Quality of life during usual epilepsy care for anxiety or depression symptoms: Secondary patient-reported outcomes in a randomized trial of remote assessment methods.

BACKGROUND AND OBJECTIVES: Anxiety and depression are highly prevalent and impactful in epilepsy. American Academy of Neurology quality measures emphasize anxiety and depression screening and quality of life (QOL) measurement, yet usual epilepsy care QOL and anxiety/depression outcomes are poorly characterized. The main objective was to assess 6-month QOL, anxiety and depression during routine care among adults with epilepsy and baseline anxiety or depression symptoms; these were prespecified secondary outcomes within a pragmatic randomized trial of remote assessment methods. METHODS: Adults with anxiety or depression symptoms and no suicidal ideation were recruited from a tertiary epilepsy clinic via an electronic health record (EHR)-embedded process. Participants were randomized 1:1 to 6 month outcome collection via patient portal EHR questionnaires vs. telephone interview. This report focuses on an a priori secondary outcomes of the overall trial, focused on patient-reported health outcomes in the full sample. Quality of life, (primary health outcome), anxiety, and depression measures were collected at 3 and 6 months (Quality of Life in Epilepsy-10, QOLIE-10, Generalized Anxiety Disorder-7, Neurological Disorders Depression Inventory-Epilepsy). Change values and 95 % confidence intervals were calculated. In post-hoc exploratory analyses, patient-reported anxiety/depression management plans at baseline clinic visit and healthcare utilization were compared with EHR-documentation, and agreement was calculated using the kappa statistic. RESULTS: Overall, 30 participants (15 per group) were recruited and analyzed, of mean age 42.5 years, with 60 % women. Mean 6-month change in QOLIE-10 overall was 2.0(95 % CI -6.8, 10.9), and there were no significant differences in outcomes between the EHR and telephone groups. Mean anxiety and depression scores were stable across follow-up (all 95 % CI included zero). Outcomes were similar regardless of whether an anxiety or depression action plan was documented. During the baseline interview, most participants with clinic visit EHR documentation indicating action to address anxiety and/or depression reported not being offered a treatment(7 of 12 with action plan, 58 %), and there was poor agreement between patient report and EHR documentation (kappa=0.22). Healthcare utilization was high: 40 % had at least one hospitalization or emergency/urgent care visit reported and/or identified via EHR, but a third (4/12) failed to self-report an EHR-identified hospitalization/urgent visit. DISCUSSION: Over 6 months of usual care among adults with epilepsy and anxiety or depression symptoms, there was no significant average improvement in quality of life or anxiety/depression, suggesting a need for interventions to enhance routine neurology care and achieve quality of life improvement for this group.

Rapid-onset dystonia-parkinsonism is associated with reduced cerebral blood flow without gray matter changes.

Purpose: Previous research showed discrete neuropathological changes associated with rapid-onset dystonia-parkinsonism (RDP) in brains from patients with an ATP1A3 variant, specifically in areas that mediate motor function. The purpose of this study was to determine if magnetic resonance imaging methodologies could identify differences between RDP patients and variant-negative controls in areas of the brain that mediate motor function in order to provide biomarkers for future treatment or prevention trials. Methods: Magnetic resonance imaging voxel-based morphometry and arterial spin labeling were used to measure gray matter volume and cerebral blood flow, respectively, in cortical motor areas, basal ganglia, thalamus, and cerebellum, in RDP patients with ATP1A3 variants (n = 19; mean age = 37 ± 14 years; 47% female) and variant-negative healthy controls (n = 11; mean age = 34 ± 19 years; 36% female). Results: We report age and sex-adjusted between group differences, with decreased cerebral blood flow among patients with ATP1A3 variants compared to variant-negative controls in the thalamus (p = 0.005, Bonferroni alpha level < 0.007 adjusted for regions). There were no statistically significant between-group differences for measures of gray matter volume. Conclusions: There is reduced cerebral blood flow within brain regions in patients with ATP1A3 variants within the thalamus. Additionally, the lack of corresponding gray matter volume differences may suggest an underlying functional etiology rather than structural abnormality.

