Is There Chronic Brain Damage in Retired NFL Players? Neuroradiology, Neuropsychology, and Neurology Examinations of 45 Retired Players

BACKGROUND: Neuropathology and surveys of retired National Football League (NFL) players suggest that chronic brain damage is a frequent result of a career in football. There is limited information on the neurological statuses of living retired players. This study aimed to fill the gap in knowledge by conducting in-depth neurological examinations of 30- to 60-year-old retired NFL players. HYPOTHESIS: In-depth neurological examinations of 30- to 60-year-old retired players are unlikely to detect objective clinical abnormalities in the majority of subjects. STUDY DESIGN: A day-long medical examination was conducted on 45 retired NFL players, including state-of-the-art magnetic resonance imaging (MRI; susceptibility weighted imaging [SWI], diffusion tensor imaging [DTI]), comprehensive neuropsychological and neurological examinations, interviews, blood tests, and APOE (apolipoprotein E) genotyping. LEVEL OF EVIDENCE: Level 3. METHODS: Participants\u27 histories focused on neurological and depression symptoms, exposure to football, and other factors that could affect brain function. The neurological examination included Mini-Mental State Examination (MMSE) evaluation of cognitive function and a comprehensive search for signs of dysarthria, pyramidal system dysfunction, extrapyramidal system dysfunction, and cerebellar dysfunction. The Beck Depression Inventory (BDI) and Patient Health Questionnaire (PHQ) measured depression. Neuropsychological tests included pen-and-paper and ImPACT evaluation of cognitive function. Anatomical examination SWI and DTI MRI searched for brain injuries. The results were statistically analyzed for associations with markers of exposure to football and related factors, such as body mass index (BMI), ethanol use, and APOE4 status. RESULTS: The retired players\u27 ages averaged 45.6 +/- 8.9 years (range, 30-60 years), and they had 6.8 +/- 3.2 years (maximum, 14 years) of NFL play. They reported 6.9 +/- 6.2 concussions (maximum, 25) in the NFL. The majority of retired players had normal clinical mental status and central nervous system (CNS) neurological examinations. Four players (9%) had microbleeds in brain parenchyma identified in SWI, and 3 (7%) had a large cavum septum pellucidum with brain atrophy. The number of concussions/dings was associated with abnormal results in SWI and DTI. Neuropsychological testing revealed isolated impairments in 11 players (24%), but none had dementia. Nine players (20%) endorsed symptoms of moderate or severe depression on the BDI and/or met criteria for depression on PHQ; however, none had dementia, dysarthria, parkinsonism, or cerebellar dysfunction. The number of football-related concussions was associated with isolated abnormalities on the clinical neurological examination, suggesting CNS dysfunction. The APOE4 allele was present in 38% of the players, a larger number than would be expected in the general male population (23%-26%). CONCLUSION: MRI lesions and neuropsychological impairments were found in some players; however, the majority of retired NFL players had no clinical signs of chronic brain damage. CLINICAL RELEVANCE: These results need to be reconciled with the prevailing view that a career in football frequently results in chronic brain damage

White matter changes and confrontation naming in retired aging national football league athletes

Using diffusion tensor imaging (DTI), we assessed the relationship of white matter integrity and performance on the Boston Naming Test (BNT) in a group of retired professional football players and a control group. We examined correlations between fractional anisotropy (FA) and mean diffusivity (MD) with BNT T-scores in an unbiased voxelwise analysis processed with tract-based spatial statistics (TBSS). We also analyzed the DTI data by grouping voxels together as white matter tracts and testing each tract's association with BNT T-scores. Significant voxelwise correlations between FA and BNT performance were only seen in the retired football players (p < 0.02). Two tracts had mean FA values that significantly correlated with BNT performance: forceps minor and forceps major. White matter integrity is important for distributed cognitive processes, and disruption correlates with diminished performance in athletes exposed to concussive and subconcussive brain injuries, but not in controls without such exposure

Elevated homocysteine levels, white matter abnormalities and cognitive impairment in patients with late-life depression

