Delis-Kaplan Executive Function System Trail Research Articles

4 Relationships Between Task-Switching Performance and Adaptive Behavior Outcomes in Survivors of Pediatric Brain Tumor

Objective:Survivors of pediatric brain tumor (BT) experience impaired executive function (EF) and adaptive behavior (i.e. the ability to complete daily living tasks independently). The literature hypothesizes that executive dysfunction contributes to suboptimal adaptive behavior outcomes in BT survivors; however, the aspects of EF that drive this relationship remain unexplored. Task-switching is an EF component that involves switching between concurrently presented tasks. This skill is critical for many day-to-day activities and may therefore contribute to observed adaptive functioning difficulties. This study investigates relationships between performance on two task-switching measures and adaptive behavior outcomes in BT survivors compared to healthy controls.Participants and Methods:86 survivors of pediatric BT (Mage(SD)= 23.42(4.24), 44 females) and 86 age- and sex-matched controls (Mage(SD) = 23.09(4.40), 44 females) from the Atlanta area completed the Delis-Kaplan Executive Function System Trail Making Test (TMT) and Verbal Fluency Test (VFT). Respectively, the Letter-Number Sequencing (LNS) and Category Switching (CS) conditions were isolated as measures of task-switching. Baseline conditions, representing the foundational skills needed to perform these timed task-switching measures rapidly (TMT: Letter Sequencing, Number Sequencing; VFT: Category Fluency), were included as covariates in all regressions. Informants familiar with the participants’ daily living were interviewed with the Scales of Independent Behavior-Revised (SIB-R) to measure adaptive behavior in four domains (Motor Skills, Social Communication, Personal Living, Community Living). Linear regressions and t-tests confirmed group differences on task-switching performance and on adaptive functioning outcomes, respectively. Then, linear regressions investigated relationships between performance on each task-switching measure (LNS, CS) and SIB-R scores for survivors. A group by task-switching interaction was added to directly explore group differences in these relationships. α=.0125 was used due to Bonferroni correction for the four SIB-R comparisons within each task-switching measure.Results:BT survivors were more impaired than controls on LNS, CS, and SIB-R scores (p<.05, except Personal Living p=.058). For TMT, decreased performance on LNS predicted lower SIB-R scores in Social Communication (p=.001, r2semipartial=.14), Personal Living (p=.002, r2semipartial=.13), and Community Living (p=.003, r2semipartial =.11), but not Motor Skills (p=.184) in BT survivors. Strength of significant relationships was greater for survivors than controls (all p<.002). For VFT, decreased performance on CS predicted lower SIB-R scores in Personal Living (p=.036, r2semipartial =.06) and Community Living (p=.04, r2semipartial =.05), but not in Motor Skills (p=.716) or Social Communication (p=.14) in BT survivors. Positive relationships between CS and SIB-R scores for all 4 domains were greater in survivors than controls (p<.0125).Conclusions:These findings reveal a robust, positive relationship between task-switching performance and independent, daily behaviors that is specific to BT survivors. The relationship between LNS and Motor Skills may have been weakened by covariates involving baseline motor abilities; however, CS results suggest that task-switching is important for motor skills in survivors relative to controls. Community living skills were impaired in survivors and consistently related to task-switching performance. This work may inform interventions to target task-switching abilities and consequently, promote everyday living skills. Interventions aimed at vulnerabilities in adaptive behavior may help increase independence and quality-of-life as survivors transition to adulthood.

87 The Cumulative and Unique Effect of Competitive Youth Participation in the United States’ Most Popular Sports on Executive Function

