These studies indicated an association between recurrent concussion and both clinically diagnosed MCI45 Osimertinib and an increased risk of clinical depression44 in retired professional football players with an average age ± SD of 53.8±13.4 years and an average ± SD professional football playing career of 6.6±3.6 years. Besides having cross-sectional designs, a number of methodological weaknesses exist in these studies. The response rate was only 55%, and selection bias is a threat since it is unknown whether

respondents differed from nonrespondents. Other weaknesses include the lack of control for potential confounders (eg, chronic pain and substance abuse) and the risk of information bias (ie, self-reported memory problems might not indicate real or objective memory problems).

A significant limitation of these studies was the use of a self-reported history of concussion, since imperfect recall can generate differential recall bias.47 Kerr et al47 assessed the reliability of concussion history in this same cohort of retired professional football players and found that those who reported more concussions had worse physical and mental health at follow-up. This differential recall NVP-BKM120 molecular weight bias would result in an overestimation of the risk of MCI45 and depression44 resulting from concussions. In other words, those with MCI or depression, as well as their spouses, might have overreported their concussions, while those without these conditions might have underreported their concussions. Furthermore, Kerr et al demonstrated Fluorometholone Acetate that the reliability of concussion reporting was moderate (weighted Cohen κ=.48).47 This would result in a significant amount of misclassification of exposure status. Thus, the associations observed by Guskiewicz linking recurrent concussion with late-life MCI and depression may be misleading because of differential recall bias and other study weaknesses. Injury prevention and evidence-based

management should remain a high priority for amateur and professional athletes alike regardless of these possible negative associations, since most would agree that repeated head trauma is undesirable. However, ongoing publicity about “brain damage” after sport concussion might have a deleterious effect on recovery. Iverson and Gaetz48 state that it is important to avoid over-pathologizing neuropsychological test scores and postconcussion symptoms because this can inadvertently cause athletes to feel undue stress, anxiety, and depression. Athletes who worry and focus on their symptoms are at increased risk for protracted recovery patterns.48 We found no acceptable phase III studies that investigated prognosis after sport concussion. Of the 19 acceptable studies, approximately half were phase II, with the remainder being phase I; all provided exploratory evidence for potential associations between prognostic factors and recovery from sport concussion.