Recent Submissions

  • Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution.

    Bobrowski-Khoury, Natasha; Sequeira, Jeffrey M; Quadros, Edward V (2023-02-25)
    In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD.
  • Brain Uptake of Folate Forms in the Presence of Folate Receptor Alpha Antibodies in Young Rats: Folate and Antibody Distribution

    Bobrowski-Khoury, Natasha; Sequeira, Jeffrey M.; Quadros, Edward V. (MDPI AG, 2023-02-25)
    In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD.
  • Absorption and Tissue Distribution of Folate Forms in Rats: Indications for Specific Folate Form Supplementation during Pregnancy.

    Bobrowski-Khoury, Natasha; Sequeira, Jeffrey M; Arning, Erland; Bottiglieri, Teodoro; Quadros, Edward V (2022-06-09)
    Food fortification and folic acid supplementation during pregnancy have been implemented as strategies to prevent fetal malformations during pregnancy. However, with the emergence of conditions where folate metabolism and transport are disrupted, such as folate receptor alpha autoantibody (FRαAb)-induced folate deficiency, it is critical to find a folate form that is effective and safe for pharmacologic dosing for prolonged periods. Therefore, in this study, we explored the absorption and tissue distribution of folic acid (PGA), 5-methyl-tetrahydrofolate (MTHF), l-folinic acid (levofolinate), and d,l-folinic acid (Leucovorin) in adult rats. During absorption, all forms are converted to MTHF while some unconverted folate form is transported into the blood, especially PGA. The study confirms the rapid distribution of absorbed folate to the placenta and fetus. FRαAb administered, also accumulates rapidly in the placenta and blocks folate transport to the fetus and high folate concentrations are needed to circumvent or overcome the blocking of FRα. In the presence of FRαAb, both Leucovorin and levofolinate are absorbed and distributed to tissues better than the other forms. However, only 50% of the leucovorin is metabolically active whereas levofolinate is fully active and generates higher tetrahydrofolate (THF). Because levofolinate can readily incorporate into the folate cycle without needing methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) in the first pass and is relatively stable, it should be the folate form of choice during pregnancy, other disorders where large daily doses of folate are needed, and food fortification.
  • Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention.

    Bobrowski-Khoury, Natasha; Ramaekers, Vincent T; Sequeira, Jeffrey M; Quadros, Edward V (2021-07-24)
    Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) pregnancies but is unlikely to prevent pregnancy-related complications in the presence of folate receptor autoantibodies (FRAb). In pregnancy, these autoantibodies can block folate transport to the fetus and in young children, folate transport to the brain. These antibodies are prevalent in neural tube defect pregnancies and in developmental disorders such as cerebral folate deficiency (CFD) syndrome and autism spectrum disorder (ASD). In the latter conditions, folinic acid treatment has shown clinical improvement in some of the core ASD deficits. Early testing for folate receptor autoantibodies and intervention is likely to result in a positive outcome. This review discusses the first identification of FRAb in women with a history of neural tube defect pregnancy and FRAb's association with sub-fertility and preterm birth. Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folinic acid with overall improvements in speech, language and social interaction. The diagnosis of folate receptor autoimmune disorder by measuring autoantibodies against FRα in the serum provides a marker with the potential for treatment and perhaps preventing the pathologic consequences of folate receptor autoimmune disorder.
  • Virtual Reality Hemifield Measurements for Corrective Surgery Eligibility in Ptosis Patients: A Pilot Clinical Trial.

    Labkovich, Margarita; Warburton, Andrew J; Ying, Stephanie; Valliani, Aly A; Kissel, Nicholas; Serafini, Randal A; Mathew, Raj; Paul, Megan; Hovstadius, S Malin; Navarro, Vicente N; et al.
    Purpose: We developed an accelerated virtual reality (VR) suprathreshold hemifield perimetry algorithm, the median cut hemifield test (MCHT). This study examines the ability of the MCHT to determine ptosis severity and its reversibility with an artificial improvement by eyelid taping on an HTC Vive Pro Eye VR headset and the Humphrey visual field analyzer (HVFA) to assess the capabilities of emerging technologies in evaluating ptosis. Methods: In a single visit, the MCHT was administered along with the HVFA 30-2 on ptotic untaped and taped eyelids in a randomized order. The primary end points were a superior field visibility comparison with severity of VF loss and VF improvement after taping for MCHT and HVFA. Secondary end points included evaluating patients' Likert-scaled survey responses on the comfort, speed, and overall experience with both testing modalities. Results: VR's MCHT superior field degrees visible correlated well for severe category margin to reflex distance (r = 0.78) compared with HVFA's (r = -0.21). The MCHT also demonstrated noninferiority (83.3% agreement; P = 1) against HVFA for detection of 30% or more superior visual field improvement after taping, warranting a corrective surgical intervention. In comparing hemi-VF in untaped eyes, both tests demonstrated relative obstruction to the field when comparing normal controls to severe ptosis (HVFA P < 0.05; MCHT P < 0.001), which proved sufficient to demonstrate percent improvement with taping. The secondary end point of patient satisfaction favored VR vision testing presentation mode in terms of comfort (P < 0.01), speed (P < 0.001), and overall experience (P < 0.01). Conclusions: This pilot trial supports the use of MCHT for the quantitative measurement of visual field loss owing to ptosis and the reversibility of ptosis that is tested when conducting a presurgical evaluation. We believe the adoption of MCHT testing in oculoplastic clinics could decrease patient burden and accelerate time to corrective treatment. Translational relevance: In this study, we look at vision field outputs in patients with ptosis to evaluate its severity and improvement with eyelid taping on a low-profile VR-based technology and compare it with HVFA. Our results demonstrate that alternative, portable technologies such as VR can be used to grade the degree of ptosis and determine whether ptosis surgery could provide a significant superior visual field improvement of 30% or more, all while ensuring a more comfortable experience and faster testing time.
  • Multiscale Computer Modeling of Spreading Depolarization in Brain Slices.

    Kelley, Craig; Newton, Adam J H; Hrabetova, Sabina; McDougal, Robert A; Lytton, William W (2022-08-18)
    Spreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and is associated with several neurologic conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (two voltage-gated ion channels; three leak channels; three ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thicknesses) with ion (K+, Cl-, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+ pumps. SD propagated through the slices at realistic speeds of 2-4 mm/min, which increased by as much as 50% in models incorporating the effects of hypoxia or propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make testable predictions, including the following: (1) SD can be inhibited by enlarging ECS volume; (2) SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; (3) SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; (4) Slice thickness influences SD because of relative hypoxia in the slice core, exacerbated by SD in a pathologic cycle; and (5) SD and high neuronal spike rates will be observed in the core of the slice. Cells in the periphery of the slice near an oxygenated bath will resist SD.