Longitudinal MRI Research Articles

The shape of things to come. Mapping spatiotemporal progression of striatal morphology in Huntington disease: The IMAGE-HD study

Mapping the spatiotemporal progression of neuroanatomical change in Huntington's Disease (HD) is fundamental to the development of bio-measures for prognostication. Statistical shape analysis to measure the striatum has been performed in HD, however there have been a limited number of longitudinal studies. To address these limitations, we utilised the Spherical Harmonic Point Distribution Method (SPHARM-PDM) to generate point distribution models of the striatum in individuals, and used linear mixed models to test for localised shape change over time in pre-manifest HD (pre-HD), symp-HD (symp-HD) and control individuals. Longitudinal MRI scans from the IMAGE-HD study were used (baseline, 18 and 30 months). We found significant differences in the shape of the striatum between groups. Significant group-by-time interaction was observed for the putamen bilaterally, but not for caudate. A differential rate of shape change between groups over time was observed, with more significant deflation in the symp-HD group in comparison with the pre-HD and control groups. CAG repeats were correlated with bilateral striatal shape in pre-HD and symp-HD. Robust statistical analysis of the correlates of striatal shape change in HD has confirmed the suitability of striatal morphology as a potential biomarker correlated with CAG-repeat length, and potentially, an endophenotype.

Quantifying Typical Progression of Adolescent Idiopathic Scoliosis: Longitudinal Three-Dimensional MRI Measures of Disc and Vertebral Deformities.

Prospective cohort study. Detail typical three-dimensional segmental deformities and their rates of change that occur within developing adolescent idiopathic scoliosis (AIS) spines over multiple timepoints. AIS is a potentially progressive deforming condition that occurs in three-dimensions of the scoliotic spine during periods of growth. However, there remains a gap for multiple time-point segmental deformity analysis in AIS cohorts during development. Thirty-six female patients with Lenke 1 AIS curves underwent two to six sequential MRIs. Scans were reformatted to produce images in orthogonal dimensions. Wedging angles and rotatory values were measured for segmental elements within the major curve. Two-tailed, paired t-tests compared morphological differences between sequential scans. Rates of change were calculated for variables given the actual time between successive scans. Pearson correlation coefficients were determined for multi-dimensional deformity measurements. Vertebral bodies (VBs) were typically coronally convexly wedged, locally lordotic, convexly axially rotated and demonstrated evidence of local mechanical torsion. Between first and final scans, apical measures of coronal wedging and axial rotation were all greater in both vertebral and intervertebral disc (IVD) morphology than non-apical regions (all reaching differences where P<0.05). No measures of sagittal deformity demonstrated a statistically significant change between scans. Cross-planar correlations were predominantly apparent between coronal and axial planes, with sagittal plane parameters rarely correlating across dimensions. Rates of segmental deformity changes between earlier scans were characterised by coronal plane convex wedging and convexly directed axial rotation. The major locally lordotic deformity changes which did occur in the sagittal plane were static between scans. This novel investigation documented a three-dimensional characterisation of segmental elements of the growing AIS spine and reported these changes across multiple timepoints. Segmental elements are typically deformed from initial presentation and subsequent changes occur in separate orthogonal planes at unique times.

P10.04.B LONGITUDINAL [18F ]FET-PET-BASED IMAGING AND PROFILING OF PDGFB-DRIVEN EXPERIMENTAL GLIOMA USING THE RCAS-TVA SYSTEM

