Hopkins Verbal Learning Test-Revised Total Recall Research Articles

92 Teleneuropsychological Evaluation of Bariatric Surgery Candidates: Cognitive Profiles and Recommendations for Future Practice

Objective:Vascular complications, including elevated body mass index (BMI), are known risk factors for cognitive impairment. Obtaining a cognitive baseline is commonplace in pre-surgical protocols, including for Parkinson’s disease and epilepsy. Currently, routine evaluations for bariatric surgery candidates do not include neuropsychological assessment. This setting provides a unique opportunity to identify cognitive profiles of younger individuals at risk for cognitive impairment. Here, we argue for the standard implementation of a brief, online cognitive battery via telemedicine, to enhance existing protocols of bariatric pre-surgical evaluations.Participants and Methods:Nineteen bariatric surgery candidates were referred to a private neuropsychological assessment practice for pre-surgical cognitive/psychological evaluation. Assessments were conducted by a neuropsychologist and a psychology graduate student, via remote video conferencing, between April 2020 and June 2022. Candidates completed a clinical interview, intake form, and the Behavior Rating Inventory of Executive Function for Adults (BRIEF-A), and were administered a battery of cognitive measures: Wechsler Test of Adult Reading (WTAR), Hopkins Verbal Learning Test-Revised (HVLT-R); and select subtests from the TestMyBrain Digital Neuropsychology Toolkit: Trail Making Tests A and B (TMT-A/B), Matrix Reasoning (MR), Digit Span Forward and Backward (DSF, DSB), Gradual Onset Continuous Performance Test (CPT), and Simple and Choice Reaction Time (SRT, CRT). Descriptive statistics were conducted to analyze sample demographics. Raw scores on cognitive measures were converted to z-scores and averaged across the sample.Results:The average age at evaluation was 38.2 (9.6) years and average pre-surgical BMI was 46.6k/m2 (9.3), indicating morbid obesity (BMI>40k/ m2). Ten (52.6%) candidates identified as female, 10 (52.6%) identified as White, 8 (42.1%) had 12 years of education or less, 4 (21.1%) were unemployed, and 9 (47.4%) had comorbid psychiatric diagnoses. BRIEF-A sub-scales were within the average range (T’s= 47.9 - 52.9, SD’s [10.1 - 12.8]). Estimated premorbid IQ was average at 102.7 (11.4). Neuropsychological data revealed group performance within the average range on DSF and DSB (z’s= 0.00), TMT-A (z= -0.16), MR (z= -0.53), CPT (z= -0.39), and HVLT-R False Positives (z= 0.05) and Recognition Discriminability (z= -0.44). SRT (z= -0.70), CRT Accuracy (z= -1.37), TMT-B (z= -0.79), HVLT-R Total Recall and Percent Retained (z’s= -0.88), and Delayed Recall and True Positives (z’s= -1.27) were low average.Conclusions:In this sample of pre-surgical bariatric candidates with average intelligence, baseline evaluations revealed mild deficits in reaction time accuracy, visual motoric set-shifting, and verbal learning/memory. These deficits may be the result of microvascular changes in the brain secondary to physical compromise. Results provide additional insight into potential early-onset executive dysfunction, psychomotor slowing, and verbal learning/memory difficulties. In addition to these relative areas of neuropsychological weakness, candidates demonstrated relative strengths in attention, working memory, and visuospatial functioning. These insights provide pre-surgical evaluators with additional information to tailor recommendations and treatment approaches that foster surgical success. With a remote, concise, easy-to-administer battery of tests, routine neuropsychological assessment for bariatric surgery candidates is both a feasible and a useful tool for identifying areas of cognitive strengths and weaknesses. Documenting a patients’ cognitive baseline can assist with monitoring long-term vascular risk-factors and potential cognitive impairment.