Objective:Engagement in sporting activities has shown improvement in executive function among youth (Contreras-Osorio et al., 2021). Additionally, participation in specific sports such as soccer has been shown to enhance executive function in youth athletes compared to same-aged non-athletes (Yongtawee et al., 2021). The present study aimed to examine the effects of competitive participation in the United States’ four most popular sports on executive function among youth athletes. The most popular sports, as defined by viewership, revenue, and youth participation in the U.S. are American football, basketball, baseball, and soccer (Injai, 2022; Aspen Institute, 2020).Participants and Methods:Data from the following three executive functioning subtests were analyzed in a sample of youth athletes (n=76), aged 8-18 years (mean age=11.94): Delis-Kaplan Executive Function System Trail Making Letter-Number Sequencing (cognitive flexibility), Wechsler Intelligence Scale for Children Fourth Edition Working Memory Index, and Golden Stroop Color-Word Inhibition. Participants completed these measures as part of a larger neuropsychological baseline assessment. Multivariate General Linear Model (GLM) regression was used to examine the influence of total cumulative years playing in one or more of the four most popular sports on executive functioning. A multivariate GLM regression also investigated the unique contributions of total years playing soccer (n=40; mean age=12.40) and total years playing American football (n=32; mean age=12.03) on subtest performance. The unique contributions of basketball (n=14) and baseball (n=21) were not analyzed due to small sample size.Results:Total cumulative years playing > one of the four most popular sports significantly predicted cognitive flexibility (p=.007) and working memory (p=.002), but not inhibition (p=0.639). Total years playing soccer also significantly predicted cognitive flexibility (p=.029) and working memory (p=0.05), but not inhibition (p=.310). Total years playing American football did not significantly predict performance on tasks requiring cognitive flexibility (p=.186), working memory (p=0.150), or inhibition (p=0.277).Conclusions:In congruence with previous research, sports participation predicted enhanced cognitive flexibility and working memory on certain executive tasks. Among youth athletes, prolonged competitive participation in one or more of the four most popular sports in the U.S. predicted better performance on measures of cognitive flexibility and working memory. Furthermore, protracted participation in soccer predicted enhanced performance on measures of cognitive flexibility and working memory, whereas extended participation in American football did not. Future research should examine this effect in larger samples within all four sports. Examining the cumulative length of competitive participation in these popular sports on executive function could present a favorable developmental outcome of youth participation if competitive participation is sustained. Additionally, the present data on executive function performance between lasting soccer participation and lasting American football participation suggests that executive function development and performance may be influenced by the sport played. The direction of this possible influence is unclear. More research is needed to establish this observed difference, and to better understand its existence and directionality.

Microstructural Cerebellar Injury Independently Associated With Processing Speed in Adult Patients With Primary Brain Tumors: Implications for Cognitive Preservation

The cerebellum's role in posttreatment neurocognitive decline is unexplored. This study investigated associations between cerebellar microstructural integrity using quantitative neuroimaging biomarkers and neurocognition among patients with primary brain tumors receiving partial-brain radiation therapy (RT). In a prospective trial, 65 patients underwent volumetric brain magnetic resonance imaging, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment before RT and at 3, 6, and 12 months after RT. Delis-Kaplan Executive Function System-Trail Making (D-KEFS-TM) visual scanning and number and letter sequencing and Wechsler Adult Intelligence Scale, Fourth Edition, coding were used to evaluate PS. The cerebellar cortex and white matter (WM) and supratentorial structures subserving the previously mentioned cognitive domains were autosegmented. Volume was measured within each structure at each time point along with diffusion biomarkers (fractional anisotropy and mean diffusivity) in WM structures. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If associated, cerebellar biomarkers were evaluated as independent predictors of cognitive scores controlling for domain-specific supratentorial biomarkers. Left (P=.04) and right (P < .001) cerebellar WM volume declined significantly over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Smaller left cerebellar cortex volume was associated with worse D-KEFS-TM number (P=.01) and letter (P=.01) sequencing scores. A smaller right cerebellar cortex volume correlated with worse D-KEFS-TM visual scanning (P=.02) and number (P=.03) and letter (P=.02) sequencing scores. Greater right cerebellar WM mean diffusivity, indicating WM injury, was associated with worse D-KEFS-TM visual scanning performance (P=.03). Associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers. Injury to the cerebellum as measured with quantitative biomarkers correlates with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Efforts to preserve cerebellar integrity may preserve PS.

Fine Motor Skill Decline After Brain Radiation Therapy—A Multivariate Normal Tissue Complication Probability Study of a Prospective Trial

Brain radiation therapy can impair fine motor skills (FMS). Fine motor skills are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for the decline in FMS after fractionated brain radiation therapy (RT). On a prospective trial, 44 patients with primary brain tumors received fractioned RT; underwent high-resolution volumetric magnetic resonance imaging, diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS]; and Grooved Pegboard dominant/nondominant hands) at baseline and 6 months postRT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, cerebellum, and white matter tracts) were autosegmented using validated methods and manually verified. Dosimetric and clinical variables were included in multivariate NTCP models using automated bootstrapped logistic regression, least absolute shrinkage and selection operator logistic regression, and random forests with nested cross-validation. Half of the patients showed a decline on grooved pegboard test of nondominant hands, 17 of 42 (40.4%) on grooved pegboard test of -dominant hands, and 11 of 44 (25%) on DKEFS-MS. Automated bootstrapped logistic regression selected a 1-term model including maximum dose to dominant postcentral white matter. The least absolute shrinkage and selection operator logistic regression selected this term and steroid use. The top 5 variables in the random forest were all dosimetric: maximum dose to dominant thalamus, mean dose to dominant caudate, mean and maximum dose to the dominant corticospinal tract, and maximum dose to dominant postcentral white matter. This technique performed best with an area under the curve of 0.69 (95% CI, 0.68-0.70) on nested cross-validation. We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated regions of interest correlated with a decline in dominant-hand fine motor dexterity in patients with primary brain tumors in multivariate models, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT.