Abstract BACKGROUND Glioblastoma are aggressive and incurable primary tumors of the central nervous system. As patients present with already established tumors, longitudinal imaging by MRI and [18F]FET-PET in human glioblastoma for characterizing temporal and spatial metabolic alterations is only possible to characterize alterations during therapy, but not during tumor evolution. In this regard, genetically engineered preclinical models are very relevant. The replication-competent avian sarcoma-leukosis virus (RCAS)/tumor virus receptor-A (tva) system provides a high grade of spatial and temporal control of somatic gene delivery in vivo. In this study, we used longitudinal MRI and [18F]FET-PET to characterize the evolution and growth of platelet-derived growth factor B (PDGFB)-driven glioma model using the RCAS-tva system. MATERIAL AND METHODS DF-1 cells transfected with PDGFB were implanted into adult 129S.Tg(NES-TVA)-Cdkn2a−/− mice intracranially. Mice received MRI twice and [18F]FET-PET measurements once per week. Longitudinal growth pattern and [18F]FET-PET uptake were assessed and analyzed. We measured symptom-free survival and performed immunohistochemistry on collected tumor tissue samples. RESULTS We observed robust tumor formation with highly reproducible symptom-free survival times of treatment-naïve experimental animals. Contrast-enhanced MRI volumetry revealed exponential growth dynamics starting around day 25 after DF-1 inoculation. Here, the PDGFB-driven gliomas present an escalating [18F]FET-PET uptake as well as increasing BBB permeability over time. These imaging features match the clinical scenario, which underlines the translational relevance of this model. Histology corroborated the imaging findings and an immunogenic glioma-associated microenvironment. CONCLUSION These data provide further valuable insights into this RCAS/tva-based PDGFB-driven murine glioma model and advocates for an imaging-stratified design of preclinical therapeutic interventions.

The integrity of dopaminergic and noradrenergic brain regions is associated with different aspects of late-life memory performance

Changes in dopaminergic neuromodulation play a key role in adult memory decline. Recent research has also implicated noradrenaline in shaping late-life memory. However, it is unclear whether these two neuromodulators have distinct roles in age-related cognitive changes. Here, combining longitudinal MRI of the dopaminergic substantia nigra–ventral tegmental area (SN-VTA) and noradrenergic locus coeruleus (LC) in younger (n = 69) and older (n = 251) adults, we found that dopaminergic and noradrenergic integrity are differentially associated with memory performance. While LC integrity was related to better episodic memory across several tasks, SN-VTA integrity was linked to working memory. Longitudinally, we found that older age was associated with more negative change in SN-VTA and LC integrity. Notably, changes in LC integrity reliably predicted future episodic memory. These differential associations of dopaminergic and noradrenergic nuclei with late-life cognitive decline have potential clinical utility, given their degeneration in several age-associated diseases.

Dorsal visual stream and LIMK1: hemideletion, haplotype, and enduring effects in children with Williams syndrome

BackgroundWilliams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed “hypersociability”) and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS.MethodsWe tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5–22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population.ResultsIPS structural (p < 10−4 FDR corrected) and functional (p < .05 FDR corrected) anomalies previously reported in adults were confirmed in children with WS, and, consistent with an enduring genetic mechanism, were stable from early childhood into adulthood. In the short hemideletion cohort, IPS deficits similar to those in WS were found, although effect sizes were smaller than those found in WS for both structural and functional findings. Finally, in each of the two general population cohorts stratified by LIMK1 haplotype, IPS gray matter volume (pdiscovery < 0.05 SVC, preplication = 0.0015) and imputed LIMK1 expression (pdiscovery = 10−15, preplication = 10−23) varied according to LIMK1 haplotype.ConclusionsThis work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders.

Early prediction of pathologic complete response of breast cancer after neoadjuvant chemotherapy using longitudinal ultrafast dynamic contrast-enhanced MRI

PurposeThe purpose of this study was to evaluate the temporal trends of ultrafast dynamic contrast-enhanced (DCE)-MRI during neoadjuvant chemotherapy (NAC) and to investigate whether the changes in DCE-MRI parameters could early predict pathologic complete response (pCR) of breast cancer. Materials and methodsThis longitudinal study prospectively recruited consecutive participants with breast cancer who underwent ultrafast DCE-MRI examinations before treatment and after two, four, and six NAC cycles between February 2021 and February 2022. Five ultrafast DCE-MRI parameters (maximum slope [MS], time-to-peak [TTP], time-to-enhancement [TTE], peak enhancement intensity [PEI], and initial area under the curve in 60 s [iAUC]) and tumor size were measured at each timepoint. The changes in parameters between each pair of adjacent timepoints were additionally measured and compared between the pCR and non-pCR groups. Longitudinal data were analyzed using generalized estimating equations. The performance for predicting pCR was assessed using area under the receiver operating characteristic curve (AUC). ResultsSixty-seven women (mean age, 50 ± 8 [standard deviation] years; age range: 25–69 years) were included, 19 of whom achieved pCR. MS, PEI, iAUC, and tumor size decreased, while TTP increased during NAC (all P < 0.001). The AUC (0.92; 95% confidence interval [CI]: 0.83–0.97) of the model incorporating ultrafast DCE-MRI parameter change values (from timepoints 1 to 2) and clinicopathologic characteristics was greater than that of the clinical model (AUC, 0.79; 95% CI: 0.68–0.88) and ultrafast DCE-MRI parameter model at timepoint 2 when combined with clinicopathologic characteristics (AUC, 0.82; 95% CI: 0.71–0.90) (P = 0.01 and 0.02). ConclusionEarly changes in ultrafast DCE-MRI parameters after NAC combined with clinicopathologic characteristics could serve as predictive markers of pCR of breast cancer.