19 Accuracy of Self- and Informant-Reported Domain-Specific Cognitive Ratings

Objective:Diagnostic criteria for mild cognitive impairment (MCI) include a report of cognitive decline from the patient or a close informant. It is therefore important to understand the relationship between self- and informant-rated cognition and actual patient performance. Furthermore, it is unknown whether the nature of the relationship between the patient and their informant impacts accuracy of subjective reports. This study aimed to determine the association between informant report, self-report and objective cognitive performance based on relationship factors. We predicted that informant report would be more closely associated with objective performance than self-report after controlling for demographics and mood (Geriatric Depression Scale [mean= 1.4, SD=2]), especially among those who live with the participant and those who are spouses/partners.Participants and Methods:Participants (n = 338; age= 73.5 ±6.7) of varying diagnoses and their respective informants were drawn from the longitudinal cohort of the Michigan Alzheimer’s Disease Research Center (MADRC). The majority of informants were spouses/significant others (55.6%), followed by 23.7% being other family members and 20.7% were non- family members; 58.9% of informants live with the participant. Both respondents completed the Cognitive Change Index (CCI) to rate the patient’s cognitive status (higher scores indicating worsening cognition) across three domains: memory (12 questions), language (1 question), and attention/executive functioning (7 questions). These domains were matched to objective cognitive performance measured using the MADRC neuropsychological battery. Executive functioning and attention were assessed using Number Span Test Forward and Backward (NSF, NSB) and Trail Making Test Part B and Trail- Making Test Part A and B ratio (TMTB, TMTB: A); memory was measured using Craft Story 21 (Immediate and Delayed), Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall, Delayed Recall, and Benson Complex Figure (BCF) Delayed Recall; and Language was measured by the Controlled Oral Word Association Test (COWAT) and Animal fluency.Results:Linear regression adjusted for sex, race, and mood indicated that both patient and informant CCI ratings were significantly (p<.05) associated with objective cognitive performance. For every one unit increase on executive CCI items, there was a significant decline in executive functioning (NSF patient and informant ß= -0.09, NSB: [ßP= -.14; ßp-0.13]) and TMTB [ßP= 3.85; ß= 3.10 [% change]). Memory performance also declined per unit increase on CCI memory items: (Craft Story 21 Immediate [ßP=-0.32; ß= -0.37] and Delayed [ßP=-.40; ßp -.47], HVLT-R Total Recall [ßP= -.31; ßI=-.37] and Delayed Recall [ßP= -.16; ß=-.20], and BCF Delayed Recall [ßP= -.18; ß= -.23]. Similarly, one unit increase on the single CCI language item was associated with a decline in COWAT (ßP= -2.27; ß= -4.61) and Animal fluency (ßP= -1.88; ß= -3.03). Effect modification by participant-informant relationship type or participant-informant cohabitation was not significant.Conclusions:Patient and informant ratings are associated with objective measures of cognition regardless of the relationship between informant and patient or if they live together. This study was limited by a well-educated sample (mean= 16.1 years of education, SD= 2.4 years) with relatively limited diversity among participant-informant relationships. Future studies should replicate analyses across a larger and more diverse sample.

49 A Preliminary Neurocognitive Profile Characterization of Treatment Resistant Depression

Objective:Major Depressive Disorder (MDD) subtypes have been shown to differentially impact psychiatric symptom presentation, clinical features, and functional abilities. While there is extensive research regarding MDD subtypes and clinical characteristics, there has been limited information regarding the relationship between MDD subtypes and neurocognitive functioning. In particular, the neurocognitive impact of the subtype of treatment resistant depression (TRD), defined as MDD that is unresponsive to treatment, is unknown. The aim of this preliminary study was to address this gap by characterizing the neurocognitive profile of TRD. We characterized the performance of older adults with TRD on measures across multiple neurocognitive domains, and explored whether performance varied based on age and education.Participants and Methods:Data utilized were drawn from a broader NIMH-funded, randomized, controlled study conducted at the University of New Mexico that investigated the clinical and cognitive outcomes of varying pulse amplitudes during acute electroconvulsive therapy (ECT) in adults with MDD. Participants in the study were age 50+ with a diagnosis of MDD, and further delineated by subtype as TRD. For this analysis, we utilized demographic and baseline neurocognitive data collected prior to start of treatment for those diagnosed with MDD, recurrent, severe (TRD). Neurocognitive measures included the Delis Kaplan Executive Function System (D-KEFS) Verbal Fluency and Color-Word Interference Subtests, Hopkins Verbal Learning Test-Revised (HVLT-R), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV) Digit Spans. Demographic-adjusted scaled scores were computed, and descriptive statistics were used to characterize the demographic and neurocognitive features of the sample. Multiple Analysis of Variance (MANOVA) was used to investigate difference in performance across neurocognitive measures based on level of education, with age as a covariate.Results:The sample (n = 42) had a mean age of 65 (SD=8), education level between12 and 14 years, 66.6% were female and 93% were Caucasian. DKEFS Verbal Fluency Category Switching Total Switching Accuracy fell in the Average range (Mean SS=9.5, SD=3.1), and Color Word Inhibition Total Completion Time fell in the Average range (Mean SS=8.5, SD=3.3). HVLT-R Total Recall Correct fell in the Mildly Impaired range (Mean T=35.5, SD=9.9) and Delayed Recall Correct fell in the Mildly to Moderately Impaired range (Mean T=32.9, SD=11.0). WAIS-IV Digit Span fell in the Average range (Mean SS=9.5, SD=2.2). Results indicated that age did not adjust outcomes on the neurocognitive variables, Wilks's λ=0.63, F(6, 23)=2.13, p=0.08. We found no evidence for significant effect of level of education on neurocognitive functioning when controlling for the covariate of age, Wilks's λ=-0.16, F(36, 103.7)=1.47, p=0.07.Conclusions:To our knowledge, this is one of two studies to examine neurocognitive functioning in patients with TRD. The analysis indicated generally intact performance in the neurocognitive domains of executive function (inclusive of verbal fluency, cognitive flexibility, and inhibition), auditory attention and working memory, and Impaired performance on indices of verbal learning and memory. Age did not impact performance on neurocognitive measures, and there was no significant effect for level of education. Further research is warranted to confirm these findings and further explicate the neurocognitive profile of TRD.

