James R Connor1,2, Kari Duck3, Stephanie Patton3, Ian A Simpson4, Lynn Marie Trotti5, Richard Allen6, Christopher J Earley6, David Rye5. 1. Department of Neurosurgery, Penn State Hershey Medical Center, University Dr (H110), 850, Hershey, PA, 17033, USA. jconnor@pennstatehealth.psu.edu. 2. Department of Neural and Behavioral Sciences, Penn State Hershey Medical Center, Hershey, PA, USA. jconnor@pennstatehealth.psu.edu. 3. Department of Neurosurgery, Penn State Hershey Medical Center, University Dr (H110), 850, Hershey, PA, 17033, USA. 4. Department of Neural and Behavioral Sciences, Penn State Hershey Medical Center, Hershey, PA, USA. 5. Department of Neurology, Emory University, Atlanta, GA, USA. 6. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Abstract
BACKGROUND: Iron is crucial for proper functioning of all organs including the brain. Deficiencies and excess of iron are common and contribute to substantial morbidity and mortality. Whereas iron's involvement in erythropoiesis drives clinical practice, the guidelines informing interventional strategies for iron repletion in neurological disorders are poorly defined. The objective of this study was to determine if peripheral iron status is communicated to the brain. METHODS: We used a bi-chamber cell culture model of the blood-brain-barrier to determine transcytosis of iron delivered by transferrin as a metric of iron transport. In the apical chamber (representative of the blood) we placed transferrin complexed with iron59 and in the basal chamber (representative of the brain) we placed human cerebrospinal fluid. Cerebrospinal fluid (CSF) samples (N = 24) were collected via lumbar puncture. The integrity of the tight junctions were monitored throughout the experiments using RITC-Dextran. RESULTS: We demonstrate that iron transport correlates positively with plasma hemoglobin concentrations but not serum ferritin levels. CONCLUSIONS: The clinical ramifications of these findings are several- fold. They suggest that erythropoietic demands for iron take precedence over brain requirements, and that the metric traditionally considered to be the most specific test reflecting total body iron stores and relied upon to inform treatment decisions-i.e., serum ferritin-may not be the preferred peripheral indicator when attempting to promote brain iron uptake. The future direction of this line of investigation is to identify the factor(s) in the CSF that influence iron transport at the level of the BBB.
BACKGROUND:Iron is crucial for proper functioning of all organs including the brain. Deficiencies and excess of iron are common and contribute to substantial morbidity and mortality. Whereas iron's involvement in erythropoiesis drives clinical practice, the guidelines informing interventional strategies for iron repletion in neurological disorders are poorly defined. The objective of this study was to determine if peripheral iron status is communicated to the brain. METHODS: We used a bi-chamber cell culture model of the blood-brain-barrier to determine transcytosis of iron delivered by transferrin as a metric of iron transport. In the apical chamber (representative of the blood) we placed transferrin complexed with iron59 and in the basal chamber (representative of the brain) we placed human cerebrospinal fluid. Cerebrospinal fluid (CSF) samples (N = 24) were collected via lumbar puncture. The integrity of the tight junctions were monitored throughout the experiments using RITC-Dextran. RESULTS: We demonstrate that iron transport correlates positively with plasma hemoglobin concentrations but not serum ferritin levels. CONCLUSIONS: The clinical ramifications of these findings are several- fold. They suggest that erythropoietic demands for iron take precedence over brain requirements, and that the metric traditionally considered to be the most specific test reflecting total body iron stores and relied upon to inform treatment decisions-i.e., serum ferritin-may not be the preferred peripheral indicator when attempting to promote brain iron uptake. The future direction of this line of investigation is to identify the factor(s) in the CSF that influence iron transport at the level of the BBB.
Authors: Eric J Earley; Maria Didriksen; Bryan R Spencer; Joseph E Kiss; Christian Erikstrup; Ole B Pedersen; Erik Sørensen; Kristoffer S Burgdorf; Steven H Kleinman; Alan E Mast; Michael P Busch; Henrik Ullum; Grier P Page Journal: Sleep Date: 2021-04-09 Impact factor: 5.849