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia.

Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline. We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p < 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p < 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p < 0.001), but conversion-free follow-up time varied greatly across participants. NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.

Microstructural Alterations in Tract Development in College Football and Volleyball Players: A Longitudinal Diffusion MRI Study.

Repeated impacts in high-contact sports such as American football can affect the brain's microstructure, which can be studied using diffusion MRI. Most imaging studies are cross-sectional, do not include low-contact players as controls, or lack advanced tract-specific microstructural metrics. We aimed to investigate longitudinal changes in high-contact collegiate athletes compared with low-contact controls using advanced diffusion MRI and automated fiber quantification. We examined brain microstructure in high-contact (football) and low-contact (volleyball) collegiate athletes with up to 4 years of follow-up. Inclusion criteria included university and team enrollment. Exclusion criteria included history of neurosurgery, severe brain injury, and major neurologic or substance abuse disorder. We investigated diffusion metrics along the length of tracts using nested linear mixed-effects models to ascertain the acute and chronic effects of subconcussive and concussive impacts, and associations between diffusion changes with clinical, behavioral, and sports-related measures. Forty-nine football and 24 volleyball players (271 total scans) were included. Football players had significantly divergent trajectories in multiple microstructural metrics and tracts. Longitudinal increases in fractional anisotropy and axonal water fraction, and decreases in radial/mean diffusivity and orientation dispersion index, were present in volleyball but absent in football players (all findings |T-statistic|> 3.5, p value <0.0001). This pattern was present in the callosum forceps minor, superior longitudinal fasciculus, thalamic radiation, and cingulum hippocampus. Longitudinal differences were more prominent and observed in more tracts in concussed football players (n = 24, |T|> 3.6, p < 0.0001). An analysis of immediate postconcussion scans (n = 12) demonstrated a transient localized increase in axial diffusivity and mean/radial kurtosis in the uncinate and cingulum hippocampus (|T| > 3.7, p < 0.0001). Finally, within football players, those with high position-based impact risk demonstrated increased intracellular volume fraction longitudinally (T = 3.6, p < 0.0001). The observed longitudinal changes seen in football, and especially concussed athletes, could reveal diminished myelination, altered axonal calibers, or depressed pruning processes leading to a static, nondecreasing axonal dispersion. This prospective longitudinal study demonstrates divergent tract-specific trajectories of brain microstructure, possibly reflecting a concussive and repeated subconcussive impact-related alteration of white matter development in football athletes.

Use of longitudinal functional MRI to demonstrate translocation of language function in patients with brain tumors.