BackgroundCognitive impairment in late−life depression (LLD) is considered to be caused by neurodegenerative changes. Elevated homocysteine (Hcy) levels may be linked to cognitive abnormalities associated with LLD. The important role of white matter (WM) damage in cognitive impairment and pathogenesis in patients with LLD has been widely reported. However, no research has explored the interrelationships of these features in patients with LLD.ObjectiveThe goal of the study was to examine the interrelationship between Hcy levels, cognition, and variations in WM microstructure detected by diffusion tensor imaging (DTI) in patients with LLD.MethodsWe recruited 89 healthy controls (HCs) and 113 patients with LLD; then, we measured the plasma Hcy levels of participants in both groups. All individuals performed a battery of neuropsychological tests to measure cognitive ability. Seventy-four patients with LLD and 68 HCs experienced a DTI magnetic resonance imaging (MRI) scan.ResultsPatients with LLD showed significantly lower fractional anisotropy (FA) values in the bilateral inferior longitudinal fasciculus than those of healthy participants. Only in LLD patients was Hcy concentration inversely associated to FA values in the forceps minor. Finally, multiple regression analyses showed that an interaction between Hcy levels and FA values in the right cingulum of the cingulate cortex and right inferior longitudinal fasciculus were independent contributors to the executive function of patients with LLD.ConclusionOur results highlight the complex interplay between elevated homocysteine levels and WM abnormalities in the pathophysiology of LLD-related cognitive impairment, consistent with the neurodegeneration hypothesis

Diffusion Tensor Imaging in HIV and hepatitis C coinfection

Previous studies have demonstrated that infection with both human immune deficiency virus (HIV) and hepatitis C (HCV) is associated with impaired cognitive function. It is unclear whether co-infection is associated with neuroimaging markers of brain dysfunction. The purpose of the present study was to compare HIV+ individuals, HIV/HCV+ individuals, and seronegative controls using diffusion tensor imaging (DTI) to assess the microstructural integrity of white matter tissue. Methods: Twenty-five HIV+ patients, 25 HIV/HCV+ patients, and 25 seronegative controls matched for age were included in the study. All participants completed an MRI session, neuropsychological testing, and an evaluation of clinical variables including liver health. White matter regions of interest (ROI) were determined using a semi-automatic method based on individual anatomy. DTI metrics including mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) were compared across groups using ANOVA. A regression model including DTI metrics, an index of liver function, and self-reported physical and mental health was performed to determine the relationship between those variables and cognitive performance in the co-infected group. Results: The co-infected group was similar to the mono-infected group in terms of HIV clinical variables. None of the participants met criteria for cirrhosis or fibrosis. There were no differences between groups on DTI metrics in the frontal ROI. In the anterior corpus callosum there was a significant difference between the HIV+ groups compared to controls with both patient groups having lower FA values. Additionally, the HIV/HCV+ group had significantly higher RD compared to controls in the corpus callosum, particularly in the anterior sections. Increased RD in the corpus callosum was associated with performance on executive function/working memory measures only at a trend level (p=0.07) in the co-infected group. Conclusions: Co-infection with HIV and HCV may result in significant alterations in white matter structural integrity as measured by DTI, especially in the anterior corpus callosum. The effect of HIV/HCV co-infection was greater than the effect of HIV mono-infection compared to controls in all regions sampled. These results suggest that the combined effects of the viruses in the brain result in compromised white matter microstructural integrity

Chronic social stress and hippocampal memory system in older adults

Perceived social discrimination, a salient chronic psychosocial stressor, has an adverse effect on physical and mental health. Cumulative stress compromises adaptive physiologic processes and triggers changes in hypothalamic-pituitary-adrenocortical (HPA) axis functioning. The hippocampus is critical for episodic memory and mediates the HPA stress response. Animal models have demonstrated increased vulnerability of the hippocampus to stress-induced morphological alterations and dysfunction. Previous research has shown that greater psychosocial stress is related to poorer episodic memory performance in older adults. Diffusion-weighted imaging (DWI) studies strongly support the role of the uncinate fasciculus (UF) in episodic memory. Furthermore, psychosocial stress has been associated with white matter (WM) microstructural abnormalities in the UF. Although the effect of chronic psychosocial stress is well established, the effects of social discrimination on WM integrity and episodic memory are not well understood. In this study, we tested the hypothesis that greater perceived social discrimination in older adults is associated with poorer episodic memory performance and structural abnormalities of the UF tract. Twenty-eight participants (63.8 – 73 years, 57.1% female, 42.9% African American) reported experiences of discrimination (EoD) and perceived stress (PSS) and were assessed for episodic memory. High angular resolution diffusion imaging (HARDI) scans were analyzed with probabilistic tractography to examine associations of UF diffusion metrics with EoD scores and episodic memory performance. Spearman’s rank correlation determined a significant positive association between EoD and PSS scores (rs(28) = 0.45, p = 0.017), suggesting perceived discrimination is a chronic stressor and may be a social determinant of health. However, contrary to our expectations, neither EoD nor PSS were significantly related to episodic memory performance and UF diffusion metrics. Future longitudinal research to examine associations between perceived discrimination, episodic memory and WM microstructure in a large cohort is warranted