Maternal influenza vaccination preferentially boosts hemagglutinin stem-specific antibody resulting in efficient transplacental transfer of stem-specific IgG.

OBJECTIVE: The objective of this study was to evaluate hemagglutinin stem-specific antibody response to the influenza vaccine during pregnancy and its transfer to the infant. METHODS: The authors assessed antibody titers among maternal participants and their paired neonate's cord blood (CB) using enzyme-linked immunoassay. Fifteen pregnant participants pre-2019 and post-2019 seasonal influenza vaccine were compared with 18 prenatally vaccinated participants with paired neonatal CB samples. Total IgG and IgG subclass titers specific for whole vaccine antigens versus recombinant hemagglutinin stem-specific antigen were compared using Wilcoxon exact test. RESULTS: Hemagglutinin stem-specific IgG was boosted more robustly than whole vaccine titers when comparing postvaccine versus prevaccine log2 IgG ratios (P = 0.04). Hemagglutinin stem-specific IgG titers were boosted postvaccination (prevaccine: 14.5 [95% confidence interval, 13.8-15.2] vs. postvaccine: 16 [95% confidence interval, 15.2-16.8], P = 0.004). While IgG to whole vaccine was similar in neonatal CB and maternal plasma (P = 0.09), hemagglutinin stem-specific IgG concentrated in CB (P = 0.002), which was dominated by IgG1 subclass (analysis of variance P < 0.05). CONCLUSION: These data demonstrate the ability of pregnant women to generate a more robust antibody response to the stem region compared with the head region of hemagglutinin with transplacental transfer of IgG.

Predictors of Influenza and Pneumococcal Vaccination Among Participants in the Women's Health Initiative.

OBJECTIVE: Older adults typically experience higher rates of severe disease and mortality than the general population after contracting an infectious disease. Vaccination is critical for preventing disease and severe downstream outcomes; however, vaccination rates among older adults are suboptimal. We assessed predictors associated with pneumococcal and seasonal influenza vaccination among older women. METHODS: We used data from the Women's Health Initiative, a nationwide cohort of women. We ascertained seasonal influenza and pneumococcal vaccination status through a questionnaire administered in 2013. We limited analyses to women aged ≥65 years at questionnaire administration. We used logistic regression to estimate associations between demographic, lifestyle, and health-related factors and vaccination and explored stratification by race. RESULTS: Of participants who responded to each question, 84.3% (n = 60 578) reported being vaccinated for influenza and 85.5% (n = 59 015) for pneumonia. The odds of reporting influenza vaccination were significantly lower among non-Hispanic Black participants than among non-Hispanic White participants (odds ratio [OR] = 0.53; 95% CI, 0.49-0.58), women with no health insurance versus private health insurance (OR = 0.61; 95% CI, 0.54-0.68), and women living in rural versus urban settings (OR = 0.84; 95% CI, 0.73-0.96). Current smoking, lower education levels, and having comorbid conditions were associated with lower likelihood of being vaccinated for influenza (than not); past pneumonia diagnosis and being currently married were associated with a higher likelihood. We observed similar associations for pneumococcal vaccination coverage. CONCLUSIONS: These findings reinforce the need to enact policy and implement programs to improve access to, education and awareness about, and provider recommendations for these critical disease-prevention tools. Results from our study should guide strategies for SARS-CoV-2 vaccination.

Positive anxiety or depression screen despite ongoing antidepressant prescription in people with epilepsy: A large cross-sectional analysis.