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 .

A-38 Sport-related Concussion as a Stressor: Differential Memory for Emotion and Neutral Words

Abstract Purpose: To explore if the acute stress associated with sport-related concussion (SRC) leads to differential memory for neutral versus emotion words. Based on a Roozendaal and colleagues’ (2002) model of stress and memory, we hypothesized: Following SRC, athletes will demonstrate better recall for neutral compared to emotion words at immediate recall but demonstrate the reverse pattern on delayed recall, with better recall for emotion compared to neutral words. Methods: 80 (73 Males,7 Females) collegiate athletes completed a neuropsychological evaluation within 14 days of SRC. Two verbal learning and memory tasks were administered: neutral words [Hopkins Verbal Learning Test-Revised (HVLT-R)] and emotion words [Affective Word List (AWL)]. Both tasks had three learning trials and a delayed (20–25 minutes) recall. Paired samples t-tests were conducted to compare memory for emotion words (AWL) and neutral words (HVLT-R): AWL Total Immediate Recall vs. HVLT-R Total Immediate Recall and AWL Delayed Recall vs. HVLT-R Delayed Recall. Results: Following concussion, athletes’ memory for neutral words (M = 94.92, SD = 16.17) did not significantly differ from memory for emotion words (M = 96.83, SD = 18.28) on immediate recall trials, (t(79) = −0.91, p = 0.37, d = 0.11). However, memory for emotion words (M = 96.83, SD = 16.98) was significantly better than memory for neutral words (M = 90.84, SD = 20.58) after a delay, (t(79) = 2.97, p = 0.004, d = −0.33). Conclusions: Our results demonstrate that the stress associated with SRC differentially impacts delayed retrieval of neutral compared to emotion words. Because memory is often impaired following SRC, a more nuanced examination of learning and memory can help clinicians understand neuropsychological deficits associated with SRC, and possibly have implications for addressing memory difficulties.

Test-Retest Reliability and Minimal Detectable Change of Four Cognitive Tests in Community-Dwelling Older Adults.

Cognitive test-retest reliability measures can be used to evaluate meaningful changes in scores. This analysis aimed to develop a comprehensive set of test-retest reliability values and minimal detectable change (MDC) values for a cognitive battery for community-dwelling older individuals in Australia and the U.S., for use in clinical practice. Cognitive scores collected at baseline and year 1, in the ASPirin in Reducing Events in the Elderly clinical trial were used to calculate intraclass correlation coefficients (ICC) for four tests: Modified Mini-Mental State examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), single-letter Controlled Oral Word Association Test (COWAT-F), and Symbol Digit Modalities Test (SDMT). 16,956 participants aged 70 years and over (65 years and over for U.S. minorities) were included. ICCs were used to calculate MDC values for eight education and ethno-racial subgroups. All four cognitive tests had moderate (ICC > 0.5) to good (ICC > 0.7) test-retest reliability. ICCs ranged from 0.53 to 0.63 (3MS), 0.68 to 0.77 (SDMT), 0.56 to 0.64 (COWAT-F), 0.57 to 0.69 (HVLT-R total recall), and 0.57 to 0.70 (HVLT-R delayed recall) across the subgroups. MDC values ranged from 6.60 to 9.95 (3MS), 12.42 to 15.61 (SDMT), 6.34 to 8.34 (COWAT-F), 8.13 to 10.85 (HVLT-R total recall), and 4.00 to 5.62 (HVLT-R delayed recall). This large cohort of older individuals provides test-retest reliability and MDC values for four widely employed tests of cognitive function. These results can aid interpretation of cognitive scores and decline instead of relying on cross-sectional normative data alone.

Quality of Life Is Independently Associated With Neurocognitive Function in Patients With Brain Tumors: Analysis of a Prospective Clinical Trial

