Cortical asymmetries at different spatial hierarchies relate to phonological processing ability.

The ability to map speech sounds to corresponding letters is critical for establishing proficient reading. People vary in this phonological processing ability, which has been hypothesized to result from variation in hemispheric asymmetries within brain regions that support language. A cerebral lateralization hypothesis predicts that more asymmetric brain structures facilitate the development of foundational reading skills like phonological processing. That is, structural asymmetries are predicted to linearly increase with ability. In contrast, a canalization hypothesis predicts that asymmetries constrain behavioral performance within a normal range. That is, structural asymmetries are predicted to quadratically relate to phonological processing, with average phonological processing occurring in people with the most asymmetric structures. These predictions were examined in relatively large samples of children (N = 424) and adults (N = 300), using a topological asymmetry analysis of T1-weighted brain images and a decoding measure of phonological processing. There was limited evidence of structural asymmetry and phonological decoding associations in classic language-related brain regions. However, and in modest support of the cerebral lateralization hypothesis, small to medium effect sizes were observed where phonological decoding accuracy increased with the magnitude of the largest structural asymmetry across left hemisphere cortical regions, but not right hemisphere cortical regions, for both the adult and pediatric samples. In support of the canalization hypothesis, small to medium effect sizes were observed where phonological decoding in the normal range was associated with increased asymmetries in specific cortical regions for both the adult and pediatric samples, which included performance monitoring and motor planning brain regions that contribute to oral and written language functions. Thus, the relevance of each hypothesis to phonological decoding may depend on the scale of brain organization.

Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts.

High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.

The Stria Vascularis in Mice and Humans Is an Early Site of Age-Related Cochlear Degeneration, Macrophage Dysfunction, and Inflammation.

Age-related hearing loss, or presbyacusis, is a common degenerative disorder affecting communication and quality of life for millions of older adults. Multiple pathophysiologic manifestations, along with many cellular and molecular alterations, have been linked to presbyacusis; however, the initial events and causal factors have not been clearly established. Comparisons of the transcriptome in the lateral wall (LW) with other cochlear regions in a mouse model (of both sexes) of "normal" age-related hearing loss revealed that early pathophysiological alterations in the stria vascularis (SV) are associated with increased macrophage activation and a molecular signature indicative of inflammaging, a common form of immune dysfunction. Structure-function correlation analyses in mice across the lifespan showed that the age-dependent increase in macrophage activation in the stria vascularis is associated with a decline in auditory sensitivity. High-resolution imaging analysis of macrophage activation in middle-aged and aged mouse and human cochleas, along with transcriptomic analysis of age-dependent changes in mouse cochlear macrophage gene expression, support the hypothesis that aberrant macrophage activity is an important contributor to age-dependent strial dysfunction, cochlear pathology, and hearing loss. Thus, this study highlights the SV as a primary site of age-related cochlear degeneration and aberrant macrophage activity and dysregulation of the immune system as early indicators of age-related cochlear pathology and hearing loss. Importantly, novel new imaging methods described here now provide a means to analyze human temporal bones in a way that had not previously been feasible and thereby represent a significant new tool for otopathological evaluation.SIGNIFICANCE STATEMENT Age-related hearing loss is a common neurodegenerative disorder affecting communication and quality of life. Current interventions (primarily hearing aids and cochlear implants) offer imperfect and often unsuccessful therapeutic outcomes. Identification of early pathology and causal factors is crucial for the development of new treatments and early diagnostic tests. Here, we find that the SV, a nonsensory component of the cochlea, is an early site of structural and functional pathology in mice and humans that is characterized by aberrant immune cell activity. We also establish a new technique for evaluating cochleas from human temporal bones, an important but understudied area of research because of a lack of well-preserved human specimens and difficult tissue preparation and processing approaches.

Deep learning classification of reading disability with regional brain volume features.

