The diagnostic potential of fluid and imaging biomarkers in chronic traumatic encephalopathy (CTE).

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by cognitive, affective, and motor dysfunction. The main pathophysiological mechanisms are chronic neuroinflammation, hyper-phosphorylated tau (p-tau) accumulation and neurodegeneration. CTE is mostly caused by exposure to multiple mild traumatic brain injuries, placing people participating in, for example, high contact sports at increased risk. Currently, CTE can solely be diagnosed post mortem based on the spatial pattern of tau-accumulation. Herein, we review candidate imaging and molecular biomarkers for their sensitivity and specificity and we look whether these are sufficient for reliable ante mortem diagnosis. Of the imaging biomarkers, PET appears to have the best potential. Candidate fluid biomarkers consist of genes and proteins found in brain derived extracellular vesicles, as well as cerebrospinal fluid (CSF) p-tau levels. However, neither these biomarkers nor the imaging biomarkers have the discriminatory power to differentiate between CTE and other tauopathies, highlighting the need for further validation. Future research could incorporate machine learning methodologies to differentiate between the tau accumulation patterns detected by PET/fMRI in Alzheimer's and CTE patients. Additionally, proteomic and metabolomic profiling of CSF and plasma associated with chronic mild traumatic brain injuries could highlight potential biomarkers for identifying at risk patients.

Fluid Biomarkers for Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neuropathological condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. Currently, there is no fluid or imaging biomarker for diagnosing CTE during life. Based on retrospective clinical data, symptoms of CTE include changes in behavior, cognition, and mood, and may develop after a latency phase following the injuries. However, these symptoms are often nonspecific, making differential diagnosis based solely on clinical symptoms unreliable. Thus, objective biomarkers for CTE pathophysiology would be helpful in understanding the course of the disease as well as in the development of preventive and therapeutic measures. Herein, we review the literature regarding fluid biomarkers for repetitive concussive and subconcussive head trauma, postconcussive syndrome, as well as potential candidate biomarkers for CTE. We also discuss technical challenges with regard to the current fluid biomarkers and potential pathways to advance the most promising biomarker candidates into clinical routine.

Chronic traumatic encephalopathy: fluid biomarkers.

Chronic traumatic encephalopathy (CTE) is a neuropathologic condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. CTE cannot currently be diagnosed during life. Clinical symptoms of CTE (including changes in mood, behavior, and cognition) are nonspecific and may develop after a latency phase following the injuries. Differential diagnosis based solely on clinical features is, therefore, difficult. For example, some younger patients who do not experience the latency phase (i.e., symptoms of CTE may begin while still being exposed to the repetitive head impacts) may be clinically diagnosed with postconcussive syndrome, a vaguely defined condition that is described in a minority of concussed patients. Some older patients whose initial features of CTE include memory and executive dysfunction and progress to impaired activities of daily living may be clinically diagnosed with Alzheimer disease or another dementia. Although concussions are common in athletes and nonathletes, contact/collision sport athletes, such as boxers, American football players, and ice hockey players, are at greater risk of exposure to both concussion and repetitive subconcussive head impacts. Biomarkers for CTE pathophysiology would be of great value to study and improve our understanding of when and how the disease process starts and develops, as well as how it can be prevented or treated. Here, we review the literature regarding fluid biomarkers for repetitive subconcussive impacts, concussion, postconcussive syndrome, and CTE. We also discuss technical issues and potential pathways forward regarding how to move the most promising biomarker candidates into clinical laboratory practice.

Cerebrospinal fluid tau, Aß, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration.

INTRODUCTION: Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid ß1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy. METHODS: Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau181, amyloid ß1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI. RESULTS: No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P = .041), and higher sTREM2 levels were associated with higher t-tau concentrations (P = .009). DISCUSSION: In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.