Neuroimaging Markers for Determining Former American Football Players at Risk for Alzheimer's Disease.

NFL players, by virtue of their exposure to traumatic brain injury (TBI), are at higher risk of developing dementia and Alzheimer's disease (AD) than the general population. Early recognition and intervention before the onset of clinical symptoms could potentially avert/delay the long-term consequences of these diseases. Given that AD is thought to have a long pre-clinical incubation period, the aim of the current research was to determine whether former NFL players show evidence of incipient dementia in their structural imaging before diagnosis of AD. To identify neuroimaging markers of AD, against which former NFL players would be compared, we conducted a whole-brain volumetric analysis using a cohort of AD patients (ADNI clinical database) to produce a set of brain regions demonstrating sensitivity to early AD pathology (i.e., the "AD fingerprint"). A group of 46 former NFL players' brain magnetic resonance images were then interrogated using the AD fingerprint, that is, the former NFL subjects were compared volumetrically to AD patients using a T1-weighted magnetization-prepared rapid gradient echo sequence. The FreeSurfer image analysis suite (version 6.0) was used to obtain volumetric and cortical thickness data. The Automated Neuropsychological Assessment Metric-Version 4 was used to assess current cognitive functioning. A total of 55 brain regions demonstrated significant atrophy or ex vacuo dilatation bilaterally in AD patients versus controls. Of the 46 former NFL players, 41% demonstrated a greater than expected number of atrophied/dilated AD regions compared with age-matched controls, presumably reflecting AD pathology.

The relation between cognitive dysfunction and diffusion tensor imaging parameters in traumatic brain injury.

PURPOSE OF THE STUDY: To investigate the association among global and regional white matter fractional anisotropy (FA) values following traumatic brain injury (TBI) and cognitive functioning. MATERIALS AND METHODS: This research was conducted in an urban rehabilitation hospital. Participants included adults who were healthy controls (n = 18) or who had a TBI (n = 27). Diffusion tensor imaging using a Siemens VERIO 3T scanner and calculation of global and regional FA values were undertaken. FA values were correlated with neuropsychological test scores and injury severity variables. Logistic regression and receiver operating characteristic (ROC) curve analysis were used to investigate discriminative ability of the FA values. Neuropsychological measures, including the Symbol Digit Modalities Test (SDMT), Trail Making Test, Wechsler Test of Adult Reading, California Verbal Learning Test 2nd Edition, Digit Vigilance Test, and Wisconsin Card Sorting Test, comprised the cognitive measures. RESULTS: Within the TBI group, regional FA values were significantly lower across regions compared with controls; global FA and five brain regions were associated with SDMT scores. The FA value within the body of the corpus callosum (CC) yielded excellent discrimination between groups. CONCLUSIONS: Convergent findings support the discriminability and potential clinical utility of the CC body FA value in the context of TBI.

MR imaging findings in mild traumatic brain injury with persistent neurological impairment.

Traumatic brain injury (TBI) is a widespread cause of neurologic disability, with >70% of cases being mild in severity. Magnetic resonance imaging provides objective biomarkers in the diagnosis of brain injury by detecting brain lesions resulting from trauma. This paper reports on the detection rates of presumed trauma-related pathology using fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) in TBI patients with chronic, persistent symptoms. METHODS: 180 subjects with persistent neurobehavioral symptoms following head trauma referred by personal injury attorneys and 94 asymptomatic, age-matched volunteers were included in the study. 83% of TBI subjects were classified as mild. RESULTS: TBI subjects had a significantly greater number of lesions detected by FLAIR than controls (42% vs. 22%) and more lesions detected by SWI than controls (28% vs. 3%). To reduce the confounding effects of aging, we examined mild TBI subjects <45years of age, which reduced the rate of lesions detected by FLAIR (26% vs. 2%) and SWI (15% vs. 0%). This younger group, which contained few age-related lesions, also demonstrated that subcortical lesions on FLAIR are more specific for TBI than deeper lesions. CONCLUSIONS: While the presence of litigation in mild TBI cases with incomplete recovery has been associated with greater expression of symptomatology and, by extension, poorer outcomes, this study shows that mild TBI patients in litigation with chronic, persistent symptoms may have associated brain injury underlying their symptoms detectable by MRI biomarkers.

