The role of genetic polymorphisms in executive functioning performance in temporal lobe epilepsy.

OBJECTIVE: To explore the role of several genetic polymorphisms (APOE ε4, BDNF Met, and COMT Val) in executive functioning performance in patients with pharmacoresistant temporal lobe epilepsy (TLE). METHODS: Ninety-three adults (51 female, mean age = 39 years) with TLE completed executive functioning measures as part of a comprehensive preoperative neuropsychological evaluation, including Trail Making Test (Part B), Wisconsin Card Sorting Test (Conceptual Level Responses and Perseverative Errors), Color Word Interference from the Delis Kaplan Executive Function System, and measures of phonemic and semantic verbal fluency. Genotyping of the APOE, BDNF, and COMT genes was conducted using DNA extracted from peripheral blood or brain tissue (from epilepsy surgery). RESULTS: After adjustment for general cognitive ability, COMT Val carriers showed poorer performance on semantic verbal fluency and color word interference than non-carriers, and BDNF Met carriers showed poorer performance on phonemic verbal fluency than those without a Met allele. SIGNIFICANCE: Results suggest that COMT and BDNF polymorphisms are associated with performance on several EF measures in patients with TLE, including tasks assessing verbal fluency and response inhibition and account for up to 16% of the variance in test performance. The APOE polymorphism was not significantly associated with any of the executive function measures analyzed.

Nomograms to Predict Verbal Memory Decline After Temporal Lobe Resection in Adults With Epilepsy.

OBJECTIVE: To develop and externally validate models to predict the probability of postoperative verbal memory decline in adults following temporal lobe resection (TLR) for epilepsy using easily-accessible preoperative clinical predictors. METHODS: Multivariable models were developed to predict delayed verbal memory outcome on three commonly used measures: Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) and Verbal Paired Associates (VPA) subtests from Wechsler Memory Scale-Third Edition. Using Harrell's step-down procedure for variable selection, models were developed in 359 adults who underwent TLR at Cleveland Clinic and validated in 290 adults at one of five epilepsy surgery centers in the United States or Canada. RESULTS: Twenty-nine percent of the development cohort and 26% of the validation cohort demonstrated significant decline on at least one verbal memory measure. Initial models had good to excellent predictive accuracy (calibration (c) statistic range=0.77-0.80) in identifying patients with memory decline; however, models slightly underestimated decline in the validation cohort. Model coefficients were updated using data from both cohorts to improve stability. The model for RAVLT included surgery side, baseline memory score, and hippocampal resection. The models for LM and VPA included surgery side, baseline score, and education. Updated model performance was good to excellent (RAVLT c=0.81, LM c=0.76, VPA c=0.78). Model calibration was very good, indicating no systematic over- or under-estimation of risk. CONCLUSIONS: Nomograms are provided in two easy-to-use formats to assist clinicians in estimating the probability of verbal memory decline in adults considering TLR for treatment of epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that multivariable prediction models accurately predict verbal memory decline after temporal lobe resection for epilepsy in adults.

Prescription Medications and Co-Morbidities in Late Middle-Age are Associated with Greater Cognitive Declines: Results from WRAP.

The present study investigated: 1) sex differences in polypharmacy, comorbidities, self-rated current health (SRH), and cognitive performance, 2) associations between comorbidities, polypharmacy, SRH, and objective measures of health, and 3) associations of these factors with longitudinal cognitive performance. Analyses included 1039 eligible Wisconsin Registry for Alzheimer's Prevention (WRAP) participants who were cognitively unimpaired at baseline and had ≥2 visits with cognitive composites, self-reported health history, and concurrent medication records. Repeated measures correlation (rmcorr) examined the associations between medications, co-morbidities, SRH, and objective measures of health (including LIfestyle for BRAin Health Index (LIBRA), and depression). Linear mixed-effect models examined associations between medications, co-morbidities, and cognitive change over time using a preclinical Alzheimer's cognitive composite (PACC3) and cognitive domain z-scores (executive function, working memory, immediate learning, and delayed recall). In secondary analyses, we also examined whether the number of medications interacted with co-morbidities and whether they modified age-related cognitive trajectories. The number of prescribed medications was associated with worse SRH and a higher number of self-reported co-morbidities. More prescribed medications were associated with a faster decline in executive function, and more comorbidities were associated with faster PACC3 decline. Those with a non-elevated number of co-morbidities and medications performed an average of 0.26 SD higher (better) in executive function and an average of 0.18 SD higher on PACC3 than those elevated on both. Associations between medications, co-morbidities, and executive function, and PACC3 suggest that persons with more co-morbidities and medications may be at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers.

