107 results found
Fletcher EJR, Finlay CJ, Amor Lopez A, et al., 2020, Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats, FRONTIERS IN NEUROSCIENCE, Vol: 14
Aboagye E, Sharma R, Inglese M, et al., 2020, Monitoring response to transarterial chemoembolization in hepatocellular carcinoma using 18F-Fluorothymidine Positron Emission Tomography, The Journal of Nuclear Medicine, ISSN: 0161-5505
Accurate disease monitoring is essential following transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) due to potential for profound adverse event and large variation in survival outcome. Post-treatment changes on conventional imaging can confound determination of residual/recurrent disease, magnifying the clinical challenge. Based on increased expression of thymidylate synthase (TYMS), thymidine kinase-1 (TK-1) and SLC29A1 (Equilibrative nucleoside transporter 1, ENT1) in HCC compared with liver tissue, we conducted a proof of concept study evaluating the efficacy of 18F-fluorothymidine (18F-FLT)-PET to assess response to TACE. As previous PET studies in HCC have been hampered by high background liver signal, we investigated if a temporal-intensity voxel-clustering (“Kinetic Spatial Filtering”) (KSF) improved lesion detection. Methods: A tissue microarray (TMA) was built from 36 HCC samples and matched surrounding cirrhotic tissue and was stained for thymidine kinase-1 (TK-1). A prospective study was conducted; eighteen patients with a diagnosis of HCC by American Association for the Study of Liver Diseases criteria (AALSD) who were eligible to treatment with TACE were enrolled. Patients underwent baseline conventional imaging and dynamic 18F-FLT-PET/KSF followed by TACE. Repeat imaging was performed 6-8 weeks post TACE. PET parameters were compared with modified-Response Evaluation in Solid Tumours (mRECIST) enhancement-based criteria. Results: Cancer Genome Atlas analysis revealed increased RNA expression of TYMS, TK-1 and SLC29A1 in HCC. TK-1 protein expression was significantly higher in HCC (p<0.05). The sensitivity of 18F-FLT-PET for baseline HCC detection was 73% (SUVmax of 9.7 ± 3.0; tumour to liver ratio of 1.2 ± 0.3). Application of KSF did not improve lesion detection. Lesion response following TACE by mRECIST criteria was 58% (14 patients with 24 lesions). A 30% reduction in mean 18F-FLT-PET uptake was o
Ashmore J, Pemberton HG, Crum WD, et al., 2020, Implementation of clinical tractography for pre-surgical planning of space occupying lesions: An investigation of common acquisition and post-processing methods compared to dissection studies, PLoS One, Vol: 15, ISSN: 1932-6203
BACKGROUND AND PURPOSE: There is limited standardization of acquisition and processing methods in diffusion tractography for pre-surgical planning, leading to a range of approaches. In this study, a number of representative acquisition variants and post processing methods are considered, to assess their importance when implementing a clinical tractography program. METHODS: Diffusion MRI was undertaken in ten healthy volunteers, using protocols typical of clinical and research scanning: a 32-direction diffusion acquisition with and without peripheral gating, and a non-gated 64 diffusion direction acquisition. All datasets were post-processed using diffusion tensor reconstruction with streamline tractography, and with constrained spherical deconvolution (CSD) with both streamline and probabilistic tractography, to delineate the cortico-spinal tract (CST) and optic radiation (OR). The accuracy of tractography results was assessed against a histological atlas using a novel probabilistic Dice overlap technique, together with direct comparison to tract volumes and distance of Meyer's loop to temporal pole (ML-TP) from dissections studies. Three clinical case studies of patients with space occupying lesions were also investigated. RESULTS: Tracts produced by CSD with probabilistic tractography provided the greatest overlap with the histological atlas (overlap scores of 44% and 52% for the CST and OR, respectively) and best matched tract volume and ML-TP distance from dissection studies. The acquisition protocols investigated had limited impact on the accuracy of the tractography. In all patients, the CSD based probabilistic tractography created tracts with greatest anatomical plausibility, although in one case anatomically plausible pathways could not be reconstructed without reducing the probabilistic threshold, leading to an increase in false positive tracts. CONCLUSIONS: Advanced post processing techniques such as CSD with probabilistic tractography are vital for pre-su
