title: Longitudinal regional brain volume changes quantified in normal aging and Alzheimer's APP x PS1 mice using MRI.
abstract: In humans, mutations of amyloid precursor protein (APP) and presenilins (PS) 1 and 2 are associated with amyloid deposition, brain structural change and cognitive decline, like in Alzheimer's disease (AD). Mice expressing these proteins have illuminated neurodegenerative disease processes but, unlike in humans, quantitative imaging has been little used to systematically determine their effects, or those of normal aging, on brain structure in vivo. Accordingly, we investigated wildtype (WT) and TASTPM mice (expressing human APP(695(K595N, M596L)) x PS1(M146V)) longitudinally using MRI. Automated global and local image registration, allied to a standard digital atlas, provided pairwise segmentation of 13 brain regions. We found the mature mouse brain, unlike in humans, enlarges significantly from 6-14 months old (WT 3.8+/-1.7%, mean+/-SD, P<0.0001). Significant changes were also seen in other WT brain regions, providing an anatomical benchmark for comparing other mouse strains and models of brain disorder. In TASTPM, progressive amyloidosis and astrogliosis, detected immunohistochemically, reflected even larger whole brain changes (5.1+/-1.4%, P<0.0001, transgenexage interaction P=0.0311). Normalising regional volumes to whole brain measurements revealed significant, prolonged, WT-TASTPM volume differences, suggesting transgene effects establish at <6 months old of age in most regions. As in humans, gray matter-rich regions decline with age (e.g. thalamus, cerebral cortex and caudoputamen); ventricles and white matter (corpus callosum, corticospinal tract, fornix system) increase; in TASTPMs such trends often varied significantly from WT (especially hippocampus). The pervasive, age-related structural changes between WT and AD transgenic mice (and mouse and human) suggest subtle but fundamental species differences and AD transgene effects.
authors.affiliation: Department of Computing, Imperial College, London, UK.
authors.forename: Satheesh
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Hervé
authors.initials: H
authors.lastname: Barjat
authors.forename: Daniel
authors.initials: D
authors.lastname: Rueckert
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bate
authors.forename: David R
authors.initials: DR
authors.lastname: Howlett
authors.forename: Lorna
authors.initials: L
authors.lastname: Tilling
authors.forename: Sean C
authors.initials: SC
authors.lastname: Smart
authors.forename: Andreas
authors.initials: A
authors.lastname: Pohlmann
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartkens
authors.forename: Derek L G
authors.initials: DL
authors.lastname: Hill
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Jo V
authors.initials: JV
authors.lastname: Hajnal
authors.forename: Michael F
authors.initials: MF
authors.lastname: James
mesh_terms: D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000686:Amyloidosis / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D019076:Transgenes / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1