Biology subjects

Keenan, R.

Publications and source records attributed to Keenan, R..

9 recordsLinked to original sources

bioRxiv2026

Source-space EEG functional connectivity and prediction of cognition in Parkinsons disease: No added benefit of individualized head models over standard templates

IntroductionCognitive decline is a major non-motor feature of Parkinsons disease (PD), but reliable and accessible biomarkers remain limited. Resting-state electroencephalography (EEG) is a promising candidate because it is low-cost, portable, and well suited to repeated assessment. Recent work has increasingly focused on source-space functional connectivity (FC) for the prediction of cognition. However, the influence of source modelling based on an individualized MRI-based head model relative to that based on standard template model is unknown. MethodsTo compare these two source-space EEG FC methods, we analysed EEG data from the New Zealand Parkinsons Progression Programme, including 136 people with PD and 51 age-similar controls. Source space resting-state EEG, parcellated with the HCP-MMP1 atlas, was used to derive amplitude envelope correlation (AEC) and debiased weighted phase lag index (dwPLI) across six canonical frequency bands. The resulting twenty-four FC modalities were evaluated using six machine-learning regression algorithms within a nested cross-validation framework. ResultsTheta-, alpha-, and beta-band FC showed the most consistent prediction of global cognition. The strongest performance was observed for theta- and alpha-band AEC and dwPLI features (max R{superscript 2} = 0.170, 95% CI = 0.067-0.262; max r = 0.439, 95% CI = 0.328-0.537). Standard and individualized head models showed comparable predictive performance across nearly all modalities. The feature-importance neuroanatomical patterns for Cole-Anticevic networks were also similar between the two head-model options. ConclusionsWe found that source-space resting-state EEG FC can predict cognitive performance in PD. The comparability of the two head models suggests that the more user-friendly and less resource-intensive standard template head model is sufficient for this purpose. This supports feasible, scalable, and clinically accessible EEG-based FC biomarkers of cognition in PD.

neuroscience↗

bioRxiv2026

IL1β/IL1R1/IRAK4 Drives Inflammatory Ovarian Cancer Seeding at the inflamed sites and Is Reversed by an IRAK4 inhibitor UR241-2

Inflammation-driven tumor implantation, such as port-site metastasis (PSM) following laparoscopic gynecologic surgery and peritoneal seeding during post-surgical recurrence, represents an aggressive clinical problem that remains poorly understood and lacks targeted therapies. To address this, we developed a non-surgical Mesothelium-Inflammation/Injury-Metastasis (MIM) model and investigated the role of the IL-1{beta}/IL1R1/MYD88/IRAK1/4 axis and NLRP3 in epithelial ovarian cancer (EOC) seeding at inflamed or injured sites. This model created by a needle injury recapitulates inflammation-driven peritoneal seeding and mimics PSM and inflammation associated dissemination in peritoneum during recurrence. Seeding was dependent on Il1r1 but not Nlrp3, despite its role in regulating IL-1{beta} production, as Il1ra-/- and Nlrp3-/- mice phenocopied wild-type C57BL/6 mice. Given the limited antitumor efficacy of IL-1{beta}-targeting agents such as Anakinra and Canakinumab, we focused on IRAK4 as a therapeutic target. IRAK4 knockdown significantly prolonged survival, reduced tumor cell adhesion, downregulated E-cadherin and Wnt4, and induced S-phase/mitotic arrest. This led to the development of UR241-2, a small-molecule IRAK4 inhibitor, which was validated through molecular simulations, hotspot analysis, nanoBRET, global kinome profiling, and NF-{kappa}{beta} reporter assays. UR241-2 inhibited NF-{kappa}{beta} nuclear translocation and blocked IL-1{beta}-induced IRAK4 phosphorylation. UR241-2 exhibited favorable drug-like properties, including absence of CYP or hERG inhibition, and acceptable CaCo-2 permeability, plasma protein binding, microsomal stability, and pharmacokinetics. In vivo, UR241-2 reduced SKOV3 xenograft growth, suppressed mesothelial seeding, and increased MHC-II macrophages and activated neutrophils in syngeneic high-grade epithelial ovarian HGS3 tumors. RNA-seq revealed enrichment of neutrophil activation signatures and suppression of extracellular matrix (ECM) gene programs. Together, these findings establish a role for the IL-1{beta}/IL1R1/IRAK4 axis in inflammation-driven PSM and peritoneal seeding and ECM regulation in EOC, and demonstrate that IRAK4 inhibition activates antitumor immune responses, providing a therapeutic strategy to block metastatic seeding and improve tumor control.

