Multi-domain neurocognitive classification of primary brain tumor patients prior to radiotherapy on a prospective clinical trial.

INTRODUCTION: We investigated multi-domain baseline neurocognition of primary brain tumor patients prior to radiotherapy (RT), including clinical predictors of function and association between pre-RT and post-RT impairment on a prospective trial. METHODS: A multi-domain neuropsychological battery (memory, executive functioning, language, attention, processing) was performed on 37 patients, pre-RT and 3-(n = 21), 6-(n = 22) and 12-(n = 14) months post-RT. Impairment rate was the proportion of patients with standardized T-scores ≤ 1.5 standard deviations below normative means. Per-patient impairment across all domains was calculated using a global deficit score (GDS; higher value indicates more impairment). Associations between baseline GDS and clinical variables were tested. Global GDS impairment rate at each time point was the fraction of patients with GDS scores > 0.5. RESULTS: Statistically significant baseline neurocognitive impairments were identified on 4 memory (all p ≤ 0.03) and 2 out of 3 (p = 0.01, p = 0.027) executive functioning tests. Per-patient baseline GDS was significantly associated with tumor volume (p = 0.048), tumor type (p = 0.043), seizure history (p = 0.007), and use of anti-epileptics (p = 0.009). The percentage of patients with the same impairment status at 3-, 6-, and 12-months as at baseline were 88%, 85%, and 85% respectively. CONCLUSIONS: Memory and executive functioning impairment were the most common cognitive deficits prior to RT. Patients with larger tumors, more aggressive histology, and use of anti-epileptics had higher baseline GDS values. GDS is a promising tool to encompass multi-domain neurocognitive function, and baseline GDS can identify those at risk of cognitive impairment.

Selective phosphorylation of the Dlg1AB variant is critical for TCR-induced p38 activation and induction of proinflammatory cytokines in CD8+ T cells.

CD8(+) T cells respond to TCR stimulation by producing proinflammatory cytokines, and destroying infected or malignant cells through the production and release of cytotoxic granules. Scaffold protein Discs large homolog 1 (Dlg1) specifies TCR-dependent functions by channeling proximal signals toward the activation of p38-dependent proinflammatory cytokine gene expression and/or p38-independent cytotoxic granule release. Two Dlg1 variants are expressed in CD8(+) T cells via alternative splicing, Dlg1AB and Dlg1B, which have differing abilities coordinate TCR-dependent functions. Although both variants facilitate p38-independent cytotoxicity, only Dlg1AB coordinates p38-dependent proinflammatory cytokine expression. In this study, we identify TCR-induced Dlg1 tyrosine phosphorylation as a key regulatory step required for Dlg1AB-mediated p38-dependent functions, including proinflammatory cytokine expression. We find that Dlg1AB but not Dlg1B is tyrosine phosphorylated by proximal tyrosine kinase Lck in response to TCR stimulation. Furthermore, we identify Dlg1 tyrosine 222 (Y222) as a major site of Dlg1 phosphorylation required for TCR-triggered p38 activation and NFAT-dependent expression of proinflammatory cytokines, but not for p38-independent cytotoxicity. Taken together, our data support a model where TCR-induced phosphorylation of Dlg1 Y222 is a key point of control that endows Dlg1AB with the ability to coordinate p38 activation and proinflammatory cytokine production. We propose blocking Dlg1AB phosphorylation as a novel therapeutic target to specifically block proinflammatory cytokine production but not cytotoxicity.

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

PURPOSE: 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). METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

PURPOSE: 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). METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

Dose-Dependent Atrophy in Bilateral Amygdalae and Nuclei After Brain Radiation Therapy and Its Association With Mood and Memory Outcomes on a Longitudinal Clinical Trial.

PURPOSE: Amygdalae are bilateral, almond-shaped structures located anterior to the hippocampi, critical to limbic system functions of emotional processing and memory consolidation. The amygdalae are heterogeneous, composed of multiple nuclei with distinct structural and functional properties. We prospectively assessed associations between longitudinal changes in amygdala morphometry, including component nuclei, and functional outcomes in patients with primary brain tumors receiving radiation therapy (RT). METHODS AND MATERIALS: On a prospective longitudinal trial, 63 patients underwent high-resolution volumetric brain magnetic resonance imaging and testing for mood (Beck Depression Inventory and Beck Anxiety Inventory), memory (Brief Visuospatial Memory Test-Revised [BVMT] Total Recall and Delayed Recall; Hopkins Verbal Learning Test-Revised [HVLT] Total Recall and Delayed Recall), and health-related quality-of-life outcomes (Functional Assessment of Cancer Therapy-Brain Social/Family Well-Being and Emotional Well-Being) at baseline and 3, 6, and 12 months after RT. Amygdalae, including 8 nuclei, were autosegmented bilaterally using validated techniques. Linear mixed-effects models assessed longitudinal change in amygdalae and nuclei volumes and associations with dose and outcomes. Wilcoxon rank sum tests compared amygdala volume change between patient groups with worse and more stable outcomes at each time point. RESULTS: Atrophy was found in the right amygdala at 6 months (P = .001) and the left amygdala at 12 months (P = .046). A higher dose was associated with atrophy of the left amygdala (P = .013) at 12 months. The right amygdala showed dose-dependent atrophy at 6 months (P = .016) and 12 months (P = .001). Worse BVMT-Total, HVLT-Total, and HVLT-Delayed performance was associated with smaller left lateral (P = .014, P = .004, and P = .007, respectively) and left basal (P = .034, P = .016, and P = .026, respectively) nuclei volumes. Increased anxiety at 6 months was associated with greater combined (P = .031) and right (P = .007) amygdala atrophy. Greater left amygdala atrophy (P = .038) was noted in patients with decreased emotional well-being at 12 months. CONCLUSIONS: Bilateral amygdalae and nuclei undergo time- and dose-dependent atrophy after brain RT. Atrophy in amygdalae and specific nuclei was associated with poorer memory, mood, and emotional well-being. Amygdalae-sparing treatment planning may preserve neurocognitive and neuropsychiatric outcomes in this population.

