Controlled Oral Word Association Research Articles

Predicting the risk of neurocognitive decline after brain irradiation in adult patients with a primary brain tumor.

Deterioration of neurocognitive function in adult patients with a primary brain tumor is the most concerning side effect of radiotherapy. This study aimed to develop and evaluate normal-tissue complication probability (NTCP) models using clinical and dose-volume measures for 6-month, 1-year, and 2-year Neurocognitive Decline (ND) postradiotherapy. A total of 219 patients with a primary brain tumor treated with radical photon and/or proton radiotherapy (RT) between 2019 and 2022 were included. Controlled oral word association test, Hopkins verbal learning test-revised, and trail making test were used to objectively measure ND. A comprehensive set of potential clinical and dose-volume measures on several brain structures were considered for statistical modeling. Clinical, dose-volume and combined models were constructed and internally tested in terms of discrimination (area under the curve, AUC), calibration (mean absolute error, MAE), and net benefit. Fifty percent, 44.5%, and 42.7% of the patients developed ND at 6-month, 1-year, and 2-year time points, respectively. The following predictors were included in the combined model for 6-month ND: age at radiotherapy > 56 years (OR = 5.71), overweight (OR = 0.49), obesity (OR = 0.35), chemotherapy (OR = 2.23), brain V20 Gy ≥ 20% (OR = 3.53), brainstem volume ≥ 26 cc (OR = 0.39), and hypothalamus volume ≥ 0.5 cc (OR = 0.4). Decision curve analysis showed that the combined models had the highest net benefits at 6-month (AUC = 0.79, MAE = 0.021), 1-year (AUC = 0.72, MAE = 0.027), and 2-year (AUC = 0.69, MAE = 0.038) time points. The proposed NTCP models use easy-to-obtain predictors to identify patients at high risk of ND after brain RT. These models can potentially provide a base for RT-related decisions and post-therapy neurocognitive rehabilitation interventions.

Design and Rationale of a Two-Armed Randomized Controlled Trial on Yoga/Brisk Walking-Based Lifestyle Modification on Dementia Risk Reduction, and Influence of ApoE Genotypes on the Intervention.

Though considered a late-onset disease, the 2020 report of the Lancet Commission emphasizes the necessity of conducting primary prevention trials with an approach of never too early in the life course for dementia prevention. Driven by the same notion, we hereby aim to compare the dementia risk reduction potential of two potential interventions, 48 weeks (12 months) of yoga and brisk walking, in middle-aged high-risk subjects. A randomized controlled trial. Community in India. In total, 323 at-risk dementia subjects will be recruited from community settings through health awareness camps and door-to-door surveys across Delhi, India. Participants will be randomized into yoga or brisk-walking groups (1:1). The yoga intervention group will receive 60 contact yoga sessions per 60-min/day at the community parks, followed by continued tele-supervised home practice, further followed by at-home self-practice, and will be tested at 3-time points (baseline, 24-week and 48-week, post-randomization) to test the efficacy of the intervention. The control group will be asked to do brisk walking daily for 45 minutes at their convenience, followed by weekly telephone follow-ups. Applying the intention-to-treat principle, the primary endpoint will be the change from baseline at the 12th month in the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) Scores. Secondary outcomes will include the composite scores derived from a comprehensive neuropsychology battery, comprising the Trail Making Test, Digit Span Test, N Back, Color Trail, Animal Fluency Test, COWA (Controlled Oral Word Association Test), and Digit Symbol Substitution. The primary outcome will be analyzed using mixed-effect models for repeated measures, adjusted for covariates as fixed effects. The study has been prospectively registered (CTRI/2023/02/049746) on February 15, 2023. The protocol was conceptualized in 2021 and approved by the Institutional Ethics Committee of SVYASA. Recruitment began in February 2023 and is underway with patient enrollment. To our knowledge, this is the first controlled trial to investigate the longitudinal effects of a yoga-based intervention on dementia risk reduction using the CAIDE risk score. The findings of this trial will also provide insight into a better understanding of genotype-dependent responses to yoga intervention and open up avenues for understanding the implications of gene-intervention interactions for precision prevention using yoga.

BIOM-03. LACK OF CORRELATION OF MR-DETERMINED WHITE MATTER INJURY(WMI)WITH NEUROCOGNITIVE FUNCTION (NCF)6 MONTHS FOLLOWING WBRT+/-HIPPOCAMPAL AVOIDANCE(HA)+MEMANTINE:SECONDARY ANALYSIS OF NRG ONCOLOGY NRGCC001

Abstract PURPOSE Previous analysis of NRG-CC001 suggested pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggested patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not standard-WBRT. The current analysis examined the relationship between changes in MR-determined WMI and NCF 6-months following WBRT+memantine+/-HA. METHODS NCF-testing was performed at baseline, 2, 4, 6, and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR-volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (met vol) (FLAIR-volume/(whole brain volume–met-vol). Pearson correlation coefficients were used to assess the correlation between pre-treatment WMI and change from baseline to 6-months for each standardized NCF score. RESULTS Of the 518 randomized patients, 443 (217 patients WBRT+Memantine and 226 HA-WBRT+Memantine) had WMI data available at baseline, and of those, 162 patients (89 patients WBRT+Memantine and 73 HA-WBRT+Memantine) had both baseline and 6-month imaging available. For these patients, there was only a trend toward significance for change in corrected FLAIR-volume from baseline to 6-months (p = 0.174) but no significant change in met-vol (p = 0.438) or whole brain volume (p = 0.977). The change in standardized TMT Part A and B and the change in composite 6-month change scores were moderately correlated with change in corrected FLAIR volume adjusted for met-vol but only in the WBRT+Memantine arm (rho=-0.35, -0.34, -0.39 and p-value = 0.003, 0.006, 0.001). CONCLUSIONS Despite an increase in post-WBRT MR-WMI at 6-months, analysis did not show strong correlation between NCF and MR-WMI as determined by FLAIR-volume change between baseline and 6-months. Similar analyses are underway for the NRG-CC003 imaging data.

