Examination of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation in former elite American football players.

INTRODUCTION: Blood-based biomarkers offer a promising approach for the detection of neuropathologies from repetitive head impacts (RHI). We evaluated plasma biomarkers of amyloid, tau, neurodegeneration, and inflammation in former football players. METHODS: The sample included 180 former football players and 60 asymptomatic, unexposed male participants (aged 45-74). Plasma assays were conducted for beta-amyloid (Aß) 40, Aß42, hyper-phosphorylated tau (p-tau) 181+231, total tau (t-tau), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), interleukin-6 (IL-6), Aß42/p-tau181 and Aß42/Aß40 ratios. We evaluated their ability to differentiate the groups and associations with RHI proxies and traumatic encephalopathy syndrome (TES). RESULTS: P-tau181 and p-tau231(padj = 0.016) were higher and Aß42/p-tau181 was lower(padj = 0.004) in football players compared to controls. Discrimination accuracy for p-tau was modest (area under the curve [AUC] = 0.742). Effects were not attributable to AD-related pathology. Younger age of first exposure (AFE) correlated with higher NfL (padj = 0.03) and GFAP (padj = 0.033). Plasma GFAP was higher in TES-chronic traumatic encephalopathy (TES-CTE) Possible/Probable (padj = 0.008). DISCUSSION: Plasma p-tau181 and p-tau231, GFAP, and NfL may offer some usefulness for the characterization of RHI-related neuropathologies. HIGHLIGHTS: Former football players had higher plasma p-tau181 and p-tau231 and lower Aß42/ptau-181 compared to asymptomatic, unexposed men. Younger age of first exposure was associated with increased plasma NfL and GFAP in older but not younger participants. Plasma GFAP was higher in participants with TES-CTE possible/probable compared to TES-CTE no/suggestive.

Natural Language Processing Applied to Spontaneous Recall of Famous Faces Reveals Memory Dysfunction in Temporal Lobe Epilepsy Patients.

Objective and Background: Epilepsy patients rank memory problems as their most significant cognitive comorbidity. Current clinical assessments are laborious to administer and score and may not always detect subtle memory decline. The Famous Faces Task (FF) has robustly demonstrated that left temporal lobe epilepsy (LTLE) patients remember fewer names and biographical details compared to right TLE (RTLE) patients and healthy controls (HCs). We adapted the FF task to capture subjects' entire spontaneous spoken recall, then scored responses using manual and natural language processing (NLP) methods. We expected to replicate previous group level differences using spontaneous speech and semi-automated analysis. Methods: Seventy-three (N=73) adults (28 LTLE, 18 RTLE, and 27 HCs) were included in a case-control prospective study design. Twenty FF in politics, sports, and entertainment (active 2008-2017) were shown to subjects, who were asked if they could recognize and spontaneously recall as much biographical detail as possible. We created human-generated and automatically-generated keyword dictionaries for each celebrity, based on a randomly selected training set of half of the HC transcripts. To control for speech output, we measured the speech duration, total word count and content word count for the FF task and a Cookie Theft Control Task (CTT), in which subjects were merely asked to describe a visual scene. Subjects' responses to FF and CTT tasks were recorded, transcribed, and analyzed in a blinded manner with a combination of manual and automated NLP approaches. Results: Famous face recognition accuracy was similar between groups. LTLE patients recalled fewer biographical details compared to HCs and RTLEs using both the gold-standard human-generated dictionary (24%±12% vs. 31%±12% and 30%±12%, p=0.007) and the automated dictionary (24%±12% vs. 31%±12% and 32%±13%, p=0.007). There were no group level differences in speech duration, total word count, or content word count for either the FF and CTT to explain difference in recall performance. There was a positive, statistically significant relationship between MOCA score and FF recall performance as scored by the human-generated (ρ= .327, p= .029) and automatically-generated dictionaries (ρ= .422, p= .004) for TLE subjects, but not HCs, an effect that was driven by LTLE subjects. Discussion: LTLE patients remember fewer details of famous people than HCs or RTLE patients, as discovered by NLP analysis of spontaneous recall. Decreased biographical memory was not due to decreased speech output and correlated with lower MOCA scores. NLP analysis of spontaneous recall can detect memory dysfunction in clinical populations in a semi-automated, objective, and sensitive manner.

Visual tests, touch responses: Computer-based neuropsychological tools.