The ability of functional MRI (fMRI) to localize patient-specific eloquent areas has proved worthwhile in efforts to maximize resection while minimizing risk of iatrogenic damage in patients with brain tumors. Although cortical reorganization has been described, the frequency of its occurrence and the factors that influence incidence are not well understood. The authors investigated changes in language laterality between 2 fMRI studies in patients with brain tumors to elucidate factors contributing to cortical reorganization. The authors analyzed 33 patients with brain tumors involving eloquent language areas who underwent 2 separate presurgical, language task-based fMRI examinations (fMRI1 and fMRI2). Pathology consisted of low-grade glioma (LGG) in 15, and high-grade glioma (HGG) in 18. The mean time interval between scans was 35 ± 38 months (mean ± SD). Regions of interest were drawn for Broca's area (BA) and the contralateral BA homolog. The laterality index (LI) was calculated and categorized as follows: > 0.2, left dominance; 0.2 to -0.2, codominance; and < -0.2, right dominance. Translocation of language function was defined as a shift across one of these thresholds between the 2 scans. Comparisons between the 2 groups, translocation of language function (reorganized group) versus no translocation (constant group), were performed using the Mann-Whitney U-test. Nine (27%) of 33 patients demonstrated translocation of language function. Eight of 9 patients with translocation had tumor involvement of BA, compared to 5/24 patients without translocation (p < 0.0001). There was no difference in LI between the 2 groups at fMRI1. However, the reorganized group showed a decreased LI at fMRI2 compared to the constant group (-0.1 vs 0.53, p < 0.01). The reorganized cohort showed a significant difference between LI1 and LI2 (0.50 vs -0.1, p < 0.0001) whereas the constant cohort did not. A longer time interval was found in the reorganized group between fMRI1 and fMRI2 for patients with LGG (34 vs 107 months, p < 0.002). Additionally, the reorganized cohort had a greater proportion of local tumor invasion into eloquent areas at fMRI2 than the constant group. Aphasia was present following fMRI2 in 13/24 (54%) patients who did not exhibit translocation, compared to 2/9 (22%) patients who showed translocation. Translocation of language function in patients with brain tumor is associated with tumor involvement of BA, longer time intervals between scans, and is seen in both LGG and HGG. The reduced incidence of aphasia in the reorganized group raises the possibility that reorganization supports the conservation of language function. Therefore, longitudinal fMRI is useful because it may point to reorganization and could affect therapeutic planning for patients.

Differential and correlational tractography as tract-based biomarkers in mild traumatic brain injury: A longitudinal MRI study.

We evaluated the fiber bundles in mild traumatic brain injury (mTBI) patients using differential and correlational tractography in a longitudinal analysis. Diffusion MRI data were acquired in 34 mTBI patients at 7 days (acute stage) and 3 months or longer (chronic stage) after mTBI. Trail Making Test A (TMT-A) and Digital Symbol Substitution Test changes were used to evaluate the cognitive performance. Longitudinal correlational tractography showed decreased anisotropy in the corpus callosum during the chronic mTBI stage. The changes in anisotropy in the corpus callosum were significantly correlated with the changes in TMT-A (false discovery rate [FDR] = 0.000094). Individual longitudinal differential tractography found that anisotropy decreased in the corpus callosum in 30 mTBI patients. Group cross-sectional differential tractography found that anisotropy increased (FDR = 0.02) in white matter in the acute mTBI patients, while no changes occurred in the chronic mTBI patients. Our study confirms the feasibility of using correlational and differential tractography as tract-based monitoring biomarkers to evaluate the disease progress of mTBI, and indicates that normalized quantitative anisotropy could be used as a biomarker to monitor the injury and/or repairs of white matter in individual mTBI patients.

The added value of spinal cord lesions to disability accrual in multiple sclerosis.

Spinal cord MRI is not routinely performed for multiple sclerosis (MS) monitoring. Here, we explored whether spinal cord MRI activity offers any added value over brain MRI activity for clinical outcomes prediction in MS. This is a retrospective, monocentric study including 830 MS patients who underwent longitudinal brain and spinal cord MRI [median follow-up 7years (range: < 1-26)]. According to the presence (or absence) of MRI activity defined as at least one new T2 lesion and/or gadolinium (Gd) enhancing lesion, each scan was classified as: (i) brain MRI negative/spinal cord MRI negative; (ii) brain MRI positive/spinal cord MRI negative; (iii) brain MRI negative/spinal cord MRI positive; (iv) brain MRI positive/spinal cord MRI positive. The relationship between such patterns and clinical outcomes was explored by multivariable regression models. When compared with the presence of brain MRI activity alone: (i) Gd + lesions in the spine alone and both in the brain and in the spinal cord were associated with an increased risk of concomitant relapses (OR = 4.1, 95% CI 2.4-7.1, p < 0.001 and OR = 4.9, 95% CI 4.6-9.1, p < 0.001, respectively); (ii) new T2 lesions at both locations were associated with an increased risk of disability worsening (HR = 1.4, 95% CI = 1.0-2.1, p = 0.05). Beyond the presence of brain MRI activity, new spinal cord lesions are associated with increased risk of both relapses and disability worsening. In addition, 16.1% of patients presented asymptomatic, isolated spinal cord activity (Gd + lesions). Monitoring MS with spinal cord MRI may allow a more accurate risk stratification and treatment optimization.