Using diffusion imaging to explore the anatomical nature of early course schizophrenia

Schizophrenia (SCZ) is a serious brain disorder that affects around 1% of the world population. Despite a long history of research in diagnosis and treatment of SCZ, we are still far from being able to explain the origin of the disease and the interindividual differences in the trajectory of the disease. The neurodevelopmental hypothesis states that SCZ is caused by early maturational abnormalities, which interact with later brain development. Neuroimaging provides a noninvasive opportunity to study this theory in vivo. Traditionally, Magnetic resonance imaging (MRI) has been used to examine macrostructural gray matter features such as gray matter volume or cortical thickness and SCZ has been established as a brain disorder hereinafter. Diffusion tensor imaging (DTI) allows to investigate the microstructure of brain tissue. It measures the magnitude and direction of water molecule`s diffusion and is highly sensitive to alterations of gray and white matter organization. Gray matter contains the neurons and the white matter contains myelinated axons and provides long and middle range connectivity between cortical neurons. White matter alterations observed in SCZ, therefore, support the disconnection theory stating that SCZ is a brain disorder with disrupted integration of different brain systems. Finally, while early imaging research focused on chronic states of SCZ a shift of the field towards studying early stages can be observed in more recent years. Understanding early course SCZ raises the hope to improve diagnosis and subsequently prevention and intervention. In line with this research the aim of the presented studies is to characterize microstructural white and gray matter alterations in early course SCZ using diffusion MRI combined with advanced post-processing techniques, which are sufficiently sensitive to detect subtle brain conspicuities. Implications of and associations with neuropsychological and clinical symptoms and diagnosis of SCZ will be discussed subsequently. Paper 1 The purpose of the first project is to characterize white matter organization in patients with early course SCZ. To my knowledge this is the first study investigating five main intra-hemispheric corti-cocortical white matter tracts using manual guided tractography in early course SCZ. The tracts were selected based on previous findings: uncinate fasciculus (UF), cingulum bundle (CB), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF) and arcuate fasciculus (AF). Diffusion parameters (fractional anisotropy [FA], trace, axial diffusivity [AD] and radial diffusivity [RD]) were computed for each tract and compared between patients with early course SCZ (number [n]=30) and healthy controls (HC) (n=30). The association of the diffusion parameters of the tracts with clinical symptoms, memory performance, and processing speed was examined afterwards. A significant group effect, represented by reduced FA and increased RD and trace in the patients’ group compared to HC was observed for the right AF (FA [F=5.94, df=1, p=.016]; RD [F=5.60, df=1, p=.020]), CB (FA [F=9.35, df=1, p=.003]; RD [F=11.55, df=1, p=.0010] and ILF (FA [F=14.77, df=1, p=.004]; RD [F=13.25, df=1, p<.0001]). The pattern of lower FA and higher RD is indicative for myelin abnormalities. Structural alterations were correlated with positive symptoms (ILF, AF), and cognitive performance (CB), which points to the clinical relevance of the observed white matter conspicuities. Paper 2 In the past, DTI has mainly been used to study white mater, because technical challenges limited the use of DTI for the characterization of gray matter organization. However, as an extension of the classical disconnection theory one would not only expect dysconnectivity in white matter, but also a disruption of gray matter organization. The aim of this study therefore is to use novel DTI method- heterogeneity- to study the microstructural gray matter organization over the course of SCZ. In comparison to traditional diffusion indices, which focus on intra-voxel diffusion properties, heterogeneity captures the microstructural organization of a larger cortical area. After applying a free water correc-tion to control for partial volume effects, T1 and diffusion images were registered to each other and the variability (=heterogeneity) of diffusion parameters within the four brain lobes defined by auto-matic parcellation method was calculated. Patients with chronic SCZ (n=27) did not show differences of cortical organization when compared to HC (n=22). However, patients with early course SCZ (n=19) showed increased heterogeneity in the frontal lobe when compared to HC (n=15) (F=10.68, df=1, p<.0030). This indicates a lower grade of cortical organization in patients than in HC. It is suggested that this can be explained by neurodevelopmental abnormalities, plausibly caused by abnormal synaptic reorganization and pruning during adolescence and early adulthood in SCZ

The relationship between neurocognitive disorders, prospective memory impairment and white matter damage in clade C HIV-positive subjects

