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.

Keywords: SCA1; cerebellum; histology; magnetic resonance spectroscopy; mouse model; neurodegeneration.

Fig. 1

(a) Mid-sagittal (top row) and coronal (bottom row) T₂-weighted images showing the placement of the cerebellar volume-of-interest in a Sca1^154Q/2Q mouse (right) and a wild-type mouse (left) at 39 weeks. (b) Histological assessment in a Sca1^154Q/2Q mouse (right) and a wild-type mouse (left) at 39 weeks. The top slides show the entire cerebellum, the bottom slides show an area indicated on the mid-sagittal cerebellum scheme. Slides were stained with hematoxylin-and-eosin and the bars indicate dimensions, 1 mm or 100 µm.

Fig. 2

Mean (a) weights, (b) molecular layer thickness in the primary fissure and (c) global pathological severity scores of the Sca1^154Q/2Q and wild-type mice at 6, 12, 24, and 39 weeks of age. Error bars indicate standard deviations. * indicates p < 0.05.

Fig. 3

Localized proton MR spectra [localization by adiabatic selective refocusing (LASER), TE = 15 ms, TR = 5 s] obtained from one wild-type (upper row) and one Sca1^154Q/2Q mouse (lower row) across their life spans. The spectra were processed identically, weighted with the same Gaussian function prior to Fourier transformation and scaled based on neurochemical concentrations obtained by LCModel. The longitudinal alterations in total choline and taurine in the spectra of the Sca1^154Q/2Q mouse are shown with arrows.

Fig. 4

Cerebellar neurochemical profiles of the Sca1^154Q/2Q (white bars) and wild-type (black bars) mice at four ages. Error bars indicate standard deviations. * indicates p ≤ 0.05, ** indicates p ≤ 0.01.

Fig. 5

Time courses of taurine, total choline, glutamine, and total creatine in the cerebella of the Sca1^154Q/2Q (white squares) and wild-type (black squares) mice. Error bars indicate standard deviations. * indicates p ≤ 0.05, ** indicates p ≤ 0.01.

Fig. 6

Separation of Sca1^154Q/2Q (white circles) from wild-type mice (black circles) at each age. Concentrations of taurine and total choline obtained from the cerebella of individual mice are plotted.