NCOG-37. MICROSTRUCTURAL CEREBELLAR INJURY IS ASSOCIATED WITH PROCESSING SPEED DECLINE IN ADULTS WITH PRIMARY BRAIN TUMORS: IMPLICATIONS FOR COGNITIVE PRESERVATION

Abstract PURPOSE We investigated associations between imaging biomarkers of cerebellar injury and neurocognitive function among primary brain tumor patients receiving partial brain radiotherapy (RT). METHODS On a prospective trial, 65 patients underwent volumetric brain MRI, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment pre-, 3, 6, and 12 months post-RT. Delis-Kaplan Executive Function System Trail Making [DKEFS-TM] Visual Scanning and Number and Letter Sequencing and Wechsler-Adult Intelligence Scale-IV [WAIS] Coding subtests evaluated PS. Cerebellar regions of interest (ROIs) were autosegmented, including cortex and white matter (WM). Supratentorial cortical and WM structures subserving the above cognitive domains were also autosegmented. Supratentorial PS-associated ROIs included the posterior, mid-posterior, central, mid-anterior, and anterior corpus callosum along with the bilateral intrahemispheric WM. Volume (cm3) was measured in all ROIs at each timepoint. Diffusion biomarkers (fractional anisotropy [FA] and mean diffusivity [MD]) were measured in all WM structures at each timepoint. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If found to be associated, cerebellar biomarkers were subsequently evaluated as predictors of cognitive scores controlling for domain-specific supratentorial ROI biomarkers. RESULTS Left (p=0.04) and right (p&amp;lt; 0.001) cerebellar WM volume declined over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Left cerebellar cortex atrophy correlated with worse DKEFS-TM Number (p=0.01) and Letter (p=0.01) Sequencing scores. Right cerebellar cortex atrophy correlated with worse DKEFS-TM Visual Scanning (p=0.02) and Number (p=0.03) and Letter (p=0.02) Sequencing scores. Greater right cerebellar WM MD correlated with worse DKFS-TM Visual Scanning performance (p=0.03). These associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers. CONCLUSION Biomarkers of cerebellar injury correlated with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Cerebellar dose avoidance may preserve PS.

D-KEFS trail making test as an embedded performance validity measure

ABSTRACT Objective The Delis-Kaplan Executive Function System (D-KEFS) Trail Making Test (TMT) is a commonly used measure of processing speed and executive functioning that may also be useful as an embedded performance validity test (PVT). We evaluated the utility of several multi-condition indices on the D-KEFS TMT in three independent samples to determine an optimal multi-condition index and cutoff on the D-KEFS TMT. Method Classification accuracy statistics for multiple multi-condition indices on the D-KEFS TMT were evaluated in three independent samples, including a sample with history of mild traumatic brain injury (TBI; n = 267) classified into psychometrically defined performance-valid and performance-invalid subgroups, the D-KEFS national normative sample (n = 1713), and a sample of middle- and older-aged adults diagnosed with mild cognitive impairment (MCI; n = 70). Results The D-KEFS TMT Conditions 1–5 summation index maximized sensitivity at .31 while maintaining adequate specificity at ≥.9. This index also had acceptable classification accuracy in both the D-KEFS national normative and MCI cross-validation samples, with the exception of the oldest subgroup of the national norming sample (i.e., individuals’ ages 80–89), in which the observed failure rates for all multi-condition indices tested were greater than 10%. Conclusion Our study provides support for the use the D-KEFS TMT Conditions 1–5 summation index as an embedded PVT among individuals younger than 80 years-old and from a range of conditions spanning from cognitively normal to mildly impaired; however, further validation is necessary.

Low Dose to White Matter Predicts Attention and Processing Speed Decline After Fractionated Brain RT

