Age-Specific Adult Rat Brain MRI Templates and Tissue Probability Maps

Age-specific resources in human MRI mitigate processing biases that arise from structural changes across the lifespan. There are fewer age-specific resources for preclinical imaging, and they only represent developmental periods rather than adulthood. Since rats recapitulate many facets of human aging, it was hypothesized that brain volume and each tissue's relative contribution to total brain volume would change with age in the adult rat. Data from a longitudinal study of rats at 3, 5, 11, and 17 months old were used to test this hypothesis. Tissue volume was estimated from high resolution structural images using a priori information from tissue probability maps. However, existing tissue probability maps generated inaccurate gray matter probabilities in subcortical structures, particularly the thalamus. To address this issue, gray matter, white matter, and CSF tissue probability maps were generated by combining anatomical and signal intensity information. The effects of age on volumetric estimations were then assessed with mixed-effects models. Results showed that herein estimation of gray matter volumes better matched histological evidence, as compared to existing resources. All tissue volumes increased with age, and the tissue proportions relative to total brain volume varied across adulthood. Consequently, a set of rat brain templates and tissue probability maps from across the adult lifespan is released to expand the preclinical MRI community's fundamental resources.

Comparing Brain Asymmetries Independently of Brain Size

Studies examining cerebral asymmetries typically divide the L-R Measure (e.g., Left-Right Volume) by the L+R Measure to obtain an Asymmetry Index (AI). However, contrary to widespread belief, such a division fails to render the AI independent from the L+R Measure and/or from total brain size. As a result, variations in brain size may bias correlation estimates with the AI or group differences in AI. We investigated how to analyze brain asymmetries in to distinguish global from regional effects, and report unbiased group differences in cerebral asymmetries. We analyzed the extent to which the L+R Measure, Total Cerebral Measure (TCM, e.g., Total Brain Volume), and L-R TCM predict regional asymmetries. As a case study, we assessed the consequences of omitting each of these predictors on the magnitude and significance of sex differences in asymmetries. We found that the L+R Measure, the TCM, and the L-R TCM predicted the AI of more than 89% of regions and that their relationships were generally linear. Removing any of these predictors changed the significance of sex differences in 33% of regions and the magnitude of sex differences across 13-42% of regions. Although we generally report similar sex and age effects on cerebral asymmetries to those of previous large-scale studies, properly adjusting for regional and global brain size revealed additional sex and age effects on brain asymmetry.

Global dissociation of the amygdala from the rest of the brain during REM sleep

Rapid-eye-movement sleep (REMS) or paradoxical sleep is associated with intense neuronal activity, fluctuations in autonomic control, body paralysis and brain-wide hyperemia. The mechanisms and functions of these energy-demanding patterns remain elusive and a global picture of brain activation during REMS is currently missing. In the present work, we performed functional ultrasound (fUS) imaging at the whole-brain scale during hundreds of REMS episodes to provide the spatiotemporal dynamics of vascular activity in 259 brain regions spanning more than 2/3 of the total brain volume. We first demonstrate a dissociation between basal/midbrain and cortical structures, the first ones sustaining tonic activation during REMS while the others are activated in phasic bouts. Second, we isolated the vascular compartment in our recordings and identified arteries in the anterior part of the brain as strongly involved in the blood supply during REMS episodes. Finally, we report a peculiar activation pattern in the amygdala, which is strikingly disconnected from the rest of the brain during most but not all REMS episodes. This last finding shows that amygdala undergoes specific processing during REMS and may be linked to the regulation of emotions and the creation of dream content during this very state.