Four-dimensional mapping of dynamic longitudinal brain subcortical development and early learning functions in infants

Brain subcortical structures are paramount in many cognitive functions and their aberrations during infancy are predisposed to various neurodevelopmental and neuropsychiatric disorders, making it highly essential to characterize the early subcortical normative growth patterns. This study investigates the volumetric development and surface area expansion of six subcortical structures and their associations with Mullen scales of early learning by leveraging 513 high-resolution longitudinal MRI scans within the first two postnatal years. Results show that (1) each subcortical structure (except for the amygdala with an approximately linear increase) undergoes rapid nonlinear volumetric growth after birth, which slows down at a structure-specific age with bilaterally similar developmental patterns; (2) Subcortical local area expansion reveals structure-specific and spatiotemporally heterogeneous patterns; (3) Positive associations between thalamus and both receptive and expressive languages and between caudate and putamen and fine motor are revealed. This study advances our understanding of the dynamic early subcortical developmental patterns.

1353-P: Glycemic Control and Longitudinal Brain MRI in Children Diagnosed with Diabetes before 3 Years of Age (CLARiFY Study)

Though early childhood onset of type 1 diabetes (T1D) is associated with brain development alterations, the affected brain regions and role of glycemic control are unknown. We aimed to examine associations between of HbA1c mean and variability and brain structure in a cohort of children diagnosed with T1D before 3 years of age. We recruited children presenting to a tertiary hospital in Australia from 1990-1992 in the Cognition and Longitudinal Assessment of Risk Factors over 30 Years (CLARiFY) Study. HbA1c was serially measured over 30 years after T1D diagnosis. Brain MRI was performed at ~12- and 30-years post diagnosis. We used linear mixed effects modelling to examine associations between mean HbA1c and HbA1c coefficient of variation and brain MRI structural measures. Data were available for 10 subjects (6 female). The mean age of diabetes diagnosis was 1.9 years. The mean HbA1c at 12- and 30-years post diagnosis was 8.5%. We did not find an association between mean HbA1c and any of the brain structures. Greater HbA1c coefficient of variation was associated with less sub-cortical gray matter volume (β=-41537, p=0.006) and greater cortical thickness (β=0.47, p=0.02) but not other brain structure measures (Table 1). In these preliminary analyses, we found HbA1c variability associated with measures of gray matter. Work is ongoing to confirm and understand the implications of these results. Disclosure C.Moran: None. O.Gbadeyan: None. A.Brown: None. S.A.Sakowski: None. V.Srikanth: None. F.Cameron: None. E.A.Northam: None. E.L.Feldman: None. R.Beare: None. Funding National Institutes of Health (R01DK129320)

Network anatomy in logopenic variant of primary progressive aphasia.

The logopenic variant of primary progressive aphasia (lvPPA) is a neurodegenerative syndrome characterized linguistically by gradual loss of repetition and naming skills resulting from left posterior temporal and inferior parietal atrophy. Here, we sought to identify which specific cortical loci are initially targeted by the disease (epicenters) and investigate whether atrophy spreads through predetermined networks. First, we used cross-sectional structural MRI data from individuals with lvPPA to define putative disease epicenters using a surface-based approach paired with an anatomically fine-grained parcellation of the cortical surface (i.e., HCP-MMP1.0 atlas). Second, we combined cross-sectional functional MRI data from healthy controls and longitudinal structural MRI data from individuals with lvPPA to derive the epicenter-seeded resting-state networks most relevant to lvPPA symptomatology and ascertain whether functional connectivity in these networks predicts longitudinal atrophy spread in lvPPA. Our results show that two partially distinct brain networks anchored to the left anterior angular and posterior superior temporal gyri epicenters were preferentially associated with sentence repetition and naming skills in lvPPA. Critically, the strength of connectivity within these two networks in the neurologically-intact brain significantly predicted longitudinal atrophy progression in lvPPA. Taken together, our findings indicate that atrophy progression in lvPPA, starting from inferior parietal and temporoparietal junction regions, predominantly follows at least two partially nonoverlapping pathways, which may influence the heterogeneity in clinical presentation and prognosis.

