title: C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence.
abstract: OBJECTIVE
  To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective.
  
  
  METHODS
  Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing. Regional neuronal loss was measured in an independent autopsy series (n = 35) of C9orf72 repeat expansion patients.
  
  
  RESULTS
  GM analysis revealed that hippocampus, frontal cortex, and thalamus are associated with hypermethylation and thus appear to be relatively protected from mutant C9orf72. Neuropathologic analysis demonstrated an association between reduced neuronal loss and hypermethylation in hippocampus and frontal cortex. Longitudinal neuroimaging revealed that hypermethylation is associated with reduced longitudinal decline in GM regions protected by hypermethylation and longitudinal neuropsychological assessment demonstrated that longitudinal decline in verbal recall is protected by hypermethylation.
  
  
  CONCLUSIONS
  These cross-sectional and longitudinal neuroimaging studies, along with neuropathologic validation studies, provide converging evidence for neuroprotective properties of C9orf72 promoter hypermethylation. These findings converge with prior postmortem studies suggesting that C9orf72 promoter hypermethylation may be a neuroprotective target for drug discovery.
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Corey T
authors: CT
authors: McMillan
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Jenny
authors: J
authors: Russ
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Elisabeth M
authors: EM
authors: Wood
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: David J
authors: DJ
authors: Irwin
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Murray
authors: M
authors: Grossman
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Leo
authors: L
authors: McCluskey
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Lauren
authors: L
authors: Elman
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia.
authors: Vivanna
authors: V
authors: Van Deerlin
authors: From the Penn Frontotemporal Degeneration Center (C.T.M., D.J.I., M.G.), Penn Medicine Neuroscience Center at Pennsylvania Hospital (L.M., L.E.), Department of Neurology (C.T.M., D.J.I., M.G., L.M., L.E.), Translational Neuropathology Research Laboratory (J.R., E.B.L.), Center for Neurodegenerative Disease Research, Department of Pathology & Laboratory Medicine (E.M.W., D.J.I., V.V.D.), Institute for Translation Medicine & Therapeutics (C.T.M., D.J.I.), the University of Pennsylvania Perelman School of Medicine, Philadelphia. edward.lee@uphs.upenn.edu mcmillac@upenn.edu.
authors: Edward B
authors: EB
authors: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000073885:C9orf72 Protein; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D042622:DNA Repeat Expansion / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D066128:Gray Matter / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D013788:Thalamus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins