Chronic differences in white matter integrity following sport-related concussion as measured by diffusion MRI: 6-Month follow-up.

Recent studies demonstrated evidence of physiological changes in the brain following sport-related concussion (SRC) that persisted beyond the point at which athletes achieved full symptom recovery. Diffusion MRI techniques have been used to study brain white matter (WM) changes following SRC; however, longitudinal studies that follow injured athletes from the acute to chronic stages of injury are sparse. The current study explores potential persisting effects of the injury, which serves as a follow-up to our previous work that reported WM changes in the acute and subacute phase of SRC recovery. Concussed high school and collegiate football players (n = 17) and well-matched teammate controls (n = 20) were followed up at 6 months postinjury with diffusion tensor (DTI) and diffusion kurtosis imaging (DKI) as well as measures of self-reported symptoms, cognitive functioning, and balance. Results of tract-based spatial statistics (TBSS) analyses revealed continued widespread decreased mean and axial diffusivity compared to control subjects in 6-month follow-up scans. On the other hand, kurtosis metrics, which were significantly higher in concussed athletes in the acute phase, had normalized. WM tract regions-of-interest (ROIs) were created from significant clusters in the TBSS analysis, and linear mixed effects (LME) analyses were used to look at longitudinal changes in these ROIs over time. LME analyses revealed few time × group interactions indicating findings were relatively stable over time. In addition, acute concussion symptoms predicted diffusivity measures at 6 months postinjury. Findings indicate that DTI and DKI may be useful tools in assessing concussion severity, recovery, and possible long-term effects of concussion.

Abnormalities in Functional Connectivity in Collegiate Football Athletes with and without a Concussion History: Implications and Role of Neuroactive Kynurenine Pathway Metabolites.

There is a great need to identify potential long-term consequences of contact sport exposure and to identify molecular pathways that may be associated with these changes. We tested the hypothesis that football players with (Ath-mTBI) (n = 25) and without a concussion history (Ath) (n = 24) have altered resting state functional connectivity in regions with previously documented structural changes relative to healthy controls without football or concussion history (HC) (n = 27). As a secondary aim, we tested the hypothesis that group differences in functional connectivity are moderated by the relative ratio of neuroprotective to neurotoxic metabolites of the kynurenine pathway. Ath-mTBI had significantly increased connectivity of motor cortex to the supplementary motor area relative to Ath and HC. In contrast, both Ath-mTBI and Ath had increased connectivity between the left orbital frontal cortex and the right lateral frontal cortex, and between the left cornu ammonis areas 2 and 3/dentate gyrus (CA2-3/DG) of the hippocampus and the middle and posterior cingulate cortices, relative to HC. The relationship between the ratio of plasma concentrations of kynurenic acid to quinolinic acid (KYNA/QUIN) and left pregenual anterior cingulate cortex connectivity to multiple regions as well as KYNA/QUIN and right CA2-3/DG connectivity to multiple regions differed significantly according to football and concussion history. The results suggest that football exposure with and without concussion history can have a significant effect on intrinsic brain connectivity and implicate the kynurenine metabolic pathway as one potential moderator of functional connectivity dependent on football exposure and concussion history.

Diffusion Tensor Imaging Predictors of Episodic Memory Decline in Healthy Elders at Genetic Risk for Alzheimer's Disease.

OBJECTIVES: White matter (WM) integrity within the mesial temporal lobe (MTL) is important for episodic memory (EM) functioning. The current study investigated the ability of diffusion tensor imaging (DTI) in MTL WM tracts to predict 3-year changes in EM performance in healthy elders at disproportionately higher genetic risk for Alzheimer's disease (AD). METHODS: Fifty-one cognitively intact elders (52% with family history (FH) of dementia and 33% possessing an Apolipoprotein E ε4 allelle) were administered the Rey Auditory Verbal Learning Test (RAVLT) at study entry and at 3-year follow-up. DTI scanning, conducted at study entry, examined fractional anisotropy and mean, radial and axial diffusion within three MTL WM tracts: uncinate fasciculus (UNC), cingulate-hippocampal (CHG), and fornix-stria terminalis (FxS). Correlations were performed between residualized change scores computed from RAVLT trials 1-5, immediate recall, and delayed recall scores and baseline DTI measures; MTL gray matter (GM) and WM volumes; demographics; and AD genetic and metabolic risk factors. RESULTS: Higher MTL mean and axial diffusivity at baseline significantly predicted 3-year changes in EM, whereas baseline MTL GM and WM volumes, FH, and metabolic risk factors did not. Both ε4 status and DTI correlated with change in immediate recall. CONCLUSIONS: Longitudinal EM changes in cognitively intact, healthy elders can be predicted by disruption of the MTL WM microstructure. These results are derived from a sample with a disproportionately higher genetic risk for AD, suggesting that the observed WM disruption in MTL pathways may be related to early neuropathological changes associated with the preclinical stage of AD. (JINS, 2016, 22, 1005-1015).

