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Evolution of extra-nigral damage predicts behavioural deficits in a rat proteasome inhibitor model of Parkinson's disease.

Vernon AC, Crum WR, Johansson SM, Modo M - PLoS ONE (2011)

Bottom Line: Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5.Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor.These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, Kings College London, London, United Kingdom.

ABSTRACT
Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

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Related in: MedlinePlus

Deformation Based Morphometry confirms and extends manual segmentation analysis.Comparisons between the saline and lactacystin mean normalised MR images are shown for each time-point (p<0.02 uncorrected). The coloured overlay shows the scale factor of local apparent volume differences (on a logarithmic scale). Red/yellow indicates local tissue volume expansions, whilst blue/cyan indicates local tissue volume contractions.
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pone-0017269-g005: Deformation Based Morphometry confirms and extends manual segmentation analysis.Comparisons between the saline and lactacystin mean normalised MR images are shown for each time-point (p<0.02 uncorrected). The coloured overlay shows the scale factor of local apparent volume differences (on a logarithmic scale). Red/yellow indicates local tissue volume expansions, whilst blue/cyan indicates local tissue volume contractions.

Mentions: This analysis identified several areas of local tissue volume change in cortical and sub-cortical areas, which evolved with time (Figure 5). At wk 1, increases in CSF space in lactacystin-treated animals are evident and persist until wk 5. At wk 3, local volume decreases in the ipsilateral VM were evident and continued to expand at wk 5. Similarly, volume decreases were observed in the ipsilateral STR at wk 3 and 5, but interestingly, DBM analysis suggests that volume change is confined to the lateral and medial dorsal regions of the ipsilateral STR. Decreases in the ipsilateral CTX volume were not readily apparent from wk 1 onwards, but small, localized areas of volume decrease may be observed in frontal cortical areas. By wk 3 and wk 5 however, cortical volume decreases are widespread in the ipsilateral hemisphere. Intriguingly, DBM analysis also suggests volume decreases in the contralateral CTX by wk 5. No local tissue volume changes were observed in the hippocampus. Apparent changes in the cerebellum were a reflection of the general brain volume decrease that resulted in a larger gap between cerebrum and cerebellum. Taken together, DBM analysis confirms the manual segmentation results.


Evolution of extra-nigral damage predicts behavioural deficits in a rat proteasome inhibitor model of Parkinson's disease.

Vernon AC, Crum WR, Johansson SM, Modo M - PLoS ONE (2011)

Deformation Based Morphometry confirms and extends manual segmentation analysis.Comparisons between the saline and lactacystin mean normalised MR images are shown for each time-point (p<0.02 uncorrected). The coloured overlay shows the scale factor of local apparent volume differences (on a logarithmic scale). Red/yellow indicates local tissue volume expansions, whilst blue/cyan indicates local tissue volume contractions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045435&req=5

pone-0017269-g005: Deformation Based Morphometry confirms and extends manual segmentation analysis.Comparisons between the saline and lactacystin mean normalised MR images are shown for each time-point (p<0.02 uncorrected). The coloured overlay shows the scale factor of local apparent volume differences (on a logarithmic scale). Red/yellow indicates local tissue volume expansions, whilst blue/cyan indicates local tissue volume contractions.
Mentions: This analysis identified several areas of local tissue volume change in cortical and sub-cortical areas, which evolved with time (Figure 5). At wk 1, increases in CSF space in lactacystin-treated animals are evident and persist until wk 5. At wk 3, local volume decreases in the ipsilateral VM were evident and continued to expand at wk 5. Similarly, volume decreases were observed in the ipsilateral STR at wk 3 and 5, but interestingly, DBM analysis suggests that volume change is confined to the lateral and medial dorsal regions of the ipsilateral STR. Decreases in the ipsilateral CTX volume were not readily apparent from wk 1 onwards, but small, localized areas of volume decrease may be observed in frontal cortical areas. By wk 3 and wk 5 however, cortical volume decreases are widespread in the ipsilateral hemisphere. Intriguingly, DBM analysis also suggests volume decreases in the contralateral CTX by wk 5. No local tissue volume changes were observed in the hippocampus. Apparent changes in the cerebellum were a reflection of the general brain volume decrease that resulted in a larger gap between cerebrum and cerebellum. Taken together, DBM analysis confirms the manual segmentation results.

Bottom Line: Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5.Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor.These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, Kings College London, London, United Kingdom.

ABSTRACT
Establishing the neurological basis of behavioural dysfunction is key to provide a better understanding of Parkinson's disease (PD) and facilitate development of effective novel therapies. For this, the relationships between longitudinal structural brain changes associated with motor behaviour were determined in a rat model of PD and validated by post-mortem immunohistochemistry. Rats bearing a nigrostriatal lesion induced by infusion of the proteasome inhibitor lactacystin into the left-medial forebrain bundle and saline-injected controls underwent magnetic resonance imaging (MRI) at baseline (prior to surgery) and 1, 3 and 5 weeks post-surgery with concomitant motor assessments consisting of forelimb grip strength, accelerating rotarod, and apormorphine-induced rotation. Lactacystin-injected rats developed early motor deficits alongside decreased ipsilateral cortical volumes, specifically thinning of the primary motor (M1) and somatosensory cortices and lateral ventricle hypertrophy (as determined by manual segmentation and deformation-based morphometry). Although sustained, motor dysfunction and nigrostriatal damage were maximal by 1 week post-surgery. Additional volume decreases in the ipsilateral ventral midbrain; corpus striatum and thalamus were only evident by week 3 and 5. Whilst cortical MRI volume changes best predicted the degree of motor impairment, post-mortem tyrosine hydroxylase immunoreactivity in the striatum was a better predictor of motor behaviour overall, with the notable exception of performance in the accelerating rotarod, in which, M1 cortical thickness remained the best predictor. These results highlight the importance of identifying extra-nigral regions of damage that impact on behavioural dysfunction from damage to the nigrostriatal system.

Show MeSH
Related in: MedlinePlus