Verbal memory dysfunction is associated with alterations in brain transcriptome in dominant temporal lobe epilepsy.

OBJECTIVE: Memory dysfunction is prevalent in many neurological disorders and can have a significant negative impact on quality of life. The genetic contributions to memory impairment in epilepsy, particularly temporal lobe epilepsy (TLE), remain poorly understood. Here, we compare the brain transcriptome between TLE patients with and without verbal memory impairments to identify genes and signaling networks important for episodic memory. METHODS: Brain tissues were resected from 23 adults who underwent dominant temporal lobectomy for treatment of pharmacoresistant epilepsy. To control for potential effects of APOE on memory, only those homozygous for the APOE ε3 allele were included. A battery of memory tests was performed, and patients were stratified into two groups based on preoperative memory performance. The groups were well matched on demographic and disease-related variables. Total RNA-Seq and small RNA-Seq were performed on RNA extracted from the brain tissues. Pathway and integrative analyses were subsequently performed. RESULTS: We identified 1092 differentially expressed transcripts (DETs), with the majority (71%) being underexpressed in brain tissues from patients with impaired memory compared to those from patients with intact memory. Enrichment analysis revealed overrepresentation of genes in pathways pertaining to brain-related neurological dysfunction, including a subset associated with neurodegenerative diseases, memory, and cognition (APP, MAPT, PINK1). Despite including patients with identical APOE genotypes, we identify APOE as a differentially expressed gene associated with memory status. Small RNA-Seq identified four differentially expressed microRNAs (miRNAs) that were predicted to target a subset (22%) of all DETs. Integrative analysis showed that these miRNA-predicted DET targets impact brain-related pathways and biological processes also pertinent to memory and cognition. SIGNIFICANCE: TLE-associated memory status may be influenced by differences in gene expression profiles within the temporal lobe. Upstream processes influencing differential expression signatures, such as miRNAs, could serve as biomarkers and potential treatment targets for memory impairment in TLE.

Epilepsy and aging.

The intersection of epilepsy and aging has broad, significant implications. Substantial increases in seizures occur both in the elderly population, who are at a higher risk of developing new-onset epilepsy, and in those with chronic epilepsy who become aged. There are notable gaps in our understanding of aging and epilepsy at the basic and practical levels, which have important consequences. We are in the early stages of understanding the complex relationships between epilepsy and other age-related brain diseases such as stroke, dementia, traumatic brain injury (TBI), and cancer. Furthermore, the clinician must recognize that the presentation and treatment of epilepsy in the elderly are different from those of younger populations. Given the developing awareness of the problem and the capabilities of contemporary, multidisciplinary approaches to advance understanding about the biology of aging and epilepsy, it is reasonable to expect that we will unravel some of the intricacies of epilepsy in the elderly; it is also reasonable to expect that these gains will lead to further improvements in our understanding and treatment of epilepsy for all age groups.

Measuring longitudinal cognition: Individual tests versus composites.

INTRODUCTION: Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aß). METHODS: Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aß modified cognitive trajectories. RESULTS: Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aß interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics. DISCUSSION: These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.

Indications and expectations for neuropsychological assessment in epilepsy surgery in children and adults.