ATRT-03. THE ORAL IRON-MIMETIC GALLIUM MALTOLATE INHIBITS ATRT IN VIVO – IMAGING AND HISTOLOGICAL CHARACTERIZATION

Abstract BACKGROUND Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of many solid cancers, including brain tumors. Our published studies show that the ferrobiology of brain tumors can be exploited for therapeutic purposes. Here, we further demonstrate the inhibitory effects of oral gallium maltolate (GaM) in pediatric ATRT in vivo. METHODS Pediatric CHLA-266 ATRT cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison (as indicator of tumor growth rate). RESULTS In concordance with our previous in vitro work, in vivo ATRT xenografts were found to be highly sensitive to oral GaM. Median overall survival was 89 days in the control group and 170 days in the treatment group (p=0.011). GaM-treated xenograft tumors grew at a significantly slower rate than control tumors (p&amp;lt;0.0001). On MRI, untreated ATRT xenograft tumors, as their clinical counterparts, tended to localize near the ventricle and occasionally invade it. Histologically, xenograft tumors in our rat model recapitulated the histological features of human ATRT. A significant reduction in MIB-1% and mitotic index (p&amp;lt;0.001 and p&amp;lt;0.05, respectively) was seen in the treatment group. Transferrin receptor and H-ferritin expression in GaM-treated tumors illustrated cellular iron deprivation. CONCLUSION Monotherapy with GaM profoundly inhibited ATRT growth and prolonged survival in vivo.

HGG-06. CHARACTERIZATION OF THE EFFECT OF THE ORAL IRON-MIMETIC GALLIUM MALTOLATE ON PEDIATRIC GLIOBLASTOMA GROWTH IN VIVO

Abstract BACKGROUND Glioblastoma (GBM) is a highly aggressive CNS tumor that is associated with poor outcome. This dire prognosis is due in part to its poor response to the limited treatment options available. Iron and iron proteins play a key role in the growth of brain tumors, with our published studies showing that the ferrobiology of adult GBM can be exploited for therapeutic purposes. Here, we further elucidate the inhibitory effects of oral gallium maltolate (GaM) in pediatric GBM in vivo. METHODS Pediatric SJ-GBM2 cells were stereotactically implanted into the right striatum of male athymic rats. Advanced MR imaging at 9.4T was carried out weekly starting two weeks after implantation. Daily oral GaM (50mg/kg) or vehicle were provided on tumor confirmation. Longitudinal advanced MRI parameters were processed for enhancing tumor ROIs in OsiriX 8.5.1 (lite) with Imaging Biometrics Software (Imaging Biometrics LLC). Statistical analyses included Kaplan-Meier survival plots, linear mixed model comparisons, and t-statistic for slopes comparison. RESULTS The sensitivity of the in vivo pediatric GBM xenografts to GaM was consistent with our previous in vitro work. Median overall survival was 21 days in the controls and 49 days in the treatment group (p=0.014). GaM-treated xenograft tumors grew significantly slower than control tumors (p=0.031). Histologically, xenograft tumors recapitulated the aggressive growth features of clinical specimens, such as invasive margins. Unlike adult GBM xenografts in our previous studies, pediatric GBM xenografts did not exhibit vessel normalization or a reduction in pro-angiogenic markers in response to GaM. Additionally, MIB-1% (p=0.6583) and mitotic index (p=0.7097) were not affected by treatment. Yet, transferrin receptor and H-ferritin expression patterns in GaM-treated tumors suggested cellular iron deprivation. CONCLUSION Monotherapy with GaM provides a significant survival benefit in pediatric GBM, and further studies are planned to optimize the benefit of GaM in pediatric GBM.