Includes bibliographical references.AIMS: To examine the relationship between prospective memory, cognitive function and Diffusion tensor imaging (DTI)/ White matter integrity of human immunodeficiency virus (HIV) positive individuals in the Western Cape. We hypothesize that: 1. Individuals infected with HIV will exhibit significantly poorer microstructural integrity of the white matter than HIV negative individuals, as determined by in vivo diffusion tensor imaging. We expect that values of fractional anisotropy (FA) - a measure of directional water diffusion- in the frontal white matter will be significantly lower among HIV patients compared to controls 2. Lower FA measured in the frontal white matter will correlate significantly with impaired performance on tests of prospective memor

Later-life structural and functional consequences of youth exposure to repeated head impacts

Youth football players ages 8-12 may incur hundreds of repeated head impacts (RHI) each season. Evidence suggests concussive brain injury during childhood may disrupt normal developmental processes resulting in long-term impairments. However, little research has investigated the long-term effects of incurring RHI during critical periods of neurodevelopment. Rapid myelination and cerebral blood flow rates, peaks in regional cortical thickness and volumes of specific structures, refinement of regional connectivity, and other neurodevelopmental changes occurring in the brain from ages 10-12 could create a window of vulnerability to RHI. The objective of this research was to determine the relationship between exposure to RHI prior to age 12, during a critical period of neurodevelopment, and later-life brain structure and function. Former National Football League (NFL) players ages 40-65 were divided into two groups based on their age of first exposure (AFE) to RHI through tackle football: AFE <12 and AFE ≥12. In the first study, we observed significantly lower scores on objective tests of executive functioning, memory, and estimated verbal IQ in those who began playing football prior to age 12 compared to those who began playing at age 12 or older. Next, we used diffusion tensor imaging (DTI) to examine the structural integrity of the corpus callosum (CC) and observed that the AFE <12 group had significantly lower fractional anisotropy (FA) as well as a greater decline in FA with age in anterior CC regions than the AFE ≥12 group. Lastly, we used advanced DTI tractography techniques to examine seven CC regions. Significant differences between AFE groups in associations between CC diffusion measures and cognition, mood, and behavior were found. The results of this research suggest that incurring RHI through tackle football during a critical neurodevelopmental period prior to age 12 may result in later-life structural and functional consequences, including cognitive, mood, and behavioral impairments; alterations in white matter structure; and greater vulnerability of white matter to the normal aging process. If replicated with longitudinal designs, larger samples, and athletes whose highest level of play was youth, high school, or college, these findings may have implications for safety recommendations for youth sports

Abnormal Structural Connectivity Patterns in Large-Scale Brain Networks in Schizophrenia

Background: While cognitive impairment is a core feature of schizophrenia, a minority of patients demonstrate average to superior ability on many standard cognitive measures with no attenuation of the psychotic disease process (Heinrichs et al. 2008; Muharib et al., 2014). The data imply a dissociation of cognitive and psychosis-generating neural mechanisms whereby patients share a disease process that leads to psychosis but vary in terms of the pathophysiology that causes cognitive impairment. Furthermore, current views hold that schizophrenia involves abnormalities in the connectivity of large-scale brain networks [default mode (DMN), salience (SN), central executive (CEN), and social brain (SBN)]. However, these findings may reflect pathophysiology related to both the cognitive and psychotic features of schizophrenia. Therefore, we asked: Are aberrations in cortical thickness and/or structural connectivity within and between networks associated with cognitive impairment and/or the severity of psychotic psychopathology? Method: Structural magnetic resonance (MRI) and diffusion tensor imaging (DTI), cognitive, and clinical data were collected from 121 participants, which include 16 cognitively-intact and 48 cognitively-impaired schizophrenia patients as well as 36 cognitively normal and 21 below-normal controls. Between-group comparisons and region-of-interest analyses of cortical thickness and structural integrity in the DMN, SN, CEN, and SBN were performed on MRI and DTI data. Results: Cognitively normal controls had greater DMN and SN cortical thickness than both cognitively normal and below-normal patients. Structural integrity of the genu of the corpus callosum was significantly different between cognitively normal controls and both patient groups. Superior longitudinal fasciculus connectivity patterns differed between cognitively normal controls and below-normal patients. Lastly, the inferior longitudinal and inferior fronto-occipital fasciculi combined were significantly different between cognitively normal controls and patients. Conclusions: The results suggest that cortical thinning may represent the presence of psychotic psychopathology independent of cognitive impairment. However, tract integrity may index cognitive status, the psychotic disease process, or both. The similarities in white matter integrity associations with cognition among cognitively normal patients and controls suggest shared neurocognitive processes, and the dissimilarities may point to cortical structure aberrations that give rise to psychotic psychopathology. Taken together, this study contributes to the advancement of the literature by providing evidence for dissociable or partially dissociable disease processes in psychotic illness