Purpose: While antidepressants are recommended to manage anxiety or depression in epilepsy, limited effectiveness data exist in real-world epilepsy samples, and prior work indicated frequent positive screens despite antidepressant prescription. In response, this study evaluates factors associated with positive anxiety or depression screen during ongoing antidepressant prescription. Methods: Clinical and sociodemographic characteristics were collected among consecutive adult epilepsy clinic patients completing validated anxiety and depression instruments. The sample was divided by presence vs absence of existing antidepressant prescription at time of screening. Among those on an antidepressant, multivariable logistic regression was performed on pre-selected characteristics to evaluate for association with positive anxiety and/or depression screen. Pre-selected characteristics included: antidepressant dose, antidepressant prescriber specialty, antiseizure medications (number, potential psychotropic effects), seizure frequency, employment, visit no-shows, and medical insurance. Results: Of 563 people with epilepsy, 152 had evidence of antidepressant prescription at time of screening and 73/152(48%) had positive anxiety and/or depression screen. Multivariable modeling demonstrated low antidepressant dose and no-show visit(s) were associated with positive screens (adjusted OR 2.29, CI 1.00-5.48 and 3.11, 1.26-8.22 respectively). Conclusion: Low antidepressant dose and factors potentially associated with adherence (visit no-shows) may contribute to persistent anxiety and/or depression among epilepsy patients on an antidepressant.

Patient-reported outcomes via electronic health record portal versus telephone: a pragmatic randomized pilot trial of anxiety or depression symptoms in epilepsy.

Objective: To close gaps between research and clinical practice, tools are needed for efficient pragmatic trial recruitment and patient-reported outcome collection. The objective was to assess feasibility and process measures for patient-reported outcome collection in a randomized trial comparing electronic health record (EHR) patient portal questionnaires to telephone interview among adults with epilepsy and anxiety or depression symptoms. Materials and Methods: Recruitment for the randomized trial began at an epilepsy clinic visit, with EHR-embedded validated anxiety and depression instruments, followed by automated EHR-based research screening consent and eligibility assessment. Fully eligible individuals later completed telephone consent, enrollment, and randomization. Participants were randomized 1:1 to EHR portal versus telephone outcome assessment, and patient-reported and process outcomes were collected at 3 and 6 months, with primary outcome 6-month retention in EHR arm (feasibility target: ≥11 participants retained). Results: Participants (N = 30) were 60% women, 77% White/non-Hispanic, with mean age 42.5 years. Among 15 individuals randomized to EHR portal, 10 (67%, CI 41.7%-84.8%) met the 6-month retention endpoint, versus 100% (CI 79.6%-100%) in the telephone group (P = 0.04). EHR outcome collection at 6 months required 11.8 min less research staff time per participant than telephone (5.9, CI 3.3-7.7 vs 17.7, CI 14.1-20.2). Subsequent telephone contact after unsuccessful EHR attempts enabled near complete data collection and still saved staff time. Discussion: In this randomized study, EHR portal outcome assessment did not meet the retention feasibility target, but EHR method saved research staff time compared to telephone. Conclusion: While EHR portal outcome assessment was not feasible, hybrid EHR/telephone method was feasible and saved staff time.

Rare coding variants in RCN3 are associated with blood pressure.

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.

Analysis of longitudinal head impact exposure and white matter integrity in returning youth football players.

OBJECTIVE: The objective of this study was to characterize changes in head impact exposure (HIE) across multiple football seasons and to determine whether changes in HIE correlate with changes in imaging metrics in youth football players. METHODS: On-field head impact data and pre- and postseason imaging data, including those produced by diffusion tensor imaging (DTI), were collected from youth football athletes with at least two consecutive seasons of data. ANCOVA was used to evaluate HIE variations (number of impacts, peak linear and rotational accelerations, and risk-weighted cumulative exposure) by season number. DTI scalar metrics, including fractional anisotropy, mean diffusivity, and linear, planar, and spherical anisotropy coefficients, were evaluated. A control group was used to determine the number of abnormal white matter voxels, which were defined as 2 standard deviations above or below the control group mean. The difference in the number of abnormal voxels between consecutive seasons was computed for each scalar metric and athlete. Linear regression analyses were performed to evaluate relationships between changes in HIE metrics and changes in DTI scalar metrics. RESULTS: There were 47 athletes with multiple consecutive seasons of HIE, and corresponding imaging data were available in a subsample (n = 19) of these. Increases and decreases in HIE metrics were observed among individual athletes from one season to the next, and no significant differences (all p > 0.05) in HIE metrics were observed by season number. Changes in the number of practice impacts, 50th percentile impacts per practice session, and 50th percentile impacts per session were significantly positively correlated with changes in abnormal voxels for all DTI metrics. CONCLUSIONS: These results demonstrate a significant positive association between changes in HIE metrics and changes in the numbers of abnormal voxels between consecutive seasons of youth football. Reducing the number and frequency of head impacts, especially during practice sessions, may decrease the number of abnormal imaging findings from one season to the next in youth football.