Automatic Assessment of Stereotactic Radiation Therapy Outcome in Brain Metastasis Using Longitudinal Segmentation on Serial MRI.

The standard clinical approach to assess the radiotherapy outcome in brain metastasis is through monitoring the changes in tumour size on longitudinal MRI. This assessment requires contouring the tumour on many volumetric images acquired before and at several follow-up scans after the treatment that is routinely done manually by oncologists with a substantial burden on the clinical workflow. In this work, we introduce a novel system for automatic assessment of stereotactic radiation therapy (SRT) outcome in brain metastasis using standard serial MRI. At the heart of the proposed system is a deep learning-based segmentation framework to delineate tumours longitudinally on serial MRI with high precision. Longitudinal changes in tumour size are then analyzed automatically to assess the local response and detect possible adverse radiation effects (ARE) after SRT. The system was trained and optimized using the data acquired from 96 patients (130 tumours) and evaluated on an independent test set of 20 patients (22 tumours; 95 MRI scans). The comparison between automatic therapy outcome evaluation and manual assessments by expert oncologists demonstrates a good agreement with an accuracy, sensitivity, and specificity of 91%, 89%, and 92%, respectively, in detecting local control/failure and 91%, 100%, and 89% in detecting ARE on the independent test set. This study is a step forward towards automatic monitoring and evaluation of radiotherapy outcome in brain tumours that can streamline the radio-oncology workflow substantially.

Longitudinal MRI-based radiomic model to complement sentinel lymph node biopsy assessment after neoadjuvant chemotherapy in initially clinically node-positive breast cancer: A multicentre, diagnostic study.

e13623 Background: The high false-negative rate (FNR) of sentinel lymph node biopsy (SLNB) alone results in unnecessary axillary lymph node dissection (ALND) in initially clinically node-positive (cN+) breast cancer after neoadjuvant chemotherapy (NAC). This study aimed to reduce the FNR by establishing a longitudinal MRI radiomics-assisted SLNB model compared with SLNB alone. Methods: We established and tested a machine learning algorithm (RMLM) based on pre-NAC, post-NAC and longitudinal MRI radiomics features to detect axillary complete response (ypN0) to neoadjuvant chemotherapy in cN+ breast cancer. In total, 234 eligible patients who underwent SLNB and ALND were retrospectively recruited in the primary cohort (PC), 723 patients were in external validation cohorts (EVC) 1-3, and 81 patients from two multicentre prospective clinical trials (ClinicalTrials.gov, NCT03154749, NCT04858529) were enrolled in the prospective validation cohort (PVC). The U test and least absolute shrinkage and selection operator with tenfold cross-validation were used to select the most significant features. The specificity and FNR of RMLM-assisted SLNB were compared with those of SLNB alone. Results: In the primary (n=234 patients), external validation (n=723) and prospective validation sets (n=81), RMLM achieved excellent performance in detecting metastatic axillary lymph nodes (AUC=0.938 in the primary cohort, 0.842-0.913 in the external cohorts, 0.865 in the prospective validation cohort). RMLM-assisted SLNB achieved an FNR of 4.96% in PC, 5.83-8.08% in EVC1-3, and 9.09% in the prospective validation cohort. The removal of more than two SLNs combined with RMLM could further reduce the FNR to 2.78% in PC, 3.28-7.27% in EVC1-3, and 6.67% in the prospective validation cohort. Conclusions: RMLM combined with SLNB provides a potential tool to evaluate residual nodal disease after NAC and reduce unnecessary ALND.