<h3>Purpose/Objective(s)</h3> Attention and processing speed, an important neurocognitive function, is subserved in the brain by critical white matter (WM): the corpus callosum (CC) and intra-hemispheric white matter tracts (IHWM). We sought to characterize the dose-response relationship of these structures with decline in attention/processing speed at 6 months post-RT in patients with primary brain tumors, with particular attention to low doses. <h3>Materials/Methods</h3> On a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric MRI, diffusion tensor imaging, and neurocognitive assessments (for processing speed: Delis-Kaplan Executive Function System Trail Making (D-KEFS-TM) Number Sequencing (TM-NS), D-KEFS-TM Letter Sequencing (TM-LS), and Weschler Adult Intelligence Scale (WAIS-IV) Coding; for attention: D-KEFS-TM Visual Scanning (TM-VS) test and WAIS-IV Digit Span Digits Forward (DF) test. Reliable change indices were calculated and adjusted for practice effects (RCI-PE), with decrease in RCI-PE scored as decline. Regions of interest (ROIs) were autosegmented using open source software and atlas-based tractography, including: CC, all WM w/wo CC, total IHWM without CC, and right/left IHWM without CC. Censoring masks excluded tumor, surgical cavity, scarring, and edema. Planning CTs were co-registered to MRIs to extract DVH parameters for each ROI, including V10 Gy and V20 Gy. Univariate logistic regressions were used to test for dosimetric predictors of decline. <h3>Results</h3> Median age was 47y. Most patients (61.5%) had gliomas. Median prescription RT dose was 59.4 Gy. At baseline and 6 months, 37-43 patients completed the neurocognitive assessments, with 61-78% showing decline. Several significant associations between increasing relative volumes exposed to low dose and decline were seen in all assessments except TM-NS (Table). Investigation of mean and maximum dose parameters yielded similar results. <h3>Conclusion</h3> While maximum dose is typically considered the most relevant dosimetric parameter for toxicity endpoints in the brain, we also detected several significant logistic relationships between V10 and V20 to more diffuse white matter networks (CC and IHWM) and decline in attention and processing speed post-RT. Minimization of low dose bath, whether by planning optimization or use of more conformal modalities like protons, may be clinically relevant for preservation of these critical neurocognitive functions.

Higher Radiation Doses to Motor Regions Predict Decline in Fine Motor Skills After Brain RT: NTCP Analysis of a Prospective Trial

Impairment in fine motor skills (FMS), including motor speed and coordination, can occur after brain radiotherapy. FMS are essential for activities of daily living including writing, typing, and eating. Using a normal tissue complication probability (NTCP) framework, we sought to determine dosimetric predictors of FMS decline in a prospective cohort of brain tumor patients treated with RT.On a prospective clinical trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant [PDH] and Non-dominant [PNDH] Hands) at baseline and 6 months post-RT. Reliable change indices adjusting for practice effects (RCI-PEs) were calculated, with RCI-PE > 0.5 considered FMS decline. Motor regions of interest (ROIs) were autosegmented using an open-source software for processing and analyzing brain MRI images and atlas-based tractography, including: sensorimotor cortices and superficial white matter (WM), corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Censoring masks excluded tumor, surgical cavity, scarring, and edema from analyses. Planning CTs were co-registered to MRIs to extract DVH parameters for each ROI, including maximum/mean doses and Vx (structure volume receiving ≥ x Gy). Fisher's exact test on median splits and logistic regressions were used to test for dosimetric predictors of FMS decline.At baseline and 6 months, 41 and 39 patients completed DKEFS-MS and PDH/PNDH tests, respectively. Median prescription dose was 59.4 Gy. Most patients (84.3%) were right-handed. There were several significant associations between increasing doses in left-sided ROIs and decline on PDH performance at 6 months, which occurred in 14 of 41 patients (Table, P < 0.001-0.048). Overall, these normalized slopes (γ50) ranged from 0.31 to 0.80. Within sub-volumes of the left corticospinal tract (corona radiata, posterior limb of the internal capsule [PLIC], crus cerebri, and pontine segment), increasing mean and max dose, V10, and V20 to PLIC; as well as increasing V20 to corona radiata, showed association with PDH decline (P < 0.014). No relationships were found with respect to decline on PNDH and DKEFS-MS.Increasing doses to left-sided motor ROIs including cortical, WM, and basal ganglia structures were associated with decline in dominant hand FMS at 6 months post-RT in this largely right-handed cohort. These areas may represent avoidance targets for preserving FMS in brain tumor patients.

A-176 Undercover Performance Validity Testing: Proposed Embedded Validity Indicators for Pediatric Neuropsychological Assessment