Text Messaging and Home Blood Pressure Monitoring for Patients with Uncontrolled Hypertension: Proposal for a Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: A decrease in blood pressure, even modestly (ie, 2 mmHg), lowers cardiovascular morbidity and mortality. Low patient adherence to antihypertensive medication is the most significant modifiable patient-related barrier to achieving controlled blood pressure. Preliminary studies have shown that SMS text messaging and home blood pressure monitoring (HBPM) can be effective in promoting medication adherence and blood pressure control. The best strategy to engage with older patients of low socioeconomic status who are low adopters of technology and disproportionally affected by uncontrolled hypertension is still unknown. OBJECTIVE: The objective of this study is to improve blood pressure control in the older, low socioeconomic status population. The study will test two aims: First, we aim to evaluate the feasibility of conducting a randomized controlled trial by using an SMS-based approach among nonadherent, older patients of low socioeconomic status who have uncontrolled hypertension. Feasibility will be assessed in terms of recruitment rates per month (primary outcome); patient acceptability will be evaluated by monitoring retention rates and SMS response rates and using the validated Systems Usability Scale (secondary outcomes). Second, we aim to estimate the effects of the SMS approach on lowering blood pressure and adherence to antihypertensive medications. METHODS: We will recruit 24 patients of low socioeconomic status with uncontrolled hypertension (systolic BP>140 mmHg or diastolic BP>90 mmHg) showing low medication adherence and taking at least two antihypertensives, who have presented to two outpatient clinics of Wake Forest Baptist Health (Winston Salem, North Carolina, USA). Participants will be randomly assigned to either SMS and HBPM (n=12) or usual care and HBPM (n=12) intervention. Clinicians adjusting the patients' medications will be blinded to the study assignment. Text messages will be sent from a secure platform to assess medication adherence and HBPM on a weekly basis. The content and delivery frequency of the proposed SMS intervention are based on input from three focus groups conducted in Spring 2019. Participants in both study arms will receive education on HBPM and using an HBPM device. We hypothesize that we will successfully recruit 24 participants and the intervention will be acceptable to the participants. It will also improve medication adherence (assessed by question Medication Adherence Questionnaire scores) and blood pressure control. RESULTS: Our study was funded in July 2020. As of May 2021, we have enrolled 6 participants. CONCLUSIONS: Our findings will help design a larger efficacy trial to advance the field of eHealth delivery systems particularly for older adults of low socioeconomic status. This study addresses a highly significant topic and targets a population of high morbidity and mortality that has been traditionally underrepresented in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT03596242; https://clinicaltrials.gov/ct2/show/NCT03596242. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/18984.

Examining brief and ultra-brief anxiety and depression screening methods in a real-world epilepsy clinic sample.

