OBJECTIVE: Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation. METHODS: We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically-defined lesions with contrast-weighted and diffusion-weighted high-field ex vivo MRI data. RESULTS: Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined 2 novel hypointense signal abnormalities on T(2) -weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity. INTERPRETATION: These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.
OBJECTIVE: Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white-matter injury (WMI) in preterm survivors, the histopathological features of MRI-defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation. METHODS: We employed a preterm fetal sheep model of global cerebral ischemia in which acute WMI results in selective preOL degeneration. We developed novel algorithms to register histopathologically-defined lesions with contrast-weighted and diffusion-weighted high-field ex vivo MRI data. RESULTS: Despite mild delayed preOL degeneration, preOL density recovered to control levels by 7 days after ischemia and was ~2 fold greater at 14 days. However, premyelinating OLs were significantly diminished at 7 and 14 days. WMI evolved to mostly gliotic lesions where arrested preOL differentiation was directly proportional to the magnitude of astrogliosis. A reduction in cerebral WM volume was accompanied by four classes of MRI-defined lesions. Each lesion type displayed unique astroglial and microglial responses that corresponded to distinct forms of necrotic or non-necrotic injury. High-field MRI defined 2 novel hypointense signal abnormalities on T(2) -weighted images that coincided with microscopic necrosis or identified astrogliosis with high sensitivity and specificity. INTERPRETATION: These studies support the potential of high-field MRI for early identification of microscopic necrosis and gliosis with preOL maturation arrest, a common form of WMI in preterm survivors.
Authors: Stephen M Smith; Mark Jenkinson; Mark W Woolrich; Christian F Beckmann; Timothy E J Behrens; Heidi Johansen-Berg; Peter R Bannister; Marilena De Luca; Ivana Drobnjak; David E Flitney; Rami K Niazy; James Saunders; John Vickers; Yongyue Zhang; Nicola De Stefano; J Michael Brady; Paul M Matthews Journal: Neuroimage Date: 2004 Impact factor: 6.556
Authors: K Reddy; C Mallard; J Guan; K Marks; L Bennet; M Gunning; A Gunn; P Gluckman; C Williams Journal: Pediatr Res Date: 1998-05 Impact factor: 3.756
Authors: David Pitt; Aaron Boster; Wei Pei; Eric Wohleb; Adam Jasne; Cherian R Zachariah; Kottil Rammohan; Michael V Knopp; Petra Schmalbrock Journal: Arch Neurol Date: 2010-07
Authors: Shannon E G Hamrick; Steven P Miller; Carol Leonard; David V Glidden; Ruth Goldstein; Vijay Ramaswamy; Robert Piecuch; Donna M Ferriero Journal: J Pediatr Date: 2004-11 Impact factor: 4.406
Authors: K Schmierer; F Scaravilli; G J Barker; R Gordon; D G MacManus; D H Miller Journal: Neuropathol Appl Neurobiol Date: 2003-12 Impact factor: 8.090
Authors: Art Riddle; Jennifer Maire; Xi Gong; Kevin X Chen; Christopher D Kroenke; A Roger Hohimer; Stephen A Back Journal: Stroke Date: 2011-11-10 Impact factor: 7.914
Authors: Joshua R Buser; Jennifer Maire; Art Riddle; Xi Gong; Thuan Nguyen; Kerst Nelson; Ning Ling Luo; Jennifer Ren; Jaime Struve; Larry S Sherman; Steven P Miller; Vann Chau; Glenda Hendson; Praveen Ballabh; Marjorie R Grafe; Stephen A Back Journal: Ann Neurol Date: 2012-01 Impact factor: 10.422
Authors: Justin M Dean; Evelyn McClendon; A Roger Hohimer; Christopher D Kroenke; Kelly Hansen; Aryan Azimi-Zonooz; Kevin Chen; Art Riddle; Xi Gong; Elica Sharifnia; Matthew Hagen; Tahir Ahmad; Lindsey A Leigland; Stephen A Back Journal: Sci Transl Med Date: 2013-01-16 Impact factor: 17.956
Authors: Vann Chau; Anne Synnes; Ruth E Grunau; Kenneth J Poskitt; Rollin Brant; Steven P Miller Journal: Neurology Date: 2013-11-08 Impact factor: 9.910
Authors: Susan R Criswell; Gill Nelson; Luis F Gonzalez-Cuyar; John Huang; Joshua S Shimony; Harvey Checkoway; Christopher D Simpson; Russell Dills; Noah S Seixas; Brad A Racette Journal: Neurotoxicology Date: 2015-04-23 Impact factor: 4.294