Objective: Investigate three new computer tests of visual abilities relative to traditional paper-and-pencil (P&P) tests on groups with and without cerebral neurological impairment (CNI, Non-CNI) based on MRI and EEG criteria. The new tests employ an intuitive interface with audio instructions, touch responses, non-response prompts, and videography of test behavior. The Presidents Test was designed as an achievement-related measure of visual knowledge; the Railroad Test - visual perception and delayed recognition; and the Swamp Test - visual attention. Attitudes toward testing were assessed with an original Testing Experience Questionnaire (TEQ). Method: Of the 129 participants, 84 were women, 73 identified as non-White, average age 45.5 and education 14.3 years. Procedures included the new computer tests and a selection of standard neuropsychological measures including performance validity tests (PVT). Participants who failed two or three PVTs or had missing PVT data were excluded from main analyses, resulting in N = 115. Results: The new computer tests demonstrated adequate reliability. Correlations and factor analyses confirmed the computer tests as functioning in accordance with design. The Presidents Test was associated with academic achievement. The Railroad and Swamp Tests were linked to visual perception and visual attention. Correlations between computer total test duration time and traditional speed of processing tasks were modest. Computer and traditional tests demonstrated similar discriminability between CNI and Non-CNI groups. TEQ indicated positive attitudes toward testing in general, and computer testing in particular. Conclusions: The new computer tests evaluated in this study were found to be reliable, functioned to assess the designed cognitive domains, and discriminated between CNI and Non-CNI participants similarly to the traditional neuropsychological measures. Attitudes toward computer testing were favorable.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Background and Objectives: Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. Methods: The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Results: Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Discussion: Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.

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

BACKGROUND AND OBJECTIVES: 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: Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid ß1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE 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: In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men. DISCUSSION: Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 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.

Examination of parkinsonism in former elite American football players.

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.

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

INTRODUCTION: 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: 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: Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

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

RATIONALE: 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.

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.

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: 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.

Neuropsychological test performance of former American football players.

BACKGROUND: Patterns of cognitive impairment in former American football players are uncertain because objective neuropsychological data are lacking. This study characterized the neuropsychological test performance of former college and professional football players. METHODS: One hundred seventy male former football players (n=111 professional, n=59 college; 45-74 years) completed a neuropsychological test battery. Raw scores were converted to T-scores using age, sex, and education-adjusted normative data. A T-score ≤ 35 defined impairment. A domain was impaired if 2+ scores fell in the impaired range except for the language and visuospatial domains due to the limited number of tests. RESULTS: Most football players had subjective cognitive concerns. On testing, rates of impairments were greatest for memory (21.2% two tests impaired), especially for recall of unstructured (44.7%) versus structured verbal stimuli (18.8%); 51.8% had one test impaired. 7.1% evidenced impaired executive functions; however, 20.6% had impaired Trail Making Test B. 12.1% evidenced impairments in the attention, visual scanning, and psychomotor speed domain with frequent impairments on Trail Making Test A (18.8%). Other common impairments were on measures of language (i.e., Multilingual Naming Test [21.2%], Animal Fluency [17.1%]) and working memory (Number Span Backward [14.7%]). Impairments on our tasks of visuospatial functions were infrequent. CONCLUSIONS: In this sample of former football players (most of whom had subjective cognitive concerns), there were diffuse impairments on neuropsychological testing with verbal memory being the most frequently impaired domain.

Investigating the association between subjective and objective performance-based cognitive function among former collegiate football players.

OBJECTIVE: Studies have observed variable associations of prior contact sport participation with subjective and objective measures of cognitive function. This study directly investigated the association between subjective self-report and objective performance-based cognition among former collegiate football players, as well as its relationship to self-reported concussion history. METHODS: Former collegiate football players (N = 57; mean age = 37.9 years [SD = 1.49]) retired from sport 15-years prior were enrolled. Linear regression models examined associations between subjective cognition (Quality of Life in Neurological Disorders Cognitive Functioning-Short Form), and performance on a neuropsychological battery. Domain specific (executive function) metrics of subjective (Behavior Rating Inventory of Executive Function-Adult) and objective cognition were also exclusively examined. Associations between self-reported concussion history with subjective and objective measures were tested. Potential influential factors (sleep quality and distress) were included as covariates. RESULTS: Subjective cognition was not significantly associated with any objective measures of cognitive functioning (p's > .05). Greater self-reported concussion history was inversely associated with subjective cognition (B = -2.49, p = .004), but not objective performance-based cognition (p's > .05). Distress was significantly related to all metrics of subjective cognition (p's < .001) as well as performance on delayed recall and verbal fluency (p's < .05). Sleep quality was only significantly related to timed visuospatial sequencing (p = .033). CONCLUSIONS: Reliance on self-reported measures of cognitive functioning alone is insufficient when assessing cognition in former contact sport athletes. Assessment of other factors known to influence subjective cognitive complaints should also be examined in determining the presence of cognitive deficits.

White matter hyperintensities in former American football players.

INTRODUCTION: 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: In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS: 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.

Overlapping and distinct phenotypic profiles in Alzheimer's disease and late onset epilepsy: a biologically-based approach.