Abstract Objective Literature supports the use of the Delis-Kaplan Executive Function System Trail Making Test Conditions 4/2 ratio (TMT 4/2) and Stroop Color Word Test Word Reading (WR) as embedded validity indicators (EVIs) with adults (Erdodi et al., 2018; Guise et al., 2012) and the Wechsler Abbreviated Scale of Intelligence, 2nd Edition Matrix Reasoning (MR) as an EVI with children (Sussman et al., 2017). This study assessed the utility of these measures as EVIs in healthy children, compared to the Test of Memory Malingering Trial 1 (TOMM1 &amp;lt; 45; Perna &amp; Loughan, 2013) and Reliable Digit Span (RDS). Method Participants (n = 99, 68.7% male, Mage = 11.9) completed baseline neuropsychological evaluations for sport participation, including the aforementioned measures. Receiver operator characteristic curve analysis was used to determine whether TMT 4/2, MR, and WR accurately categorized valid performance. Results TMT 4/2 yielded adequate sensitivity (0.83–1.00) but poor specificity (0.07–0.09) when predicting TOMM1 and RDS pass/fail performances. MR yielded adequate sensitivity (1.00) and specificity (0.92) when predicting RDS pass/fail performance and adequate specificity (0.92) and poor sensitivity (0.18) when predicting TOMM1 pass/fail performance. The only EVI that produced better than chance accuracy was MR when predicting RDS pass/fail performance (area under the curve [AUC] = 0.98). All participants failed the WR cutoff, suggesting poor specificity. Conclusion Results suggest that MR was the only EVI that achieved minimally acceptable specificity (≥0.90) in children. MR performed adequately when detecting valid performances but variably when detecting invalid performances; therefore, MR may be used alongside well-established performance validity tests with children but not independently.

Chemokine MCP1 is associated with cognitive flexibility in schizophrenia: A preliminary analysis

BackgroundPeripheral levels of pro-inflammatory biomarkers have been shown to be altered in schizophrenia (SZ) and associated with cognitive impairments, but their relevance to specific cognitive domains remains unclear. MethodsPlasma levels of cytokines, chemokines, and vascular biomarkers were quantified and compared between SZ and healthy comparison (HC) groups. Cognition was assessed using the Delis-Kaplan Executive Function System Trail Making (TM) and Color Word Interference (CWI) tests. Linear regression analyses examined differential relationships of inflammatory biomarkers with executive function between groups. ResultsPlasma levels of TNFα, ICAM1, and MCP1 were higher in individuals with SZ compared to HCs. Higher level of MCP1 was associated with increased CWI Inhibition Switching Errors in SZ but not HCs. ConclusionLike other studies, we found evidence for increased peripheral inflammation in SZ. We also showed that SZ with particularly high MCP1 levels had poor cognitive flexibility. Interventions to reduce chemokine elevations might prove beneficial for cognitive performance.

Longitudinal change in fine motor skills after brain radiotherapy and in vivo imaging biomarkers associated with decline.

We explored fine motor skills (FMS) before and after brain radiotherapy (RT), analyzing associations between longitudinal FMS and imaging biomarkers of cortical and white matter (WM) integrity in motor regions of interest (ROIs). On a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric brain MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant Hands [PDH], and Grooved Pegboard Nondominant Hands [PNDH]) at baseline and 3-, 6-, and 12-month post-RT. Motor ROIs autosegmented included: sensorimotor cortices and superficial WM, corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Volume (cc) was measured in all ROIs at each timepoint. Diffusion biomarkers (FA [fractional anisotropy] and MD [mean diffusivity]) were additionally measured in WM ROIs. Linear mixed-effects models assessed biomarkers as predictors of FMS scores. P values were corrected for multiple comparisons. Higher RT dose was associated with right paracentral cortical thinning (β = -2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (β = 0.69 Gy/(month × µm2/ms), P = .04). Higher left (β = 38.7 points/(month × µm2/ms), P = .004) and right (β = 42.4 points/(month × µm2/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (β = -8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (β = -0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (β = -17.3 points/(month × mm), P = .02). Left (β = -0.87 points/(month × cm3), P = .001) and right (β = -0.64 points/(month × cm3), P = .02) cerebellar cortex, left pons (β = -19.8 points/(month × cm3), P = .02), and right pallidum (β = -10.8 points/(month × cm3), P = .02) atrophy and reduced right internal capsule FA (β = -1.02 points/month, P = .03) were associated with worse PNDH performance. Biomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS.

Microstructural Injury to Corpus Callosum and Intrahemispheric White Matter Tracts Correlate With Attention and Processing Speed Decline After Brain Radiation