Kang J, Tsai C-C, Hasegawa H, et al., 2019, The effect of hyper-buoyancy floatation (HBF), a model of simulated microgravity, on sleep and cognitive function in humans, 15th World Sleep Congress, September 20-25, 2019 World Sleep 2019, Publisher: ELSEVIER, Pages: S392-S392, ISSN: 1389-9457
Introduction: Microgravity is known to alter various physiological variables in humans. However, changes in neuroanatomy, cognition, and sleep have not been significantly studied in the literature. The aim of the present study was to determine the effect of seven-days of supine unloading on a supersaturated saline-filled water bed (hyper-buoyancy floatation, HBF), a novel Earth-based microgravity analogue, on cognition and sleep.Materials and methods: Twelve healthy male subjects were subject to seven continuous days of HBF, during which subjects' (floatonauts') major cognitive domains (psychomotor speed, attention, memory, executive function, and social cognition) and sleep were monitored by CANTAB testing batteries and 64-lead EEG respectively. Ten control subjects underwent identical cognitive testing regime protocol for comparison.Results: The unloading period of seven days resulted in a significant (p< 0.05) impairment in psychomotor speed and spatial working memory. However, a significant improvement was recorded in several domains of verbal memory. Various physiological changes, including the altered sleep architecture were recorded in floatonauts. Seven days of exposure lead to overall decreased sleep time, decreased non-rapid eye movement 2 sleep stage (N2) duration and decrease in overall NREM duration. Conversely, an increase in mean REM duration, sleep latency, along with increases in height and spine length were demonstrated. Postural changes appeared negatively related to changes in NREM duration, and verbal memory performance.Conclusions: Overall, the results suggest several cognitive and physiological changes induced by an intervention period of only seven days of HBF. These are hypothesized to occur due to the changes in neuroanatomical homeostasis, cephalic body fluid shift, physical activity, and sleep architecture. Further studies are required to investigate potential mechanisms underlying the observed multiple domain cognitive changes and the
Worker A, Dima D, Combes A, et al., 2018, Test-retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing and Alzheimer's disease populations, Human Brain Mapping, Vol: 39, Pages: 1743-1754, ISSN: 1065-9471
The hippocampal formation is a complex brain structure that is important in cognitive processes such as memory, mood, reward processing and other executive functions. Histological and neuroimaging studies have implicated the hippocampal region in neuropsychiatric disorders as well as in neurodegenerative diseases. This highly plastic limbic region is made up of several subregions that are believed to have different functional roles. Therefore, there is a growing interest in imaging the subregions of the hippocampal formation rather than modelling the hippocampus as a homogenous structure, driving the development of new automated analysis tools. Consequently, there is a pressing need to understand the stability of the measures derived from these new techniques. In this study, an automated hippocampal subregion segmentation pipeline, released as a developmental version of Freesurfer (v6.0), was applied to T1-weighted magnetic resonance imaging (MRI) scans of 22 healthy older participants, scanned on 3 separate occasions and a separate longitudinal dataset of 40 Alzheimer's disease (AD) patients. Test-retest reliability of hippocampal subregion volumes was assessed using the intra-class correlation coefficient (ICC), percentage volume difference and percentage volume overlap (Dice). Sensitivity of the regional estimates to longitudinal change was estimated using linear mixed effects (LME) modelling. The results show that out of the 24 hippocampal subregions, 20 had ICC scores of 0.9 or higher in both samples; these regions include the molecular layer, granule cell layer of the dentate gyrus, CA1, CA3 and the subiculum (ICC > 0.9), whilst the hippocampal fissure and fimbria had lower ICC scores (0.73-0.88). Furthermore, LME analysis of the independent AD dataset demonstrated sensitivity to group and individual differences in the rate of volume change over time in several hippocampal subregions (CA1, molecular layer, CA3, hippocampal tail, fissure and presubiculum). T