28 Factor Structure of Conventional Neuropsychological Tests and NIH-Toolbox in Healthy Older Adults

Objective:The National Institutes of Health-Toolbox cognition battery (NIH-TCB) is widely used in cognitive aging studies and includes measures in cognitive domains evaluated for dimensional structure and psychometric properties in prior research. The present study addresses a current literature gap by demonstrating how NIH-TCB integrates into a battery of traditional clinical neuropsychological measures. The dimensional structure of NIH-TCB measures along with conventional neuropsychological tests is assessed in healthy older adults.Participants and Methods:Baseline cognitive data were obtained from 327 older adults. The following measures were collected: NIH-Toolbox cognitive battery, Controlled Oral Word Association (COWA) letter and animals tests, Wechsler Test of Adult Reading (WTAR), Stroop Color-Word Interference Test, Paced Auditory Serial Addition Test (PASAT), Brief Visuospatial Memory Test (BVMT), Letter-Number Sequencing (LNS), Hopkins Verbal Learning Test (HVLT), Trail Making Test A&B, Digit Span. Hmisc, psych, and GPARotation packages for R were used to conduct exploratory factor analyses (EFA). A 5-factor solution was conducted followed by a 6-factor solution. Promax rotation was used for both EFA models.Results:The 6-factor EFA solution is reported here. Results indicated the following 6 factors: working memory (Digit Span forward, backward, and sequencing, PASAT trials 1 and 2, NIH-Toolbox List Sorting, LNS), speed/executive function (Stroop color naming, word reading, and color-word interference, NIH-Toolbox Flanker, Dimensional Change, and Pattern Comparison, Trail Making Test A&B), verbal fluency (COWA letters F-A-S), crystallized intelligence (WTAR, NIH-Toolbox Oral Recognition and Picture Vocabulary), visual memory (BVMT immediate and delayed), and verbal memory (HVLT immediate and delayed. COWA animals and NIH-Toolbox Picture Sequencing did not adequately load onto any EFA factor and were excluded from the subsequent CFA.Conclusions:Findings indicate that in a sample of healthy older adults, these collected measures and those obtained through the NIH-Toolbox battery represent 6 domains of cognitive function. Results suggest that in this sample, picture sequencing and COWA animals did not load adequately onto the factors created from the rest of the measures collected. These findings should assist in interpreting future research using combined NIH-TCB and neuropsychological batteries to assess cognition in healthy older adults.

96 Proof of Principle: Can Paragraph Recall Pauses and Speech Frequencies Correctly Classify Cognitively Compromised Older Adults?

Objective:Recent research has found that machine learning based analysis of patient speech can be used to classify Alzheimer’s Disease. We know of no studies, however, which systematically explore the value of pausing events in speech for detecting cognitive limitations. Using retrospectively acquired voice data from paragraph memory tests, we created two types of pause features: a) the number and duration of pauses, and b) frequency components in speech immediately following pausing. Multiple machine learning models were used to assess how these features could effectively discriminate individuals classified into two groups: Cognitively Compromised versus Cognitively Well.Participants and Methods:Participants (age> 65 years, n= 67) completed the Newcomer paragraph memory test and a neuropsychological protocol as part of a federally funded prospective IRB approved investigation at the University of Florida. Participant vocal recordings were acquired for the immediate and delay conditions of the test. Speaker diarization was performed on the immediate free recall test condition to separate voices of patients from examiners. Features extracted from both test conditions included a) 3 pause characteristics (total number of pauses, total pause duration, and length of the longest pause), and b) 20 Mel Frequency Cepstral Coefficients (MFCC) pertaining to speech immediately (2.7 seconds) following pauses. These were combined with demographics (age, sex, race, education, and handedness) to create a total of 105 features that were used as inputs for multiple machine learning analytic models (random forest, logistic regression, naive Bayes, AdaBoost, Gradient Boost, and multi-layered perceptron). External neuropsychological metrics were used to initially classify Cognitively Compromised (i.e., < -1.0 standard deviation on > two of five test metrics: total immediate, delay, discrimination Hopkins Verbal Learning Test-Revised (HVLT-R),Controlled Oral Word Association (COWA) test, category fluency ('animals')). Pearson Product Moment Correlations were used to assess the linear relationships between pauses and speech frequency categories and neuropsychological metrics.Results:Neuropsychology metric classification using -1SD cut-off identified 27% (18/67 participants) as Cognitively Compromised. The Cognitively Compromised group and the Cognitively Well group did not show any difference in distributions of individual pause/frequency features (Mann Whitney U-test, p> 0.11). A negative correlation was found between total duration of short pauses and HVLT total immediate free recall, while a positive correlation was found between MFCC-10 and HVLT total immediate free recall. The best classification model was AdaBoost Classifier which predicted the Cognitively Compromised label with 0.91 area under receiver operating curve, 0.81 accuracy, 0.43 sensitivity, 1.0 specificity, 1.0 precision, 0.6 f1 score.Conclusions:Pause characteristics and frequency profiles of speech immediately following pauses from a paragraph memory test accurately identified older adults with compromised cognition, as measured by verbal learning and verbal fluency metrics. Furthermore, individuals with reduced HVLT immediate free recall generated more pauses, while individuals who recalled more words had higher power in mid-frequency bands (10th MFCC). Future research needs to replicate how paragraph recall pause characteristics and frequency the profile of speech immediately following pauses potentially provides a low resource alternative to automatic speech recognition models for detecting cognitive impairments.

