Aldridge, CM, Armstrong, ND, Sunmonu, NA, Becker, C, Palakshappa, D, Lindgren, AG, Pedersen, A, Stanne, TM, Jern, C, Maguire, J, Hsu, F-C, Keene, KL, Sale, M, Irvin, MR, Worrall, BB, Aldridge, CM, Armstrong, ND, Sunmonu, NA, Becker, C, Palakshappa, D, Lindgren, AG, Pedersen, A, Stanne, TM, Jern, C, Maguire, J, Hsu, F-C, Keene, KL, Sale, M, Irvin, MR, and Worrall, BB
Herrada SP, Sunmonu NA, Meschia JF, Worrall BB, Greene CL, and Kittner SJ
Huo S, Rivier CA, Clocchiatti-Tuozzo S, Renedo D, Sunmonu NA, de Havenon A, Sarpong DF, Rosendale N, Sheth KN, and Falcone GJ
Background and Objectives: Sexual and gender minority (SGM) groups have been historically underrepresented in neurologic research, and their brain health disparities are unknown. We aim to evaluate whether SGM persons are at higher risk of adverse brain health outcomes compared with cisgender straight (non-SGM) individuals., Methods: We conducted a cross-sectional study in the All of Us Research Program, a US population-based study, including all participants with information on gender identity and sexual orientation. We used baseline questionnaires to identify sexual minority (lesbian, gay, bisexual, diverse sexual orientation; nonstraight sexual orientation) and gender minority (gender diverse and transgender; gender identity different from sex assigned at birth) participants. The primary outcome was a composite of stroke, dementia, and late-life depression, assessed using electronic health record data and self-report. Secondarily, we evaluated each disease separately. Furthermore, we evaluated all subgroups of gender and sexual minorities stratified by sex assigned at birth. We used multivariable logistic regression (adjusted for age, sex assigned at birth, race/ethnicity, cardiovascular risk factors, other relevant comorbidities, and neighborhood deprivation index) to assess the relationship between SGM groups and the outcomes., Results: Of 413,457 US adults enrolled between May 31, 2017, and June 30, 2022, we included 393,041 participants with available information on sexual orientation and gender identity (mean age 51 [SD 17] years), of whom 39,632 (10%) belonged to SGM groups. Of them, 38,528 (97%) belonged to a sexual minority and 4,431 (11%) to a gender minority. Compared with non-SGM, SGM persons had 15% higher odds of the brain health composite outcome (odds ratio [OR] 1.15, 95% CI 1.08-1.22). In secondary analyses, these results persisted across sexual and gender minorities separately (all 95% CIs > 1). Assessing individual diseases, all SGM groups had higher odds of dementia (SGM vs non-SGM: OR 1.14, 95% CI 1.00-1.29) and late-life depression (SGM vs non-SGM: OR 1.27, 95% CI 1.17-1.38) and transgender women had higher odds of stroke (OR 1.68, 95% CI 1.04-2.70)., Discussion: In a large US population study, SGM persons had higher odds of adverse brain health outcomes. Further research should explore structural causes of inequity to advance inclusive and diverse neurologic care.
Ruff IM, de Havenon A, Bergman DL, Dugue R, Frontera JA, Goldstein JN, Hemphill JC, Marulanda-Londono E, Prabhakaran S, Richards CT, Sunmonu NA, Vilar P, and Wolfe SQ
The American Heart Association/American Stroke Association released a revised spontaneous intracerebral hemorrhage guideline in 2022. A working group of stroke experts reviewed this guideline and identified a subset of recommendations that were deemed suitable for creating performance measures. These 15 performance measures encompass a wide spectrum of intracerebral hemorrhage patient care, from prehospital to posthospital settings, highlighting the importance of timely interventions. The measures also include 5 quality measures and address potential challenges in data collection, with the aim of future improvements.
Rivier CA, Renedo DB, Sunmonu NA, de Havenon A, Sheth KN, and Falcone GJ
Competing Interests: Disclosures None.