Modo M, Crum WR, Gerwig M, et al., 2017, Magnetic resonance imaging and tensor-based morphometry in the MPTP non-human primate model of Parkinson's disease, PLoS ONE, Vol: 12, ISSN: 1932-6203
Parkinson’s disease (PD) is the second most common neurodegenerative disorder producing a variety of motor and cognitive deficits with the causes remaining largely unknown. The gradual loss of the nigrostriatal pathway is currently considered the pivotal pathological event. To better understand the progression of PD and improve treatment management, defining the disease on a structural basis and expanding brain analysis to extra-nigral structures is indispensable. The anatomical complexity and the presence of neuromelanin, make the use of non-human primates an essential element in developing putative imaging biomarkers of PD. To this end, ex vivo T2-weighted magnetic resonance images were acquired from control and 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets. Volume measurements of the caudate, putamen, and substantia nigra indicated significant atrophy and cortical thinning. Tensor-based morphometry provided a more extensive and hypothesis free assessment of widespread changes caused by the toxin insult to the brain, especially highlighting regional cortical atrophy. The results highlight the importance of developing imaging biomarkers of PD in non-human primate models considering their distinct neuroanatomy. It is essential to further develop these biomarkers in vivo to provide non-invasive tools to detect pre-symptomatic PD and to monitor potential disease altering therapeutics.
Crum WR, Sawiak SJ, Chege W, et al., 2017, Evolution of structural abnormalities in the rat brain following in utero exposure to maternal immune activation: A longitudinal in vivo MRI study, Brain, Behavior, and Immunity, Vol: 63, Pages: 50-59, ISSN: 0889-1591
Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.
Rattray I, Smith EJ, Crum WR, et al., 2017, Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the HdhQ150/Q150 Mouse Model of Huntington's Disease, PLOS ONE, Vol: 12, ISSN: 1932-6203
A variety of mouse models have been developed that express mutant huntingtin (mHTT) leading to aggregates and inclusions that model the molecular pathology observed in Huntington’s disease. Here we show that although homozygous HdhQ150 knock-in mice developed motor impairments (rotarod, locomotor activity, grip strength) by 36 weeks of age, cognitive dysfunction (swimming T maze, fear conditioning, odor discrimination, social interaction) was not evident by 94 weeks. Concomitant to behavioral assessments, T2-weighted MRI volume measurements indicated a slower striatal growth with a significant difference between wild type (WT) and HdhQ150 mice being present even at 15 weeks. Indeed, MRI indicated significant volumetric changes prior to the emergence of the “clinical horizon” of motor impairments at 36 weeks of age. A striatal decrease of 27% was observed over 94 weeks with cortex (12%) and hippocampus (21%) also indicating significant atrophy. A hypothesis-free analysis using tensor-based morphometry highlighted further regions undergoing atrophy by contrasting brain growth and regional neurodegeneration. Histology revealed the widespread presence of mHTT aggregates and cellular inclusions. However, there was little evidence of correlations between these outcome measures, potentially indicating that other factors are important in the causal cascade linking the molecular pathology to the emergence of behavioral impairments. In conclusion, the HdhQ150 mouse model replicates many aspects of the human condition, including an extended pre-manifest period prior to the emergence of motor impairments.