Psychometric Properties of Controlled Oral Word Association (COWA) Test and Associations With Education and Bilingualism in American Indian Adults: The Strong Heart Study.

The Controlled Oral Word Association (COWA) test is used to assess phonemic fluency and executive function. Formal validation of test scores is important for accurate cognitive evaluation. However, there is a dearth of psychometric validation among American Indian adults. Given high burden of dementia risk and key contextual factors associated with cognitive assessments, this represents a critical oversight. In a large, longitudinal population-based cohort study of adult American Indians, we examined several validity inferences for COWA, including scoring, generalization, and extrapolation inferences, by investigation of factor structure, internal consistency, test-retest reliability, and differential test functioning. We found adequate unidimensional model fit, with high factor loadings. Internal consistency reliability and test-retest reliability were 0.88 and 0.77, respectively, for the full group. COWA scores were lowest among the oldest, lowest education, bilingual speakers; group effects for sex and bilingual status were small; age effect was medium; and education effect was largest. However, Wide Range Achievement Test (WRAT) score effect was stronger than education effect, suggesting better contextualization may be needed. These results support interpretation of total COWA score, including across sex, age, or language use strata.

Neurocognitive function outcomes in NRG/RTOG 0534, the SPPORT trial.

12022 Background: RTOG 0534 established the benefit of adding of short term androgen deprivation therapy (PBRT+STADT, Arm 2) to prostate bed salvage radiotherapy (PBRT, Arm 1), and demonstrated that elective pelvic lymph node irradiation combined with STADT (PBRT+STADT+PLNRT, Arm 3) results in further reductions in progression. Longitudinal monitoring of neurocognitive function (NCF) was conducted to evaluate the hypothesis that patients treated with STADT will demonstrate greater decline in NCF compared to patients receiving PBRT alone. Methods: Patients were administered the Clinical Trial Battery [Hopkins Verbal Learning Test – Revised (HVLT-R), Trail Making Test (TMT), and the Controlled Oral Word Association (COWA) test] by certified test administrators at baseline, and at 6 weeks (6w), 1 year (1yr), and 5 years after the end of RT (5yr). Raw NCF tests scores were converted to standardized z-scores adjusted for age and education when necessary. Analyses included z-score change and reliable change index (RCI) determined decline compared to baseline, and longitudinal mixed effect regression models using z-scores. To control for multiplicity, p < 0.025 is required for statistical significance. Results: Among the 1716 analyzable patients, 429 consented to NCF monitoring. There were no significant differences in sociodemographic or clinical characteristics between arms. NCF test completion was 82, 76, 63 and 30% at baseline, 6w, 1yr, and 5yr, respectively. RCI-based NCF deterioration was more frequent in Arm 3 compared to Arm 1 at 6 weeks on Delayed Recall (16% vs. 7%, p = 0.023). Patients in Arm 3 evidenced greater z-score decline compared to patients in Arm 1 at 6w on HVLT-R Total Recall [M(SD) Z-score∆ = -0.1(1.0) vs 0.2(0.9), (p = 0.020)] and Delayed Recall [M(SD) Z-score∆ = -0.4(1.5) vs 0.1(1.2), (p = 0.012)]. Mixed effects models identified statistically significant differences in z-scores between Arm 3 and 1 at 6w on Delayed Recall [-0.541 (SE 0.178, p = 0.002)]. A statistically significant difference was observed between Arm 2 and 1 at 6w on TMTB [1.498 (SE 0.626, p = 0.017) favoring Arm 2]. Between arm differences were not seen at any other time point, or on other NCF outcomes. Conclusions: Compared to patients treated with PBRT alone, patients treated with PBRT+STADT+PLNRT exhibited greater worsening in episodic verbal learning and memory processes at 6 weeks after the end of RT, while patients treated with PBRT+STADT exhibited greater improvement in processing speed. The absence of long term or progressive cognitive decline associated with STADT-containing regimens is promising but limited by substantial missing data at year 5. FUNDING This project was supported by grants 10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), CTEP from the National Cancer Institute (NCI). Clinical trial information: NCT00567580 .

Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001

Initial report of NRG Oncology CC001, a phase 3 trial of whole-brain radiation therapy plus memantine (WBRT+memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with a median follow-up of fewer than 8 months. Herein, we report the final results with complete cognition, patient-reported outcomes, and longer-term follow-up exceeding 1 year. Adult patients with brain metastases were randomized to HA-WBRT+memantine or WBRT+memantine. The primary endpoint was time to cognitive function failure, defined as decline using the reliable change index on the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association, or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L. Between July 2015 and March 2018, 518 patients were randomized. The median follow-up for living patients was 12.1 months. The addition of HA to WBRT+memantine prevented cognitive failure (adjusted hazard ratio, 0.74, P=.016) and was associated with less deterioration in TMT-B at 4 months (P=.012) and HVLT-R recognition at 4 (P=.055) and 6 months (P=.011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (P < .005). Patients who received HA-WBRT+Memantine reported less symptom burden at 6 (P < .001 using imputed data) and 12 months (P=.026 using complete-case data; P < .001 using imputed data), less symptom interference at 6 (P=.003 using complete-case data; P=.0016 using imputed data) and 12 months (P=.0027 using complete-case data; P=.0014 using imputed data), and fewer cognitive symptoms over time (P=.043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival, or toxicity. With median follow-up exceeding 1 year, HA during WBRT+memantine for brain metastases leads to sustained preservation of cognitive function and continued prevention of patient-reported neurologic symptoms, symptom interference, and cognitive symptoms with no difference in survival or toxicity.

Acutil® in Mild Cognitive Impairment or Early Dementia: An Exploratory Observational Pilot Study

Background: With no approved treatment for mild cognitive impairment (MCI), attention increasingly turns to qualified food supplements. Objective: To conduct a 12-month rater-blinded exploratory outpatient trial with Acutil®, a supplement consisting of ω-3 polyunsaturated fatty acids, Ginkgo biloba extract, and vitamins, in 50 persons with amnestic MCI or mild to moderate Alzheimer or mixed-type dementia. Methods: The used cognitive tools were the Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog), the Mini-Mental State Exam (MMSE), and Controlled Oral Word Association Test (COWAT). Patients were randomized in the ratio of 40:10 to additional Acutil® or no additional supplementation; all continued on their existing medications during the entire study. Results: Only the COWAT produced a clear positive signal in the Acutil® group between individual baseline and study endpoint, but the between-group comparison was not statistically significant. The MMSE score remained stable in the Acutil® group while deteriorating in the control group; post hoc examination suggests that the Acutil® group might have contained responders. The ADAS-Cog and Clinical Dementia Rating (CDR) scores showed marginal deterioration in both groups. Conclusions: We tentatively interpret our results as potentially indicating positive effects of Acutil® on verbal fluency and some aspects of executive function, with an onset after 6 months of continuous treatment. However, much larger and double-blinded studies will be required to make firm statements.

Social cognitive deficits in schizophrenia and their neurocognitive correlates across the different phases of illness.

This study aimed to assess the relationship between neurocognition (NC) and social cognition (SC) in patients with schizophrenia during the symptomatic phase and the phase of clinical remission. Thirty-two patients were assessed on Color trail test (CTT), Hopkins verbal learning test (HVLT), Controlled oral word association (COWA) test, Wisconsin card sorting test (WCST), Ravens standard progressive matrices (SPM) and Social cognition rating tool in Indian setting (SOCRATIS) during symptomatic and remission phases of illness at least 3 months apart. Compared to baseline assessment, even after controlling for PANSS scores except for social perception index all other domains of SC showed significant improvement at the time of remission. Although there was significant improvement in a few subtests of verbal learning, IQ and number of correct responses of COWA, colour trail test, no significant difference was seen in performance on WCST. Although second order theory of mind task had some association with IQ at the baseline assessment, no association was seen between SC and NC in the remission phase. To conclude, present study suggests that impairments in all the domains of SC (except for social perception index) and NC (except for WCST) improve in the remission phase.

NCOG-04. PRETREATMENT VOLUME OF MR-DETERMINED WHITE MATTER INJURY (WMI) PREDICTS NEUROCOGNITIVE DECLINE AFTER HIPPOCAMPAL AVOIDANT (HA) WBRT+MEMANTINE FOR BRAIN METASTASES: SECONDARY ANALYSIS OF NRG ONCOLOGYCC001

Abstract PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p&amp;lt; 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.