Developmental reading disability is a prevalent and often enduring problem with varied mechanisms that contribute to its phenotypic heterogeneity. This mechanistic and phenotypic variation, as well as relatively modest sample sizes, may have limited the development of accurate neuroimaging-based classifiers for reading disability, including because of the large feature space of neuroimaging datasets. An unsupervised learning model was used to reduce deformation-based data to a lower-dimensional manifold and then supervised learning models were used to classify these latent representations in a dataset of 96 reading disability cases and 96 controls (mean age: 9.86 ± 1.56 years). A combined unsupervised autoencoder and supervised convolutional neural network approach provided an effective classification of cases and controls (accuracy: 77%; precision: 0.75; recall: 0.78). Brain regions that contributed to this classification accuracy were identified by adding noise to the voxel-level image data, which showed that reading disability classification accuracy was most influenced by the superior temporal sulcus, dorsal cingulate, and lateral occipital cortex. Regions that were most important for the accurate classification of controls included the supramarginal gyrus, orbitofrontal, and medial occipital cortex. The contribution of these regions reflected individual differences in reading-related abilities, such as non-word decoding or verbal comprehension. Together, the results demonstrate an optimal deep learning solution for classification using neuroimaging data. In contrast with standard mass-univariate test results, results from the deep learning model also provided evidence for regions that may be specifically affected in reading disability cases.

Probability Distributions for Associations Between Cognitive Screening and Pure-tone Thresholds in Older Adults.

OBJECTIVES: Lower general cognitive function is frequently reported in older adults with elevated pure-tone thresholds. Here, we examined reason(s) for this association, including whether this relationship is dependent on the frequency range or extent of hearing loss and cognitive screening performance. DESIGN: Linear regression was used to examine associations between better-ear pure-tone thresholds and Mini-Mental Status Exam (MMSE) performance in a cross-sectional sample of relatively healthy older adults (N = 508; 68% women, 60-89+ years; M age = 72). Quantile regression was also used to identify the ranges of 0.5 and 4.0 kHz thresholds and MMSE scores where these variables exhibited significant associations. RESULTS: MMSE scores and pure-tone thresholds exhibited small but significant associations, particularly for better-ear 0.5 kHz thresholds. This hearing threshold and cognitive screening association was present among participants with better hearing, including the oldest older adults. There was limited evidence for mediating health condition effects on this association. An item analysis of the MMSE revealed that the MMSE and pure-tone threshold associations were largely due to the delayed recall item of the MMSE. CONCLUSIONS: Together, the small effect results are consistent with the extant literature and suggest that there are multiple reasons for modest pure-tone threshold and cognitive screening performance associations.

Neural Presbyacusis in Humans Inferred from Age-Related Differences in Auditory Nerve Function and Structure.

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual differences in neural synchrony were the strongest predictor of speech recognition, such that poorer synchrony predicted poorer recognition of time-compressed speech and poorer speech recognition in noise for both younger and older adults. These results have broad clinical implications and are consistent with an interpretation that age-related atrophy at the level of the AN contributes to poorer neural synchrony and may explain some of the perceptual difficulties of older adults.SIGNIFICANCE STATEMENT Differences in auditory nerve (AN) pathophysiology may contribute to the large variations in hearing and communication abilities of older adults. However, current diagnostics focus largely on the increase in detection thresholds, which is likely because of the absence of indirect measures of AN function in standard clinical test batteries. Using novel metrics of AN function, combined with estimates of AN structure and auditory function, we identified age-related differences across measures that we interpret to represent age-related reductions in AN engagement and poorer neural synchrony. Structure-function associations are consistent with an explanation of AN deficits that arise from age-related atrophy of the AN. Associations between neural synchrony and speech recognition suggest that individual and age-related deficits in neural synchrony contribute to speech recognition deficits.

Evidence for cortical adjustments to perceptual decision criteria during word recognition in noise.