Vestibular, balance, microvascular and white matter neuroimaging characteristics of blast injuries and mild traumatic brain injury: Four case reports.

BACKGROUND: Case reports are presented on four Veterans, aged 29-46 years, who complained of chronic dizziness and/or postural instability following blast exposures. Two of the four individuals were diagnosed with mild traumatic brain injury and three of the four were exposed to multiple blasts. Comprehensive vestibular, balance, gait, audiometry and neuroimaging procedures were used to characterize their injuries. CASE REPORT: Vestibular assessment included videonystagmography, rotary chair and cervical and ocular vestibular evoked myogenic potentials. Balance and gait testing included the sensory organization test, preferred gait speed and the dynamic gait index. Audiometric studies included pure tone audiometry and middle-ear measurements. Neuroimaging procedures included high resolution structural magnetic resonance imaging, susceptibility-weighted imaging and diffusion-tensor imaging. FINDINGS: Based on the neuroimaging and vestibular and balance test results, it was found that all individuals had diffuse axonal injuries and all had one or more micro-hemorrhages or vascular anomalies. Three of the four individuals had abnormal vestibular function, all had abnormally slow walking speeds and two had abnormal gait and balance dysfunction. CONCLUSION: The use of contemporary neuroimaging studies in conjunction with comprehensive vestibular and balance assessment provided a better understanding of the pathophysiology and pathoanatomy of dizziness following blast exposures than standard vestibular and balance testing alone.

Left hemisphere fractional anisotropy increase in noise-induced tinnitus: a diffusion tensor imaging (DTI) study of white matter tracts in the brain.

Diffusion tensor imaging (DTI) is a contemporary neuroimaging modality used to study connectivity patterns and microstructure of white matter tracts in the brain. The use of DTI in the study of tinnitus is a relatively unexplored methodology with no studies focusing specifically on tinnitus induced by noise exposure. In this investigation, participants were two groups of adults matched for etiology, age, and degree of peripheral hearing loss, but differed by the presence or absence (+/-) of tinnitus. It is assumed that matching individuals on the basis of peripheral hearing loss, allows for differentiating changes in white matter microstructure due to hearing loss from changes due to the effects of chronic tinnitus. Alterations in white matter tracts, using the fractional anisotropy (FA) metric, which measures directional diffusion of water, were quantified using tract-based spatial statistics (TBSS) with additional details provided by in vivo probabilistic tractography. Our results indicate that 10 voxel clusters differentiated the two groups, including 9 with higher FA in the group with tinnitus. A decrease in FA was found for a single cluster in the group with tinnitus. However, seven of the 9 clusters with higher FA were in left hemisphere thalamic, frontal, and parietal white matter. These foci were localized to the anterior thalamic radiations and the inferior and superior longitudinal fasciculi. The two right-sided clusters with increased FA were located in the inferior fronto-occipital fasciculus and superior longitudinal fasciculus. The only decrease in FA for the tinnitus-positive group was found in the superior longitudinal fasciculus of the left parietal lobe.

Combining biochemical and imaging markers to improve diagnosis and characterization of mild traumatic brain injury in the acute setting: results from a pilot study.

BACKGROUND: Mild traumatic brain injury (mTBI) is a significant healthcare burden and its diagnosis remains a challenge in the emergency department. Serum biomarkers and advanced magnetic resonance imaging (MRI) techniques have already demonstrated their potential to improve the detection of brain injury even in patients with negative computed tomography (CT) findings. The objective of this study was to determine the clinical value of a combinational use of both blood biomarkers and MRI in mTBI detection and their characterization in the acute setting (within 24 hours after injury). METHODS: Nine patients with mTBI were prospectively recruited from the emergency department. Serum samples were collected at the time of hospital admission and every 6 hours up to 24 hours post injury. Neuronal (Ubiquitin C-terminal Hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels were analyzed. Advanced MRI data were acquired at 9 ± 6.91 hours after injury. Patients' neurocognitive status was assessed by using the Standard Assessment of Concussion (SAC) instrument. RESULTS: The median serum levels of UCH-L1 and GFAP on admission were increased 4.9 folds and 10.6 folds, respectively, compared to reference values. Three patients were found to have intracranial hemorrhages on SWI, all of whom had very high GFAP levels. Total volume of brain white matter (WM) with abnormal fractional anisotropy (FA) measures of diffusion tensor imaging (DTI) were negatively correlated with patients' SAC scores, including delayed recall. Both increased and decreased DTI-FA values were observed in the same subjects. Serum biomarker level was not correlated with patients' DTI data nor SAC score. CONCLUSIONS: Blood biomarkers and advanced MRI may correlate or complement each other in different aspects of mTBI detection and characterization. GFAP might have potential to serve as a clinical screening tool for intracranial bleeding. UCH-L1 complements MRI in injury detection. Impairment at WM tracts may account for the patients' neurocognitive symptoms.