PREVALENCE OF EXECUTIVE DYSFUNCTION IN ICU SURVIVORS AND ITS ASSOCIATION WITH DAILY FUNCTIONAL ABILITY

SESSION TITLE: Critical Care Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Cognitive impairment is common in survivors of critical illness and occurs in between 30% and 50% of individuals in the first year after discharge from the ICU. While cognitive impairment has been widely studied in this population, relatively little attention has been paid to the characterization of executive functioning. We undertook the current study both to describe the prevalence and nature of executive deficits in survivors of critical illness and to determine which dimensions of executive functioning were the most predictive of daily functional decrements. METHODS: A total of 184 participants were prospectively enrolled in a sub-study nested within an NIH-funded parent study (BRAIN-ICU). Patients were adult mechanically ventilated ICU survivors from two large medical centers who were followed at 3 months and 12 months after discharge with a comprehensive testing of both executive functioning and daily functional ability (via the Functional Activities Questionnaire or FAQ). Descriptive statistics were employed to characterize patient demographics and the prevalence of executive impairment. Proportional odds logistic regression was used to find the association between executive dysfunction and functional difficulties RESULTS: At 3- and 12-month follow-up, 135 and 105 patients were assessed, respectively. Global executive functioning was impaired (reflecting pervasive deficits across multiple domains) in nearly a quarter (22%) of study subjects at 3-month follow-up and in 10% at 12-months. Executive dysfunction was highly prevalent on tests of fluency (verbal and figural) and set-shifting, reflected in impairment on the Ruff Figural Fluency Test (44 % at 3 months and 30% at 12 months), the Controlled Oral Word Association (COWA) Test (39% at 3 months and 32% at 12 months), and the Trails B Test (31% at 3 months and 24% at 12 months). Deficits in executive ability were closely associated with impaired daily functional ability as seen in significant associations between scores on the Ruff, COWA, and Trails B tests and the FAQ, particularly at 3 months (p<0.001), with this relationship decreasing slightly at 12 months on Trails B. Analysis also revealed that lower (worse) scores on the Ruff, COWA, Trails B, and Color Word tests at 3 months predicted the presence of greater functional impairment (FAQ) (p<0.01) CONCLUSIONS: Executive dysfunction is highly prevalent in ICU survivors up to a year after discharge particularly in areas of fluency and set shifting. The presence of early executive dysfunction appears to be correlated with longer-term deficits in daily functioning. CLINICAL IMPLICATIONS: Future investigations should strive to better characterize executive functioning after critical illness and researchers and clinicians should seek to identify ways to improve executive dysfunction in this ICU survivors DISCLOSURES: no disclosure on file for Wes Ely; No relevant relationships by Timothy Girard, source=Web Response no disclosure on file for James Jackson; No relevant relationships by Amy Kiehl, source=Web Response no disclosure on file for Caroline Lassen Green; No relevant relationships by Deepanjali Radhakrishnan Nair, source=Web Response No relevant relationships by Rameela Raman, source=Web Response

Depression Symptoms and Cognitive Test Performance in Older American Indians: The Strong Heart Study.

American Indians have excess risk of depression, which can contribute to cerebrovascular and cognitive disability, with effects on memory, processing speed, executive function, and visuospatial ability. However, studies examining depression and cognition in American Indians are limited; this study aims to report associations of depression with general cognition, verbal fluency and memory, and processing speed. Cohort study. The Cerebrovascular Disease and its Consequences in American Indians study was an ancillary examination of Strong Heart Study participants from 3 U.S. regions. All eligible were included in this analysis (N=818). Participants completed evaluations for depressive symptomology, cognition, and physical function-including Center for Epidemiologic Studies Depression (CESD), Modified Mini-Mental State Examination (3MSE), Wechsler Adult Intelligence Scale-Fourth Edition coding (WAIS), Controlled Oral Word Association (COWA), California Verbal and Learning Test, Halstead finger tapping, grip strength, and Short Physical Performance Battery (SPPB) tests. Linear mixed models were adjusted for site, age, sex, education, income, marital status, alcohol, smoking, diabetes, hypertension, obesity, cholesterol, stroke, infarct, and hemorrhage. Symptoms of depression were common, with 20% (N=138) endorsing CES-D scores of 16+. More depressive symptoms were associated with older age, female sex, lower education, lower income, non-married status, not using alcohol, not smoking, hypertension, diabetes, and stroke. In adjusted analyses, processing speed (WAIS: β -0.13, 95%CI -0.25, -0.03), general cognition (3MSE: β -0.10, 95%CI -0.17, -0.03), verbal fluency (COWA: β -0.10, 95%CI -0.19, -0.01), and motor function (SPPB: β -0.05, 95%CI -0.07, -0.03) were significantly associated with more symptoms of depression. These findings maybe informative for health disparities populations, especially those with depressive risk. Clinicians may require particular training in cultural humility. Future studies should validate use of the CES-D scale in this population; longitudinal studies may focus on causal mechanisms and potential secondary prevention, such as social support. J Am Geriatr Soc 68:1739-1747, 2020.

Dysfunctional personality beliefs and executive performance in patients with juvenile myoclonic epilepsy

