Abstract
BackgroundPredominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.ResultsLactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model.ConclusionsA pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo.
Highlights
Magnetic resonance imaging (MRI) studies in animal models of Parkinson’s disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed
Patterns of morphometric change which can be readily detected by magnetic resonance imaging (MRI) are already utilised clinically to aid differential diagnosis of idiopathic PD (iPD) from other forms of parkinsonism, including the a-synucleinopathy multiple system atrophy (MSA) and the tauopathy progressive supranuclear palsy (PSP) [13,14]
In summary, this study has identified a pattern of morphological changes in lactacystin lesioned animals, as well as alterations in nigral T2 relaxivity, that are somewhat consistent with published clinical neuroimaging data from iPD patients
Summary
Magnetic resonance imaging (MRI) studies in animal models of Parkinson’s disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder characterised by a selective vulnerability and degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) [1]. This is accompanied by formation of eosinophilic cytoplasmic inclusions in remaining neurons, termed Lewy bodies (LB), composed primarily of fibrillar aggregates of a-synuclein [2]. Voxel-based morphometry (VBM) studies have reported significant morphological changes, including atrophy of the head of the left caudate nucleus and cortical changes in both early and advanced iPD, which correlated robustly with clinical symptoms [4,11]. Patterns of morphometric change which can be readily detected by MRI are already utilised clinically to aid differential diagnosis of iPD from other forms of parkinsonism, including the a-synucleinopathy multiple system atrophy (MSA) and the tauopathy progressive supranuclear palsy (PSP) [13,14]
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