Acute white matter changes following sport-related concussion: A serial diffusion tensor and diffusion kurtosis tensor imaging study.

Recent neuroimaging studies have suggested that following sport-related concussion (SRC) physiological brain alterations may persist after an athlete has shown full symptom recovery. Diffusion MRI is a versatile technique to study white matter injury following SRC, yet serial follow-up studies in the very acute stages following SRC utilizing a comprehensive set of diffusion metrics are lacking. The aim of the current study was to characterize white matter changes within 24 hours of concussion in a group of high school and collegiate athletes, using Diffusion Tensor and Diffusion Kurtosis Tensor metrics. Participants were reassessed a week later. At 24 hours post-injury, the concussed group reported significantly more concussion symptoms than a well-matched control group and demonstrated poorer performance on a cognitive screening measure, yet these differences were nonsignificant at the 8-day follow-up. Similarly, within 24-hours after injury, the concussed group exhibited a widespread decrease in mean diffusivity, increased axial kurtosis and, to a lesser extent, decreased axial and radial diffusivities compared with control subjects. At 8 days post injury, the differences in these diffusion metrics were even more widespread in the injured athletes, despite improvement of symptoms and cognitive performance. These MRI findings suggest that the athletes might not have reached full physiological recovery a week after the injury. These findings have significant implications for the management of SRC because allowing an athlete to return to play before the brain has fully recovered from injury may have negative consequences. Hum Brain Mapp 37:3821-3834, 2016. © 2016 Wiley Periodicals, Inc.

Psychometric properties and normative data for the Brief Symptom Inventory-18 (BSI-18) in high school and collegiate athletes.

OBJECTIVE: Assessment of emotional functioning is important in sport-related concussion (SRC) management, although few standardized measures have been validated in this population, and appropriate normative data are lacking. We investigated the psychometric properties of the Brief Symptom Inventory-18 (BSI-18) in high school and collegiate athletes at risk of SRC and compiled normative data. METHOD: Athletes (n = 2,031) completed the BSI-18 and other measures of concussion symptoms, cognition, and psychological functioning. A subset of healthy individuals was re-evaluated at approximately 7, 30, 45, and 165 days. Psychometric analyses of test-retest reliability, internal consistency reliability, and concurrent validity were performed. Given significant differences between sexes and education levels (high school or college student) on the BSI-18 Global Severity Index and all subscales, normative conversion tables were produced after stratifying by these variables. RESULTS: The BSI-18 showed good internal consistency, fair to poor test-retest reliability, and good convergent validity with other measures of emotional functioning. CONCLUSIONS: These data indicate that the BSI-18 may be a valuable measure of emotional state in concussed athletes and may provide unique information beyond post-concussive symptoms for research on the role of psychological factors in SRC recovery. The limited divergent validity of the BSI-18 depression and anxiety scales implies that they tap into general distress more so than specific mood or anxiety symptoms; therefore, BSI-18 scores should be not relied upon for differential diagnosis of mood and anxiety disorders. Normative data provided can be readily applied to clinical cases with high school and collegiate athletes.

Interactive effects of physical activity and APOE-ε4 on white matter tract diffusivity in healthy elders.