Jin T, Nicholls FJ, Crum WR, et al., 2016, Diamagnetic chemical exchange saturation transfer (diaCEST) affords magnetic resonance imaging of extracellular matrix hydrogel implantation in a rat model of stroke, Biomaterials, Vol: 113, Pages: 176-190, ISSN: 1878-5905
Extracellular matrix (ECM) is widely used as an inductive biological scaffold to repair soft tissue after injury by promoting functional site-appropriate remodeling of the implanted material. However, there is a lack of non-invasive analysis methods to monitor the remodeling characteristics of the ECM material after implantation and its biodegradation over time. We describe the use of diamagnetic chemical exchange saturation transfer (CEST) magnetic resonance imaging to monitor the distribution of an ECM hydrogel after intracerebral implantation into a stroke cavity. In vitro imaging indicated a robust concentration-dependent detection of the ECM precursor and hydrogel at 1.8 and 3.6 ppm, which broadly corresponded to chondroitin sulfate and fibronectin. This detection was robust to changes in pH and improved at 37 °C. In vivo implantation of ECM hydrogel into the stroke cavity in a rat model corresponded macroscopically to the distribution of biomaterial as indicated by histology, but mismatches were also evident. Indeed, CEST imaging detected an endogenous “increased deposition”. To account for this endogenous activity, pre-implantation images were subtracted from post-implantation images to yield a selective visualization of hydrogel distribution in the stroke cavity and its evolution over 7 days. The CEST detection of ECM returned to baseline within 3 days due to a decrease in fibronectin and chondroitin sulfate in the hydrogel. The distribution of ECM hydrogel within the stroke cavity is hence feasible in vivo, but further advances are required to warrant a selective long-term monitoring in the context of biodegradation.
Walker T, Michaelides C, Ekonomou A, et al., 2016, Dissociation between iron accumulation and ferritin upregulation in the aged substantia nigra: attenuation by dietary restriction, Aging-Us, Vol: 8, Pages: 2488-2508, ISSN: 1945-4589
Despite regulation, brain iron increases with aging and may enhance aging processes including neuroinflammation. Increases in magnetic resonance imaging transverse relaxation rates, R2 and R2*, in the brain have been observed during aging. We show R2 and R2* correlate well with iron content via direct correlation to semi-quantitative synchrotron-based X-ray fluorescence iron mapping, with age-associated R2 and R2* increases reflecting iron accumulation. Iron accumulation was concomitant with increased ferritin immunoreactivity in basal ganglia regions except in the substantia nigra (SN). The unexpected dissociation of iron accumulation from ferritin-upregulation in the SN suggests iron dyshomeostasis in the SN. Occurring alongside microgliosis and astrogliosis, iron dyshomeotasis may contribute to the particular vulnerability of the SN. Dietary restriction (DR) has long been touted to ameliorate brain aging and we show DR attenuated age-related in vivo R2 increases in the SN over ages 7 – 19 months, concomitant with normal iron-induction of ferritin expression and decreased microgliosis. Iron is known to induce microgliosis and conversely, microgliosis can induce iron accumulation, which of these may be the initial pathological aging event warrants further investigation. We suggest iron chelation therapies and anti-inflammatory treatments may be putative ‘anti-brain aging’ therapies and combining these strategies may be synergistic.
Hamburg H, Trossbach SV, Bader V, et al., 2016, Simultaneous effects on parvalbumin-positive interneuron and dopaminergic system development in a transgenic rat model for sporadic schizophrenia, Scientific Reports, Vol: 6, ISSN: 2045-2322
To date, unequivocal neuroanatomical features have been demonstrated neither for sporadic nor for familial schizophrenia. Here, we investigated the neuroanatomical changes in a transgenic rat model for a subset of sporadic chronic mental illness (CMI), which modestly overexpresses human full-length, non-mutant Disrupted-in-Schizophrenia 1 (DISC1), and for which aberrant dopamine homeostasis consistent with some schizophrenia phenotypes has previously been reported. Neuroanatomical analysis revealed a reduced density of dopaminergic neurons in the substantia nigra and reduced dopaminergic fibres in the striatum. Parvalbumin-positive interneuron occurrence in the somatosensory cortex was shifted from layers II/III to V/VI, and the number of calbindin-positive interneurons was slightly decreased. Reduced corpus callosum thickness confirmed trend-level observations from in vivo MRI and voxel-wise tensor based morphometry. These neuroanatomical changes help explain functional phenotypes of this animal model, some of which resemble changes observed in human schizophrenia post mortem brain tissues. Our findings also demonstrate how a single molecular factor, DISC1 overexpression or misassembly, can account for a variety of seemingly unrelated morphological phenotypes and thus provides a possible unifying explanation for similar findings observed in sporadic schizophrenia patients. Our anatomical investigation of a defined model for sporadic mental illness enables a clearer definition of neuroanatomical changes associated with subsets of human sporadic schizophrenia.