We conducted the first prospective longitudinal study examining the independent association between patient-reported health-related quality of life (hrQoL) (physical, social/family, emotional, functional, and brain cancer-specific) and neurocognitive function (NCF), while controlling for mood symptoms in patients with primary brain tumors. Patients with primary brain tumors (n=59) receiving brain radiation therapy underwent hrQOL (Functional Assessment of Cancer Therapy-Brain), mood (Beck Depression and Anxiety Inventories), and neurocognitive evaluation at baseline and 3, 6, and 12 months postradiation therapy in a prospective clinical trial. Neurocognitive assessments measured attention/processing speed, memory, and executive function, including the Delis-Kaplan Executive Function System Verbal Fluency, Hopkins Verbal Learning Test Revised (HVLT-R), and Brief Visuospatial Memory Test. Subjects underwent neurocognitive, mood, and hrQoL assessments in the same testing session. Multivariable linear mixed-effects models assessed associations between hrQOL and NCF over time, controlling for patient, tumor, and treatment characteristics as well as timepoint-specific patient-reported mood (ie, anxiety and depression symptoms). P values were adjusted for multiple comparisons. Higher physical hrQoL was associated with better verbal memory (HVLT-R Total Recall, P=.047), and higher functional hrQoL was associated with better executive function (Delis-Kaplan Executive Function System Verbal Fluency Switching Total, P=.009) and verbal memory (HVLT-R Delayed Recall, P=.006). Higher brain tumor-specific hrQoL was associated with better verbal and nonverbal memory (HVLT-R Total, P=.004 and Delayed Recall, P=.030; Brief Visuospatial Memory Test Total, P=.049 and Delayed Recall, P=.049). There was no association between social/family or emotional hrQoL and NCF after controlling for mood. Higher physical, functional, and brain tumor-specific hrQoL were associated with better executive function and memory among patients with primary brain tumors. Physical and functional impairments are correlated with cognitive performance. Interventions to maximize quality of life after treatment may influence neurocognition and vice versa.

Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: A randomized controlled trial (PAM study).

12015 Background: Chemotherapy is associated with cognitive problems. Physical exercise is a promising intervention. We investigated whether exercise improves cognition in chemotherapy-exposed breast cancer (BC) patients 2-4 years after diagnosis. Methods: In the PAM study, we randomized chemotherapy-exposed BC patients with self-reported and test-confirmed cognitive problems to an exercise or control group. The 6-month exercise intervention consisted of 2 hours of supervised aerobic and resistance training and two hours of Nordic/power walking. Memory function measured with the Hopkins Verbal Learning Test-Revised (HVLT-R) was our primary outcome. Further measurements included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognitive complaints (MDASI-MM, EORTC QLQ C-30 cognitive functioning), physical fitness (VO2peak), fatigue (MFI, EORTC fatigue), quality of life (QoL; EORTC), anxiety (HADS) and depression (HADS, PHQ9). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement of ≥5 words. Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. An hypothesis driven but not pre-specified analysis in patients with high baseline EORTC fatigue levels (≥39) was performed. Results: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise program and physical fitness significantly improved compared to the control patients ( VO2peak1.4 ml/min/kg, 95% CI 0.6; 2.2). No difference in favor of the intervention group was seen on the primary cognitive outcome or other cognitive tests. However, significant beneficial intervention effects were found for self-reported cognition (MDASI-MM Severity (-0.7, -1.2;-0.1)), fatigue (general fatigue (-2.2, -3.3; -1.1), physical fatigue (-3.3, -4.4; -2.2), mental fatigue (-1.0, -2.0; 0.0), reduced motivation (-1.1, -2.0; -0.2) and reduced activity (-2.1, -3.2; -1.1)), QoL (summary score (4.0, 1.2; 6.7), global health status (5.8, 1.1; 10.6), role functioning (7.2, 1.3; 13.1) and social functioning (5.9, 0.2; 11.6)) and depression (PHQ9 (-1.16, -2.19; -0.13)). In high-fatigued patients, exercise did show significant positive effects on objective cognitive function (ACS Reaction Time (-26.8, -52.9; -0.6) and ACS Wordlist Learning (4.4, 0.5; 8.3)). Conclusions: A 6-month exercise intervention did not improve objectively measured cognitive function in chemotherapy-exposed BC patients with cognitive problems. However, self-reported cognitive function, physical fitness, fatigue, QoL and depression did improve. Unplanned analysis indicated a small positive effect of exercise on cognitive functioning in high-fatigued patients. Clinical trial information: NTR6104.

Rivastigmine Transdermal Patch Treatment for Moderate to Severe Cognitive Impairment in Veterans with Traumatic Brain Injury (RiVET Study): A Randomized Clinical Trial.