Due to shared hippocampal dysfunction, patients with Alzheimer's dementia and late-onset epilepsy (LOE) report memory decline. Multiple studies have described the epidemiological, pathological, neurophysiological, and behavioral overlap between Alzheimer's Disease and LOE, implying a bi-directional relationship. We describe the neurobiological decline occurring at different spatial in AD and LOE patients, which may explain why their phenotypes overlap and differ. We provide suggestions for clinical recognition of dual presentation and novel approaches for behavioral testing that reflect an "inside-out," or biologically-based approach to testing memory. New memory and language assessments could detect-and treat-memory impairment in AD and LOE at an earlier, actionable stage.

Moving towards a taxonomy of cognitive impairments in epilepsy: application of latent profile analysis to 1178 patients with temporal lobe epilepsy.

In efforts to understand the cognitive heterogeneity within and across epilepsy syndromes, cognitive phenotyping has been proposed as a new taxonomy aimed at developing a harmonized approach to cognitive classification in epilepsy. Data- and clinically driven approaches have been previously used with variability in the phenotypes derived across studies. In our study, we utilize latent profile analysis to test several models of phenotypes in a large multicentre sample of patients with temporal lobe epilepsy and evaluate their demographic and clinical profiles. For the first time, we examine the added value of replacing missing data and examine factors that may be contributing to missingness. A sample of 1178 participants met the inclusion criteria for the study, which included a diagnosis of temporal lobe epilepsy and the availability of comprehensive neuropsychological data. Models with two to five classes were examined using latent profile analysis and the optimal model was selected based on fit indices, posterior probabilities and proportion of sample sizes. The models were also examined with imputed data to investigate the impact of missing data on model selection. Based on the fit indices, posterior probability and distinctiveness of the latent classes, a three-class solution was the optimal solution. This three-class solution comprised a group of patients with multidomain impairments, a group with impairments predominantly in language and a group with no impairments. Overall, the multidomain group demonstrated a worse clinical profile and comprised a greater proportion of patients with mesial temporal sclerosis, a longer disease duration and a higher number of anti-seizure medications. The four-class and five-class solutions demonstrated the lowest probabilities of a group membership. Analyses with imputed data demonstrated that the four-class solution was the optimal solution; however, there was a weak agreement between the missing and imputed data sets for the four-Class solutions (κ = 0.288, P < 0.001). This study represents the first to use latent profile analysis to test and compare multiple models of cognitive phenotypes in temporal lobe epilepsy and to determine the impact of missing data on model fit. We found that the three-phenotype model was the most meaningful based on several fit indices and produced phenotypes with unique demographic and clinical profiles. Our findings demonstrate that latent profile analysis is a rigorous method to identify phenotypes in large, heterogeneous epilepsy samples. Furthermore, this study highlights the importance of examining the impact of missing data in phenotyping methods. Our latent profile analysis-derived phenotypes can inform future studies aimed at identifying cognitive phenotypes in other neurological disorders.

Religious conversion in an older male with longstanding epilepsy.

Religious experiences in epilepsy patients have provoked much interest with suggestions that hyperreligiosity is associated with temporal lobe seizures. Extreme varieties of religious behavior may be more frequent in epilepsy patients during ictal activity or during post-ictal psychotic episodes. We report a 75 year-old man with epilepsy who developed a progressive decline in cognition and behavior following a religious conversion 15 years earlier. He subsequently developed religious delusions of increasing severity and symptoms of Capgras syndrome. Brain imaging revealed bilateral posterior cortical atrophy, chronic right parieto-occipital encephalomalacia, and right mesial temporal sclerosis. Electroencephalograms and neuropsychological testing revealed initial right temporal lobe abnormalities followed by progressive frontal and bilateral dysfunction. The case highlights how a history of seizures, superimposed on sensory deprivation and a progressive impairment of right posterior and bilateral anterior brain function, may have contributed to religious conversion, which was followed by dementia and delusions involving religious content.

Cognitive phenotypes in frontal lobe epilepsy.