Crum WR, Danckaers F, Huysmans T, et al., 2016, Chronic exposure to haloperidol and olanzapine leads to common and divergent shape changes in the rat hippocampus in the absence of grey-matter volume loss, Psychological Medicine, Vol: 46, Pages: 3081-3093, ISSN: 1469-8978
One of the most consistently reported brain abnormalities in schizophrenia (SCZ) is decreased volume and shape deformation of the hippocampus. However, the potential contribution of chronic antipsychotic medication exposure to these phenomena remains unclear.We examined the effect of chronic exposure (8 weeks) to clinically relevant doses of either haloperidol (HAL) or olanzapine (OLZ) on adult rat hippocampal volume and shape using ex vivo structural MRI with the brain retained inside the cranium to prevent distortions due to dissection, followed by tensor-based morphometry (TBM) and elastic surface-based shape deformation analysis. The volume of the hippocampus was also measured post-mortem from brain tissue sections in each group.Chronic exposure to either HAL or OLZ had no effect on the volume of the hippocampus, even at exploratory thresholds, which was confirmed post-mortem. In contrast, shape deformation analysis revealed that chronic HAL and OLZ exposure lead to both common and divergent shape deformations (q = 0.05, FDR-corrected) in the rat hippocampus. In particular, in the dorsal hippocampus, HAL exposure led to inward shape deformation, whereas OLZ exposure led to outward shape deformation. Interestingly, outward shape deformations that were common to both drugs occurred in the ventral hippocampus. These effects remained significant after controlling for hippocampal volume suggesting true shape changes.Chronic exposure to either HAL or OLZ leads to both common and divergent effects on rat hippocampal shape in the absence of volume change. The implications of these findings for the clinic are discussed.
Rosenzweig I, Glasser M, Crum WR, et al., 2016, Changes in Neurocognitive Architecture in Patients with Obstructive Sleep Apnea Treated with Continuous Positive Airway Pressure., EBioMedicine, Vol: 7, Pages: 221-229, ISSN: 2352-3964
BACKGROUND: Obstructive sleep apnea (OSA) is a chronic, multisystem disorder that has a bidirectional relationship with several major neurological disorders, including Alzheimer's dementia. Treatment with Continuous Positive Airway Pressure (CPAP) offers some protection from the effects of OSA, although it is still unclear which populations should be targeted, for how long, and what the effects of treatment are on different organ systems. We investigated whether cognitive improvements can be achieved as early as one month into CPAP treatment in patients with OSA. METHODS: 55 patients (mean (SD) age: 47.6 (11.1) years) with newly diagnosed moderate-severe OSA (Oxygen Desaturation Index: 36.6 (25.2) events/hour; Epworth sleepiness score (ESS): 12.8 (4.9)) and 35 matched healthy volunteers were studied. All participants underwent neurocognitive testing, neuroimaging and polysomnography. Patients were randomized into parallel groups: CPAP with best supportive care (BSC), or BSC alone for one month, after which they were re-tested. FINDINGS: One month of CPAP with BSC resulted in a hypertrophic trend in the right thalamus [mean difference (%): 4.04, 95% CI: 1.47 to 6.61], which was absent in the BSC group [-2.29, 95% CI: -4.34 to -0.24]. Significant improvement was also recorded in ESS, in the CPAP plus BSC group, following treatment [mean difference (%): -27.97, 95% CI: -36.75 to -19.19 vs 2.46, 95% CI: -5.23 to 10.15; P=0.012], correlated to neuroplastic changes in brainstem (r=-0.37; P=0.05), and improvements in delayed logical memory scores [57.20, 95% CI: 42.94 to 71.46 vs 23.41, 95% CI: 17.17 to 29.65; P=0.037]. INTERPRETATION: One month of CPAP treatment can lead to adaptive alterations in the neurocognitive architecture that underlies the reduced sleepiness, and improved verbal episodic memory in patients with OSA. We propose that partial neural recovery occurs during short periods of treatment with CPAP.