Extensive increases in cingulo-opercular frontal activity are typically observed during speech recognition in noise tasks. This elevated activity has been linked to a word recognition benefit on the next trial, termed "adaptive control," but how this effect might be implemented has been unclear. The established link between perceptual decision making and cingulo-opercular function may provide an explanation for how those regions benefit subsequent word recognition. In this case, processes that support recognition such as raising or lowering the decision criteria for more accurate or faster recognition may be adjusted to optimize performance on the next trial. The current neuroimaging study tested the hypothesis that pre-stimulus cingulo-opercular activity reflects criterion adjustments that determine how much information to collect for word recognition on subsequent trials. Participants included middle-age and older adults (N = 30; age = 58.3 ± 8.8 years; m ± sd) with normal hearing or mild sensorineural hearing loss. During a sparse fMRI experiment, words were presented in multitalker babble at +3 dB or +10 dB signal-to-noise ratio (SNR), which participants were instructed to repeat aloud. Word recognition was significantly poorer with increasing participant age and lower SNR compared to higher SNR conditions. A perceptual decision-making model was used to characterize processing differences based on task response latency distributions. The model showed that significantly less sensory evidence was collected (i.e., lower criteria) for lower compared to higher SNR trials. Replicating earlier observations, pre-stimulus cingulo-opercular activity was significantly predictive of correct recognition on a subsequent trial. Individual differences showed that participants with higher criteria also benefitted the most from pre-stimulus activity. Moreover, trial-level criteria changes were significantly linked to higher versus lower pre-stimulus activity. These results suggest cingulo-opercular cortex contributes to criteria adjustments to optimize speech recognition task performance.

Impact of Effortful Word Recognition on Supportive Neural Systems Measured by Alpha and Theta Power.

OBJECTIVES: The goal of this study was to use theta and alpha electroencephalography (EEG) frequency power and self-report measures to examine performance monitoring, cognitive inhibition, and perceived effort required for speech understanding in noise. It was hypothesized that with a linear increase in word recognition task difficulty, there would be a linear increase in listening effort and word recognition performance would decrease in the challenging conditions. In addition, theta and alpha power would have an inverted U-shape across easy to challenging listening conditions. The inverted U-shape would reflect the neural underpinnings of listening effort that cannot be measured by task performance alone. DESIGN: EEG data were collected in 34 normal-hearing adults (18 to 33 years old) during the Words-In-Noise (WIN) test, which was presented in sound field. EEG frequency data were averaged and analyzed at three frontal channels for theta power (4 to 8 Hz), which is thought to reflect performance monitoring, and three parietal channels for alpha power (8 to 12 Hz), which is thought to reflect cognitive inhibition. A ten-point visual analog scale was administered after each WIN signal-to-noise ratio (SNR) condition to capture self-reported required and invested listening effort (RLE and ILE, respectively). The WIN SNR conditions were presented in descending and random order. RESULTS: The SNR presentation (descending or random SNR) had a null effect on word recognition performance; however, presentation did have an effect on theta power, alpha power, and ILE. When controlling for presentation, there were significant effects of SNR and presentation on both theta and alpha frequency power. Theta and alpha power had an inverted U-shape as a function of SNR from easy to challenging, with peak power in the moderate SNR conditions. RLE and ILE both significantly increased as task difficulty increased as expected; however, RLE showed a stronger relation to task performance than ILE. Alpha power was a significant predictor of RLE, ILE, and WIN performance when controlling for SNR. CONCLUSIONS: The elevated theta and alpha power in the easy to moderate SNRs and alpha power predicting self-reported listening effort suggest the activation of supportive neural systems during word recognition that could be considered a marker of listening effort. Moreover, the measures of neural support systems and listening effort were independent from task performance, which is a key element to further understanding the neural bases for listening effort. In the context of the broader literature, these results are consistent with (1) a parietal alpha role in supporting inhibitory control to suppress irrelevant information and (2) a frontal theta role in supporting performance monitoring in difficult listening conditions where speech recognition is feasible.

Ultrasensitive, multiplexed chemoproteomic profiling with soluble activity-dependent proximity ligation.