The corpus callosum (CC) and intrahemispheric white matter tracts (IHWM) subserve critical aspects of attention and processing speed. We analyzed imaging biomarkers of microstructural injury within these regions and association with attention and processing speed performance before and after radiation therapy in primary brain tumor patients. In a prospective clinical trial, 44 primary brain tumor patients underwent cognitive testing and magnetic resonance imaging/diffusion-weighted imaging at baseline (pre-radiation therapy) and 3-, 6-, and 12-months post-radiation therapy. CC (subregions, total) and IHWM tracts (left/right without CC, total) were autosegmented; tumor, tumor bed, and edema were censored. Biomarkers included volume changes (cm3), mean diffusivity ([MD]; higher values indicate white matter injury), fractional anisotropy ([FA]; lower values indicate white matter injury). Reliable-change indices measured changes in attention (Weschler Adult Intelligence Scale [WAIS-IV] digits-forward; Delis-Kaplan Executive Function System Trail Making [D-KEFS-TM] visual-scanning), and processing speed (WAIS-IV coding; D-KEFS-TM number-sequencing, letter-sequencing), accounting for practice effects. Linear mixed-effects models evaluated associations between mean radiation dose and biomarkers (volume, MD, FA) and imaging biomarkers and neurocognitive performance. Statistics were corrected for multiple comparisons. Processing speed declined at 6 months following radiation therapy (number sequencing, letter sequencing; P < .04). Seizures and antiepileptic drug therapy were associated with lower visual-scanning attention reliable-change indices at 6 months (P = .039). Higher radiation dose correlated with smaller midanterior CC volume (P = .023); lower FA in posterior CC, anterior CC, and total CC (all P < .03); and higher MD in anterior CC (P = .012). Smaller midanterior CC and left IHWM volume correlated with worse processing speed (coding, letter-sequencing, number-sequencing; all P < .03). Higher FA in right, left, and total IHWM correlated with better coding scores (all P < .01). Lower FA in total IHWM (P = .009) was associated with worse visual-scanning attention scores. Higher FA in midposterior CC (P = .029) correlated with better digits-forward attention scores. The CC demonstrated radiation dose-dependent atrophy and WM injury. Microstructural injury within the CC and IHWM was associated with attention and processing speed decline after radiation therapy. These areas represent possible avoidance regions for preservation of attention and processing speed.

Longitudinal Analysis Of Quality Of Life As An Independent Predictor Of Neurocognitive Function In Brain Tumor Patients

Primary brain tumor patients experience reduced health-related quality of life (hrQoL), which may be compounded by treatments including radiation therapy (RT). We conducted a prospective longitudinal study to examine the association between hrQoL (physical, social/family, emotional, functional, and brain cancer-specific) and domain-specific neurocognitive function in primary brain tumor patients. Primary brain tumor patients (n = 59) receiving fractionated brain RT underwent comprehensive hrQOL (Functional Assessment of Cancer Therapy-Brain [FACT-Br]) and neurocognitive evaluation at baseline and 3, 6, and 12 months post-RT. Neurocognitive assessments measured attention and processing speed (Delis-Kaplan Executive Function System Trail Making Test [DKEFS-TMT] Visual Scanning, Number Sequencing, and Letter Sequencing and Weschler-Adult Intelligence Scale-IV [WAIS-IV] Digit Span and Coding), memory (Hopkins Verbal Learning Test-Revised [HVLT-R] Total and Delayed Recall and Brief Visuospatial Memory Test [BVMT] Total and Delayed Recall), and executive function (DKEFS Verbal Fluency [DKEFS-VF] Letter Fluency and Category Switching and Wisconsin Card Sorting Test [WCST] Perseverative Errors). Cognitive scores were transformed to t-scores controlling for age and sex; higher cognitive t-scores and hrQOL scores reflect better function. Multivariable linear mixed-effects models assessed independent association between hrQOL scores and neurocognitive function over time, controlling for patient, tumor, and treatment characteristics as well as timepoint-specific patient-reported anxiety and depression symptoms. P-values were corrected for multiple comparisons using false discovery rate. Median age of the cohort was 47 years. Most were male (61%) and married (71%). Higher physical hrQoL showed significant independent association with better verbal memory (HVLT Total Recall p = 0.047), while higher functional hrQoL correlated with better executive function (DKEFS-VF Switching Total p = 0.009) and verbal memory (HVLT Delayed Recall p = 0.006). Higher brain cancer-specific hrQoL was associated with better performance on tests of verbal and non-verbal memory (HVLT Total p = 0.004 and Delayed Recall p = 0.030; BVMT Total p = 0.049 and Delayed Recall p = 0.049). There was no significant association between social/family or emotional hrQoL and neurocognitive scores. This is the first prospective study to assess the independent association of hrQOL and neurocognition in primary brain tumor patients. We found that reduced physical, functional, and brain cancer-specific hrQoL were independently associated with worse executive function and memory among primary brain tumor patients receiving RT. Physical and functional impairments may impact cognitive performance in this population after RT.

Oculomotor Treatment in Traumatic Brain Injury Rehabilitation: A Randomized Controlled Pilot Trial.