Harrison IF, Crum WR, Vernon AC, et al., 2015, Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up-regulation of neurotrophic factors, British Journal of Pharmacology, Vol: 172, Pages: 4200-4215, ISSN: 1476-5381
Background and PurposeHistone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti-epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD.Experimental ApproachThe irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague–Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects.Key ResultsDespite producing a distinct pattern of structural re-modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors.Conclusions and ImplicationsThe histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the re
Towgood K, Barker GJ, Caceres A, et al., 2015, Bringing Memory fMRI to the Clinic: Comparison of Seven Memory fMRI Protocols in Temporal Lobe Epilepsy, HUMAN BRAIN MAPPING, Vol: 36, Pages: 1595-1608, ISSN: 1065-9471
Rosenzweig I, Glasser M, Crum WR, et al., 2015, Neuroanatomical Correlates Of Cognitive Dysfunction In Obstructive Sleep Apnoea, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Vernon AC, Crum WR, Lerch JP, et al., 2014, Reduced Cortical Volume and Elevated Astrocyte Density in Rats Chronically Treated With Antipsychotic Drugs-Linking Magnetic Resonance Imaging Findings to Cellular Pathology, BIOLOGICAL PSYCHIATRY, Vol: 75, Pages: 982-990, ISSN: 0006-3223
Vernon AC, Natesan S, Chege W, et al., 2014, IMPACT OF CHRONIC ANTIPSYCHOTIC DRUG TREATMENT ON BRAIN MORPHOLOGY: A CAUSE FOR CONCERN?, Publisher: ELSEVIER SCIENCE BV, Pages: S69-S70, ISSN: 0920-9964
Rattray I, Smith EJ, Crum WR, et al., 2013, Correlations of Behavioral Deficits with Brain Pathology Assessed through Longitudinal MRI and Histopathology in the R6/1 Mouse Model of Huntington's Disease, PLOS One, Vol: 8, ISSN: 1932-6203
Huntington’s disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI), as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear.
Rosenzweig I, Kempton MJ, Crum WR, et al., 2013, Hippocampal Hypertrophy and Sleep Apnea: A Role for the Ischemic Preconditioning?, PLOS One, Vol: 8, ISSN: 1932-6203
The full impact of multisystem disease such as obstructive sleep apnoea (OSA) on regions of the central nervous system is debated, as the subsequent neurocognitive sequelae are unclear. Several preclinical studies suggest that its purported major culprits, intermittent hypoxia and sleep fragmentation, can differentially affect adult hippocampal neurogenesis. Although the prospective biphasic nature of chronic intermittent hypoxia in animal models of OSA has been acknowledged, so far the evidence for increased ‘compensatory’ neurogenesis in humans is uncertain. In a cross-sectional study of 32 patients with mixed severity OSA and 32 non-apnoeic matched controls inferential analysis showed bilateral enlargement of hippocampi in the OSA group. Conversely, a trend for smaller thalami in the OSA group was noted. Furthermore, aberrant connectivity between the hippocampus and the cerebellum in the OSA group was also suggested by the correlation analysis. The role for the ischemia/hypoxia preconditioning in the neuropathology of OSA is herein indicated, with possible further reaching clinical implications.
