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Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players

Ly, Monica T; Tuz-Zahra, Fatima; Tripodis, Yorghos; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Zetterberg, Henrik; Blennow, Kaj; Peskind, Elaine R; Au, Rhoda; Banks, Sarah J; Barr, William B; Wethe, Jennifer V; Bondi, Mark W; Delano-Wood, Lisa M; Cantu, Robert C; Coleman, Michael J; Dodick, David W; McClean, Michael D; Mez, Jesse B; Palmisano, Joseph; Martin, Brett; Hartlage, Kaitlin; Lin, Alexander P; Koerte, Inga K; Cummings, Jeffrey L; Reiman, Eric M; Shenton, Martha E; Stern, Robert A; Bouix, Sylvain; Alosco, Michael L; ,
BACKGROUND AND OBJECTIVES/OBJECTIVE:Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS:ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS:(158%), and FA (287%) than the unexposed men. DISCUSSION/CONCLUSIONS:and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.
PMID: 38165330
ISSN: 1526-632x
CID: 5625972

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project

Su, Yi; Protas, Hillary; Luo, Ji; Chen, Kewei; Alosco, Michael L; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Au, Rhoda; Banks, Sarah J; Barr, William B; Coleman, Michael J; Dodick, David W; Katz, Douglas I; Marek, Kenneth L; McClean, Michael D; McKee, Ann C; Mez, Jesse; Daneshvar, Daniel H; Palmisano, Joseph N; Peskind, Elaine R; Turner, Robert W; Wethe, Jennifer V; Rabinovici, Gil; Johnson, Keith; Tripodis, Yorghos; Cummings, Jeffrey L; Shenton, Martha E; Stern, Robert A; Reiman, Eric M; ,
INTRODUCTION/BACKGROUND:Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD/METHODS:We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS:Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION/CONCLUSIONS:Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.
PMID: 38134231
ISSN: 1552-5279
CID: 5611852

Examination of parkinsonism in former elite American football players

Alosco, Michael L; Adler, Charles H; Dodick, David W; Tripodis, Yorghos; Balcer, Laura J; Bernick, Charles; Banks, Sarah J; Barr, William B; Wethe, Jennifer V; Palmisano, Joseph N; Martin, Brett; Hartlage, Kaitlin; Cantu, Robert C; Geda, Yonas E; Katz, Douglas I; Mez, Jesse; Cummings, Jeffery L; Shenton, Martha E; Reiman, Eric M; Stern, Robert A; ,
BACKGROUND:Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE:Former football players were prospectively assessed for parkinsonism. METHODS:120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS:Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS:Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.
PMID: 37981539
ISSN: 1873-5126
CID: 5608152

Application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) to frontal lobe epilepsy using multicenter data

Arrotta, Kayela; Swanson, Sara J; Janecek, Julie K; Hamberger, Marla J; Barr, William B; Baxendale, Sallie; McDonald, Carrie R; Reyes, Anny; Hermann, Bruce P; Busch, Robyn M
RATIONALE/BACKGROUND:The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) was recently introduced as a consensus-based, empirically-driven taxonomy of cognitive disorders in epilepsy and has been effectively applied to patients with temporal lobe epilepsy (TLE). The purpose of this study was to apply the IC-CoDE to patients with frontal lobe epilepsy (FLE) using national multicenter data. METHODS:Neuropsychological data of 455 patients with FLE aged 16 years or older were available across four US-based sites. First, we examined test-specific impairment rates across sites using two impairment thresholds (1.0 and 1.5 standard deviations below the normative mean). Following the proposed IC-CoDE guidelines, patterns of domain impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) to construct phenotypes. Impairment rates and distributions across phenotypes were then compared with those found in patients with TLE for which the IC-CoDE classification was initially validated. RESULTS:The highest rates of impairment were found among tests of naming, verbal fluency, speeded sequencing and set-shifting, and complex figure copy. The following IC-CoDE phenotype distributions were observed using the two different threshold cutoffs: 23-40% cognitively intact, 24-29% single domain impairment, 13-20% bi-domain impairment, and 18-33% generalized impairment. Language was the most common single domain impairment (68% for both thresholds) followed by attention and processing speed (15-18%). Overall, patients with FLE reported higher rates of cognitive impairment compared with patients with TLE. CONCLUSIONS:These results demonstrate the applicability of the IC-CoDE to epilepsy syndromes outside of TLE. Findings indicated generally stable and reproducible phenotypes across multiple epilepsy centers in the U.S. with diverse sample characteristics and varied neuropsychological test batteries. Findings also highlight opportunities for further refinement of the IC-CoDE guidelines as the application expands.
PMID: 37866248
ISSN: 1525-5069
CID: 5590222