Vision impairments are common after traumatic brain injury (TBI). Little evidence exists to assist clinicians with effective interventions for impaired oculomotor skills in people with TBI. To pilot a randomized controlled trial (RCT) of oculomotor treatment in TBI rehabilitation. An impairment-based oculomotor protocol was compared with an activity-based standard of care in a two-group RCT. Participants were masked to assignment. Inpatient rehabilitation. For 1 yr, 138 people with TBI, ages 18-65 yr, were screened. Twenty-six were eligible; 6 declined. Inclusion criteria: oculomotor impairment. Exclusion criteria: inpatient stay <6 wk, blind, no functional arm use, unable to follow a three-step command, attention <30 min, or in another clinical trial. Participants were randomized into an experimental group (n = 10) receiving the Six Eye Exercises protocol or a control group (n = 10) receiving a standard-of-care protocol for 30 min/day, 5 days/wk, for 4 wk. Oculomotor and related functional impairments were measured at baseline and posttreatment. Measures were chosen before the start. Primary outcome measure: Craig Hospital Eye Evaluation Rating Scale for oculomotor status. Secondary measures for functional status: King-Devick Test, Delis-Kaplan Executive Function System Trail Making Test: Condition 1 Visual Scanning, Modified Nelson-Denny Reading Test, and Subjective Vision Symptom Scale. Sixteen participants finished. Fatigue was the primary reason for withdrawal. No other negative effects were noted. Selected outcome measures captured positive improvements in both groups. Study findings suggest conducting an appropriately powered RCT to evaluate efficacy of oculomotor treatment in this population. Oculomotor dysfunction seems to improve during inpatient TBI rehabilitation with remedial treatment. Best practice in occupational therapy has not yet been established. An appropriately powered RCT could positively contribute to the evidence available to clinicians.

Diffusion Imaging Biomarkers of Corpus Callosum Injury and Dose-Dependent Volumetric Changes Correlate with Attention and Processing Speed Changes after Brain Radiotherapy

Attention and processing speed are core cognitive functions subserved by the corpus callosum (CC), a critical white matter structure. We hypothesized that CC volume changes and diffusion weighted imaging (DWI) biomarkers of CC injury would correlate with changes in attention and processing speed function after brain radiotherapy (RT). We prospectively studied 29 patients with primary brain tumors who received fractionated RT. Patients underwent formal neuropsychological testing and high resolution volumetric MRI with DWI (b-values 0, 500, 1500 s/mm2 fit to single tensor) prior to and 6 months post RT. Auditory attention was measured with the Weschler Adult Intelligence Scale (WAIS-IV) Digit Span Forward test; processing speed was measured with the Delis-Kaplan Executive Function System Trail Making number sequencing (TM-NS) and letter sequencing (TM-LS) subtests. Reliable change indices accounting for practice effects (RCI-PE) were calculated to determine 0-6 month change on each measure. Image processing at each time point included auto-segmentation with volume calculations of regions of interest (ROIs): the entire CC and anterior, mid-anterior, central, mid-posterior, and posterior subdivisions. Tumor, tumor bed, edema, and segmentation errors were censored. DWI biomarkers including mean diffusivity (MD, increases with injury) and fractional anisotropy (FA, decreases with injury) were calculated. Mean dose to each ROI was determined. One sample t-tests (H0=0) were performed to determine significant group cognitive decline. Pearson correlation coefficients evaluated the relationship between RCI-PEs and clinical variables, dose, changes in volume, MD, and FA. Statistical significance was set at α=0.05. Processing speed (TM-LS) significantly declined 6-months post-RT (mean change -0.472, p = 0.003). Age and years of education did not influence attention or processing speed changes. Significant dose-dependent atrophy was seen in the mid-anterior (r = -0.432, p = 0.024), mid-posterior (r = -0.408, p = 0.031), and posterior CC (r = -0.600, p = 0.001). Smaller mid-anterior CC volume was associated with worse processing speed (TM-LS, r = 0.424, p = 0.031). Decreased FA in the anterior CC was associated with worse attention (digits forward, r = 0.401, p = 0.038) and decreased FA in the posterior CC was correlated with worse processing speed (TM-LS, r = 0.444, p = 0.02). Increased MD in the anterior CC (r = -0.386, p = 0.046) was correlated with worse attention (digits forward). In this prospective study, dose-dependent atrophy of CC subdivisions was seen after fractionated brain RT. Microstructural damage, including atrophy and white matter injury, within CC subdivisions was significantly associated with worse attention and processing speed. Damage to this critical structure is highly implicated in attention/processing speed changes after brain RT.