BackgroundThis article intends to verify the association of dysfunctional beliefs of personality disorders with the executive performance in people with juvenile myoclonic epilepsy (JME). MethodsFifty-two patients (35 women, 67.3%) with JME aged 18–50 yrs. (32.3 ± 9.7) were evaluated between May 2017 and April 2018 and compared with controls. All subjects were submitted to the Personality Beliefs Questionnaire (PBQ) (Beck & Beck, 1991; Savoia et al., 2006), Dysexecutive Questionnaire (DQ; Wilson et al., 1996; Macuglia et al., 2016), estimated intelligence quotient (IQ) using Vocabulary and Block Design tests, attention and executive functions evaluation (Controlled Oral Word Association (COWA), Digit Span, Trail Making Tests (TMT) A and B, Stroop and Wisconsin Card Sorting Test (WCST)). The inclusion criteria were as follows: diagnosis of JME (ILAE, 1989); age ≥18 yrs., schooling ≥ 11 yrs. and IQ ≥70. The inclusion criteria for the control group were the same except diagnosis of epilepsy. ResultsCompared with controls, patients presented higher scores in PBQ for personality disorders, namely Narcissistic (z = −0.79; p < 0.001), Borderline (z = −0.58; p = 0.002), Paranoid (z = −0.43; p = 0.017), and Histrionic (z = −0.39; p = 0.041). Executive functions were impaired when compared with controls in TMT A (z = −0.97; p = 0.038), TMT B (z = −0.65; p = 0.023), and COWA (z = −0.51; p = 0.001). Patients showed higher WCST scores for Errors (z = −1.62; p ≤ 0.001), Perseverative Errors (z = −0.77; p = 0.001), Non-Perseverative Errors (z = −1.01; p = 0.001), Conceptual Level Response (z = −1.56; p ≤ 0.001), Completed Categories (z = −2.12; p = 0.002), and Failure to Maintain Context (z = −0.49; p = 0.015). Personality Beliefs Questionnaire results showed correlation with lower values in TMT A, Antisocial (r = −0.298; p = 0.032), Narcissistic (r = −0.303; p = 0.029), Schizoid (r = − 0.410; p = 0.003), Histrionic (r = −0.341; p = 0.013), Passive-aggressive (r = −0.341; p = 0.015), and Obsessive–compulsive (r = −0.319; p = 0.021); TMT B results showed a trend for Obsessive–compulsive traits (r = −0.261; p = 0.052); COWA was correlated to Dependent (r = 0.319; p = 0.021); and Digit Span to Passive-aggressive (r = 0.287; p = 0.039). On WCST, Failure to Maintain Context was correlated to Avoidant (r = 0.335; p = 0.017). The DQ was not correlated with PBQ. ConclusionPeople with JME presented dysfunctional beliefs of personality disorder that were correlated with executive dysfunction. These findings reinforce the need for psychological rehabilitation in these patients.

Effects of computer-assisted cognitive rehabilitation in benign multiple sclerosis

Background/aim: Benign multiple sclerosis (BMS) patients display preserved somatic neurological functions but nevertheless may develop cognitive dysfunction. Our aim was to explore the impact of computer-assisted cognitive rehabilitation (CCR) on cognitive functions of BMS patients. Materials and methods: Age- and sex-matched BMS patients (n = 21), non-BMS patients (n = 22), and healthy individuals (n = 38) were recruited for evaluation of cognitive functions. CCR was administered to 10 BMS patients and a panel of neuropsychological tests were employed at baseline and 6 months. CCR was based on mental exercise software containing attention, memory, reasoning, visual, and verbal task modules. Results: BMS and non-BMS patients showed impaired selective reminding, spatial recall, symbol digit modalities (SDMTs), controlled oral word association (COWAT), paced auditory serial addition-3 (PASAT-3), and Stroop tests. Timed 25-foot walk and 9-hole peg test results of BMS patients were comparable to those of healthy controls. BMS patients with CCR showed significantly improved SDMTs, COWAT, and Stroop test results compared to those without CCR. Conclusion: Several cognitive domains including memory and executive functions are impaired in BMS patients. CCR has an ameliorating impact particularly on sustained attention, information processing speed, verbal fluency, categorical reasoning, and executive functions of BMS patients.

1667PD - Impact of early prophylactic cranial irradiation with hippocampal avoidance on neurocognitive function in patients with limited disease small cell lung cancer: A multicenter phase II trial (SAKK 15/12)

Background: In limited disease small-cell lung cancer (LD SCLC) prophylactic cranial irradiation (PCI) is the standard of care following chemotherapy (CHT) and thoracic radiotherapy (tRT) in patients with a good clinical response. It is unknown if PCI concomitant with CHT and tRT has an impact on neurocognitive function (NCF) and clinical outcome. Methods: In a phase II trial, patients with LD SCLC received hippocampal avoidance (HA)-PCI concomitant to the 2nd cycle of CHT (cisplatin or carboplatin and etoposide) and tRT. All patients underwent objective NCF testing before starting HA-PCI (baseline), at 6 weeks, and at 6 and 12 months after HA-PCI. NCF tests included the Hopkins Verbal Learning Test Revised (HVLT-R) for verbal learning and memory, the Controlled Oral Word Association (COWAT) for verbal fluency, and Trail Making Tests A and B (TMT A&B) for visual search, scanning, speed of processing and executive function. The primary endpoint was NCF decline at 6 months after HA-PCI, defined as a decrease of one standard error of measurement in any of the tests. We assumed a rate of ≤ 30% of patients with no NCF decline as unpromising and a rate of ≥ 50% as promising. Secondary endpoints included overall survival (OS) and quality of life. Results: Among the 44 patients enrolled in the trial, 37 had evaluable NCF assessment at 6 months after HA-PCI (2 had no CHT, 2 had no BL TMT B assessment, 1 died and 2 have pending NCF results). At the time of analysis, 13 patients (35%; 90% CI: 22-50%) showed no NCF decline. The median follow-up was 12 months with a 1-year OS rate of 84% (95% CI: 65-93%). Four patients died due to SCLC, 1 due to respiratory failure, 1 due to hemorrhage, and 1 for unknown reason. The most common acute adverse events grade ≥3 were anemia (21%), febrile neutropenia (19%) and fatigue (14%). Conclusions: The rate of patients with no NCF decline 6 months after HA-PCI in LD SCLC does not seem to be better, but rather similar to that observed in patients receiving sequential PCI. Early HA-PCI appears feasible. OS was promising in this selected population. Updated and additional results will be presented. Legal entity responsible for the study: SAKK (Swiss Group for Clinical Cancer Research). Funding: Schweizerische Stiftung für Klinische Krebsforschung (SSKK); Hirslanden Klinik Zuerich; Krebsliga Zuerich Schweizerische Stiftung für Klinische Krebsforschung (SSKK). Disclosure: All authors have declared no conflicts of interest.