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

Pellinen, Jacob; Pardoe, Heath; Sillau, Stefan; Barnard, Sarah; French, Jacqueline; Knowlton, Robert; Lowenstein, Daniel; Cascino, Gregory D; Glynn, Simon; Jackson, Graeme; Szaflarski, Jerzy; Morrison, Chris; Meador, Kimford J; Kuzniecky, Ruben; ,
OBJECTIVE:Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. METHODS:Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. RESULTS:Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. SIGNIFICANCE/CONCLUSIONS:This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.
PMID: 37517050
ISSN: 1528-1167
CID: 5618932

Immediate and Differential Response to Emotional Stimuli Associated With Transcranial Direct Current Stimulation for Depression: A Visual-Search Task Pilot Study

Pilloni, Giuseppina; Cho, Hyein; Tian, Tian Esme; Beringer, Joerg; Bikson, Marom; Charvet, Leigh
OBJECTIVES/OBJECTIVE:When administered in repeated daily doses, transcranial direct current stimulation (tDCS) directed to the prefrontal cortex has cumulative efficacy for the treatment of depression. Depression can be marked by altered processing of emotionally salient information. An acute marker of response to tDCS may be measured as an immediate change in emotional information processing. Using an easily administered web-based task, we tested immediate changes in emotional information processing in acute response to tDCS in participants with and without depression. MATERIALS AND METHODS/METHODS:We enrolled n = 21 women with mild-to-moderate depression and n = 20 controls without depression to complete a web-based visual search task before and after 30 minutes of tDCS directed to the prefrontal cortex. The timed task required participants to identify a target face among arrays showing sad, neutral, or mixed (distractor) expressions. RESULTS:At baseline, as predicted, the participants with depression differed from those without in emotional processing speed (mean z score difference -0.66 ± 0.27, p = 0.022) and accuracy in identifying sad stimuli (error rate: 4.4% vs 1.8%, p = 0.039). In response to tDCS, the participants with depression became significantly faster on the distractor condition (pre- vs post-tDCS z scores: -0.45 ± 0.65 vs -0.85 ± 0.65, p = 0.009), suggesting a specific reduction in bias toward negative emotional information. In response to tDCS, the depressed group also had significant improvements in self-reported mood (increased happy, decreased sad and anxious mood). CONCLUSIONS:Participants with depression vs those without were differentiated by their performance of the visual search task at baseline and in response to tDCS. Given that measurable effects on depression scales may require weeks of tDCS treatments, acute change in emotional information processing can serve as an easily obtainable marker of depression and its response to tDCS. CLINICAL TRIAL REGISTRATION/BACKGROUND:The registration number for the study is NCT05188248.
PMID: 37598327
ISSN: 1525-1403
CID: 5598122

White matter hyperintensities in former American football players

Alosco, Michael L; Tripodis, Yorghos; Baucom, Zachary H; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Mariani, Megan L; Au, Rhoda; Banks, Sarah J; Barr, William B; Wethe, Jennifer V; Cantu, Robert C; Coleman, Michael J; Dodick, David W; McClean, Michael D; McKee, Ann C; Mez, Jesse; Palmisano, Joseph N; Martin, Brett; Hartlage, Kaitlin; Lin, Alexander P; Koerte, Inga K; Cummings, Jeffrey L; Reiman, Eric M; Stern, Robert A; Shenton, Martha E; Bouix, Sylvain
INTRODUCTION/BACKGROUND:The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS:A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS:In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION/CONCLUSIONS:In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS/CONCLUSIONS:Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.
PMID: 35996231
ISSN: 1552-5279
CID: 5331552

Moving intra-individual variability (IIV) towards clinical utility: IIV measured using a commercial testing platform

Cho, Hyein; Pilloni, Giuseppina; Tahsin, Raisa; Best, Pamela; Krupp, Lauren; Oh, Cheongeun; Charvet, Leigh
OBJECTIVES:Intra-individual variability (IIV), measured across repeated response times (RT) during continuous psychomotor tasks, is an early marker of cognitive change in the context of neurodegeneration. To advance IIV towards broader application in clinical research, we evaluated IIV from a commercial cognitive testing platform and compared it to the calculation approaches used in experimental cognitive studies. METHODS:-transformed standard deviation or "LSD"). We calculated IIV from the raw RTs using coefficient of variation (CoV), regression-based, and ex-Gaussian methods. The IIV from each calculation was then compared by rank across participants. RESULTS:A total of n = 120 participants with MS aged 20-72 (Mean ± SD, 48.99 ± 12.09) completed the baseline cognitive measures. For each task, the interclass correlation coefficient was generated. Each ICC showed that LSD, CoV, ex-Gaussian, and regression methods clustered strongly (Average ICC for DET: 0.95 with 95% CI [0.93, 0.96]; Average ICC for IDN: 0.92 with 95% CI [0.88 to 0.93]; Average ICC for ONB: 0.93 with 95% CI [0.90 to 0.94]). Correlational analyses indicated the strongest correlation between LSD and CoV for all tasks (rs ≥ 0.94). CONCLUSION:The LSD was consistent with research-based methods for IIV calculations. These findings support the use of LSD for the future measurement of IIV for clinical studies.
PMID: 36812823
ISSN: 1878-5883
CID: 5430202

Development and application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE): Initial results from a multi-center study of adults with temporal lobe epilepsy

McDonald, Carrie R; Busch, Robyn M; Reyes, Anny; Arrotta, Kayela; Barr, William; Block, Cady; Hessen, Erik; Loring, David W; Drane, Daniel L; Hamberger, Marla J; Wilson, Sarah J; Baxendale, Sallie; Hermann, Bruce P
OBJECTIVE:and to assess the ability of the IC-CoDE to produce definable and stable cognitive phenotypes in a large, multi-center temporal lobe epilepsy (TLE) patient sample. METHOD/METHODS:were derived across samples using the IC-CoDE and compared to distributions of phenotypes reported in existing studies. RESULTS:Impairment rates were highest on tests of language, followed by memory, executive functioning, attention/processing speed, and visuospatial ability. Application of the IC-CoDE using varying operational definitions of impairment (≤ 1.0 and ≤ 1.5 SD) produced cognitive phenotypes with the following distribution: cognitively intact (30%-50%), single-domain (26%-29%), bi-domain (14%-19%), and generalized (10%-22%) impairment. Application of the ≤ 1.5 cutoff produced a distribution of phenotypes that was consistent across cohorts and approximated the distribution produced using data-driven approaches in prior studies. CONCLUSIONS:The IC-CoDE is the first iteration of a classification system for harmonizing cognitive diagnostics in epilepsy research that can be applied across neuropsychological tests and TLE cohorts. This proof-of-principle study in TLE offers a promising path for enhancing research collaborations globally and accelerating scientific discoveries in epilepsy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
PMID: 35084879
ISSN: 1931-1559
CID: 5171882

Establishing the cross-cultural applicability of a harmonized approach to cognitive diagnostics in epilepsy: Initial results of the International Classification of Cognitive Disorders in Epilepsy in a Spanish-speaking sample

Reyes, Anny; Salinas, Lilian; Hermann, Bruce P; Baxendale, Sallie; Busch, Robyn M; Barr, William B; McDonald, Carrie R
OBJECTIVE:This study was undertaken to evaluate the cross-cultural application of the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) to a cohort of Spanish-speaking patients with temporal lobe epilepsy (TLE) living in the United States. METHODS:Eighty-four Spanish-speaking patients with TLE completed neuropsychological measures of memory, language, executive function, visuospatial functioning, and attention/processing speed as part of the Neuropsychological Screening Battery for Hispanics. The contribution of demographic and clinical variables to cognitive performance was evaluated. A sensitivity analysis was conducted by examining the base rates of impairment across several impairment thresholds. The IC-CoDE taxonomy was then applied, and the base rate of cognitive phenotypes for each cutoff was calculated. The distribution of phenotypes was compared to the published IC-CoDE taxonomy data, which utilized a large, multicenter cohort of English-speaking patients with TLE. RESULTS:Across the different impairment cutoffs, memory was the most impaired cognitive domain, with impairments in list learning ranging from 50% to 78%. Application of the IC-CoDE taxonomy utilizing a -1.5-SD cutoff revealed an intact cognitive profile in 47.6% of patients, single-domain impairment in 23.8% of patients, bidomain impairment in 14.3% of patients, and generalized impairment in 14.3% of the sample. This distribution was comparable to the phenotype distribution observed in the IC-CoDE validation sample. SIGNIFICANCE/CONCLUSIONS:We demonstrate a similar pattern and distribution of cognitive phenotypes in a Spanish-speaking epilepsy cohort compared to an English-speaking sample. This suggests stability in the underlying phenotypes associated with TLE and applicability of the IC-CoDE for guiding cognitive diagnostics in epilepsy research that can be applied to culturally and linguistically diverse samples.
PMID: 36625416
ISSN: 1528-1167
CID: 5419022