Dosimetric Predictors of Cognitive Decline in Attention and Processing Speed after Fractionated Brain Radiation Therapy

Neurocognitive decline, including changes in attention/processing speed, can be an unfortunate consequence of brain radiation therapy (RT). The corpus callosum (CC) and right-sided subcortical white matter (WM) are known to subserve this cognitive function. We aimed to determine dosimetric predictors of attention/processing decline at 6 months after fractionated RT in patients with primary brain tumors. Twenty-three patients with primary brain tumors were enrolled on a prospective cohort study. Patients had neurocognitive assessments and high-resolution diffusion and volumetric MRI imaging pre-RT and 6 months post RT. Subjects were tested on Delis-Kaplan Executive Function System trail making number and letter sequencing. Reliable change indices accounting for practice effects (RCI-PE) scores were calculated as a normalized measure of cognition change from pre-RT to post-RT. Practice effects accounts for expected improvements in tasks with repetition. Binary variables decline and substantial decline were defined as RCI-PE <0 and <-1, respectively. Brain WM regions were segmented using a validated probabilistic diffusion tensor WM atlas. Regions of interest (ROIs) were CC and total right-sided subcortical WM with and without CC. Tumor and edema were censored from ROIs. Data including Vx (structure volume receiving ≥ x Gy) in 5 Gy intervals, minimum, maximum, and mean doses to each ROI were extracted from RT plans. A general linear model on dosimetric/volumetric data was created to identify predictors of decline (significance defined as p<0.05). Most patients (n=15, 62%) had benign or low-grade tumors. Median age at RT was 51 years (range 20-75) and 48% of patients were male. Fifteen patients (65%) underwent resection pre-RT and 9 (39%) patients received concurrent chemotherapy. Between 60-69% of patients experienced a decline; substantial number and letter sequencing decline was seen in 5 (22%) and 2 (9%) patients, respectively. Minimum dose to CC predicted for substantial letter sequencing decline (p<0.001), but there were no significant predictors of number sequencing. In right sided subcortical WM excluding CC, V30 predicted for substantial number sequencing decline (p<0.001) while minimum dose (p<0.001) and V30-V40 (all p<0.001) predicted for substantial letter sequencing decline. Within right-sided subcortical WM including CC, V30 predicted for substantial number sequencing decline (p<0.001) while V30-V35 (p<0.001) predicted for substantial letter sequencing decline. In this prospective cohort study, increasing volume receiving 30-40Gy within the right-sided total subcortical WM predicted for decreased attention/processing speed at 6 months after RT. Minimum dose to CC also predicted for decline. This suggests that dose-dependent subcortical WM effects contribute to cognitive decline. Further complex modeling is needed to generate normal tissue parameters for WM structures to guide cognitive sparing brain RT.

C - 50Investigation of Embedded Performance Validity Tests in the Delis-Kaplan Executive Function System Trail Making Subtest

C - 50Investigation of Embedded Performance Validity Tests in the Delis-Kaplan Executive Function System Trail Making Subtest

Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder

Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. Cross-sectional study. University of California San Diego and the Veterans Administration San Diego Healthcare System. 33 euthymic BD and 38 HC participants. Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

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.

Inferior Prefrontal Cortex Mediates the Relationship between Phosphatidylcholine and Executive Functions in Healthy, Older Adults.

Objectives: This study examines the neural mechanisms that mediate the relationship between phosphatidylcholine and executive functions in cognitively intact older adults. We hypothesized that higher plasma levels of phosphatidylcholine are associated with better performance on a particular component of the executive functions, namely cognitive flexibility, and that this relationship is mediated by gray matter structure of regions within the prefrontal cortex (PFC) that have been implicated in cognitive flexibility.Methods: We examined 72 cognitively intact adults between the ages of 65 and 75 in an observational, cross-sectional study to investigate the relationship between blood biomarkers of phosphatidylcholine, tests of cognitive flexibility (measured by the Delis–Kaplan Executive Function System Trail Making Test), and gray matter structure of regions within the PFC. A three-step mediation analysis was implemented using multivariate linear regressions and we controlled for age, sex, education, income, depression status, and body mass index.Results: The mediation analysis revealed that gray matter thickness of one region within the PFC, the left inferior PFC (Brodmann’s Area 45), mediates the relationship between phosphatidylcholine blood biomarkers and cognitive flexibility.Conclusion: These results suggest that particular nutrients may slow or prevent age-related cognitive decline by influencing specific structures within the brain. This report demonstrates a novel structural mediation between plasma phosphatidylcholine levels and cognitive flexibility. Future work should examine the potential mechanisms underlying this mediation, including phosphatidylcholine-dependent cell membrane integrity of the inferior PFC and phosphatidylcholine-dependent cholinergic projections to the inferior PFC.