Chemoproteomic methods can report directly on endogenous, active enzyme populations, which can differ greatly from measures of transcripts or protein abundance alone. Detection and quantification of family-wide probe engagement generally requires LC-MS/MS or gel-based detection methods, which suffer from low resolution, significant input proteome requirements, laborious sample preparation, and expensive equipment. Therefore, methods that can capitalize on the broad target profiling capacity of family-wide chemical probes but that enable specific, rapid, and ultrasensitive quantitation of protein activity in native samples would be useful for basic, translational, and clinical proteomic applications. Here we develop and apply a method that we call soluble activity-dependent proximity ligation (sADPL), which harnesses family-wide chemical probes to convert active enzyme levels into amplifiable barcoded oligonucleotide signals. We demonstrate that sADPL coupled to quantitative PCR signal detection enables multiplexed "writing" and "reading" of active enzyme levels across multiple protein families directly at picogram levels of whole, unfractionated proteome. sADPL profiling in a competitive format allows for highly sensitive detection of drug-protein interaction profiling, which allows for direct quantitative measurements of in vitro and in vivo on- and off-target drug engagement. Finally, we demonstrate that comparative sADPL profiling can be applied for high-throughput molecular phenotyping of primary human tumor samples, leading to the discovery of new connections between metabolic and proteolytic enzyme activity in specific tumor compartments and patient outcomes. We expect that this modular and multiplexed chemoproteomic platform will be a general approach for drug target engagement, as well as comparative enzyme activity profiling for basic and clinical applications.

Germline mutations in Black patients with ovarian, fallopian tube and primary peritoneal carcinomas.

OBJECTIVE: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions. METHODS: Fifty-one Black patients with invasive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were identified via institutional tissue banks over a 20-year time-period. Germline DNA was sequenced using BROCA, a targeted capture and parallel sequencing assay that identified pathogenic germline mutations in ovarian carcinoma susceptibility genes. RESULTS: Germline mutations in ovarian cancer susceptibility genes were found in 25.5% of women, most commonly BRCA1 and BRCA2. This mutation frequency mirrors those previously described among predominantly White populations. Our data suggests there may be an advantage in survival among those with germline mutations, although this was not statistically significant. CONCLUSIONS: Given similar frequencies of germline mutations between Black and White patients with ovarian cancer, we conclude that there are not major differences in the genetic predisposition to ovarian carcinoma. Equitable access to genomic advancements including germline and tumor sequencing would facilitate equal access to PARP inhibitors, the standard of care for patients with BRCA mutated advanced ovarian cancer.

Fully synthetic neuroimaging data for replication and exploration.

Scientific transparency, data exploration, and education are advanced through data sharing. However, risk for disclosure of personal information and institutional data sharing regulations can impede human subject/patient data sharing and thus limit open science initiatives. Sharing fully synthetic data is an alternative when it is not possible to share real or observed data. Here we describe a data sharing approach that borrows principles and methods from multiple imputation to replace observed values with synthetic values, thereby creating a fully synthetic neuroimaging dataset that accurately represents the covariance structure of the observed dataset. Predictor tables composed of demographic, site, behavioral and total intracranial volume (ICV) variables from 264 pediatric cases were used to create synthetic predictor tables, which were then used to synthesize gray matter images derived from T1-weighted data. The synthetic predictor tables demonstrated pooled variance and statistical estimates that closely approximated the observed data, as reflected in measures of efficiency and statistical bias. Similarly, the synthetic gray matter data accurately represented the variance and voxel-level associations with predictor variables (age, sex, verbal IQ, and ICV). The magnitude and spatial distribution of gray matter effects in the observed imaging data were replicated in the pooled results from the synthetic datasets. This approach for generating fully synthetic neuroimaging data has widespread potential for data sharing, including replication, new discovery, and education. Fully synthetic neuroimaging datasets can enable data-sharing because it accurately represents patterns of variance in the original data, while diminishing the risk of privacy disclosures that can accompany neuroimaging data sharing.

Intra- and interhemispheric white matter tract associations with auditory spatial processing: Distinct normative and aging effects.

Declining auditory spatial processing is hypothesized to contribute to the difficulty older adults have detecting, locating, and selecting a talker from among others in noisy listening environments. Though auditory spatial processing has been associated with several cortical structures, little is known regarding the underlying white matter architecture or how age-related changes in white matter microstructure may affect it. The arcuate fasciculus is a target for understanding age-related differences in auditory spatial attention based on normative spatial attention findings in humans. Similarly, animal and human clinical studies suggest that the corpus callosum plays a role in the cross-hemispheric integration of auditory spatial information important for spatial localization and attention. The current investigation used diffusion imaging to examine the extent to which age-group differences in the identification of spatially cued speech were accounted for by individual differences in the white matter microstructure of the right arcuate fasciculus and the corpus callosum. Higher right arcuate and callosal fractional anisotropy (FA) predicted better segregation and identification of spatially cued speech across younger and older listeners. Further, individual differences in callosal microstructure mediated age-group differences in auditory spatial processing. Follow-up analyses suggested that callosal tracts connecting left and right pre-frontal and posterior parietal cortex are particularly important for auditory spatial processing. The results are consistent with previous work in animals and clinical human samples and provide a cortical mechanism to account for age-related deficits in auditory spatial processing. Further, the results suggest that both intrahemispheric and interhemispheric mechanisms are involved in auditory spatial processing.

