It turns out that white matter matters. Researchers have found greater changes in white matter in connection with more years of playing American football – a novel discovery that paints a more complete picture of the risk of dementia outside the tau protein and other factors known to contribute to dementia .
A study following the deaths of 180 former players who donated their brains supports previous findings that a greater amount of phosphorylated tau protein in the brain is associated with dementia and duration of play.
The study advances a field of discoveries about the direct link between the severity of white matter changes, the number of years playing football and the risk of dementia in those former athletes who have been diagnosed with chronic traumatic encephalopathy (ETS).
Another new discovery has emerged – that a non-recurring factor (RIC) contributes equally to the risk of aging-related atherosclerosis associated with aging and cardiovascular disease.
"The findings underscore that the etiology of dementia and other clinical signs and symptoms among older former American football players is multifaceted and is probably related to tau and non-tau pathologies," lead author Michael L. Alosco, Ph.D., assistant professor of Neurology and Clinical Care and co-director of the Boston University Alzheimer's Disease Center and the CTE Center of the Boston University School of Medicine in Boston, said Medscape Medical News.
"It is therefore essential for physicians to consider these multifaceted etiologies of clinical signs and symptoms when treating and coordinating care for symptomatic individuals who have been exposed to recurrent blows to the head," he said.
The study was published online on August 5th JAMA Neurology,
Arteriosclerosis is an equal participant
The association between phosphorylated tau and dementia "is in line with what we see in other areas of neurodegenerative diseases, such as Alzheimer's disease," Alosco added. "However, it was quite noticeable that the dilution of white matter and arteriosclerosis also contributed to the dementia in this sample."
Previous studies have shown that tau and non-tau pathways, including cerebrovascular disease, are associated with the delayed effects of recurrent head injuries on dementia in individuals with CT.
The contribution of phosphorylated tau pathological changes, comorbid neurodegenerative disease or other pathological conditions to dementia in KTE remains unclear, the researchers note.
To find out more, investigators examined 180 men who were 40 years of age or older at the time of death and who played American football. Everyone was neuropathologically diagnosed with CTE.
Their brains were donated to the brain bank of the Veterans Foundation – University of Boston – Concussion Legacy as part of an ongoing study to understand neurological injuries and traumatic encephalopathy (UNITE).
The researchers performed a semi-qualitative assessment of white matter dilution and arteriosclerosis. Refraction reflects the overall integrity of the white matter, including the degree of loss of myelin, the degree of attenuation or vacuolation of tissues around small blood vessels, and the density of reactive astrocytes.
They also conducted telephone interviews with informants and recorded medical and clinical histories, including the presence, nature and timing of symptoms associated with cognition, behavior or mood, and daily functioning.
The number of years playing football was a proxy for the RHI experience.
Of the 180 donors with ETS, 120 had dementia before death.
Researchers associate increasing age with more severe white matter dilution (β, 0.37; 95% confidence interval [CI], 025 – 0.50), a stage with high CTE (β, 0.32; 95% CI, 0.19 – 0.45) and an increased likelihood of dementia (β, 0.27; 95% CI, 0.13 – 0.42). All these differences were statistically significant (P <.001).
The race did not significantly affect white matter dilution, CTE grade, dorsolateral neurofibrillary severity of the frontal cortex, or dementia.
Corrected analysis showed that, compared to participants with lower severity of dorsolateral neurofibrillary plexus of the frontal cortex, those with high severity had a 2.65 greater increased risk of dementia (coefficient of coefficient [OR], 2.65; 95% CI, 1.24 – 5.70; P = .01).
Although arteriosclerosis was not associated with the number of years playing football, it was independently associated with dementia (β, 0.21; 95% CI, 0.07 – 0.35; P = .003).
Alosco and colleagues noted that dilution of white matter and arteriosclerosis “appear to be due to various causes, with dilution of white matter associated with recurrent head exposure… and arteriosclerosis from cardiovascular disease.
"The findings speak to the variety of pathologies found with CTE and how each contributes uniquely to clinical signs and symptoms, including dementia," they added.
Future research is warranted, Alosco said. Longitudinal studies in living individuals exposed to recurrent head injuries that use different in vivo biomarkers to evaluate white matter and cerebrovascular disease and other pathologies "are essential in determining how these pathologies can contribute to the clinical course and presentation of ETS or other neurological disorders associated with recurrent head injuries.
"In this way, we continue to investigate risk factors and biomarkers for CTE to facilitate the diagnosis of this disease during life," he added. "This is the critical next step."
New data, intriguing data
"The authors have uncovered some important and emerging insights into the pathological pathways to dementia in deceased people who have played soccer and had an ETS," Dr. Julie A. Schneider of the Rush Alzheimer's Center for Diseases, Department of Neurological Sciences, Rush Medical University The Center, Chicago, Illinois notes in an accompanying editorial.
Researchers have shown that the number of years of playing football is related to the severity of tau pathology, regardless of other neurodegenerative disorders, she noted.
"More intriguing was the second pathway in white matter, which linked years of play to dementia through the severity of white matter dilution, regardless of the path of tau," Schnieder wrote.
Therefore, "the authors provide intriguing data on the importance of both the white matter and the path of the tau," says Schneider, who is also affiliated with the pathology department at Rush University Medical Center.
In addition, the study is noteworthy, as investigators also "found that small vascular diseases in the form of arteriosclerosis provide a third and clear path to dementia in CTE players," she writes.
Comprehensive neuropathological studies, sophisticated statistical techniques and multiple sensitivity analyzes are the strengths of the study, Schneider notes.
Breeding bias is an "important limitation". Researchers rated a convenient sample of people who played football, died, became involved or were approved for brain donation and found to have CTE.
"Thus, the incidence of pathological characteristics in this group should not be aggregated in order to assess the prevalence of neuropathological conditions in living individuals who have played or played football in the United States," she writes. We recall that addiction is an additional potential limitation, she notes.
"Despite these limitations, the authors need to be applauded for elegant work and overwhelming support for the many pathological pathways to dementia in CTE players," Schneider said.
The research was supported by a grant from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Department of Veterans Service Award, the Nick and Lyn Buonikonti Foundation, and the National Center for the Advancement of Translational Sciences. The relevant financial relationships of the study authors are listed in the original article. Schneider has been an expert advisor to the National Football League and the National Hockey League.
JAMA Neurol. Published online August 5, 2019 Summary, ed
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