Older adult apolipoprotein-E epsilon 4 (APOE-ε4) allele carriers vary considerably in the expression of clinical symptoms of Alzheimer's disease (AD), suggesting that lifestyle or other factors may offer protection from AD-related neurodegeneration. We recently reported that physically active APOE-ε4 allele carriers exhibit a stable cognitive trajectory and protection from hippocampal atrophy over 18months compared to sedentary ε4 allele carriers. The aim of this study was to examine the interactions between genetic risk for AD and physical activity (PA) on white matter (WM) tract integrity, using diffusion tensor imaging (DTI) MRI, in this cohort of healthy older adults (ages of 65 to 89). Four groups were compared based on the presence or absence of an APOE-ε4 allele (High Risk; Low Risk) and self-reported frequency and intensity of leisure time physical activity (PA) (High PA; Low PA). As predicted, greater levels of PA were associated with greater fractional anisotropy (FA) and lower radial diffusivity in healthy older adults who did not possess the APOE-ε4 allele. However, the effects of PA were reversed in older adults who were at increased genetic risk for AD, resulting in significant interactions between PA and genetic risk in several WM tracts. In the High Risk-Low PA participants, who had exhibited episodic memory decline over the previous 18-months, radial diffusivity was lower and fractional anisotropy was higher, compared to the High Risk-High PA participants. In WM tracts that subserve learning and memory processes, radial diffusivity (DR) was negatively correlated with episodic memory performance in physically inactive APOE-ε4 carriers, whereas DR was positively correlated with episodic memory performance in physically active APOE-ε4 carriers and the two Low Risk groups. The common model of demyelination-induced increase in radial diffusivity cannot directly explain these results. Rather, we hypothesize that PA may protect APOE-ε4 allele carriers from selective neurodegeneration of individual fiber populations at locations of crossing fibers within projection and association WM fiber tracts.

Patients' comprehension of their emergency department encounter: a pilot study using physician observers.

STUDY OBJECTIVE: The current study examines patients' comprehension of their emergency department (ED) encounter, using physician observers to document both physician communication and details of the encounter. METHODS: Eighty-nine patients were recruited from a convenience sample in an urban ED. To be included in this study, patients had to have low triage levels (4 and 5) and be discharged from the ED. Physician observers were present throughout the encounter, documenting physician communication and procedures performed. Patients were then interviewed by physician observers about their communication with physicians, accuracy in recalling facts about the encounter, and understanding of information provided during the encounter. RESULTS: The majority of patients were black and had a high school education. Physicians typically engaged in behaviors related to building rapport and diagnosing patients. However, physicians informed patients about test results and diagnoses less frequently. In terms of patients' accuracy and understanding of the visit, patients were generally aware of basic facts in regard to their ED encounter (ie, whether they had blood drawn), but 65.9% of patients demonstrated less than "good" understanding in at least 1 area assessed. CONCLUSION: The findings of the current study indicate physicians could improve communication with patients, particularly in regard to care received in the ED. This study also indicates that a large percentage of patients fail to understand information about their ED encounter even when physicians provide it. A primary limitation of the current study is the relatively homogenous physician sample.

Recognition of famous names predicts cognitive decline in healthy elders.

OBJECTIVE: The ability to recognize familiar people is impaired in both Mild Cognitive Impairment (MCI) and Alzheimer's Dementia (AD). In addition, both groups often demonstrate a time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently. In this study, we examined the TG in cognitively intact elders for remote famous names (1950-1965) compared to more recent famous names (1995-2005). We hypothesized that the TG pattern on a famous name recognition task (FNRT) would predict future cognitive decline, and also show a significant correlation with hippocampal volume. METHOD: Seventy-eight healthy elders (ages 65-90) with age-appropriate cognitive functioning at baseline were administered a FNRT. Follow-up testing 18 months later produced two groups: Declining (≥ 1 SD reduction on at least one of three measures) and Stable (< 1 SD). RESULTS: The Declining group (N = 27) recognized fewer recent famous names than the Stable group (N = 51), although recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampi were significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining vs. Stable) independent of chronological age and APOE ε4 inheritance. CONCLUSIONS: The TG for famous name recognition may serve as an early preclinical cognitive marker of cognitive decline in healthy older individuals.

Comparison of semantic and episodic memory BOLD fMRI activation in predicting cognitive decline in older adults.

Previous studies suggest that task-activated functional magnetic resonance imaging (fMRI) can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively "Stable" or "Declining" based on ≥ 1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with Apolipoprotein E (APOE) ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R(2) = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R(2) = .285; C index = .787), whereas the addition of EM did not (R(2) = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer's disease.

Lifestyle and genetic contributions to cognitive decline and hippocampal structure and function in healthy aging.

BACKGROUND: Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ε4 allele could moderate the effect of PA or CA on hippocampal structure or function. METHODS: Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI. RESULTS: After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE 4 status such that engagement in PA reduced the risk of cognitive decline in APOE 4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus. CONCLUSIONS: Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.

Does physical activity influence semantic memory activation in amnestic mild cognitive impairment?

The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event-related functional magnetic resonance imaging during fame discrimination. Significantly greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients, (P=0.03), suggesting PA may enhance memory-related caudate activation in aMCI.