cancer biology↗

bioRxiv2025

IL-1β/IRAK4 Axis Promotes Ovarian Tumor Development at the Mesothelium Injury Sites

Epithelial ovarian cancer (EOC) cells seed at mesothelial inflammation or injury sites. Lack of animal models recapitulating tumor cells seeding at inflamed sites in EOC hinders mechanistic studies and therapy developments. Here, we developed a non-surgical MIM (Mesothelium Inflammation/Injury Metastasis) model that recapitulates tumor cell seeding at inflamed sites. This model captures temporal changes in tumor immune microenvironment and tumor growth allowing for deeper mechanistic and preclinical therapeutic studies of EOC in-vivo. We show here that HGS-3 high-grade murine serous EOC cells seed at needle-induced injury sites in mesothelium/peritoneal wall, forming tumors both internally and protruding outward. Using MIM model, we found that deletion of IL1R1 in mice reduced EOC cell seeding at mesothelium injury/inflamed site in WT but not IL1ra-deficient mice. Treatment of MiM mice with a novel IRAK4 inhibitor we recently developed (UR241-2) revealed an essential role for IRAK4 signaling downstream IL-1{beta}/IL-1R1 in fostering an anti-tumor inflammatory environment, and reduced tumor burden. We conclude that IRAK4 inhibitors can be more effective than IL-1/IL-1R1 targeting agents to control metastasis and peritoneal tumors, an unmet medical need in EOC recurrence. Downregulation of extracellular matrix (ECM), upregulation of neutrophil activation genes, reduced cell adhesion and migration exhibit how UR241-2 corrects ECM and immune disorders in EOC, making it less conducive to metastasis and tumorigenesis.

cancer biology↗

bioRxiv2023

Functional Topography of the Neocortex Predicts Covariation in Complex Cognitive and Basic Motor Abilities

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g., hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

neuroscience↗

bioRxiv2022

Associations between thinner retinal neuronal layers and suboptimal brain structural integrity: Are the eyes a window to the brain?

We investigated the extent to which measures of retinal neuronal thickness capture variability in the structural integrity of the brain in a large population-based cohort followed from birth to midlife. Using data from the Dunedin Multidisciplinary Health and Development Study (n=1037; analytic n=828, aged 45 years), we specifically tested for associations between optical coherence tomography-measured retinal neuronal layers and MRI-measured structural brain integrity. We found that Study members who had thinner retinal neuronal layers had thinner average cortex, smaller total cortical surface area, smaller subcortical grey matter volumes, larger volume of white matter hyperintensities as well as older looking brains. This suggests that retinal neuronal thickness reflects differences in midlife structural brain integrity consistent with accelerated cognitive decline and increased risk for later dementia, further supporting the proposition that the retina may be a biomarker of brain aging as early as midlife.

neuroscience↗

bioRxiv2019

A pervasively thinner neocortex is a transdiagnostic feature of general psychopathology

ObjectiveNeuroimaging research has revealed that structural brain alterations are common across broad diagnostic families of disorders rather than specific to a single psychiatric disorder. Such overlap in the structural brain correlates of mental disorders mirrors already well-documented phenotypic comorbidity of psychiatric symptoms and diagnoses, which can be indexed by a general psychopathology or p factor. We hypothesized that if general psychopathology drives the convergence of structural alterations common across disorders then 1) there should be few associations unique to any one diagnostic family of disorders, and 2) associations with the p factor should overlap with those for the broader diagnostic families. MethodsAnalyses were conducted on structural MRI and psychopathology data collected from 861 members of the population representative Dunedin Study at age 45. ResultsStudy members with high scores across three broad diagnostic families of disorders (Externalizing, Internalizing, Thought Disorder) exhibited highly overlapping patterns of reduced global and widely distributed parcel-wise neocortical thickness. Study members with high p factor scores exhibited patterns of reduced global and parcel-wise neocortical thickness nearly identical to those associated with the three broad diagnostic families. ConclusionsA pattern of pervasively reduced neocortical thickness appears common across all forms of mental disorders and may represent a transdiagnostic feature of general psychopathology. As has been documented with regard to symptoms and diagnoses, the underlying brain structural correlates of mental disorders may not exhibit specificity, the continued pursuit of which may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.