Rivier CA, Renedo DB, de Havenon A, Sunmonu NA, Gill TM, Payabvash S, Sheth KN, and Falcone GJ
Background and Objectives: Poor oral health is a modifiable risk factor that is associated with clinically observed cardiovascular disease. However, the relationship between oral and brain health is not well understood. We tested the hypothesis that poor oral health is associated with worse neuroimaging brain health profiles in middle-aged persons without stroke or dementia., Methods: We performed a 2-stage cross-sectional neuroimaging study using UK Biobank data. First, we tested for association between self-reported poor oral health and MRI neuroimaging markers of brain health. Second, we used Mendelian randomization (MR) analyses to test for association between genetically determined poor oral health and the same neuroimaging markers. Poor oral health was defined as the presence of dentures or loose teeth. As instruments for the MR analysis, we used 116 independent DNA sequence variants linked to increased composite risk of dentures or teeth that are decayed, missing, or filled. Neuroimaging markers of brain health included white matter hyperintensity (WMH) volume and aggregate measures of fractional anisotropy (FA) and mean diffusivity (MD), 2 metrics indicative of white matter tract disintegrity obtained through diffusion tensor imaging across 48 brain regions., Results: We included 40,175 persons (mean age 55 years, female sex 53%) enrolled from 2006 to 2010, who underwent a dedicated research brain MRI between 2014 and 2016. Among participants, 5,470 (14%) had poor oral health. Poor oral health was associated with a 9% increase in WMH volume (β = 0.09, SD = 0.014, p < 0.001), 10% change in aggregate FA score (β = 0.10, SD = 0.013, p < 0.001), and 5% change in aggregate MD score (β = 0.05, SD = 0.013, p < 0.001). Genetically determined poor oral health was associated with a 30% increase in WMH volume (β = 0.30, SD = 0.06, p < 0.001), 43% change in aggregate FA score (β = 0.43, SD = 0.06, p < 0.001), and 10% change in aggregate MD score (β = 0.10, SD = 0.03, p < 0.01)., Discussion: Among middle age Britons without stroke or dementia, poor oral health was associated with worse neuroimaging brain health profiles. Genetic analyses confirmed these associations, supporting a potentially causal association. Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health.
de Havenon A, Bangad A, Skolarus LE, Aldridge CM, Braun RG, Cole JW, Cramer SC, Lindgren AG, Sunmonu NA, Worrall BB, and Lohse KR
Sunmonu NA, Ambati NK, Thomas MJ, Ulep RD, and Worrall B
Objective: To investigate potential genetic susceptibility for moyamoya disease (MMD) in an African American family., Materials and Methods: Neurovascular imaging and analyses of MMD susceptibility genes RNF213 and/or ACTA2 in a young proband with MMD and two first-degree relatives., Results: The proband presented with pseudobulbar affect and chorea, then had a right hemispheric ischaemic stroke and rapidly fatal course. One relative had a mild haemorrhagic thalamic stroke and clinically silent ischaemic infarct. Despite evidence of slowly progressive disease, he remained clinically stable. Another relative was neurologically intact with normal cerebrovascular imaging to date. All three have the rare R4131C (p.Arg4131Cys or p.R4131C, c.12391C>T) variant of the RNF213 gene. They are the first Black people and only the 5th family worldwide known to harbour this variant. MMD was confirmed in both of the patients with neurological events., Conclusions: Our report provides compelling evidence that MMD is a clinically complex, heritable genetic disease. It supports the probable pathogenicity of R4131C. Furthermore, it illustrates the wide phenotypic spectrum of R4131C, from asymptomatic carrier to late presenting, mild disease to catastrophic, rapidly fatal childhood disease. To our knowledge, this is also the first report of heritable MMD in a Black family. Finally, this study highlights the importance of racially and ethnically diverse participants in biomedical research., (Copyright © 2021 Elsevier Inc. All rights reserved.)