Cognitive impairment is common in veterans with histories of traumatic brain injury (TBI). Cholinergic deficits have been hypothesized as contributors to this impairment. We report the effects of cholinesterase inhibitor rivastigmine transdermal patch treatment in veterans with TBI and post-traumatic memory impairment. Our objective was to evaluate the efficacy and safety of a 9.5 mg/24 h (10 cm2) rivastigmine patch in veterans of military conflicts with persistent moderate to severe memory impairment at least 12 weeks after TBI. This randomized, outpatient, double-blind, placebo-controlled 12-week trial with an exploratory double-blind phase of an additional 14 weeks was conducted at 5 VA Medical Centers, among veterans with closed, non-penetrating TBI who met or exceeded modified American Congress of Rehabilitation Medicine criteria for mild TBI with verbal memory deficits, as assessed by the Hopkins Verbal Learning Test, Revised (HVLT-R). Patients were randomized 1:1 to rivastigmine or matching placebo patches after a 1-week single-blind, placebo run-in phase. At randomization, patients received 4.6 mg/24 h rivastigmine patches or matching placebo increased to a 9.5 mg/24 h patch after 4 weeks. The primary efficacy outcome measure was the proportion of participants who had at least a five-word improvement on the HVLT-R Total Recall Index (Trials 1-3). A total of 3671 participants were pre-screened, of whom 257 (7.0%) were screened; 96 (37%) randomized, and 94 included in study analyses. Responder rates were 40.8% (20 of 49) and 51.1% (23 of 45) in the rivastigmine and placebo groups, respectively (p = 0.41). A mixed-effect model including treatment, time, and treatment-by-time interaction indicated no significant difference in treatment effect over time between the groups (p = 0.24). Overall, there were no significant differences in changes for all secondary outcomes between the rivastigmine and placebo groups. The most commonly observed adverse events were application site reactions. This trial provides the largest sample to date of veterans with TBI and post-traumatic memory deficits enrolled in a pharmacological trial. Trial Registration: clinicaltrials.gov Identifier: NCT01670526.

Change in Learning and Memory Partially Mediates Effects of Compensatory Cognitive Training on Self-Reported Cognitive Symptoms.

To examine associations among compensatory cognitive training (CCT), objective cognitive functioning, and self-reported cognitive symptoms. We examined whether change in objective cognitive functioning associated with participation in CCT at 10-week follow-up mediates change in self-reported cognitive symptoms associated with CCT at 15-week follow-up. Three VA outpatient mental health clinics. Veterans with a history of mild traumatic brain injury who reported cognitive deficits. Randomized controlled trial post hoc causal mediation analysis. Self-reported cognitive symptoms were measured by the Prospective-Retrospective Memory Questionnaire and the Multiple Sclerosis Neuropsychological Screening Questionnaire. Objective cognitive functioning was measured using a battery of neuropsychological tests. Improvement on the Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall test mediated the association between participation in CCT and decrease in the Prospective-Retrospective Memory Questionnaire total score. Improvement on the HVLT-R Total Recall and HVLT-R Delayed Recall tests both meditated the association between participation in CCT and decrease in the Multiple Sclerosis Neuropsychological Screening Questionnaire total score. No other measures of objective cognitive functioning were significant mediators. Patients' perceptions of cognitive symptom improvement due to CCT are partially mediated by learning and memory, though these subjective improvements occur regardless of other changes in objective cognitive functioning associated with CCT.

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< 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.

Regression-Based Norms for the Hopkins Verbal Learning Test-Revised and the Rey-Osterrieth Complex Figure in a Portuguese Adult Population.

The principal goal of this study was to produce adjusted normative data for European Portuguese native speakers from Portugal on 2 neuropsychological tests widely used to assess learning and memory: the Hopkins Verbal Learning Test-Revised (HVLT-R) and the Rey-Osterrieth Complex Figure Test (ROCF). The study included 300 individuals aged 18-92years (M=50.4, SD=21.2), who had educational backgrounds ranging from 3 to 25years (M=10.4, SD=5.2). Age, education, and sex were significantly associated with HVLT-R and ROCF performance. These demographic variables accounted for 61% of the variance in HVLT-R total recall, 54% in HVLT-R delayed recall, 18% in HVLT-R recognition, 55% in ROCF copy, and 39% in ROCF immediate recall. The normative data are presented as regression-based algorithms to adjust direct and derived test scores for age, education, and sex. This study provides a calculator of normative data derived from the results of the regression models.

Phase III Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC

Purpose: To compare neurocognitive functioning in Small Cell Lung Cancer patients(SCLC) who received prophylactic cranial irradiation(PCI) with or without hippocampus avoidance (HA). Material and Methods: In a multicenter randomized phase III trial (NCT01780675) patients with SCLC were randomized to standard PCI (25 Gy /10 fractions) or HA-PCI. Neuropsychological tests were performed at baseline and 4, 8, 12, 18 and 24 months after PCI. The primary endpoint was total recall on the Hopkins Verbal Learning Test- Revised(HVLT-R) at 4 months; a decline of at least 5 points from baseline was considered a failure. Secondary endpoints included other cognitive outcomes, evaluation of the incidence and location of brain metastases and overall survival(OS). Results: From April 2013 until March 2018 a total of 168 patients were randomized. The median follow-up time was 26 .6 months. In both treatment arms 70% of patients had limited disease and baseline characteristics were well balanced. Decline on the HVLT-R total recall score at 4 months was not significantly different between the arms: 29% of PCI patients dropped ≥5 points and 28% of HA-PCI patients (p=1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function and processing speed did not change significantly different over time between the groups. The OS was not significantly different. The cumulative incidence of brain metastases at 2 years was 20% (95% CI: 12% - 29%) for the PCI arm and 16% (95% CI: 7% - 24%) for the HA-PCI arm. Conclusion: This randomized phase III trial did not show lower probability of cognitive decline in SCLC patients receiving hippocampus avoidance PCI compared to conventional PCI. No increase in brain metastases at 2 years was observed in the HA- PCI arm. Trial Registration: NCT01780675 Funding Statement: Maarten Lambrecht Speaker’s fee AstraZeneca, all others No Funding. Declaration of Interests: YL reports personal fees from Astra-Zeneca and RaySearch outside the context of the submitted work. All other authors have nothing to declare. Ethics Approval Statement: This trial (NCT01780675) was conducted according to the Declaration of Helsinki and approved by the Medical Ethics Committee of the Netherlands Cancer Institute.

