White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.
Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington disease (HD). In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128 mouse model of HD. Treatment with laquinimod for 6 months rescued atrophy in the striatum, in certain cortical regions, and in the corpus callosum of YAC128 HD mice. Diffusion tensor imaging showed that white matter microstructural abnormalities in the posterior corpus callosum were improved following treatment with low dose (1 mg/kg) laquinimod, and were paralleled by reduced levels of interleukin-6 in the periphery of YAC128 HD mice. Functionally, treatment with laquinimod (1 and 10 mg/kg) led to modest improvements in motor function and in depressive-like behaviour. Taken together, these results suggest that laquinimod may improve some features of pathology in HD, and provides support for the role of immune activation in the pathogenesis of HD.Huntington disease (HD) is an inherited, progressive neurodegenerative disorder caused by a dominant mutation in huntingtin (HTT), a ubiquitously expressed gene 1 . The clinical phenotype of HD includes psychiatric disturbances such as depression and psychosis, cognitive deficits, and impairment of motor function with abnormal voluntary (gait, balance, hand movements) and involuntary movements (chorea and dystonia) 1 . Neuropathologically, the disease is characterised by striking atrophy of the striatum and thinning of the cortex, which is accompanied by early and progressive white matter loss 1 . Volumetric MRI changes in HD include pronounced caudate atrophy accompanied by putaminal and whole brain atrophy early in the disease course 2 . Despite the significant unmet need and intensive efforts to develop therapies over the past three decades, no effective treatment to reverse, stop or slow the progression of HD has been identified 3 .Several disease mechanisms have been implicated in HD, including aberrant synaptic signalling, transcriptional dysregulation, altered proteolysis, impaired intracellular trafficking, and loss of neurotrophic support 4 . Increasing evidence also supports a role for abnormal immune activation and inflammatory responses in HD 5-8 . Significant accumulation of microglia, the CNS-resident macrophage, is seen in regions with neuronal
Learning is a process which induces plastic changes in the synapses and connections across different regions of the brain. It is hypothesized that these new connections can be tracked with resting state functional connectivity MRI. While most of the evidence of learning-induced plasticity arises from previous human data, data from sedated rats that had undergone training for either 1 day or 5 days in a Morris Watermaze is presented. Seed points were taken from the somatosensory and visual cortices, and the hippocampal CA3 to detect connectivity changes. The data demonstrates that 5-day trained rats showed increased correlations between the hippocampal CA3 and thalamus, septum and cingulate cortex, compared to swim control or naïve animals. Seven days after the training, persistent but reorganized networks toward the cortex were observed. Data from the 1-day trained rats, on the contrary, showed connectivity similar to the swim control and less persistent. The connectivity in several regions was highly correlated with the behavioral performance in these animals. The data demonstrates that longitudinal changes following learning-induced plasticity can be detected and tracked with resting state connectivity.
Early loss of white matter microstructure integrity is a significant cause of long-term neurological disorders following traumatic brain injury (TBI). White matter abnormalities typically involve axonal loss and demyelination. In-vivo imaging tools to detect and differentiate such microstructural changes are not well-explored. This work utilizes the conjoint potential offered by advanced magnetic resonance imaging techniques, including quantitative susceptibility mapping (QSM) and diffusion tensor imaging (DTI), to discern the underlying white matter pathology at specific time points (5 h, 1, 3, 7, 14, and 30 days) post-injury in the controlled cortical impact mouse model. A total of 42 animals were randomized into six TBI groups (n = 6 per group) and one sham group (n = 6). Histopathology was performed to validate in-vivo findings by performing myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) immunostaining for the assessment of changes to myelin and astrocytes. After 5 h of injury radial diffusivity (RD) was increased in white matter without a significant change in axial diffusivity (AxD) and susceptibility values. After 1 day post-injury RD was decreased. AxD and susceptibility changes were seen after 3 days post-injury. Susceptibility increases in white matter were observed in both ipsilateral and contralateral regions and persisted for 30 days. In histology, an increase in GFAP immunoreactivity was observed after 3 days post-injury and remained high for 30 days in both ipsilateral and contralateral white matter regions. A loss in MBP signal was noted after 3 days post-injury that continued up to 30 days. In conclusion, these results demonstrate the complementary ability of DTI and QSM in discerning the micro-pathological processes triggered following TBI. While DTI revealed acute and focal white matter changes, QSM mirrored the temporal demyelination in the white matter tracts and diffuse regions at the chronic state.