Sunmonu NA
Pseudoxanthoma elasticum (PXE) is a rare systemic genetic disorder and an uncommon cause of ischaemic and haemorrhagic strokes. Its rarity and variable presentation may delay recognition and diagnosis of the primary disorder or associated conditions. Here, we describe a patient of European ancestry diagnosed with PXE in her 20s who presented in her 50s with a haemorrhagic stroke. Subsequent workup additionally revealed clinically silent ischaemic cerebral infarcts, critical stenosis of the right internal carotid artery and intracranial vasculopathy. Though she had some typical vascular risk factors, they were well-controlled. Antiplatelet therapy has traditionally been avoided in PXE due to increased risk of GI (and potentially retinal and cerebral) haemorrhage, but the medical team opted to start aspirin for secondary stroke prevention because she had no history of GI or retinal bleed, and her risk of ischaemic stroke was considered unacceptably high compared with that of clinically significant haemorrhage. Judicious use of antiplatelet therapy may be relatively safe in carefully selected patients. Anticipatory surveillance and management of the numerous manifestations of this potentially debilitating disorder are also important to preserve function and quality of life., (Copyright © 2020 Elsevier Inc. All rights reserved.)
Sunmonu NA, Li K, and Li JY
Soluble growth factors play an important role in the coordination and integration of cell proliferation, differentiation, fate determination, and morphogenesis during development of multicellular organisms. Fibroblast growth factors (FGFs) are a large family of polypeptide growth factors that are present in organisms ranging from nematodes to humans. RNA alternative splicing of FGFs and their receptors further enhances the complexity of this ligand-receptor system. The mouse Fgf8 gene produces eight splice variants, which encode isoform proteins with different N-termini and distinct receptor-binding affinity and biological activity. In this article, we review the roles of Fgf8 in vertebrate development and summarize the recent findings on the in vivo function of different Fgf8 splice variants. We propose that multiple Fgf8 isoform proteins act in concert to regulate the overall function of Fgf8 and account for the diverse and essential role of Fgf8 during vertebrate development., (Copyright © 2010 Wiley-Liss, Inc.)
Sunmonu NA, Li K, Guo Q, and Li JY
In vertebrates, the common expression border of two homeobox genes, Otx2 and Gbx2, demarcates the prospective midbrain-hindbrain border (MHB) in the neural plate at the end of gastrulation. The presence of a compartment boundary at the MHB has been demonstrated, but the mechanism and timing of its formation remain unclear. We show by genetic inducible fate mapping using a Gbx2(CreER) knock-in mouse line that descendants of Gbx2(+) cells as early as embryonic day (E) 7.5 do not cross the MHB. Without Gbx2, hindbrain-born cells abnormally populate the entire midbrain, demonstrating that Gbx2 is essential for specifying hindbrain fate. Gbx2(+) and Otx2(+) cells segregate from each other, suggesting that mutually exclusive expression of Otx2 and Gbx2 in midbrain and hindbrain progenitors is responsible for cell sorting in establishing the MHB. The MHB organizer gene Fgf8, which is expressed as a sharp transverse band immediately posterior to the lineage boundary at the MHB, is crucial in maintaining the lineage-restricted boundary after E7.5. Partial deletion of Fgf8 disrupts MHB lineage separation. Activation of FGF pathways has a cell-autonomous effect on cell sorting in midbrain progenitors. Therefore, Fgf8 from the MHB may signal the nearby mesencephalic cells to impart distinct cell surface characteristics or induce local cell-cell signaling, which consequently prevents cell movements across the MHB. Our findings reveal the distinct function of Gbx2 and Fgf8 in a stepwise process in the development of the compartment boundary at the MHB and that Fgf8, in addition to its organizer function, plays a crucial role in maintaining the lineage boundary at the MHB by restricting cell movement.