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

BACKGROUND: 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). METHODS: 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. RESULTS: Higher RT dose was associated with right paracentral cortical thinning (ß = -2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (ß = 0.69 Gy/(month × µm2/ms), P = .04). Higher left (ß = 38.7 points/(month × µm2/ms), P = .004) and right (ß = 42.4 points/(month × µm2/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (ß = -8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (ß = -0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (ß = -17.3 points/(month × mm), P = .02). Left (ß = -0.87 points/(month × cm3), P = .001) and right (ß = -0.64 points/(month × cm3), P = .02) cerebellar cortex, left pons (ß = -19.8 points/(month × cm3), P = .02), and right pallidum (ß = -10.8 points/(month × cm3), P = .02) atrophy and reduced right internal capsule FA (ß = -1.02 points/month, P = .03) were associated with worse PNDH performance. CONCLUSIONS: Biomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS.

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

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

Microstructural Injury to Left-Sided Perisylvian White Matter Predicts Language Decline After Brain Radiation Therapy.

PURPOSE: Our purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors. METHODS AND MATERIALS: Patients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores. RESULTS: DKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores. CONCLUSIONS: Patients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation.

Longitudinal Analysis of Depression and Anxiety Symptoms as Independent Predictors of Neurocognitive Function in Primary Brain Tumor Patients.

PURPOSE: Primary brain tumor patients are vulnerable to depression and anxiety symptoms, which may affect their neurocognitive functioning. We performed a prospective longitudinal analysis to examine the association between depression and anxiety symptoms and domain-specific neurocognitive functioning in primary brain tumor patients receiving radiation therapy (RT). METHODS AND MATERIALS: On a prospective trial, 54 primary brain tumor patients receiving RT underwent comprehensive neurocognitive evaluation at baseline (pre-RT), and 3, 6, and 12 months post-RT. Neurocognitive assessments measured attention/processing speed, verbal and visuospatial memory, and executive functioning, including Delis-Kaplan Executive Function System Trail-Making Test (DKEFS-TMT), DKEFS Verbal Fluency, and Brief Visuospatial Memory Test-Revised. Depression and anxiety symptoms were also assessed at each time point with Beck Depression and Anxiety Inventories (BDI-II and BAI), respectively. Higher scores reflect more numerous or severe depression or anxiety symptoms. Univariable and multivariable linear mixed-effects models assessed associations between BDI-II and BAI scores and domain-specific neurocognitive scores over time, controlling for pre-existing depression or anxiety disorders and other patient, tumor, and treatment characteristics. RESULTS: Higher BAI scores were associated with worse attention and processing speed in univariable analyses: DKEFS-TMT visual scanning (P = .003), number sequencing (P = .011), and letter sequencing (P <.001). On multivariable analyses, these associations remained significant (all P ≤ .01). Higher BDI-II scores were also associated with poorer attention/processing speed (DKEFS-TMT Letter Sequencing) in univariable (P = .002) and multivariable (P = .013) models. Higher BAI scores were associated with worse visuospatial memory (Brief Visuospatial Memory Test-Revised Delayed Recall) on univariable (P = .012) but not multivariable analyses (P = .383). Similarly, higher BDI-II scores were associated with poorer executive functioning (DKEFS Verbal Fluency Category Switching) on univariable (P = .031) but not multivariable analyses (P = .198). CONCLUSIONS: Among primary brain tumor patients receiving RT, increased depression and anxiety were independently associated with worsened neurocognition, particularly in attention/processing speed. Depression and anxiety symptoms should be controlled for in prospective clinical trials and managed in the clinical setting to optimize neurocognitive functioning.

Quantitative Imaging Biomarkers of Damage to Critical Memory Regions Are Associated With Post-Radiation Therapy Memory Performance in Brain Tumor Patients.

PURPOSE: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT). METHODS AND MATERIALS: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory. RESULTS: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance. CONCLUSIONS: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.