Cingulo-opercular adaptive control for younger and older adults during a challenging gap detection task.

Cingulo-opercular activity is hypothesized to reflect an adaptive control function that optimizes task performance through adjustments in attention and behavior, and outcome monitoring. While auditory perceptual task performance appears to benefit from elevated activity in cingulo-opercular regions of frontal cortex before stimuli are presented, this association appears reduced for older adults compared to younger adults. However, adaptive control function may be limited by difficult task conditions for older adults. An fMRI study was used to characterize adaptive control differences while 15 younger (average age = 24 years) and 15 older adults (average age = 68 years) performed a gap detection in noise task designed to limit age-related differences. During the fMRI study, participants listened to a noise recording and indicated with a button-press whether it contained a gap. Stimuli were presented between sparse fMRI scans (TR = 8.6 s) and BOLD measurements were collected during separate listening and behavioral response intervals. Age-related performance differences were limited by presenting gaps in noise with durations calibrated at or above each participant's detection threshold. Cingulo-opercular BOLD increased significantly throughout listening and behavioral response intervals, relative to a resting baseline. Correct behavioral responses were significantly more likely on trials with elevated pre-stimulus cingulo-opercular BOLD, consistent with an adaptive control framework. Cingulo-opercular adaptive control estimates appeared higher for participants with better gap sensitivity and lower response bias, irrespective of age, which suggests that this mechanism can benefit performance across the lifespan under conditions that limit age-related performance differences.

Critical questions in ovarian cancer research and treatment: Report of an American Association for Cancer Research Special Conference.

Substantial progress has been made in understanding ovarian cancer at the molecular and cellular level. Significant improvement in 5-year survival has been achieved through cytoreductive surgery, combination platinum-based chemotherapy, and more effective treatment of recurrent cancer, and there are now more than 280,000 ovarian cancer survivors in the United States. Despite these advances, long-term survival in late-stage disease has improved little over the last 4 decades. Poor outcomes relate, in part, to late stage at initial diagnosis, intrinsic drug resistance, and the persistence of dormant drug-resistant cancer cells after primary surgery and chemotherapy. Our ability to accelerate progress in the clinic will depend on the ability to answer several critical questions regarding this disease. To assess current answers, an American Association for Cancer Research Special Conference on "Critical Questions in Ovarian Cancer Research and Treatment" was held in Pittsburgh, Pennsylvania, on October 1-3, 2017. Although clinical, translational, and basic investigators conducted much of the discussion, advocates participated in the meeting, and many presentations were directly relevant to patient care, including treatment with poly adenosine diphosphate ribose polymerase (PARP) inhibitors, attempts to improve immunotherapy by overcoming the immune suppressive effects of the microenvironment, and a better understanding of the heterogeneity of the disease.

ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions.

The Twist1 transcription factor promotes tumor invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) and invadopodia-mediated extracellular matrix (ECM) degradation. The critical transcription targets of Twist1 for mediating these events remain to be uncovered. Here, we report that Twist1 strongly induces expression of a disintegrin and metalloproteinase 12 (ADAM12). We observed that the expression levels of Twist1 mRNA and ADAM12 mRNA are tightly correlated in human breast tumors. Knocking down ADAM12 blocked cell invasion in a 3D mammary organoid culture. Suppression of ADAM12 also inhibited Twist1-induced tumor invasion and metastasis in human breast tumor xenografts, without affecting primary tumor formation. Mechanistically, knockdown of ADAM12 in breast cancer cells significantly reduced invadopodia formation and matrix degradation, and simultaneously increased overall cell adhesion to the ECM. Live-imaging analysis showed that knockdown of ADAM12 significantly inhibited focal adhesion turnover. Mechanistically, both the disintegrin and metalloproteinase domains of ADAM12 are required for its function at invadopodia, whereas the metalloproteinase domain is dispensable for its function at focal adhesions. Taken together, these data suggest that ADAM12 plays a crucial role in tumor invasion and metastasis by regulating both invadopodia and focal adhesions.