Higher IQ in juvenile myoclonic epilepsy: Dodging cognitive obstacles and “masking” impairments

Executive deficits and impulsiveness are extensively reported in juvenile myoclonic epilepsy (JME). Previous literature suggests that intelligence may mediate these deficits. In this study, we evaluated and compared the performance of adults with JME with high and low intelligence quotient (IQ) and controls on tasks for executive function (EF) and impulsive traits. We investigated the neuropsychological performance of 53 adults with JME and below average IQ (57% women; 26.9 [±7.88] years; mean IQ: 89.8 [±5.1]), 26 adults with JME and average or above average IQ (53.8% women; 28.2 [±9.33] years; mean IQ: 110.7 [±8.3]), 38 controls with below average IQ (55% women; 28.4 [±8.4] years; mean IQ: 90.1 [±5.8]), and 31 controls with average or above average IQ (61.3% women; 32.20 [±11.3] years; mean IQ: 111.6 [±10.5]) with a comprehensive battery of neuropsychological tests that measure executive/attentional function. Impulsive traits were assessed using the Cloninger et al.'s Temperament and Character Inventory (novelty seeking (NS) domain). The group with JME with higher IQ presented worse performance compared with controls with higher IQ on Controlled Oral Word Association (COWA) and Wisconsin Card Sorting Test (WCST) (errors). This group showed worse performance than controls with lower IQ on Stroop Color–Word Test (SCT) 1, Trail Making (TM) A, COWA, and WCST (errors). Patients with lower IQ showed worse performance than controls with higher IQ on Digit Span Forward (DSF), Digit Span Backward (DSB), SCT1, SCT2, SCT3, TM A, COWA, and WCST (errors and failure to maintain set). Patients with lower IQ showed worse performance than controls with lower IQ on DSF, DSB, SCT1, SCT2, SCT3, TM A, TM B, COWA, and WCST (errors and failure to maintain set). Patients from groups with low and high IQ showed higher scores than controls with higher and lower IQ on impulsivity for NS1 and NS2 (except for patients with higher IQ versus controls with lower IQ). Adults with JME and higher IQ show less evidence of EF deficits compared with those with JME and below average IQ, suggesting that a higher degree of intellectual efficiency may act as a compensatory mechanism. However, it does not minimize some aspects of impulsive traits. Patients with JME and higher cognitive reserve may create strategies to dodge their cognitive obstacles. In this context, intelligence may protect and, at the same time, “mask” impairments that could be detected earlier.

Abstract P6-12-26: The axonal damage marker, serum phosphorylated neurofilament heavy subunit, as a potential marker of chemotherapy-induced neuropathy

Abstract Background: Chemotherapy-induced neurologic disorders such as peripheral neuropathy and cognitive disturbance are clinically significant problems for cancer survivors, but their objective assessment methods have not been established. We previously reported in a cross-sectional study that the serum phosphorylated neurofilament heavy subunit (pNF-H), a biomarker of axonal damage, was increased in breast cancer patients treated with chemotherapy. The aim of this study is to temporally assess the neurological adverse events and evaluate the association of serum pNF-H level with cognitive functions and neuropathy following sequential chemotherapy. Methods: Thirty-five breast cancer patients who received neoadjuvant or adjuvant chemotherapy were enrolled prospectively. They underwent brain MRI and cognitive function tests including Controlled Oral Word Association (COWA), Trail Making Test (TMT), and Hopkins Verbal Learning Test-Revised (HVLT-R) before chemotherapy (baseline), one month after completing sequential chemotherapy (post-phase) and more than six months after completing chemotherapy (late-phase). Serum pNF-H levels and questionnaires reporting peripheral neuropathy were measured at the three phases, and every 3 weeks during chemotherapy. Brain MRI volumetry was calculated by the automatic analysis software, BAAD® (Brain Anatomical Analysis using Dartel). The correlations among cognitive functions, brain volume, peripheral neuropathy and serum pNF-H levels were statistically analyzed. Results: Patients' median age was 48 years (range 24-71). A decrease of more than 10% in cognitive function test (COWA) scores was seen in 10 cases (31%) at post-phase. A brain volume loss of more than 10% was seen in 5 cases (15%) at post-phase. The correlation between brain volume change and cognitive disturbance was not significant (p=0.45) and both changes were improved at late-phase. A peripheral neuropathy grade above CTCAE grade 2 was seen in 19 cases (54%). The neuropathy was significantly more severe in anthracycline followed by taxane regimen than taxane followed by anthracycline during chemotherapy (p=0.016), although this difference was not seen at the late-phase (p=0.08). An elevated serum pNF-H level at baseline was seen in only one case, and this case demonstrated the cognitive disturbance, brain volume loss, and peripheral neuropathy following chemotherapy. During chemotherapy, pNF-H was elevated in 24 patients (69%), with especially higher levels noted during the taxane regimen compared to the anthracycline regimen (p=0.019). In the cases treated with anthracycline followed by taxane, the taxane-phase elevation was especially significant (p=0.014). The maximum pNF-H level during taxane therapy was significantly correlated with peripheral neuropathy grade (p=0.002). At late-phase, the significant reduction of pNF-H level was seen in all cases. Conclusions: Change of cognitive function, brain volume and peripheral neuropathy was observed following chemotherapy in breast cancer patients. This study suggests that the serum axonal damage marker, pNF-H, may reflect chemotherapy-induced neuropathy. Citation Format: Kida K, Sumitani M, Ogata T, Kotake R, Natori A, Hashimoto J, Shimokawa T, Yamauchi H, Yamauchi T. The axonal damage marker, serum phosphorylated neurofilament heavy subunit, as a potential marker of chemotherapy-induced neuropathy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-26.

