title: Non-invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1.
abstract: Spinocerebellar ataxia type 1 (SCA1) is a hereditary, progressive and fatal movement disorder that primarily affects the cerebellum. Non-invasive imaging markers to detect early disease in SCA1 will facilitate testing and implementation of potential therapies. We have previously demonstrated the sensitivity of neurochemical levels measured by (1) H magnetic resonance spectroscopy (MRS) to progressive neurodegeneration using a transgenic mouse model of SCA1. In order to investigate very early neurochemical changes related to neurodegeneration, here we utilized a knock-in mouse model, the Sca1(154Q/2Q) line, which displays milder cerebellar pathology than the transgenic model. We measured cerebellar neurochemical profiles of Sca1(154Q/2Q) mice and wild-type littermates using 9.4T MRS at ages 6, 12, 24, and 39 weeks and assessed the cerebellar pathology of a subset of the mice at each time point. The Sca1(154Q/2Q) mice displayed very mild cerebellar pathology even at 39 weeks, however, were distinguished from wild types by MRS starting at 6 weeks. Taurine and total choline levels were significantly lower at all ages and glutamine and total creatine levels were higher starting at 12 weeks in Sca1(154Q/2Q) mice than controls, demonstrating the sensitivity of neurochemical levels to neurodegeneration related changes in the absence of overt pathology. We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.
authors.affiliation: Department of Radiology, Medical School, Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Uzay E
authors.initials: UE
authors.lastname: Emir
authors.forename: Howard
authors.initials: H
authors.lastname: Brent Clark
authors.forename: Manda L
authors.initials: ML
authors.lastname: Vollmers
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Eberly
authors.forename: Gülin
authors.initials: G
authors.lastname: Öz
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology*; D002794:Choline / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D055879:Gene Knock-In Techniques; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013654:Taurine / Q000378:metabolism
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D013654:Taurine; D002794:Choline
keywords: SCA1; cerebellum; histology; magnetic resonance spectroscopy; mouse model; neurodegeneration
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