury (P=0.0418).

“If a person has signs and symptoms of PTSD with mild traumatic brain injury that persist for many months, a physician might consider starting hormonal therapy for these patients,” study co-author Thomas Malone, BA, a research associate at Saint Louis University Hospital, in Missouri, told MedPage Today.

“We retrospectively reviewed 159 dedicated brain PET/CT studies,” Malone explained while presenting his study at a press c0nference at the centennial meeting of the Radiological Society of North America. “All the patients in our study had traumatic brain injuries.”

He said that researchers acquired the images in the morning and did so according to standard brain PET/CT protocol. They subsequently performed MRI scans of the brain, which were interpreted as structurally normal for all subjects by a fellowship-trained neuroradiologist. Patients with traumatic brain injury were further stratified by severity based on criteria from the Department of Defense and Veterans Affairs Consensus Definition.

PET/CT scans were read by two board-certified nuclear medicine physicians blinded to the groups, and a log recorded the SUVmax and SUVmean of the pituitary gland and the hypothalamus.

The SUVmax from the hypothalamus was significantly lower in traumatic brain injury-only patients compared with the normal controls (5.78 versus 6.46, P=0.038).

Osama Raslan, MD, MBCh, nuclear medicine resident at Saint Louis University Hospital and the lead author of the study, noted, “To our knowledge this is the first imaging study that supports other research suggesting that pituitary dysfunction may contribute to PTSD symptoms in patients with mild traumatic brain injury.”

Malone said that because of the pituitary’s location in the brain it can be subject to damage in blast-related trauma — a frequent cause of injuries in combat areas in the Middle East and elsewhere. “Research suggests that persistent self-reported neurocognitive difficulties and brain dysfunction may be related to microstructural damage that remains invisible using standard magnetic resonance imaging or computer-assisted tomography (CT) scans,” he said.

The researchers cited Department of Defense statistics that indicates 152,986 cases of PTSD between 2000 and 2014.

Previous research examining blood work suggests that hormonal abnormalities may account for PTSD symptoms in blast-related mild traumatic brain injury, Malone said.

“SUVmean in the pituitary region is a promising objective tool for differentiating mild traumatic brain injury plus PTSD patients from mild traumatic brain injury-only patients in a post-acute veteran population,” Malone said. “PTSD represents an increasing public health issue that is difficult to diagnose. PET/CT activity in pituitary/hypothalamus may provide an objective method to diagnose and differentiate PTSD.”

Press conference moderator Max Wintermark, MD, chief of neuroradiology at Stanford University Medical Center in Stanford, Calif., told MedPage Today that the studies described by Raslan and Malone are preliminary work. “I think we need more research in this area. Mild traumatic brain injury is a heterogeneous disease. PTSD is also a heterogeneous disease.”

“Here we have very interesting results but we have a very small sample size,” he continued. Wintermark said the differences in the SUVmax and SUVmean as described by the authors was not compelling at this time “for clinicians to apply that to individual patients because of the variability of the measure. I don’t think we are ready to use that tool in the clinic at this time in traumatic brain injury or PTSD patients.”

He suggested that doing hormone screening in every PTSD patient might not be a good use of resources.

Response to acute concussive injury in soccer players: is gender a modifying factor?


Several studies have suggested a gender difference in response to sports-related concussion (SRC). The Concussion in Sport group did not include gender as a modifying factor in SRC, concluding that the evidence at that point was equivocal. In the present study the authors endeavored to assess acute neurocognitive and symptom responses to an SRC in equivalent cohorts of male and female soccer players. The authors hypothesized that female athletes would experience greater levels of acute symptoms and neurocognitive impairment than males.

Methods

Baseline symptom and neurocognitive scores were determined in 40 male and 40 female soccer players by using the Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) scale prior to any SRC. After sustaining an SRC, each athlete completed postconcussion ImPACT tests and was carefully matched on a wide array of biopsychosocial variables. Baseline symptom and neurocognitive test scores were compared, and their acute symptoms and neurocognitive responses to concussive injury were assessed.

Results

Specific a priori hypotheses about differences between males and females at baseline and at postconcussion measurements of verbal and visual memory ImPACT scores were evaluated according to simple main effects of the gender variable and according to baseline-to-postconcussion main effect and interaction of 2 × 2 split-plot ANOVA. Neither the interaction nor the main effects nor the simple main effects for either ImPACT variable were found to be statistically significant. Exploratory ANOVAs applied to the remaining ImPACT variables of visualmotor speed, reaction time, impulse control, and symptom total scores revealed only a single statistically significant baseline-to-postconcussion main effect for the symptom total.

Conclusions

The results failed to replicate prior findings of gender-specific baseline neurocognitive differences in verbal and visual memory. The findings also indicated no differential gender-based acute response to concussion (symptoms or neurocognitive scores) among high school soccer players. The implications of these findings for the inclusion of gender as a modifying factor in this tightly matched cohort are addressed. Potential explanations for the null findings are discussed.

Source: Journal of Neurosurgery