neuroscience↗

bioRxiv2019

White matter hyperintensities are common in midlife and already associated with cognitive decline

White matter hyperintensities (WMHs) proliferate as the brain ages and are associated with increased risk for cognitive decline as well as Alzheimers disease and related dementias. As such, WMHs have been targeted as a surrogate biomarker in intervention trials with older adults. However, it is unclear at what stage of aging WMHs begin to relate to cognition and if they may be a viable target for early prevention. In a population-representative birth cohort of 843 45-year-olds we measured WMHs using T2-weighted MRI, and we assessed cognitive decline from childhood to midlife. We found that WMHs were common at age 45 and that WMH volume was modestly associated with both lower childhood ({beta}=-0.08, p=0.013) and adult IQ ({beta}=-0.15, p<0.001). Moreover, WMH volume was associated with greater cognitive decline from childhood to midlife ({beta}=-0.09, p<0.001). Our results demonstrate that a link between WMHs and early signs of cognitive decline is detectable decades before clinical symptoms of dementia emerge. Thus, WMHs may be a useful surrogate biomarker for identifying individuals in midlife at risk for future accelerated cognitive decline and selecting participants for dementia prevention trials.

neuroscience↗

bioRxiv2019

Reproducibility of Structural Brain Alterations Associated with Transdiagnostic Risk for Mental Illness: Evidence from a Population-Representative Birth Cohort

Transdiagnostic research has identified a general psychopathology factor - often called the p factor - that accounts for shared variation across internalizing, externalizing, and thought disorders in diverse samples. It has been argued that the p factor may reflect dysfunctional thinking present in serious mental illness. In support of this, we previously used a theory-free, data-driven multimodal neuroimaging approach to find that higher p factor scores are associated with structural alterations within a cerebello-thalamo-cortical circuit (CTCC) and visual association cortex, both of which are important for monitoring and coordinating information processing in the service of executive control. Here we attempt to replicate these associations by conducting region-of-interest analyses of CTCC and visual association cortex using data from 875 members of the Dunedin Longitudinal Study, a five-decade study of a population-representative birth cohort now 45 years old. We further sought to replicate a more recent report that p factor scores can be predicted by patterns of distributed cerebellar morphology as estimated through independent component analysis. We successfully replicated associations between higher p factor scores and both reduced grey matter volume of the visual association cortex and fractional anisotropy of pontine white matter pathways within the CTCC. In contrast, we failed to replicate prior associations between cerebellar structure and p factor scores. Collectively, our findings encourage further focus on the CTCC and visual association cortex as core neural substrates and potential biomarkers of general psychopathology.

neuroscience↗

bioRxiv2018

General Functional Connectivity: shared features of resting-state and task fMRI drive reliable individual differences in functional brain networks

Intrinsic connectivity, measured using resting-state fMRI, has emerged as a fundamental tool in the study of the human brain. However, due to practical limitations, many studies do not collect enough resting-state data to generate reliable measures of intrinsic connectivity necessary for studying individual differences. Here we present general functional connectivity (GFC) as a method for leveraging shared features across resting-state and task fMRI and demonstrate in the Human Connectome Project and the Dunedin Study that GFC offers better test-retest reliability than intrinsic connectivity estimated from the same amount of resting-state data alone. Furthermore, at equivalent scan lengths, GFC displays higher heritability on average than resting-state functional connectivity. We also show that predictions of cognitive ability from GFC generalize across datasets, performing as well or better than resting-state or task data alone. Collectively, our work suggests that GFC can improve the reliability of intrinsic connectivity estimates in existing datasets and, subsequently, the opportunity to identify meaningful correlates of individual differences in behavior. Given that task and resting-state data are often collected together, many researchers can immediately derive more reliable measures of intrinsic connectivity through the adoption of GFC rather than solely using resting-state data. Moreover, by better capturing heritable variation in intrinsic connectivity, GFC represents a novel endophenotype with broad applications in clinical neuroscience and biomarker discovery.

neuroscience↗