title: Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.
abstract: Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2compared to non-carriers within white matter association fibers in the brain. Similar R2decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2within white matter tracts of both species is speculated to be multifaceted. The R2changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. markmeadowcroft@psu.edu.|Department of Radiology (The Center for NMR Research), The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. markmeadowcroft@psu.edu.|Department of Neural and Behavioral Sciences, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA. markmeadowcroft@psu.edu.|Departments of Neurosurgery and Radiology, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, H066 - The Center for NMR Research, 500 University Drive, Hershey, PA, 17033, USA. markmeadowcroft@psu.edu.
authors.forename: Mark D
authors.identifier: 0000-0001-7544-5125
authors.initials: MD
authors.lastname: Meadowcroft
authors.affiliation: Department of Radiology (The Center for NMR Research), The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Carson J
authors.initials: CJ
authors.lastname: Purnell
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.|Department of Neural and Behavioral Sciences, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Peters
authors.affiliation: Department of Neurology, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Eslinger
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Neely
authors.affiliation: Department of Neurology, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Gill
authors.affiliation: Department of Radiology (The Center for NMR Research), The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Vasavada
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ali-Rahmani
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.|Department of Radiology (The Center for NMR Research), The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Qing X
authors.initials: QX
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University - College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D003430:Cross-Sectional Studies; D003627:Data Interpretation, Statistical; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D000071020:Hemochromatosis Protein / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008609:Mental Status Schedule; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009483:Neuropsychological Tests; D066127:White Matter / Q000000981:diagnostic imaging* / Q000503:physiopathology
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein
keywords: H63D; H67D mouse; HFE; MRI; R2; Relaxometry; White matter; rs1799945