OBJECTIVE: Recent epilepsy quality measure recommendations for depression and anxiety screening endorse ultra-brief screeners, the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder-2 (GAD-2). Thus, it is important to assess how symptom detection may be affected using ultra-brief screeners compared with slightly longer, well-validated instruments: Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) and Generalized Anxiety Disorder-7 (GAD-7). The objective was to compare symptom detection by brief versus ultra-brief depression and anxiety screeners in a large real-world epilepsy clinic sample. METHODS: This was a prospective, cross-sectional assessment of consecutive patients in an adult tertiary epilepsy practice who completed the GAD-7 and NDDI-E with embedded ultra-brief scales (GAD-2; GAD-Single Item: GAD-SI; NDDI-E 2 item: NDDIE-2) on a tablet and had clinic staff administered ultra-brief PHQ-2 (yes/no version) documented in the medical record at the same visit. Prevalences of positive anxiety and depression screens were calculated for each instrument overall, and by epilepsy status. Concordance correlation coefficients (CCC) were calculated comparing the ultra-brief with brief anxiety and depression instruments, and receiver operating curves (ROC) were calculated using the longer instruments as alternative standards. RESULTS: Among N = 422 individuals the prevalence of positive anxiety screen by GAD-7 was 24% and positive depression screen by NDDI-E was 20%. Positive anxiety and depression screens were significantly less prevalent among seizure-free individuals than those with continued seizures. The verbally administered yes/no PHQ-2 had only 1 positive screen (0.2%). Other than poor concordance between the PHQ-2 and NDDI-E, the screener pairs had acceptable concordance (CCC 0.79 to 0.92). Areas under the ROC curves were acceptable for the NDDIE-2, GAD-2 and GAD-SI (0.96, 0.98, and 0.89, respectively). SIGNIFICANCE: In this sample, clinic staff interview-administered yes/no PHQ-2 had exceedingly low sensitivity compared with the NDDI-E self-reported on a tablet. Further investigation is warranted to assess if poor detection is due to characteristics of this PHQ-2 in epilepsy samples, or method of administration in this clinic. The other ultra-brief anxiety and depression instruments demonstrated good concordance with the longer, well-validated instruments and may be useful in clinical practice.

Neurologist prescribing versus psychiatry referral: Examining patient preferences for anxiety and depression management in a symptomatic epilepsy clinic sample.

OBJECTIVE: Anxiety and depression symptoms in epilepsy are common, impactful and under-recognized and undertreated. While prior survey data suggests equipoise among epileptologists for managing anxiety and/or depression via prescribing in the epilepsy clinic versus psychiatry referral, patient preferences are unknown and should potentially influence practice habits among epileptologists. Thus, the primary objective of this study was to determine patient preference for anxiety and/or depression prescribing by neurologists versus psychiatry referral among an adult epilepsy clinic sample of symptomatic patients. METHODS: Management preferences for anxiety and/or depression were surveyed in an adult tertiary care epilepsy clinic. Individuals who screened positive for anxiety and/or depression symptoms on validated instruments during a routine care-embedded learning health system study were recruited. Demographics, social variables, psychiatric treatment history, and treatment priorities and preferences were surveyed. Preference was defined as a slightly greater than 2:1 ratio in favor neurology prescribing or psychiatry referral. The study was powered to assess this primary objective using a two-sample binomial test. Multinomial logistic regression examined an a priori multivariable model of treatment preference (secondary objective). RESULTS: The study sample included N = 63 symptomatic adults, with 64% women and mean age 42.2 years. Most reported past or current treatment for anxiety and/or depression, and treatment for these symptoms was a high or moderate priority among 65.1% of the sample. Neurologist prescribing was preferred in 83.0% (nearly 5:1) over psychiatry referral among those who chose neurology or psychiatry (as opposed to neither of the two; p < 0.001, 95% CI 0.702-0.919). Overall, 69.8% of the total study sample preferred neurology prescribing. Multivariable modeling indicated preference for neither management option (compared with neurologist prescribing) was associated with low overall treatment prioritization and having never received neurologist medication management. None of the factors examined in the a priori multivariable model were associated with selecting psychiatry referral (compared to neurologist prescribing). CONCLUSION: In this sample, most patients indicated a preference for neurologists to prescribe for anxiety or depression symptoms in the epilepsy clinic. Care models involving neurologist prescribing for anxiety and depression symptoms merit further investigation and potential adoption in clinical practice.

Auditory-perceptual voice and speech evaluation in ATP1A3 positive patients.

INTRODUCTION: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. METHODS: We analyzed recordings in 32 RDP subjects (male = 21, female = 11) and 29 mutation negative controls (male = 15, female = 14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. RESULTS: The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p < 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9-11 dysfunction (54%, p = 0.048), speech/swallowing dysfunction (96%, p = 0.0003); and oral dystonia (88%, p = 0.001). CONCLUSIONS: Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.