Global dissociation of the amygdala from the rest of the brain during REM sleep

Rapid-eye-movement sleep (REMS) or paradoxical sleep is associated with intense neuronal activity, fluctuations in autonomic control, body paralysis and brain-wide hyperemia. The mechanisms and functions of these energy-demanding patterns remain elusive and a global picture of brain activation during REMS is currently missing. In the present work, we performed functional ultrasound (fUS) imaging at the whole-brain scale during hundreds of REMS episodes to provide the spatiotemporal dynamics of vascular activity in 259 brain regions spanning more than 2/3 of the total brain volume. We first demonstrate a dissociation between basal/midbrain and cortical structures, the first ones sustaining tonic activation during REMS while the others are activated in phasic bouts. Second, we isolated the vascular compartment in our recordings and identified arteries in the anterior part of the brain as strongly involved in the blood supply during REMS episodes. Finally, we report a peculiar activation pattern in the amygdala, which is strikingly disconnected from the rest of the brain during most but not all REMS episodes. This last finding shows that amygdala undergoes specific processing during REMS and may be linked to the regulation of emotions and the creation of dream content during this very state.

Regional Microstructural Integrity in Relation to Gait Speed: The Atherosclerosis Risk in Communities Study

Brain imaging-based biomarkers of neuropathology are associated with mobility in older adults, but the relation of regional microstructural integrity to gait speed in the context of a broader neuropathological profile is less understood. We examined cross-sectional associations of microstructural integrity with 4-meter usual-pace gait speed (cm/s) in a subsample of ARIC study participants who completed 3T MRI brain scans with diffusion tensor imaging(2011-13; n=1785; mean age=76.2±5.3, 60% Female, 28% Black). We considered total brain and six regional averages of fractional anisotropy (FA; lower=worse microstructural integrity) and mean diffusivity (MD; higher=worse microstructural integrity): frontal, temporal, parietal, occipital, anterior and posterior corpus callosum. Associations were tested in multivariable linear regression models adjusted for demographics, cardiovascular risk factors, and with and without additional neuropathological indices: total brain volume, white matter hyperintensities, infarcts, and microhemorrhages. When modeled separately, all neuropathology indices were associated with slower gait speed. Every standard deviation(SD) higher total brain FA was associated with +2.56 cm/s gait speed (95%CI: 1.64,3.48) and every SD higher MD was associated with -4.27 cm/s gait speed (-5.34,-3.20). All regional estimates were comparable. When adjusted for all other neuropathology indices, only posterior corpus callosum FA (β=1.72; 0.67,2.77), total MD (β=-1.63; -3.02,-0.25), frontal lobe MD (β=-1.76; -3.03,-0.48), and temporal lobe MD (β=-1.40; -2.78,-0.02) remained significantly associated with gait speed. Microstructural integrity is an informative measure of brain pathology in relation to mobility, with regional measures tied to executive, memory, and somatosensory function being more informative when a broader neuropathological profile is considered.

Birth Cohorts and Cognitive Reserve Influence Cognitive Performances in Older Adults

Background: Evidence suggests birth cohort differences in cognitive performance of older adults. Proxies of cognitive reserve (CR), such as educational attainment and occupational complexity, could also partly account for these differences as they are influenced by the sociocultural environment of the birth cohorts. Objective: To predict cognitive performance using birth cohorts and CR and examine the moderating influence of CR on cognitive performance and structural brain health association. Methods: Using ADNI data (n = 1628), four birth cohorts were defined (1915–1928; 1929–1938; 1939–1945; 1946–1964). CR proxies were education, occupational complexity, and verbal IQ. We predicted baseline cognitive performances (verbal episodic memory; language and semantic memory; attention capacities; executive functions) using multiple linear regressions with CR, birth cohorts, age, structural brain health (total brain volume; total white matter hyperintensities volume) and vascular risk factors burden as predictors. Sex and CR interactions were also explored. Results: Recent birth cohorts, higher CR, and healthier brain structures predicted better performance in verbal episodic memory, language and semantic memory, and attention capacities, with large effect sizes. Better performance in executive functions was predicted by a higher CR and a larger total brain volume, with a small effect size. With equal score of CR, women outperformed men in verbal episodic memory and language and semantic memory in all cohorts. Higher level of CR predicted better performance in verbal episodic memory, only when total brain volume was lower. Conclusion: Cohort differences in cognitive performance favor more recent birth cohorts and suggests that this association may be partly explained by proxies of CR.