Detection of hemorrhagic and axonal pathology in mild traumatic brain injury using advanced MRI: implications for neurorehabilitation.

INTRODUCTION: There is a need to more accurately diagnose milder traumatic brain injuries with increasing awareness of the high prevalence in both military and civilian populations. Magnetic resonance imaging methods may be capable of detecting a number of the pathoanatomical and pathophysiological consequences of focal and diffuse traumatic brain injury. Susceptibility-weighted imaging (SWI) detects heme iron and reveals even small venous microhemorrhages occurring in diffuse vascular injury. Diffusion tensor imaging (DTI) reveals axonal injury by detecting alterations in water flow in and around injured axons. The overarching hypothesis of this paper is that newer, advanced MR imaging generates sensitive biomarkers of regional brain injury which allows for correlation with clinical signs and symptoms. METHODS: Studies involving subjects with a history of traumatic brain injury as well as healthy, non-trauma controls were used. Analysis involved comparison of TBI patients' imaging results with healthy controls as well as correlation of imaging findings with clinical measures of injury severity. An additional animal study of Sprague-Dawley albino rats compared imaging results with histopathological findings after the animals were sacrificed and stained for b-APP. RESULTS: SWI revealed small foci of hemosiderin for some patients while aggregate lesion volume on SWI correlated with clinical injury severity indices. Similarly, DTI showed striking group differences for fractional anisotropy over the white matter globally, while tract and voxel-based regional results colocalized with SWI and FLAIR lesions in some cases and correlated with clinical deficits. For the rats, correlations were seen between imaging findings and staining of axonal injury. DISCUSSION: Animal data gave important tissue correlations with imaging results. SWI and DTI are commercially available sequences that can improve the diagnostic and prognostic ability of the trauma clinician. These biomarkers of regional brain injury which are present in imaging shortly after acute injury and persist indefinitely can inform clinicians and researchers about not only injury severity but also which neurobehavioral systems were injured. Analogous to stroke rehabilitation, having an understanding of the distribution of brain injury should ultimately allow for development of more effective rehabilitation strategies and more efficient clinical interventional trials.

New algorithm for quantifying vascular changes in dynamic contrast-enhanced MRI independent of absolute T1 values.

In this work, we present a new method for predicting changes in tumor vascularity using only one flip angle in dynamic contrast-enhanced (DCE) imaging. The usual DCE approach finds the tissue initial T1 value T1(0) prior to injection of a contrast agent. We propose finding changes in the tissue contrast agent uptake characteristics pre- and postdrug treatment by fixing T1(0). Using both simulations and imaging pre- and postadministration of caffeine, we find that the relative change (NR50) in the median of the cumulative distribution (R50) is almost independent of T1(0). Fixing T1(0) leads to a concentration curve c(t) more robust to the presence of noise than calculating T1(0). Consequently, the NR50 for the tumor remains roughly the same as the ideal NR50 when T1(0) is exactly known. Further, variations in eating habits are shown to create significant changes in the R50 response for both liver and muscle. In conclusion, analyzing data with fixed T1(0) leads to a more stable measure of changes in NR50 and does not require knowledge of T1(0). Both caffeine and eating introduce major changes in blood flow that can significantly modify the NR50 and lead to incorrect conclusions regarding drug treatment.