Longitudinal assessment of cancer-related cognitive impairment (CRCI) up to six-months post-chemotherapy with multiple cognitive testing methods in 943 breast cancer (BC) patients and controls.

10014 Background: Large nationwide studies are needed to assess CRCI. Methods: NCORPs recruited BC patients and age-matched non-cancer controls. Computerized ((CANTAB Delayed Match to Sample (DMS), Rapid Visual Processing (RVP), Verbal Recognition Memory (VRM)), paper-based ((Controlled Oral Word Association (COWA), and Trail Making Test (TMT)) , and phone-based (category fluency, word recall, backward counting and digits backward) cognitive assessments of memory, attention, and executive function at pre-chemotherapy, post-chemotherapy, and 6 months follow-up (or time-equivalent for controls) were completed. Longitudinal mixed model (LMM)s included group, time, time*group, and adjusted for age, education, reading, anxiety, and depression. Results: 580 BC patients (mean age = 54) and 363 controls (mean age = 53) were assessed. In all LMMs, there was a significant group*time interaction depicting lower scores in patients compared to controls (p &lt; 0.005) except for TMT (p = 0.09). For longitudinal change on the DMS memory test (primary aim), we observed no significant difference between groups from pre- to post-chemotherapy but did observe a significant difference from pre-chemotherapy to follow-up (p = 0.017) where patients significantly declined (p = 0.005) and controls did not change. We observed similar results for RVP. For VRM, there was a significant pre- to post-chemotherapy group difference (p = 0.003). For COWA, patients significantly declined and controls significantly improved reflecting a significant between group difference (p &lt; 0.001) from pre- to post-chemotherapy. For TMT, both groups significantly improved with patients improving less than controls reflected by a significant between group difference (p = 0.04) that remained a trend at follow-up (p = 0.06). On all phone tests, there was a significant between group effect from both pre- to post-chemotherapy and at follow-up with patients doing less well than controls (all p &lt; 0.001). Conclusions: This nationwide study shows CRCI in BC patients persists in multiple cognitive domains up to 6 months post-chemotherapy compared to controls. Clinical trial information: NCT01382082.

The efficacy and roles of combining temozolomide with whole brain radiotherapy in protection neurocognitive function and improvement quality of life of non-small-cell lung cancer patients with brain metastases

BackgroundBrain metastasis (BM) is a poor prognostic factor for non-small-cell lung cancer (NSCLC). The efficacy and roles of combining temozolomide (TMZ) with whole brain radiotherapy (WBRT) in protection neurocognitive function (NCF) and improvement quality of life (QOL) were investigated and compared with WBRT alone in the treatment of NSCLC patients with BM.MethodsA total of 238 NSCLC patients with BM were reviewed and categorized into WBRT plus TMZ (RCT) arm and WBRT alone (RT), respectively. The efficacy was evaluated with Pearson chi-square or Fisher’s exact tests, Log-rank test and Cox proportional hazards model. NCF was assessed by using revised Hopkins Verbal Learning Test (HVLT-R), Controlled Oral Word Association (COWA) test and Trail-making Test (TMT). QOL was assessed by the Functional Assessment of Cancer Treatment-Lung (FACT-L) Chinese version 4.0 questionnaire.ResultsThe average intracranial objective response (ORR) and disease control rate (DCR) for all the patients were 26.9 and 95.8%, respectively. The intracranial ORR and DCR for RCT and RT arm were 34.9% vs. 20.2% (p = 0.01) and 98.4% vs. 92.7% (p = 0.03), respectively. The median intracranial progression-free survival (PFS) and overall survival (OS) of NSCLC patients with BM were 5.2 and 7.3 months, respectively. The median PFS of RCT arm was significantly longer than that of RT arm (5.9 vs. 4.9 months, p = 0.002). The median OS of the RCT arm was also slightly longer than that of the RT arm (8.5 vs. 5.9 months), but without statistical significance (p = 0.11). Multivariate analysis indicated that TMZ was a significant factor for PFS. Statistically significant differences on NCF and QOL were observed between CRT and RT arms at 5 months. RCT showed a trend of toxicities increase compared with RT, however, the toxicities were tolerable and manageable.ConclusionsAdding TMZ to WBRT in the treatment of NSCLC patients with BM could improve the intracranial ORR, DCR, and median PFS compared with WBRT alone. Although no remarkable difference on median OS was found, adding TMZ could prevent NCF and QOL from worsening. The side effects increased by adding TMZ, but the difference was not statistical significance and toxicities were well tolerated.