Neurological outcome and memory performance in patients with 10 or more brain metastases treated with frameless linear accelerator (LINAC)-based stereotactic radiosurgery.

To assess the neurocognitive function and neurological toxicity of frameless linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) in patients with 10 or more brain metastases (BM). Forty consecutive adult patients who received SRS for ten or more 10 BM < 3cm in maximum size were evaluated. All plans were generated using a single-isocenter multiple-target (SIMT) SRS technique with doses of 22Gy for lesions < 2cm and 16-18Gy for those ≥ 2cm in size. Survival analyses were estimated by Kaplan-Meier method from the date of SRS. Neurocognitive function using the Hopkins verbal learning test-revised (HVLT-R) and activity of daily living scale (ADLS) were collected prospectively at baseline and at 3,6 and 12-month follow-up. Toxicity was assessed by the National Cancer Institute Common Toxicity Criteria for Adverse Events (Version 5.0). With a median follow-up of 10.8months, 1-year survival and local control rates were 65% and 86%, respectively. Grade 2 or 3 toxicity occurred in eleven patients, being associated with radiological changes suggestive of radiation necrosis in seven patients. Three months after SRS, the mean relative decline was 14.2% for HVLT-R delayed recall, 12.3% for HVLT-R recognition, and 9.8% for HVLT-R total recall. A significant deterioration of HVLT-R scores ranged from 5.5 to 18.7% of patients at different time points. ADLS scores declined over time, but changes were not significant. SRS is an effective and safe approach for patients with 10 or more BM able to maintain the pretreatment neurocognitive function in the majority of patients.

EVIDENCE THAT ORAL P38 MAPK ALPHA ANTAGONISM IMPROVES EPISODIC MEMORY IN PATIENTS WITH EARLY ALZHEIMER’S DISEASE (AD)

Neflamapimod is an oral antagonist of p38α, a kinase implicated in hippocampal dysfunction in preclinical studies. Two phase 2a clinical trials with neflamapimod in early AD (reported at CTAD, Dec 2016) met their primary objectives by demonstrating disease-relevant pharmacologic activity; and secondarily demonstrated improvement in measures of episodic memory. We report herein further analyses of the episodic memory findings. Subjects: patients with MCI due to AD or mild AD (MMSE 20–28). Study 302: 15 patients received neflamapimod for 12 weeks. Memory function assessed with Wechsler Memory Scale (WMS)–IV, analyzed as Immediate-Recall composite [Logical-Memory (LM) I + Verbal-Paired-Associates (VPA) I + Visual-Reproduction (VR) I; range=0–136 points]; and Delayed-Recall composite [LM II + VPA II + VR II; range=0–92 points]. Study 303:8 patients received neflamapimod for 6 weeks. Memory function assessed with Hopkins Verbal Learning Test–Revised (HVLT-R), Total(Immediate)-Recall (range=0–36 points) and Delayed-Recall (range=0–12 points). In Study 302: the mean WMS Immediate-Recall score at baseline was 48.4(SD=14.6) and increased by 5.7(9.7) points at day 28 (p=0.03; Wilcoxon signed-rank test) and by 10.0(11.7) points at day 84 (p=0.005). The mean WMS Delayed-Recall at baseline was 13.2(10.6) and increased by 5.0(4.5) points at day 28 (p=0.001) and by 8.87(9.4) points at day 84 (p<0.001). All subcomponents of WMS composites showed statistically significant (p<0.05) increases at day 84, except VRII (p=0.053). In study 303: mean HVLT-R Total-Recall score was 19.1(4.3) at baseline and increased by 3.6(5.6) at day 40 (p=0.014; paired t-test). The mean HVLT-R Delayed-Recall was 5.4(1.7) at baseline and increased by 2.1(2.6) at day 40 (p=0.028). Within-subject effect sizes (Cohen's davg) were similar between the two studies and ranged between 0.59 and 0.86. Pharmacokinetics-Pharmacodynamics (PK-PD): linear regression model indicated individual subject plasma drug concentration profiles were significantly correlated to change in combined WMS-Immediate and Delayed-Recall (r2=.70, p=0.001). The low sample size precluded PK-PD analysis in Study 303. Consistency across the studies using different measures, robustness of statistics, effect size and drug concentration-response relationship preliminarily indicates a positive effect of neflamapimod on episodic memory. A 6-month placebo-controlled study is planned to confirm these findings.