Cerebrovascular Collateral Integrity in Pediatric Large Vessel Occlusion: Analysis of the Save ChildS Study

Background and Objectives:Robust cerebrovascular collaterals in adult stroke patients have been associated with longer treatment windows, better recanalization rates, and improved outcomes. No studies have investigated the role of collaterals in pediatric stroke. The primary aim was to determine whether favorable collaterals correlated with better radiographic and clinical outcomes in children with ischemic stroke who underwent thrombectomy.Methods:This study analyzed a subset of children enrolled in SaveChildS, a retrospective, multi-center, observational cohort study of 73 pediatric stroke patients who underwent thrombectomy between 2000-2018 at 27 US and European centers. Included patients had baseline angiographic imaging and follow-up modified Rankin Scale scores available for review. Posterior circulation occlusions were excluded. Cerebrovascular collaterals were graded on acute neuroimaging by 2 blinded neuroradiologists according to the Tan collateral score, where favorable collaterals are defined as >50% filling and unfavorable collaterals as <50% filling distal to the occluded vessel. Collateral status was correlated with clinical and neuroimaging characteristics and outcomes. Between-group comparisons were performed using the Wilcoxon rank-sum test for continuous variables or Fisher’s exact test for binary variables.Results:Thirty-three children (mean age 10.9 [SD±4.9]) years were included; 14 (42.4%) had favorable collaterals. Median final stroke volume as a percent of total brain volume (TBV) was significantly lower in patients with favorable collaterals (1.35% [IQR 1.14-3.76] versus 7.86% [1.54-11.07], p=0.049). Collateral status did not correlate with clinical outcome, infarct growth or final ASPECTS in our cohort. Patients with favorable collaterals had higher baseline ASPECTS (7 [IQR 6-8] versus 5.5 [4-6], p=0.006), smaller baseline ischemic volume (1.57% TBV [IQR 1.09-2.29] versus 3.42% TBV [IQR 1.26-5.33], p=0.035) and slower early infarct growth rate (2.4 mL/hr [IQR 1.5-5.1] versus 10.4 mL/hr [IQR 3.0-30.7], p=0.028).Discussion:Favorable collaterals were associated with smaller final stroke burden and slower early infarct growth rate, but not with better clinical outcome in our study. Prospective studies are needed to determine the impact of collaterals in childhood stroke.Classification of Evidence:This study provides Class II evidence that in children with ischemic stroke undergoing thrombectomy, favorable collaterals were associated with improved radiographic outcomes but not with better clinical outcomes.

Cerebral Blood Flow, Brain Volume, and Age Predicts Executive Function in Sickle Cell Anemia

