Recent Publications & Updates
Quickly discover all publications on Dr. Tamar Green’s Google Scholar page.
Publications
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Elucidating Microstructural Alterations in Neurodevelopmental Disorders: Application of Advanced Diffusion-Weighted Imaging in Children With Rasopathies.
Human brain mapping
2024; 45 (17): e70087
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Abstract
Neurodevelopmental disorders (NDDs) can severely impact functioning yet effective treatments are limited. Greater insight into the neurobiology underlying NDDs is critical to the development of successful treatments. Using a genetics-first approach, we investigated the potential of advanced diffusion-weighted imaging (DWI) techniques to characterize the neural microstructure unique to neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). In this prospective study, children with NF1, NS, and typical developing (TD) were scanned using a multi-shell DWI sequence optimized for neurite orientation density and dispersion imaging (NODDI) and diffusion kurtosis imaging (DKI). Region-of-interest and tract-based analysis were conducted on subcortical regions and white matter tracts. Analysis of covariance, principal components, and linear discriminant analysis compared between three groups. 88 participants (Mage = 9.36, SDage = 2.61; 44 male) were included: 31 NS, 25 NF1, and 32 TD. Subcortical regions differed between NF1 and NS, particularly in the thalamus where the neurite density index (NDI; estimated difference 0.044 [95% CI: -0.034, 0.053], d = 2.36), orientation dispersion index (ODI; estimate 0.018 [95% CI: 0.010, 0.026], d = 1.39), and mean kurtosis (MK; estimate 0.049 [95% CI: 0.025, 0.072], d = 1.39) were lower in NF1 compared with NS (all p < 0.0001). Reduced NDI was found in NF1 and NS compared with TD in all 39 white matter tracts investigated (p < 0.0001). Reduced MK was found in a majority of the tracts in NF1 and NS relative to TD, while fewer differences in ODI were observed. The middle cerebellar peduncle showed lower NDI (estimate 0.038 [95% CI: 0.021, 0.056], p < 0.0001) and MK (estimate 0.057 [95% CI: 0.026, 0.089], p < 0.0001) in NF1 compared to NS. Multivariate analyses distinguished between groups using NDI, ODI, and MK measures. Principal components analysis confirmed that the clinical groups differ most from TD in white matter tract-based NDI and MK, whereas ODI values appear similar across the groups. The subcortical regions showed several differences between NF1 and NS, to the extent that a linear discriminant analysis could classify participants with NF1 with an accuracy rate of 97%. Differences in neural microstructure were detected between NF1 and NS, particularly in subcortical regions and the middle cerebellar peduncle, in line with pre-clinical evidence. Advanced DWI techniques detected subtle alterations not found in prior work using conventional diffusion tensor imaging.
View details for DOI 10.1002/hbm.70087
View details for PubMedID 39665502
View details for PubMedCentralID PMC11635693
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Social Communication in Ras Pathway Disorders: A Comprehensive Review from Genetics to Behavior in Neurofibromatosis Type 1 and Noonan Syndrome.
Biological psychiatry
2024
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Abstract
Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are neurogenetic syndromes caused by pathogenetic variants encoding components of the Ras-ERK-MAPK signaling pathway (Ras pathway). NF1 and NS are associated with differences in social communication and related neuropsychiatric risks. During the last decade, there has been growing interest in Ras-linked syndromes as models to understand social communication deficits and autism spectrum disorders. We systematically review the literature between 2010-2023 focusing on the social communication construct of the RDoC framework. We provide an integrative summary of the research on facial and non-facial social communication processes in NF1 and NS across molecular, cellular, neural circuitry, and behavioral domains. At the molecular and cellular levels, dysregulation in the Ras pathway is intricately tied to variations in social communication through changes in GABAergic, glutamatergic, and serotonergic transmission, as well as inhibitory/excitatory imbalance. Neural circuitry typically associated with learning, attention, and memory in NF1 and NS (e.g., cortico-striatal connectivity), is also implicated in social communication. We highlight less researched, potential mechanisms for social communication, such as white matter connectivity and the default mode network. Finally, key gaps in NF1 and NS literature are identified and a roadmap for future research is provided. By leveraging genetic syndromes research, we can understand the mechanisms associated with behaviors and psychiatric disorders.
View details for DOI 10.1016/j.biopsych.2024.09.019
View details for PubMedID 39366539
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Impact of pathogenic variants of the Ras-mitogen-activated protein kinase pathway on major white matter tracts in the human brain.
Brain communications
2024; 6 (4): fcae274
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Abstract
Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras-mitogen-activated protein kinase pathway.
View details for DOI 10.1093/braincomms/fcae274
View details for PubMedID 39210910
View details for PubMedCentralID PMC11358645
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RASopathies influences on neuroanatomical variation in children.
Biological psychiatry. Cognitive neuroscience and neuroimaging
2024
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Abstract
RASopathies are a group of disorders characterized by pathogenic mutations in the Ras-mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD).This study examines the effect RASopathies (NS and NF1) has on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. We compared structural T1-weighted images, using vertex-based analysis for cortical measures and Desikan ROI parcellation for subcortical volumes on children with RASopathies (n=91, mean age = 8.81, SD = 2.12) to sex- and age-matched TD (n=74, mean age=9.07, SD = 1.77).Compared to TD, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibit divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall children with NS display decreased volumes in striatal and thalamic structures and children with NF1 display increased volumes in the hippocampus, amygdala, and thalamus.Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.
View details for DOI 10.1016/j.bpsc.2024.04.003
View details for PubMedID 38621478
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Comparing Irritability Across Childhood Psychiatric Disorders Using a Large-Scale Longitudinal Dataset
SPRINGERNATURE. 2023: 141-142
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View details for Web of Science ID 001184093500289
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Polygenic Risk for ADHD and its Contributions to Brain and Behavioral Phenotypes in Noonan Syndrome
SPRINGERNATURE. 2023: 155-156
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View details for Web of Science ID 001184093500311
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The 8th International RASopathies Symposium: Expanding research and care practice through global collaboration and advocacy.
American journal of medical genetics. Part A
2023
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Abstract
Germline pathogenic variants in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway are the molecular cause of RASopathies, a group of clinically overlapping genetic syndromes. RASopathies constitute a wide clinical spectrum characterized by distinct facial features, short stature, predisposition to cancer, and variable anomalies in nearly all the major body systems. With increasing global recognition of these conditions, the 8th International RASopathies Symposium spotlighted global perspectives on clinical care and research, including strategies for building international collaborations and developing diverse patient cohorts in anticipation of interventional trials. This biannual meeting, organized by RASopathies Network, was held in a hybrid virtual/in-person format. The agenda featured emerging discoveries and case findings as well as progress in preclinical and therapeutic pipelines. Stakeholders including basic scientists, clinician-scientists, practitioners, industry representatives, patients, and family advocates gathered to discuss cutting edge science, recognize current gaps in knowledge, and hear from people with RASopathies about the experience of daily living. Presentations by RASopathy self-advocates and early-stage investigators were featured throughout the program to encourage a sustainable, diverse, long-term research and advocacy partnership focused on improving health and bringing treatments to people with RASopathies.
View details for DOI 10.1002/ajmg.a.63477
View details for PubMedID 37969032
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THE INTERACTIVE EFFECTS OF POLYGENIC RISK SCORES AND SINGLE GENE DISORDERS ON THE SUBCORTICAL STRUCTURE
ELSEVIER. 2023: S256-S257
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View details for DOI 10.1016/j.euroneuro.2023.08.451
View details for Web of Science ID 001089437400447