Radiologic changes in the aging nasal cavity.

BACKGROUND: With an aging population, it is important to understand age-related anatomic changes in the nasal cavity and cribriform plate (CP) that may have clinical implications. METHODOLOGY: Computed tomography (CT) scans obtained for non-rhinologic conditions were divided into a young cohort (N=35, 18-34 years old) and an older adult cohort (N=32, 80-99 years old). Intranasal airspace volumes and bony anatomy of the CP were manually segmented using OsiriX software. The CP was assessed for mean Hounsfield Units (HU) and percentage of olfactory foramina. Deformation based morphometry (DBM) was then performed on the same cohort and correlated with manual measurements. RESULTS: Individual nasal cavity volumes increased 17-75% with age. Regression analysis of all scans revealed age to be the predominant variable influencing intranasal volume differences when controlling for sex and head size. Mean HU of the CP negatively correlated with age. No age-related differences in bone stenosis of olfactory foramina were identified. Automated DBM measurements of intranasal volumes, as well as CP and zygoma mean HU correlated with manual measurements. CONCLUSION: Older subjects have a global increase in intranasal volumes and diffuse bone density loss in the CP. The clinical impact of age-related anatomic changes in the nasal cavity and CP requires further investigation.

Who are the long-term survivors of high grade serous ovarian cancer?

Although the median survival for epithelial ovarian cancer (EOC) is <5years, approximately 15% of patients will survive for >10years. A better understanding of these exceptional responders could reveal opportunities to improve the dismal prognosis of most EOC patients. In this review, we examine the clinical and genomic features that have been associated with long-term survival, which is generally defined as survival of >7-10years after initial diagnosis. Clinical features influencing long-term survival have been best reported in large retrospective population-based studies. These studies find that long-term survival is associated with previously validated prognostic factors, including younger age at diagnosis, earlier clinicopathologic stage, lower grade, non-serous histology, absence of ascites, primary debulking surgery, and optimal cytoreduction at primary surgery. Duration of survival after a recurrence also contributes to long-term survival and depends both on recurrence location and response to subsequent chemotherapy or surgery. Germline BRCA mutations, although associated with short-term chemosensitivity, do not appear to improve long-term survival. Unfortunately, the relative lack of recurrent somatic mutations in EOC has made the identification of genomic signatures associated with long-term survival difficult. Although six independent gene expression analyses of long-term survivors (LTS) have identified signatures associated with prolonged survival, different gene sets are identified in each study. Genes differentially expressed in tumors of LTS are broadly involved in cell proliferation, tumor-stromal interactions, the cytoskeleton, metabolism of nutrients, and immune/stress response. We anticipate that consistent selection of control and LTS groups, combined with the use of emerging transcriptomic, epigenomic, and proteomic platforms, is likely to identify conserved features associated with long-term survival. Further elucidating the factors contributing to long-term survival has the potential to contribute to our understanding of the biology of ovarian cancer, with the goal of improving the survival of all EOC patients.

Aging-Resilient Associations between the Arcuate Fasciculus and Vocabulary Knowledge: Microstructure or Morphology?