Elevated CSF GAP43 is driven by tau aggregation rather than β‐amyloid and neurodegeneration in Alzheimer’s disease

AbstractBackgroundCerebrospinal fluid (CSF) pre‐synaptic protein growth‐associated protein 43 (GAP43) appears to be closely linked to neurodegeneration and cognitive decline in Alzheimer’s disease (AD). However, it is not well characterized about the associations of CSF GAP43 with β‐amyloid (Aβ), tau, neurodegeneration and cognitive decline.MethodWe identified 790 Alzheimer’s Disease Neuroimaging Initiative participants with concurrent CSF GAP43, Aβ PET, CSF p‐Tau181, residual hippocampal volume (rHCV), 18F‐fluorodeoxyglucose (FDG) PET and cognitive assessments within one year. Among of them, 340 individuals had longitudinal CSF GAP43 measurements. We compared baseline and longitudinal changes of CSF GAP43 among different biological stages defined by Aβ PET (A), CSF p‐Tau181 (T) and rHCV (N) in addition to their associations with Aβ PET, CSF p‐Tau181, rHCV, FDG PET and cognition cross‐sectionally and longitudinally, controlling for age, sex, APOE‐ε4 status and diagnosis.ResultAmong different A/T and A/T/N profiles, we found all CSF p‐Tau181‐positive individuals had significant higher CSF GAP43 concentrations and faster rates of CSF GAP43 increases regardless of Aβ deposition and hippocampal atrophy (Figure 1). Furthermore, increased CSF p‐Tau181 rather than Aβ PET was related to higher baseline CSF GAP43 and faster rates of CSF GAP43 increases regardless of A/T profiles (Figure 2). In the subgroups of individuals with longitudinal MRI, FDG PET and cognition data, we found that higher CSF GAP43 concentrations (n = 377) and faster rates of GAP43 increases (n = 240) were associated with faster hippocampal atrophy, hypometabolism and cognitive decline (Figure 3).ConclusionThese findings imply that tau aggregation rather than Aβ pathology is driving pre‐synaptic loss measured by CSF GAP43, which subsequently contributes to hippocampal atrophy and hypometabolism, resulting in cognitive decline in AD. Altogether, CSF GAP43 may be considered for an extra biomarker beyond A/T/N biomarkers, which can provide new insights into underlying AD pathogenesis prior to neurodegeneration.

Longitudinal MRI-based fusion novel model to predict pathological complete response in breast cancer treated with neoadjuvant chemotherapy: A multicenter, retrospective study.

599 Background: Accurate identification of pCR to neoadjuvant chemotherapy (NAC) is important for determining appropriate surgery strategy and guiding the resection extent in breast cancer. However, a non-invasive tool to predict pCR accurately is lacking. Our study aims to develop ensemble learning models using longitudinal multiparametric MRI to predict pCR for each molecular subtype of breast cancer. Methods: In this study, all patients underwent pre-NAC and post-NAC MRI examinations, and we collected multiparametric MRI sequences. Post-operation pathologic results were used to determine the pathologic complete response (pCR). We extracted 14676 radiomics and 4096 deep learning features and calculated a set of additional delta-value features. Then in the primary cohort (n = 409), inter-class correlation coefficient test, U-test, Boruta and the least absolute shrinkage and selection operator (LASSO) regression were used to select the most optimal feature set for each subtype of breast cancer. Finally, 20, 15 and 13 features were selected to construct the models based on 5 specific algorithms with cross-validation method for predicting pCR in HR+/HER2-, HER2+ and TNBC subtypes. The ensemble learning strategy was used to integrate the single-modality models outputs and improve the prediction performance. The diagnostic performances of models were evaluated in the three external cohorts with lager sample size of patients (n = 343, 170 and 340, respectively). Results: A total of 1262 patients with breast cancer from four centers were enrolled in this study, and pCR rates were 10.6% (52/491), 54.3% (323/595) and 37.5% (66/176) in HR+/HER2-, HER2+ and TNBC subtype. After model development, the Multi-Layer Perception (MLP) neural network yields the best diagnostic performances in all subtypes and feature sets. In the three subtypes, the stacking model integrating pre-, post- and delta- models yielded the highest AUCs of 0.959, 0.974 and 0.958 in the primary cohort, and AUCs of 0.882-0.908, 0.896-0.929 and 0.837-0.901 in the three external validation cohorts, respectively. In all subtypes, the stacking model had accuracies of 85.0%-88.9%, sensitivities of 80.0%-86.3%, and specificities of 87.4%-91.5% in the external validation cohorts. Conclusions: Our study established a novel tool to predict the responses of breast cancer to NAC and achieve excellent performance. The models could help to determine post-NAC surgery strategy for patients with breast cancer.