In our first paper in this series (Epilepsia 2015; 56(5): 674-681), we published recommendations for the indications and expectations for neuropsychological assessment in routine epilepsy care. This partner paper provides a comprehensive overview of the more specialist role of neuropsychological assessment in the pre and postoperative evaluation of epilepsy surgery patients. The paper is in two parts. The first part presents the framework for the mandatory role of neuropsychologists in the presurgical evaluation of epilepsy surgery candidates. A preoperative neuropsychological assessment should be comprised of standardised measures of cognitive function in addition to wider measures of behavioural and psychosocial function. The results from the presurgical assessment are used to: (1) establish a baseline against which change can be measured following surgery; (2) provide a collaborative contribution to seizure characterization, lateralization and localization; (3) provide evidence-based predictions of cognitive risk associated with the proposed surgery; and (4) provide the evidence base for comprehensive preoperative counselling, including exploration of patient expectations of surgical treatment. The second part examines the critical role of the neuropsychologist in the evaluation of postoperative outcomes. Neuropsychological changes following surgery are dynamic and a comprehensive, long-term assessment of these changes following surgery should form an integral part of the postoperative follow-up. The special considerations with respect to pre and postoperative assessment when working with paediatric populations and those with an intellectual disability are also discussed. The paper provides a summary checklist for neuropsychological involvement throughout the epilepsy surgery process, based on the recommendations discussed.

Cognitive safety of intracranial electrodes for epilepsy.

Two recent articles in Epilepsia have raised concerns about adverse cognitive effects associated with intracranial electrode implantation. However, both studies have important limitations, and their results contrast with studies that report no adverse cognitive effects of intracranial electrodes for diagnosis or neurostimulation in epilepsy. Furthermore, no data are provided on the relative safety of depth electrodes implanted along the longitudinal axis of the hippocampus vs other electrode locations or types of electrodes. Instituting changes in the use of depth electrodes based solely on these 2 studies is not clinically indicated. Further research is needed.

The relationship between carotid artery plaque stability and white matter ischemic injury.

Higher local carotid artery strain has previously been shown to be a characteristic of unstable carotid plaques. These plaques may be characterized by microvascular changes that predispose to intraplaque hemorrhage, increasing the likelihood of embolization. Little is known however, about how these strain indices correspond with imaging markers of brain health and metrics of brain structure. White matter hyperintensities (WMHs), which are bright regions seen on T2-weighted brain MRI imaging, are postulated to result from cumulative ischemic vascular injury. Consequently, we hypothesized that plaques that are more prone to microvascular changes and embolization, represented by higher strain indices on ultrasound, would be associated with an increased amount of WMH lesion volume. This relationship would suggest not only emboli as a cause for the brain degenerative changes, but more importantly, a common microvascular etiology for large and small vessel contributions to this process. Subjects scheduled to undergo a carotid endarterectomy were recruited from a neurosurgery clinic. Prior to surgery, participating subjects underwent both ultrasound strain imaging and brain MRI scans as part of a larger clinical study on vascular health and cognition. A linear regression found that maximum absolute strain and peak to peak strain in the surgical side carotid artery were predictive of WMH burden. Furthermore, the occurrence of microembolic signals monitored using transcranial Doppler (TCD) ultrasound examinations also correlated with increasing lesion burden. It is becoming increasingly recognized that cognitive decline is often multifactorial in nature. One contributing extra-brain factor may be changes in the microvasculature that produce unstable carotid artery plaques. In this study, we have shown that higher strain indices in carotid artery plaques are significantly associated with an increased WMH burden, a marker of vascular mediated brain damage.

Occupational Complexity and Cognitive Reserve in a Middle-Aged Cohort at Risk for Alzheimer's Disease.

Higher occupational attainment has previously been associated with increased Alzheimer's disease (AD) neuropathology when individuals are matched for cognitive function, indicating occupation could provide cognitive reserve. We examined whether occupational complexity (OCC) associates with decreased hippocampal volume and increased whole-brain atrophy given comparable cognitive function in middle-aged adults at risk for AD. Participants (n = 323) underwent structural MRI, cognitive evaluation, and work history assessment. Three complexity ratings (work with data, people, and things) were obtained, averaged across up to 3 reported jobs, weighted by years per job, and summed to create a composite OCC rating. Greater OCC was associated with decreased hippocampal volume and increased whole-brain atrophy when matched for cognitive function; results remained substantively unchanged after adjusting for several demographic, AD risk, vascular, mental health, and socioeconomic characteristics. These findings suggest that, in people at risk for AD, OCC may confer resilience to the adverse effects of neuropathology on cognition.