UNLABELLED: Vocabulary knowledge is one of the few cognitive functions that is relatively preserved in older adults, but the reasons for this relative preservation have not been well delineated. We tested the hypothesis that individual differences in vocabulary knowledge are influenced by arcuate fasciculus macrostructure (i.e., shape and volume) properties that remain stable during the aging process, rather than white matter microstructure that demonstrates age-related declines. Vocabulary was not associated with age compared to pronounced age-related declines in cognitive processing speed across 106 healthy adults (19.92-88.29 years) who participated in this neuroimaging experiment. Fractional anisotropy in the left arcuate fasciculus was significantly related to individual variability in vocabulary. This effect was present despite marked age-related differences in a T1-weighted/T2-weighted ratio (T1w/T2w) estimate of myelin that were observed throughout the left arcuate fasciculus and associated with age-related differences in cognitive processing speed. However, atypical patterns of arcuate fasciculus morphology or macrostructure were associated with decreased vocabulary knowledge. These results suggest that deterioration of tissue in the arcuate fasciculus occurs with normal aging, while having limited impact on tract organization that underlies individual differences in the acquisition and retrieval of lexical and semantic information. SIGNIFICANCE STATEMENT: Vocabulary knowledge is resilient to widespread age-related declines in brain structure that limit other cognitive functions. We tested the hypothesis that arcuate fasciculus morphology, which supports the development of reading skills that bolster vocabulary, could explain this relative preservation. We disentangled (1) the effects of age-related declines in arcuate microstructure (mean diffusivity; myelin content estimate) that predicted cognitive processing speed but not vocabulary, from (2) relatively stable arcuate macrostructure (shape/volume) that explained significant variance in an age-independent association between fractional anisotropy and vocabulary. This latter result may reflect differences in fiber trajectory and organization that are resilient to aging. We propose that developmental sculpting of the arcuate fasciculus determines acquisition, storage, and access of lexical information across the adult lifespan.

Cingulo-opercular activity affects incidental memory encoding for speech in noise.

Correctly understood speech in difficult listening conditions is often difficult to remember. A long-standing hypothesis for this observation is that the engagement of cognitive resources to aid speech understanding can limit resources available for memory encoding. This hypothesis is consistent with evidence that speech presented in difficult conditions typically elicits greater activity throughout cingulo-opercular regions of frontal cortex that are proposed to optimize task performance through adaptive control of behavior and tonic attention. However, successful memory encoding of items for delayed recognition memory tasks is consistently associated with increased cingulo-opercular activity when perceptual difficulty is minimized. The current study used a delayed recognition memory task to test competing predictions that memory encoding for words is enhanced or limited by the engagement of cingulo-opercular activity during challenging listening conditions. An fMRI experiment was conducted with twenty healthy adult participants who performed a word identification in noise task that was immediately followed by a delayed recognition memory task. Consistent with previous findings, word identification trials in the poorer signal-to-noise ratio condition were associated with increased cingulo-opercular activity and poorer recognition memory scores on average. However, cingulo-opercular activity decreased for correctly identified words in noise that were not recognized in the delayed memory test. These results suggest that memory encoding in difficult listening conditions is poorer when elevated cingulo-opercular activity is not sustained. Although increased attention to speech when presented in difficult conditions may detract from more active forms of memory maintenance (e.g., sub-vocal rehearsal), we conclude that task performance monitoring and/or elevated tonic attention supports incidental memory encoding in challenging listening conditions.

Cortical activity predicts which older adults recognize speech in noise and when.

Speech recognition in noise can be challenging for older adults and elicits elevated activity throughout a cingulo-opercular network that is hypothesized to monitor and modify behaviors to optimize performance. A word recognition in noise experiment was used to test the hypothesis that cingulo-opercular engagement provides performance benefit for older adults. Healthy older adults (N = 31; 50-81 years of age; mean pure tone thresholds <32 dB HL from 0.25 to 8 kHz, best ear; species: human) performed word recognition in multitalker babble at 2 signal-to-noise ratios (SNR = +3 or +10 dB) during a sparse sampling fMRI experiment. Elevated cingulo-opercular activity was associated with an increased likelihood of correct recognition on the following trial independently of SNR and performance on the preceding trial. The cingulo-opercular effect increased for participants with the best overall performance. These effects were lower for older adults compared with a younger, normal-hearing adult sample (N = 18). Visual cortex activity also predicted trial-level recognition for the older adults, which resulted from discrete decreases in activity before errors and occurred for the oldest adults with the poorest recognition. Participants demonstrating larger visual cortex effects also had reduced fractional anisotropy in an anterior portion of the left inferior frontal-occipital fasciculus, which projects between frontal and occipital regions where activity predicted word recognition. Together, the results indicate that older adults experience performance benefit from elevated cingulo-opercular activity, but not to the same extent as younger adults, and that declines in attentional control can limit word recognition.