Introduction: Individuals with sickle cell anemia (SCA) are at increased risk for deficits in multiple domains of neurocognitive functioning, including executive functions. In addition to assessing the effects of silent cerebral infarcts (SCI) and stroke on cognition, prior research has focused on hemoglobin and transcranial Doppler velocity as hemodynamic correlates. Recent studies have begun to use more precise measures of blood delivery to the brain (e.g., cerebral blood flow; CBF) to determine more sensitive indicators of cognitive risk prior to neurological injury. Nevertheless, empirical and meta-analytic findings suggest that these deficits increase with age, which can have broad impact on psychosocial functioning, including self-management and navigation through the transition from pediatric to adult medical care. This study aimed to assess brain volume as a mediator of the association between CBF and executive functioning in a sample of individuals with SCA. The secondary aim was to assess age as a moderator of hemodynamic and structural correlates of executive function. Methods: Children, adolescents, and young adults with SCA were enrolled prospectively. Each participant received a 3-Tesla non-contrast magnetic resonance imaging and magnetic resonance angiography of the brain, and a neurological examination by the study neurologist. Gray matter CBF was calculated from pseudo-continuous arterial spin labeling using the solution to the flow-modified Bloch equation after correcting for individual hematocrit. Three measures of brain volume were also computed from 3D-T1 images using Freesurfer version 7.1.1: total brain volume, gray matter volume, and white matter volume was calculated as the difference between the two. At a separate study visit, participants completed an age-appropriate Wechsler Working Memory Index (WMI). Pearson correlations assessed bivariate associations among variables, SPSS PROCESS macro was used to test gray matter volume as a mediator in the relation between CBF and working memory, and multiple linear regression analyses tested age as a moderator of the impact of CBF and brain volume on working memory. Results: Twenty-nine children and adolescents (ages 6 to 17 years) and 25 adults (ages 18 to 31 years) were enrolled. Five participants were excluded from analyses due to history of overt stroke that resulted in significant brain volume loss. Of 49 included participants, 20 had SCIs. Working memory was inversely correlated with age (r = -.30, p = .037) and CBF (r = -.36, p = .013), such that WMI decreased cross-sectionally with older age and higher CBF. Working memory was positively correlated with gray matter volume (r = .42, p = .002); however, it was not related to white matter volume (r = -.05, p = .715) or total brain volume (r = -.07, p = .642). Finally, patient age was positively correlated with CBF (r = .36, p = .014), but the association of age with gray matter volume did not reach statistical significance (r = -.27, p = .065). Analyses in Figure 1 show that although CBF and gray matter were directly related to working memory (path c and path b, respectively), gray matter volume did not mediate the association between CBF and working memory (path a*b). However, regression analyses (Table 1) showed that age moderated the association between gray matter volume and working memory, such that there was only a significant relation in children and adolescents. This association did not exist for young adults (Figure 2). Conclusions: Neurocognitive assessments has been cited as an important standard of care for children and adolescents with SCA. Given the increase in deficits with age, and the increase in mortality after transferring from pediatric to adult care, monitoring executive function abilities and potential impact on self-management should continue into adulthood. Findings from the current study provide preliminary evidence that cerebral hemodynamic compensation with elevated CBF may be insufficient to prevent gray matter volume loss in children and adolescents and decline in working memory ability. Some limitations of the current study include small sample size and whole brain gray and white matter volumes as opposed to specific regions relevant to executive functions (e.g., prefrontal cortex); however, findings from global measures provide promising evidence for future research on hemodynamic and structural predictors of executive function in SCA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

RADT-20. SINGLE INSTITUTION REVIEW OF LARGE VOLUME HIGH GRADE GLIOMA PATIENTS TREATED WITH RADIOTHERAPY

AIM Not uncommonly, we come across significantly large high grade glioma cases (HGGs). With standard delineation protocols, we end up irradiating a large volume of normal brain. Emami & QUANTEC data define normal brain tolerance doses, however they are often of limited use in clinic practice. Thus, we reviewed our patients with significant tumor volumes to derive a safe dose/ volume level for brain. METHODOLOGY Patients with HGGs over the last 3 years were extracted from Mosaiq™ information system. The output was sorted with respect to clinical target volumes from lowest to highest. The top 25 percentile i.e. patients with a CTV of &gt; 412cc (n=53) were identified for this study. Data was collected with respect to clinical, tumor characteristics and radiotherapy parameters. RESULTS Median age of population was 53 and majority (n=38) were males. Nine patients had multi-focal tumors while six had bilateral extension. Majority of the study group had Glioblastoma Multiforme (n=44), whereas 6 had Grade 3 tumors. Most of the patients could only have a biopsy (n=27). Molecular profile showed 42 were Isocitrate-Dehydrogenase negative and 26 were unmethylated tumors. Stupp’s & Perry’s regimen were the commonly used protocols, however patients (n=7) with significant volumes near critical structures were treated with doses in the range of 50.4 – 55Gy in 30 fractions. The CTV volumes in the population ranged from 412 – 1223 cc while total brain volume range was 1112 – 1667 cc. Median of 43.5% of brain volume was covered in the PTV, while median of 5% of brain volume outside the PTV was treated to BED2 of 100Gy. Median survival was 12.4 months. CONCLUSION Our study shows reasonable tolerance of radiotherapy doses of &gt; 50 Gy to larger volumes of brain. We propose a multi-center collaborative study to derive a new standardized dose volume tolerance.

RADT-08. A VOLUMETRIC ANALYSIS OF STEREOTACTIC RADIOSURGERY LOW DOSE VOLUMES IN PREVENTING FUTURE BRAIN METASTASES

PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions. MATERIALS AND METHODS Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was &lt; 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level. RESULTS The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094). CONCLUSION We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.