Interactive effects of physical activity and APOE-ε4 on BOLD semantic memory activation in healthy elders.

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer's disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65-85) cognitively intact adults. A cross-sectional design was used with four groups (n=17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous>unfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline.

Prediction of cognitive decline in healthy older adults using fMRI.

Few studies have examined the extent to which structural and functional MRI, alone and in combination with genetic biomarkers, can predict future cognitive decline in asymptomatic elders. This prospective study evaluated individual and combined contributions of demographic information, genetic risk, hippocampal volume, and fMRI activation for predicting cognitive decline after an 18-month retest interval. Standardized neuropsychological testing, an fMRI semantic memory task (famous name discrimination), and structural MRI (sMRI) were performed on 78 healthy elders (73% female; mean age = 73 years, range = 65 to 88 years). Positive family history of dementia and presence of one or both apolipoprotein E (APOE) ε4 alleles occurred in 51.3% and 33.3% of the sample, respectively. Hippocampal volumes were traced from sMRI scans. At follow-up, all participants underwent a repeat neuropsychological examination. At 18 months, 27 participants (34.6%) declined by at least 1 SD on one of three neuropsychological measures. Using logistic regression, demographic variables (age, years of education, gender) and family history of dementia did not predict future cognitive decline. Greater fMRI activity, absence of an APOE ε4 allele, and larger hippocampal volume were associated with reduced likelihood of cognitive decline. The most effective combination of predictors involved fMRI brain activity and APOE ε4 status. Brain activity measured from task-activated fMRI, in combination with APOE ε4 status, was successful in identifying cognitively intact individuals at greatest risk for developing cognitive decline over a relatively brief time period. These results have implications for enriching prevention clinical trials designed to slow AD progression.

Extrahippocampal integrity in temporal lobe epilepsy and cognition: thalamus and executive functioning.

Chronic temporal lobe epilepsy (TLE) is characterized by the presence of extra-hippocampal brain abnormality and cognitive impairment in both memory and nonmemory domains. However, the link between structural integrity and cognition has not frequently been studied. Forty-six patients with TLE and 61 age-matched controls were studied to determine the predictive relationship between baseline thalamic volume and performance on measures of executive functioning evaluated 4 years later. As expected, the TLE group had lower baseline thalamic volumes than controls and also performed more poorly on measures of executive functioning. Total thalamic volume significantly predicted subsequent performance on all three measures of executive functioning. These findings were maintained when both hippocampal volume and frontal lobe volume were taken into account. These findings add to a growing literature demonstrating a link between extra-hippocampal volume abnormalities and cognitive functioning in TLE.

Fluorodeoxyglucose-positron emission tomographic imaging for the diagnosis of mesial temporal lobe epilepsy.

OBJECTIVE: Fluorodeoxyglucose (FDG)-positron emission tomographic (PET) imaging plays an important role in the evaluation of intractable epilepsy. The metabolic defect has proven utility in the lateralization of temporal lobe epilepsy. However, the role of FDG-PET imaging in the localization of a seizure focus within the temporal lobe is uncertain. We evaluated FDG-PET imaging for the capability to localize a temporal seizure focus within the mesial structures. METHODS: Twenty-eight patients who underwent selective amygdalohippocampectomy for intractable temporal lobe epilepsy were studied. Patients were divided into 2 groups: those who were free of seizures (FS) and those with persisting seizures postoperatively. FS patients were defined by having mesial temporal lobe epilepsy (MTLE). Preoperative FDG-PET activity was evaluated in temporal lobe structures and contrasted with magnetic resonance imaging (MRI) for usefulness in identifying MTLE in an individual. RESULTS: Pathology of the hippocampus revealed mesial temporal sclerosis in all but 1 patient. Qualitative visual inspection of the MRI scan was not reliable in the identification of MTLE (P = 0.15). MRI volumetry found smaller mesial temporal structures (P = 0.04) in FS patients. Mesial temporal metabolic activity was reduced in the FS group (hippocampus, P = 0.001). However, a combination of imaging modalities was found to be the best predictor of MTLE. PET imaging plus MRI qualitative inspection identified all patients with and without MTLE correctly and was superior to MRI alone (P = 0.01 and P = 0.02, respectively). CONCLUSION: MRI volumetry and PET imaging were comparable (P = 0.73) and able to identify MTLE in most patients, but a combination of PET imaging and MRI visual inspection was superior in the recognition of MTLE.