Stille M, Smith EJ, Crum WR, et al., 2013, 3D reconstruction of 2D fluorescence histology images and registration with in vivo MR images: Application in a rodent stroke model, JOURNAL OF NEUROSCIENCE METHODS, Vol: 219, Pages: 27-40, ISSN: 0165-0270
Crum WR, Giampietro VP, Smith EJ, et al., 2013, A comparison of automated anatomical-behavioural mapping methods in a rodent model of stroke, Journal of Neuroscience Methods, Vol: 218, Pages: 170-183, ISSN: 1872-678X
Neurological damage, due to conditions such as stroke, results in a complex pattern of structural changes and significant behavioural dysfunctions; the automated analysis of magnetic resonance imaging (MRI) and discovery of structural–behavioural correlates associated with these disorders remains challenging. Voxel lesion symptom mapping (VLSM) has been used to associate behaviour with lesion location in MRI, but this analysis requires the definition of lesion masks on each subject and does not exploit the rich structural information in the images. Tensor-based morphometry (TBM) has been used to perform voxel-wise structural analyses over the entire brain; however, a combination of lesion hyper-intensities and subtle structural remodelling away from the lesion might confound the interpretation of TBM. In this study, we compared and contrasted these techniques in a rodent model of stroke (n = 58) to assess the efficacy of these techniques in a challenging pre-clinical application. The results from the automated techniques were compared using manually derived region-of-interest measures of the lesion, cortex, striatum, ventricle and hippocampus, and considered against model power calculations. The automated TBM techniques successfully detect both lesion and non-lesion effects, consistent with manual measurements. These techniques do not require manual segmentation to the same extent as VLSM and should be considered part of the toolkit for the unbiased analysis of pre-clinical imaging-based studies.
Crum WR, Modo M, Vernon AC, et al., 2013, Registration of challenging pre-clinical brain images, Journal of Neuroscience Methods, Vol: 216, Pages: 62-77, ISSN: 1872-678X
The size and complexity of brain imaging studies in pre-clinical populations are increasing, and automated image analysis pipelines are urgently required. Pre-clinical populations can be subjected to controlled interventions (e.g., targeted lesions), which significantly change the appearance of the brain obtained by imaging. Existing systems for registration (the systematic alignment of scans into a consistent anatomical coordinate system), which assume image similarity to a reference scan, may fail when applied to these images. However, affine registration is a particularly vital pre-processing step for subsequent image analysis which is assumed to be an effective procedure in recent literature describing sophisticated techniques such as manifold learning. Therefore, in this paper, we present an affine registration solution that uses a graphical model of a population to decompose difficult pairwise registrations into a composition of steps using other members of the population. We developed this methodology in the context of a pre-clinical model of stroke in which large, variable hyper-intense lesions significantly impact registration performance. We tested this technique systematically in a simulated human population of brain tumour images before applying it to pre-clinical models of Parkinson's disease and stroke.
Bozzali M, MacPherson SE, Cercignani M, et al., 2012, White matter integrity assessed by diffusion tensor tractography in a patient with a large tumor mass but minimal clinical and neuropsychological deficits, FUNCTIONAL NEUROLOGY, Vol: 27, Pages: 239-246, ISSN: 0393-5264
Vernon AC, Chege W, Crum WR, et al., 2012, Effect of chronic haloperidol treatment on the rat anterior cingulate cortex: linking neuroimaging findings with neuropathology, 25th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S347-S348, ISSN: 0924-977X
Vernon AC, Natesan S, Crum WR, et al., 2012, Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation, BIOLOGICAL PSYCHIATRY, Vol: 71, Pages: 855-863, ISSN: 0006-3223
Smith EJ, Stroemer RP, Gorenkova N, et al., 2012, Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke, STEM CELLS, Vol: 30, Pages: 785-796, ISSN: 1066-5099
Kempton MJ, Underwood TSA, Brunton S, et al., 2011, A comprehensive testing protocol for MRI neuroanatomical segmentation techniques: Evaluation of a novel lateral ventricle segmentation method, NEUROIMAGE, Vol: 58, Pages: 1051-1059, ISSN: 1053-8119
Traynor CR, Barker GJ, Crum WR, et al., 2011, Segmentation of the thalamus in MRI based on T1 and T2, NEUROIMAGE, Vol: 56, Pages: 939-950, ISSN: 1053-8119
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