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MRI and MRS alterations in the preclinical phase of murine prion disease: Association with neuropathological and behavioural changes

MRI and MRS alterations in the preclinical phase of murine prion disease: Association with neuropathological and behavioural changes
MRI and MRS alterations in the preclinical phase of murine prion disease: Association with neuropathological and behavioural changes
Prion diseases are fatal chronic neurodegenerative diseases. Previous qualitative magnetic resonance imaging (MRI) and spectroscopy (MRS) studies report conflicting results in the symptomatic stages of the disease, but little work has been carried out during the earlier stages of the disease. Here we have used the murine ME7 model of prion disease to quantitatively investigate MRI and MRS changes during the period prior to the onset of overt clinical signs (20+ weeks) and have correlated these with pathological and behavioural abnormalities. Using in vivo MRI, at the later stages of the preclinical period (18 weeks) the diffusion of tissue water was significantly reduced, coinciding with significant microglial activation and behavioural hyperactivity. Using in vivo MRS, we found early (12 weeks) decreases in the ratio of N-acetyl aspartate to both choline (NAA/Cho) and creatine (NAA/Cr) in the thalamus and hippocampus, which were associated with early behavioural deficits. Ex vivo MRS of brain extracts confirmed and extended these findings, showing early (8–12 weeks) decreases in both the neuronal metabolites NAA and glutamate, and the metabolic metabolites lactate and glucose. Increases in the glial metabolite myo-inositol were observed at later stages when microglial and astrocyte activation is substantial. These changes in MRI and MRS signals, which precede overt clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology.
magnetic resonance, diffusion, N-acetyl aspartate, prion, chronic inflammation, brain, neurodegeneration, thalamus
0969-9961
707-717
Broom, Kerry A.
48ea5f70-5512-4616-9994-d31da056c3db
Anthony, Daniel C.
928249fa-dcf4-4088-b95b-ce14c719164d
Lowe, John P.
d08a6bff-c43e-488f-a072-eaa5873c4cd7
Griffin, Julian L.
efbf2925-ee1c-4e28-8e89-c1a70d143928
Scott, Helen
7489e2f8-7d22-493f-bf58-3237ef05b8f4
Blamire, Andrew M.
9e32053d-5a8f-4358-b1c1-eb16e5d67b8d
Styles, Peter
2a4bcc97-b4cb-45c2-807c-7f4e54b916d2
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Sibson, Nicola R.
408b5626-2da8-4fc8-9fb5-bbe52a7b8aaf
Broom, Kerry A.
48ea5f70-5512-4616-9994-d31da056c3db
Anthony, Daniel C.
928249fa-dcf4-4088-b95b-ce14c719164d
Lowe, John P.
d08a6bff-c43e-488f-a072-eaa5873c4cd7
Griffin, Julian L.
efbf2925-ee1c-4e28-8e89-c1a70d143928
Scott, Helen
7489e2f8-7d22-493f-bf58-3237ef05b8f4
Blamire, Andrew M.
9e32053d-5a8f-4358-b1c1-eb16e5d67b8d
Styles, Peter
2a4bcc97-b4cb-45c2-807c-7f4e54b916d2
Perry, V. Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Sibson, Nicola R.
408b5626-2da8-4fc8-9fb5-bbe52a7b8aaf

Broom, Kerry A., Anthony, Daniel C., Lowe, John P., Griffin, Julian L., Scott, Helen, Blamire, Andrew M., Styles, Peter, Perry, V. Hugh and Sibson, Nicola R. (2007) MRI and MRS alterations in the preclinical phase of murine prion disease: Association with neuropathological and behavioural changes. Neurobiology of Disease, 26 (3), 707-717. (doi:10.1016/j.nbd.2007.04.001).

Record type: Article

Abstract

Prion diseases are fatal chronic neurodegenerative diseases. Previous qualitative magnetic resonance imaging (MRI) and spectroscopy (MRS) studies report conflicting results in the symptomatic stages of the disease, but little work has been carried out during the earlier stages of the disease. Here we have used the murine ME7 model of prion disease to quantitatively investigate MRI and MRS changes during the period prior to the onset of overt clinical signs (20+ weeks) and have correlated these with pathological and behavioural abnormalities. Using in vivo MRI, at the later stages of the preclinical period (18 weeks) the diffusion of tissue water was significantly reduced, coinciding with significant microglial activation and behavioural hyperactivity. Using in vivo MRS, we found early (12 weeks) decreases in the ratio of N-acetyl aspartate to both choline (NAA/Cho) and creatine (NAA/Cr) in the thalamus and hippocampus, which were associated with early behavioural deficits. Ex vivo MRS of brain extracts confirmed and extended these findings, showing early (8–12 weeks) decreases in both the neuronal metabolites NAA and glutamate, and the metabolic metabolites lactate and glucose. Increases in the glial metabolite myo-inositol were observed at later stages when microglial and astrocyte activation is substantial. These changes in MRI and MRS signals, which precede overt clinical signs of disease, could provide insights into the pathogenesis of this disease and may enable early detection of pathology.

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More information

Published date: June 2007
Keywords: magnetic resonance, diffusion, N-acetyl aspartate, prion, chronic inflammation, brain, neurodegeneration, thalamus

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Local EPrints ID: 56528
URI: https://eprints.soton.ac.uk/id/eprint/56528
ISSN: 0969-9961
PURE UUID: 0276b90c-2ca7-4441-b6a0-f35afac85fa5

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Date deposited: 07 Aug 2008
Last modified: 13 Mar 2019 20:35

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Contributors

Author: Kerry A. Broom
Author: Daniel C. Anthony
Author: John P. Lowe
Author: Julian L. Griffin
Author: Helen Scott
Author: Andrew M. Blamire
Author: Peter Styles
Author: V. Hugh Perry
Author: Nicola R. Sibson

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