Guo Q, Li K, Sunmonu NA, and Li JY
The single Fgf8 gene in mice produces eight protein isoforms (Fgf8a-h) with different N-termini by alternative splicing. Gain-of-function studies have demonstrated that Fgf8a and Fgf8b have distinct activities in the developing midbrain and hindbrain (MHB) due to their different binding affinities with FGF receptors. Here we have performed loss-of-function analyses to determine the in vivo requirement for these two Fgf8 spliceforms during MHB development. We showed that deletion of Fgf8b-containing spliceforms (b, d, f and h) leads to loss of multiple key regulatory genes, including Fgf8 itself, in the MHB region. Therefore, specific inactivation of Fgf8b-containing spliceforms, similar to the loss of Fgf8, in MHB progenitors results in deletion of the midbrain, isthmus, and cerebellum. We also created a splice-site mutation abolishing Fgf8a-containing spliceforms (a, c, e, and g). Mice lacking Fgf8a-containing spliceforms exhibit growth retardation and postnatal lethality, and the phenotype is variable in different genetic backgrounds, suggesting that the Fgf8a-containing spliceforms may play a role in modulating the activity of Fgf8. Surprisingly, no discernable defect was detected in the midbrain and cerebellum of Fgf8a-deficient mice. To determine if Fgf17, which is expressed in the MHB region and possesses similar activities to Fgf8a based on gain-of-function studies, may compensate for the loss of Fgf8a, we generated Fgf17 and Fgf8a double mutant mice. Mice lacking both Fgf8a-containing spliceforms and Fgf17 display the same defect in the posterior midbrain and anterior cerebellum as Fgf17 mutant mice. Therefore, Fgf8b-containing spliceforms, but not Fgf8a, are essential for the function of Fgf8 during the development of the midbrain and cerebellum., (Copyright 2009 Elsevier Inc. All rights reserved.)
Sunmonu NA, Chen L, and Li JY
The mouse homeobox gene, Gbx2, is expressed in discreet domains in the neural tube and plays a key role in forebrain and hindbrain development. Previous studies have demonstrated that mutual inhibition between Gbx2 and Otx2, which are respectively expressed in the anterior and posterior parts of the neural plate, positions the prospective midbrain-hindbrain junction. We describe here a conditional Gbx2 gain-of-function transgenic mouse line, Gbx2-GOF, which expresses Gbx2 and red fluorescence protein, mCherry, upon Cre-mediated recombination. In the absence of Cre, beta-galactosidase is broadly expressed in mouse embryos and adult brains carrying the transgene. By combining Gbx2-GOF and En1(Cre) knock-in allele, we activated expression of Gbx2 and mCherry throughout the mesencephalon (mes) and rhombomere 1 (r1). The ectopic expression of Gbx2 causes an anterior shift of the mes/r1 junction at embryonic day 10.5. Interestingly, we found that persistent expression of Gbx2 throughout the mes/r1 region largely abolishes expression of the isthmic organizer gene Fgf8, leading to deletion of the midbrain and cerebellum at later stages. Our data suggest that the juxtaposition of the expression domains of Gbx2 and Otx2 within the mes/r1 area is essential for the maintenance of Fgf8 expression. Furthermore, the Gbx2-GOF transgenic line is suitable for functional study of Gbx2 during development., ((c) 2009 Wiley-Liss, Inc.)
Nie R, Sunmonu NA, Chin AB, Lee KS, and Rutkove SB
Objective: To determine the feasibility of performing electrical impedance myography (EIM) in rats., Methods: EIM was performed on the hamstring muscles of 6 healthy adult rats with applied frequencies of 2-300 kHz. Studies were performed over a 6-week period, with 3 rats having recordings made from the skin (surface EIM) and 3 with recordings directly from the muscle (direct-muscle EIM). In addition, sciatic nerve crush was performed on one rat and comparisons made pre- and post-injury. Reactance and resistance were measured and the primary outcome variable, the phase angle (theta), calculated., Results: EIM patterns in the rat hamstring muscles were qualitatively similar to those observed in human subjects. This held true for both surface and direct-muscle recordings, although direct-muscle data appeared less repeatable. Sciatic nerve crush data in the single rat showed a dramatic reduction in phase and a relative loss of frequency-dependence., Conclusions: EIM data similar to that obtained from human subjects can be acquired from rat muscles with surface recordings proving more consistent and easier to obtain than direct-muscle recordings. Changes seen with sciatic nerve crush mirror those seen in patients with neurogenic injury., Significance: These results support the possibility of performing EIM on rat models of neuromuscular disease.
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