OBJECTIVE: Neuropsychological profiles are heterogeneous both across and within epilepsy syndromes, but especially in frontal lobe epilepsy (FLE), which has complex semiology and epileptogenicity. This study aimed to characterize the cognitive heterogeneity within FLE by identifying cognitive phenotypes and determining their demographic and clinical characteristics. METHOD: One hundred and six patients (age 16-66; 44% female) with FLE completed comprehensive neuropsychological testing, including measures within five cognitive domains: language, attention, executive function, processing speed, and verbal/visual learning. Patients were categorized into one of four phenotypes based on the number of impaired domains. Patterns of domain impairment and clinical and demographic characteristics were examined across phenotypes. RESULTS: Twenty-five percent of patients met criteria for the Generalized Phenotype (impairment in at least four domains), 20% met criteria for the Tri-Domain Phenotype (impairment in three domains), 36% met criteria for the Domain-Specific Phenotype (impairment in one or two domains), and 19% met criteria for the Intact Phenotype (no impairment). Language was the most common domain-specific impairment, followed by attention, executive function, and processing speed. In contrast, learning was the least impacted cognitive domain. The Generalized Phenotype had fewer years of education compared to the Intact Phenotype, but otherwise, there was no differentiation between phenotypes in demographic and clinical variables. However, qualitative analysis suggested that the Generalized and Tri-Domain Phenotypes had a more widespread area of epileptogenicity, whereas the Intact Phenotype most frequently had seizures limited to the lateral frontal region. SIGNIFICANCE: This study identified four cognitive phenotypes in FLE that were largely indistinguishable in clinical and demographic features, aside from education and extent of epileptogenic zone. These findings enhance our appreciation of the cognitive heterogeneity within FLE and provide additional support for the development and use of cognitive taxonomies in epilepsy.

Remote Memory in Epilepsy: Assessment, Impairment, and Implications Regarding Hippocampal Function.

Studies of epilepsy patients provide insight into the neuroscience of human memory. Patients with remote memory deficits may learn new information but have difficulty recalling events from years past. The processes underlying remote memory impairment are unclear and likely result from the interaction of multiple factors, including hippocampal dysfunction. The hippocampus likely has a continued role in remote semantic and episodic memory storage over time, and patients with mesial temporal lobe epilepsy (TLE) are at particular risk for deficits. Studies have focused on lateralization of remote memory, often with greater impairment in left TLE, which may relate to verbal task demands. Remote memory testing is restricted by methodological limitations. As a result, deficits have been difficult to measure. This review of remote memory focuses on evidence for its underlying neurobiology, theoretical implications for hippocampal function, and methodological difficulties that complicate testing in epilepsy patients.

Handedness and Cognition in Multiple Sclerosis: Potential Indications for Hemispheric Vulnerability.

BACKGROUND: Multiple sclerosis (MS) affects over 2.5 million individuals worldwide, yet much of the disease course is unknown. Hemispheric vulnerability in MS may elucidate part of this process but has not yet been studied. The current study assessed neuropsychological functioning as it relates to hemispheric vulnerability in MS. METHODS: Verbal IQ, as measured by verbal comprehension index (VCI), nonverbal IQ, as measured by perceptual reasoning index (PRI) and memory acquisition were compared in right-handed (dextral) and non-right-handed (non-dextral) persons with MS (PwMS). RESULTS: Linear mixed-effects modeling indicated a significant main effect of handedness, F(1, 195.35) = 3.95, p = .048, for a composite measure of VCI, PRI, and memory acquisition, with better performance for dextral PwMS. In examining differences for specific neuropsychological measures, the largest effect size between dextral and non-dextral participants was seen in PRI (d = 0.643), F(1,341) = 12.163, p = .001. No significant interaction effect between handedness and IQ was found, F(3, 525.60) = 0.75, p = .523. CONCLUSIONS: Dextral PwMS perform better than non-dextral PwMS when assessing neuropsychological performance for memory and IQ combined. Results are suggestive of increased vulnerability in the left brain to the pathological process of MS.

The memory assessment clinics scale for epilepsy (MAC-E): A brief measure of subjective cognitive complaints in epilepsy.

Objective: The aim of this study was to conduct item reduction of the Memory Assessment Clinics Self-Rating Scale (MAC-S) to create a briefer measure that can be used to quickly evaluate subjective memory complaints in patients with epilepsy. Method: A total of 1333 adults with focal epilepsy completed the original 49-item MAC-S. The sample was randomly split into three subsamples, and a series of analyses (i.e. exploratory factor analysis, confirmatory factor analysis, and item response theory analyses) was conducted to identify an alternative factor structure, with a reduced number of items. A panel of 5 neuropsychologists independently reviewed the final model to assess appropriateness of each individual item as well as the factor loadings and overall factor structure. Final factor titles were subsequently decided as a group. Results: Five factors were identified: Attention, Working Memory, Retrieval, Semantic Memory, and Episodic Memory. The length of the MAC-S was reduced from 49 to 30 items, with items being removed because they failed to load onto any of the factors substantially, or because of poor item discrimination or threshold levels. Conclusions: The Memory Assessment Clinics Scale for Epilepsy (MAC-E), is an updated, brief measure of subjective memory functioning that can be used to efficiently assess relevant, every-day memory abilities in patients with epilepsy within both clinical and research settings.

Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. METHODS: The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. RESULTS: Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. CONCLUSIONS: Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. TRIAL REGISTRATION: NCT02798185.