Effect of Trospium Chloride on Cognitive Function in Women Aged 50 and Older: A Randomized Trial.

This study aimed to investigate the effect of trospium chloride on cognitive function in postmenopausal women treated for overactive bladder (OAB). Randomized double-blind placebo-controlled trial conducted from April 2013 to April 2015. Women aged 50 years or older seeking treatment for OAB were randomized to either trospium chloride XR 60 mg daily or placebo. Baseline cognitive function was assessed via Hopkins Verbal Learning Test-Revised (HVLT-R), Mini Mental Status Exam, Mini Mental Status X, Digit Span, Trails A, Trails B, and Epworth Sleepiness Scale. Cognitive function was reassessed at week 1 and week 4. A priori power analysis determined that 21 subjects were needed per group. Although 59 women were enrolled and randomized (28 trospium and 31 placebo), 45 completed assessment (21 trospium and 24 placebo). Mean age was 68 years, 78% were white, and 44% had previously taken OAB medication. For the primary outcome, there was no difference in HVLT-R total score between trospium and placebo groups at week 4 (P = 0.29). There were also no differences based on the other cognitive tests. There was a correlation between age and the following week-4 tests: HVLT-R total score (r = -0.3, P = 0.02), HVLT-R total recall subscale (r = -0.4, P = 0.007), Trails A (r = 0.4, P = 0.002), and Trails B (r = 0.4, P = 0.004). A linear regression model found that HVLT-R total score decreased by 0.372 points for each increased year of age. In women aged 50 years and older, there were no changes in cognitive function between those taking trospium and placebo. Cognitive function was correlated with age.

The Impact of Cognitive Function on Adherence to Hydroxyurea Therapy in Patients with Sickle Cell Disease

Introduction:Cognitive impairment is a serious complication of sickle cell disease (SCD) that affects both children and adults. While it is known to adversely affect school performance and overall development in children, its functional impact in adults is not known. Importantly, poor disease self-management and adherence to hydroxyurea are major problems in SCD and are likely to be impacted by cognitive impairment. In the study presented herein, we hypothesized that lower cognitive function in areas of memory and executive function would be associated with worse adherence to hydroxyurea therapy in adults with SCD.Methods:We designed a cross-sectional study of patients with SCD from the University of Pittsburgh Medical Center Adult Sickle Cell Clinic. Patients who underwent neurocognitive testing between 2011 and 2016 as part of an ongoing neurocognitive study and whose adherence to hydroxyurea therapy has been monitored by a dedicated clinical nurse were included. Performance on four neurocognitive tests of verbal learning, memory and executive function - the Hopkins Verbal Learning Test-Revised (HVLT-R) retention, HVLT-R total recall, Delis-Kaplan Executive Function System Trail Making Condition 4 vs. 5, and Color Word Condition 3 - were selected a priori as explanatory variables. We explored the association between the four test scores and the most recent adherence data at the time of the study. Adherence measures included the laboratory biomarkers red blood cell corpuscular volume (MCV) and percentage of fetal hemoglobin (HbF) - whose values are expected to rise with hydroxyurea therapy - and the patient’s self-report of adherence categorized as "good" (≥ 80% adherence) or "less-than-good" (< 80% adherence). Differences between groups were compared by 2-sided t-test or chi-square tests where indicated.Results:Study participants (n=48) had a mean age of 35.2 years (range 22-60) and were predominantly female (58.3%). Fifty-two percent had higher than high-school level education, and 72.9% had a HbSS or HbS/β0 thalassemia phenotype. There were no statistically significant differences between the "good" adherence and "less-than-good" adherence groups with regard to these baseline characteristics. As expected, the mean MCV, an objective marker of hydroxyurea adherence, was significantly higher in the "good" adherence group (102.3 ± 15.0 vs. 89.1 ± 11.5 fL, p=0.005), corroborating the patients’ self-report. We observed a statistically significant positive correlation between the HVLT-R retention score and MCV that remained significant after adjustment for demographic characteristics (Pearson r=0.309, p=0.033) and a similar correlation with HVLT-R total recall (Pearson r=0.269, p=0.065). A similar trend between HVLT-R retention and HbF percentage was observed (Pearson r=0.260, p=0.081). The mean HVLT-R retention and HVLT-R total recall scores were higher in the "good" adherence group (80.1% ± 27% vs. 64.9% ± 33%, and 41.9% ± 14% vs.34.1% ± 13%, respectively), although the difference between the two groups did not reach statistical significance. There was no significant difference in performance on the Trail Making Condition 4 vs. 5 or the Color Word Condition 3 tests.Discussion:Our study suggests that adherence to hydroxyurea therapy in adult patients with SCD might be affected by impairment in episodic memory, as measured in our study through HVLT-R retention, with qualitatively similar patterns by HVLT-R total recall. Although more extensive investigation is warranted, these results suggest that a brief, targeted neurocognitive assessment should be considered as a component of any strategy aimed at improving adherence to hydroxyurea and other therapeutic interventions in patients with SCD. DisclosuresJonassaint:Sicklesoft: Other: officer of Sicklesoft. Kato:Mast Therapeutics: Consultancy; Bayer: Research Funding.