Dual-Outcome Intention-to-Treat Analyses in the Women's Health Initiative Randomized Controlled Hormone Therapy Trials.

Dual-outcome intention-to-treat hazard rate analyses have potential to complement single-outcome analyses for the evaluation of treatments or exposures in relation to multivariate time-to-response outcomes. Here we consider pairs formed from important clinical outcomes to obtain further insight into influences of menopausal hormone therapy on chronic disease. As part of the Women's Health Initiative, randomized, placebo-controlled hormone therapy trials of conjugated equine estrogens (CEE) among posthysterectomy participants and of these same estrogens plus medroxyprogesterone acetate (MPA) among participants with an intact uterus were carried out at 40 US clinical centers (1993-2016). These data provide the context for analyses covering the trial intervention periods and a nearly 20-year (median) cumulative duration of follow-up. The rates of multiple outcome pairs were significantly influenced by hormone therapy, especially over cumulative follow-up, providing potential clinical and mechanistic insights. For example, among women randomized to either regimen, hazard ratios for pairs defined by fracture during intervention followed by death from any cause were reduced and hazard ratios for pairs defined by gallbladder disease followed by death were increased, though these findings may primarily reflect single-outcome associations. In comparison, hazard ratios for diabetes followed by death were reduced with CEE but not with CEE + MPA, and those for hypertension followed by death were increased with CEE + MPA but not with CEE.

Who is willing to participate in research? A screening model for an anxiety and depression trial in the epilepsy clinic.

OBJECTIVE: Anxiety and depression in epilepsy are prevalent, associated with poor outcomes, underrecognized, undertreated, and thus a key area of need for treatment research. The objective of this study was to assess factors associated with research participation among epilepsy clinic patients who screened positive for anxiety or depression. This was accomplished by characterizing clinical and psychiatric factors among patients seen in an epilepsy clinic and evaluating which factors were associated with consent for potential research participation, via a combined clinical and research screening model. METHODS: In a pragmatic trial of anxiety and depression treatment in epilepsy, individuals with a positive screen for anxiety and/or depression at a routine epilepsy clinic visit were invited to opt-in (via brief electronic consent) to further eligibility assessment for a randomized treatment study. Information on psychiatric symptoms and treatment characteristics were collected for dual clinical care and research screening purposes. Cross-sectional association of demographic, clinical, and psychiatric factors with opting-in to research was analyzed by multiple logistic regression. RESULTS: Among N = 199 unique adults with a first positive screen for anxiety and/or depression among 786 total screening events, 154 (77.4%) opted-in to further potential research assessment. Higher depression scores and current treatment with an antidepressant were independently associated with opting-in to research (depression odds ratio (OR) = 1.13 per 1-point increase in Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) score, p = 0.028, 95% confidence interval (CI): 1.01-1.26; antidepressant OR = 2.37, p = 0.041, CI: 1.04-5.41). Nearly half of the 199 individuals (43.7%) with anxiety and/or depression symptoms were already being treated with an antidepressant, and 46.7% were receiving neither antidepressant therapy nor mental health specialty care. One-quarter (24.1%) reported a past psychiatric hospitalization, yet only half of these individuals were receiving mental health specialty care. SIGNIFICANCE: Our results demonstrate a high willingness to participate in research using a brief electronic consent approach at a routine clinic visit. Adults with persistent anxiety or depression symptoms despite antidepressant therapy and those with higher depression scores were more willing to consider a randomized treatment study. This has implications for future study design, as individuals already on treatment or those with more severe symptoms are often excluded from traditional research designs. We also found a high burden of psychiatric disease and high prevalence of persistent symptoms despite ongoing antidepressant treatment.

Cognitive resilience among APOE ε4 carriers in the oldest old.