Genetics of cognition in epilepsy.

With the completion of the Human Genome Project and the advent of more advanced sequencing platforms capable of high throughput genotyping at reduced cost, research on the genetics/genomics of cognition has expanded rapidly over the past several decades. This has been facilitated even further by global consortia including HapMap, 1000 Genomes Project, ENCODE, and others, which have made information regarding genetic variation and genomic functional elements readily available to all researchers. Thus, the goal of this Targeted Review is not to provide an exhaustive review of the existing literature on the role of genetic factors in cognition. Rather, we will highlight some of the most consistent findings in this field, review the research in epilepsy to date, and provide a background within which to set forth unique opportunities epilepsy may provide to further elucidate the role of genetics in cognition.

Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.

PURPOSE: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). METHODS AND MATERIALS: Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score ≤-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an α/ß ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. RESULTS: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). CONCLUSION: EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.

Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors.

PURPOSE: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). METHODS AND MATERIALS: Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score ≤-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD(2)) assuming an α/ß ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. RESULTS: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD(2) to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD(2) to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). CONCLUSION: EQD(2) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients should be enrolled in ongoing prospective trials of hippocampal sparing during cranial irradiation to confirm these preliminary results.

Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project.

The Common Data Element (CDE) Project was initiated in 2006 by the National Institute of Neurological Disorders and Stroke (NINDS) to develop standards for performing funded neuroscience-related clinical research. CDEs are intended to standardize aspects of data collection; decrease study start-up time; and provide more complete, comprehensive, and equivalent data across studies within a particular disease area. Therefore, CDEs will simplify data sharing and data aggregation across NINDS-funded clinical research, and where appropriate, facilitate the development of evidenced-based guidelines and recommendations. Epilepsy-specific CDEs were established in nine content areas: (1) Antiepileptic Drugs (AEDs) and Other Antiepileptic Therapies (AETs), (2) Comorbidities, (3) Electrophysiology, (4) Imaging, (5) Neurological Exam, (6) Neuropsychology, (7) Quality of Life, (8) Seizures and Syndromes, and (9) Surgery and Pathology. CDEs were developed as a dynamic resource that will accommodate recommendations based on investigator use, new technologies, and research findings documenting emerging critical disease characteristics. The epilepsy-specific CDE initiative can be viewed as part of the larger international movement toward "harmonization" of clinical disease characterization and outcome assessment designed to promote communication and research efforts in epilepsy. It will also provide valuable guidance for CDE improvement during further development, refinement, and implementation. This article describes the NINDS CDE Initiative, the process used in developing Epilepsy CDEs, and the benefits of CDEs for the clinical investigator and NINDS.

Screening for dementia in community-based memory clinics.

PROBLEM: Dementia is a significant public health problem that is underrecognized in primary care settings. This study examined the usefulness of 3 brief screening tests in detecting dementia and mild cognitive impairment (MCI) in persons seeking consultation for memory complaints within a network of memory diagnostic clinics in Wisconsin. METHODS: This prospective study of consecutive referrals for memory diagnostic evaluation analyzed data for 364 patients > or = 50 years. Scores on 3 cognitive screening measures-the Mini-Mental State Examination (MMSE), Clock Drawing, and Animal Naming--were compared to clinical diagnosis of normal cognitive aging, MCI, or dementia. RESULTS: Using the standard cut score of <24, the MMSE identified only 60% of persons diagnosed with dementia. By contrast, using a recommended cut score of <14 words per minute, Animal Naming identified 85% of persons with dementia with a relatively low (12%) false positive rate. Clock Drawing was intermediate to the other 2 measures in screening effectiveness. CONCLUSIONS: Animal Naming was moderately to highly effective in identifying dementia. The naming procedure is easy to administer and may have value as a brief initial dementia screen in busy practice settings. More demanding cognitive measures may be needed to improve screening accuracy for MCI.