Traumatic brain injury (TBI) has been linked with tauopathy. However, imaging methods that can non-invasively detect tau-protein abnormalities following TBI need further investigation. This study aimed to investigate the potential of diffusion tensor imaging (DTI) to detect tauopathy following TBI in P301L mutant-tau-transgenic-pR5-mice. A total of 24 9-month-old pR5 mice were randomly assigned to sham and TBI groups. Controlled cortical injuries/craniotomies were performed for TBI/sham groups followed by DTI data acquisition on days 1 and 7 post-injury. DTI data were analyzed by using voxelwise analysis and track-based spatial statistics for gray matter and white matter. Further, immunohistochemistry was performed for total-tau and phosphorylated-tau, astrocytes, and microglia. To detect the association of DTI with these pathological markers, a correlation analysis was performed between DTI and histology findings. At day 1 post-TBI, DTI revealed a widespread reduction in fractional anisotropy (FA) and axial diffusivity (AxD) in the TBI group compared to shams. On day 7, further reduction in FA, AxD, and mean diffusivity and increased radial diffusivity were observed. FA was significantly increased in the amygdala and cortex. Correlation results showed that in the ipsilateral hemisphere FA reduction was associated with increased phosphorylated-tau and glial-immunoreactivity, whereas in the contralateral regions, the FA increase was associated with increased immunostaining for astrocytes. This study is the first to exploit DTI to investigate the effect of TBI in tau-transgenic mice. We show that alterations in the DTI signal were associated with glial activity following TBI and would most likely reflect changes that co-occur with/without phosphorylated-tau. In addition, FA may be a promising measure to identify discrete pathological processes such as increased astroglia activation, tau-hyperphosphorylation or both in the brain following TBI.
Concussion or mild traumatic brain injury is the most common form of traumatic brain injury with potentially long-term consequences. Current objective diagnosis and treatment options are limited to clinical assessment, cognitive rest, and symptom management, which raises the real danger of concussed patients being released back into activities where subsequent and cumulative injuries may cause disproportionate damages. This study conducted a cross-sectional multi-modal examination investigation of the temporal changes in behavioural and brain changes in a mouse model of concussion using magnetic resonance imaging. Sham and concussed mice were assessed at day 2, day 7, and day 14 post-sham or injury procedures following a single concussion event for motor deficits, psychological symptoms with open field assessment, T2-weighted structural imaging, diffusion tensor imaging (DTI), neurite orientation density dispersion imaging (NODDI), stimulus-evoked and resting-state functional magnetic resonance imaging (fMRI). Overall, a mismatch in the temporal onsets and durations of the behavioural symptoms and structural/functional changes in the brain was seen. Deficits in behaviour persisted until day 7 post-concussion but recovered at day 14 post-concussion. DTI and NODDI changes were most extensive at day 7 and persisted in some regions at day 14 post-concussion. A persistent increase in connectivity was seen at day 2 and day 14 on rsfMRI. Stimulus-invoked fMRI detected increased cortical activation at day 7 and 14 post-concussion. Our results demonstrate the capabilities of advanced MRI in detecting the effects of a single concussive impact in the brain, and highlight a mismatch in the onset and temporal evolution of behaviour, structure, and function after a concussion. These results have significant translational impact in developing methods for the detection of human concussion and the time course of brain recovery.
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