OBJECTIVES: Relatively few APOE ε4+ carriers survive to old age (age 80+) without cognitive impairment (CI); thus, little is known about distinguishing characteristics of resilient APOE ε4+ carriers. Herein, we describe the sociodemographic characteristics of a large sample of resilient APOE ε4+ women from the Women's Health Initiative Memory Study (WHIMS) and compare them to noncarriers and APOE ε4+ women who developed CI before age 80. METHODS: Women were recruited for clinical trials evaluating postmenopausal hormone therapy and incidence of dementia. During posttrial follow-up, cognitive status was adjudicated annually. Among 5716 women, we compared groups by APOE ε4 status using logistic regression, covarying for treatment, demographics, lifestyle, cardiovascular and physical function, well-being, and self-rated general health. RESULTS: Among 557 APOE ε4+ women, those who survived to age 80+ without CI had higher baseline self-rated general health (odds ratio [OR]: 1.02; 95% confidence interval [CI], 1.01-1.04) and cognitive scores (OR: 1.18; 95% CI, 1.12-1.25) than those who did not reach age 80 without CI. Baseline high total cholesterol and low-density lipoprotein (LDL) levels were similar across APOE ε4+ groups but were higher compared with APOE ε4- women. Among women who survived to 80+ without CI, more APOE ε4+ women had a history of high total cholesterol (P = .003) and LDL cholesterol (OR: 1.01; 95% CI, 1.00-1.01). There were no differences in hypertension, diabetes, or other vascular risk factors in APOE ε4+ women compared with noncarriers. CONCLUSIONS: Results highlight the importance of baseline cognitive function and general health for late-life cognition among ε4+ women.

Revising rapid-onset dystonia-parkinsonism: Broadening indications for ATP1A3 testing.

BACKGROUND AND OBJECTIVES: Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. METHODS: We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. RESULTS: We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). CONCLUSIONS: Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

Dementia outcomes after addition of proxy-based assessments for deceased or proxy-dependent participants.

OBJECTIVES: As people age and the incidence of dementia increases, studies of cognitive function continue to be of importance. Ascertaining cognitive data through different mechanisms is necessary to address missing data concerns. METHODS: The Dementia Questionnaire (DQ), which utilizes proxy-based assessments, is a potential tool to determine cognitive status in participants no longer being followed per traditional study protocol. The DQ is currently being used in the Supplemental Case Ascertainment Protocol (SCAP), which is being conducted in an ongoing study of postmenopausal women as part of the Women's Health Initiative Memory Study (WHIMS). RESULTS: Ninety-four percent of the 1260 SCAP participants were eligible because of being deceased. Those who are SCAP eligible were older, were less likely to be a minority, and were more likely to have hypertension, diabetes, and prior history of cardiovascular disease (CVD) as well as being a past or current smoker. SCAP added 109 cases of probable dementia to WHIMS. Risk factor relationships were modified upon inclusion of the SCAP cases including an attenuation of a hormone therapy effect and discovery of a hypertension effect. CONCLUSIONS: Augmenting clinic-based cases with proxy-based assessments is feasible and leads to increased incident cases of dementia. When planning future clinical trials, it may be of study benefit to include a protocol of proxy-based assessments, develop strong relationships with proxies early on in the study, and attempt to maintain this relationship throughout the lifespan of the trial.

A candidate gene study of risk for dementia in older, postmenopausal women: Results from the Women's Health Initiative Memory Study.

OBJECTIVE: While a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS). METHODS: We analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non-Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model. RESULTS: One SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with the PD phenotype based on a P value accounting for multiple comparisons. An additional 12 SNPs were associated with the PD phenotype at P ≤ 0.05 (APOE: rs405509, rs439401; TOMM40: rs8106922, and KIBRA: rs4320284, rs11740112, rs10040267, rs13171394, rs6555802, rs2241368, rs244904, rs6555805, and rs10475878). Results of the sensitivity analyes excluding MCI were similar, with addition of COMT rs737865 and BDNF rs1491850 (P ≤ 0.05). CONCLUSIONS: Our results in older women provide supporting evidence that the APOE/TOMM40 genes confer dementia risk and extend these findings to COMT, BDNF, and KIBRA. Our findings may lead to a better understanding of the role these genes play in cognition and cognitive impairment.