Living Well II: a review of progress since 2003.

Epilepsy as an issue for the public health community has a relatively short history in the United States. Not since the 1970s, when Congress established the Commission for the Control of Epilepsy and Its Consequences and the publication of its formal report, "Plan for Nationwide Action on Epilepsy," has significant attention been paid to the public health implications of epilepsy. In fact, until the U.S. Congress established a small epilepsy program at the Centers for Disease Control and Prevention (CDC) 12 years ago, the condition was practically invisible at all levels of organized public health. Since then, two major conferences, and the recommendations arising from them, have generated a substantially increased level of activity in research, surveillance, and the production and distribution of public education materials, as well as a national initiative to improve access to care and to prevent epilepsy's negative social impact. Even at the state level, long devoid of any attention to epilepsy in public health planning or provision of services, things are beginning to change, and new demonstration programs designed to identify and serve vulnerable populations with epilepsy are underway. This review highlights these activities, reflects a new and heightened level of attention to epilepsy, and speculates on what may lie ahead in the ongoing effort to give epilepsy greater visibility and higher priority in the public health arena.

Screening for major depression in epilepsy with common self-report depression inventories.

PURPOSE: Major depression is a common psychiatric comorbidity in chronic epilepsy that is frequently unrecognized and untreated. A variety of self-report mood inventories are available, but their validity as well as ability to detect major depression in epilepsy remains uncertain. The purpose of this study was to determine the ability of two common depressive symptom inventories to identify major depression in people with epilepsy. METHODS: In total, 174 adult patients with epilepsy underwent standardized psychiatric interview techniques [Mini International Neuropsychiatric Interview (MINI) and Mood Disorders module of the Structured Clinical Interview for DSM-IV Axis I Disorders-Research Version (SCID-I)] to determine the presence of current major depression. Subjects completed two self-report depression inventories [Beck Depression Inventory-II (BDI-II), Center for Epidemiological Study of Depression (CES-D)]. The ability of these self-report measures to identify major depression as identified by the gold standard structured interviews was examined by using diagnostic efficiency statistics. RESULTS: Both the BDI-II and the CES-D exhibited significant ability to identify major depression in epilepsy. All ROC analyses were highly significant (mean area under the curve, 0.92). Mean sensitivity (0.93) and specificity (0.81) were strong, with excellent negative predictive value (0.98) but lower positive predictive value (0.47). CONCLUSIONS: Common self-report depression measures can be used to screen for major depression in clinical settings. Use of these measures will assist in the clinical identification of patients with major depression so that treatment can be initiated.

Long-term psychosocial outcomes of anterior temporal lobectomy.

PURPOSE: To examine the long-term psychosocial outcomes of a consecutive series of patients who underwent anterior temporal lobectomy (ATL) compared with medically managed patients. This study focused primarily on actual long-term changes (mean, 5 years) in life performance. There are relatively few long-term controlled studies of actual lifetime performance changes. METHODS: The sample consisted of 61 adults who underwent ATL and 23 individuals who were evaluated for surgery but did not proceed to surgery and continued to receive medical management. Participants were interviewed 2-9 years after surgery. A structured clinical interview and review of medical records was conducted to obtain information regarding seizure frequency and psychosocial status, focusing on employment, education, driving status, financial assistance, and independent living. In addition, two questions regarding quality of life were included. Seizure frequency was evaluated for the year before the interview. RESULTS: Significant differences in psychosocial outcome were found between the surgery group and medical management group. Favorable psychosocial outcomes were more common among those who had surgery (46 vs. 4%). Results indicated that 68% of the surgery group exhibited improved psychosocial status compared with 5% of the medical management group. Individuals who had surgery were more likely to be driving, working full-time, living independently, and being financially independent. Remaining seizure free was not a prerequisite for improvements in psychosocial outcomes. CONCLUSIONS: Compared with medical management, surgery has a significant positive impact on psychosocial outcomes in terms of employment, independent living, driving, and financial independence. Additionally, a person does not necessarily have to be seizure free to achieve positive changes in psychosocial outcomes.