NCO-14PRE-TREATMENT HIPPOCAMPAL VOLUME PREDICTS NEUROCOGNITIVE FUNCTION (NCF) FOR PATIENTS TREATED WITH HIPPOCAMPAL AVOIDANCE WHOLE BRAIN RADIOTHERAPY (HA-WBRT) FOR BRAIN METASTASES: SECONDARY ANALYSIS OF NRG ONCOLOGY/RTOG 0933

BACKGROUND: RTOG 0933 demonstrated reduced risk of NCF decline in patients with brain metastases treated with HA-WBRT versus historical controls treated with standard WBRT. Hippocampal volume (HV) derived from high resolution MRI (HR-MRI) is an established predictor of NCF in Alzheimer's disease. We assessed associations of HV with NCF of patients enrolled on RTOG 0933. METHODS: HV (-Left, -Right, -Total) was calculated from (1) the submitted treatment structure file and (2) independent processing of baseline HR-MRI with validated software (FreeSurfer, FS). HV was correlated with baseline and 4 month NCF scores (Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall (TR), Immediate Recognition (IR), and Delayed Recall (DR)) using Pearson correlation. Comparisons between deteriorated and non-deteriorated patients were made using Wilcoxon. RESULTS: 39 of the 42 evaluable patients for the RTOG 0933 primary endpoint had hippocampal contours. All 42 had HR-MRIs, but only 21 were processable by FS due to scan quality. HVs from FS were larger than plan contours (median HV-Total 7.2 vs. 5.5 cc), though were significantly correlated (ρ = 0.68, p = 0.001). Larger FS HV-Total and HV-Right were significantly correlated with improved baseline HVLT-R TR (ρ = 0.46/p = 0.04, ρ = 0.51/p = 0.02, respectively) and DR (ρ = 0.46/p = 0.04, ρ = 0.49/p = 0.03, respectively) but not IR. Plan contour HV was not correlated with baseline HVLT-R though there was a trend for HV-Left with 4 month HVLT-R TR (ρ = 0.29/p = 0.07). There were no significant associations between HV and HVLT deterioration or change from baseline to 4 months. CONCLUSIONS: Baseline HV calculated from automatic segmentation of the hippocampus is significantly associated with baseline NCF. HV is not correlated with deterioration in NCF, though analysis is limited by few events and analyzable patients. The importance of HV will be explored further in two developing NRG trials. This project was supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422 and UG1CA189867 from the National Cancer Institute (NCI).

NC-05 * ASSOCIATION OF NEUROCOGNITIVE AND PATIENT REPORTED OUTCOMES WITH THE PRESENCE OF RESIDUAL DISEASE FOLLOWING SURGICAL RESECTION IN GLIOBLASTOMA (GBM)

BACKGROUND: It is hypothesized that subtotal resection (STR) is associated with worse neurocognitive function (NCF) and patient-reported outcomes (PRO) in patients with glioblastoma treated with concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. METHODS: NCF [Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), and Controlled Oral Word Association (COWA)] and PRO [select components of the MD Anderson Symptom Inventory-Brain Tumor questionnaire (MDASI-BT), and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30/BN20 (EORTC-QLQ)] data from RTOG 0525 and the control arm of 0825 were analyzed. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between STR and gross total resection (GTR). RESULTS: 427 eligible patients were analyzed with STR identified in 37%. STR patients were less likely to have a KPS of 90-100%; there were no other differences in clinical characteristics. At baseline, patients with STR had worse NCF [HVLT-R Total Recall (p = 0.0043), COWA (p = 0.0072)]; worse MDASI-BT Cognitive Factor ratings (p = 0.006); and worse EORTC-QLQ Cognitive Function scale ratings (p = 0.001). Change in test scores from baseline to 6 and 22 weeks was compared for GTR vs. STR and no difference in the magnitude of change was detected. Longitudinal multivariate analysis demonstrated STR was associated with worse NCF [HVLT-R Total Recall (p = 0.001), Delayed Recall (p = 0.011), TMT Part A (p = 0.010), and COWA (p = 0.001)]. CONCLUSIONS: STR patients had worse objective NCF and subjective cognitive complaints before therapy. During adjuvant therapy, patients with STR had worse objective NCF. No difference in select PROs was found among GTR and STR patients.