Florey Department of Neuroscience and Mental Health - Research Publications
Now showing items 1-12 of 1844
Generative Model of Brain Microbleeds for MRI Detection of Vascular Marker of Neurodegenerative Diseases
(FRONTIERS MEDIA SA, 2021-12-16)
Cerebral microbleeds (CMB) are increasingly present with aging and can reveal vascular pathologies associated with neurodegeneration. Deep learning-based classifiers can detect and quantify CMB from MRI, such as susceptibility imaging, but are challenging to train because of the limited availability of ground truth and many confounding imaging features, such as vessels or infarcts. In this study, we present a novel generative adversarial network (GAN) that has been trained to generate three-dimensional lesions, conditioned by volume and location. This allows one to investigate CMB characteristics and create large training datasets for deep learning-based detectors. We demonstrate the benefit of this approach by achieving state-of-the-art CMB detection of real CMB using a convolutional neural network classifier trained on synthetic CMB. Moreover, we showed that our proposed 3D lesion GAN model can be applied on unseen dataset, with different MRI parameters and diseases, to generate synthetic lesions with high diversity and without needing laboriously marked ground truth.
A Preclinical Model of Computerized Cognitive Training: Touchscreen Cognitive Testing Enhances Cognition and Hippocampal Cellular Plasticity in Wildtype and Alzheimer's Disease Mice
(FRONTIERS MEDIA SA, 2021-12-06)
With the growing popularity of touchscreen cognitive testing in rodents, it is imperative to understand the fundamental effects exposure to this paradigm can have on the animals involved. In this study, we set out to assess hippocampal-dependant learning in the APP/PS1 mouse model of Alzheimer's disease (AD) on two highly translatable touchscreen tasks - the Paired Associate Learning (PAL) task and the Trial Unique Non-Matching to Location (TUNL) task. Both of these tests are based on human tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and are sensitive to deficits in both mild cognitive impairment (MCI) and AD. Mice were assessed for deficits in PAL at 9-12 months of age, then on TUNL at 8-11 and 13-16 months. No cognitive deficits were evident in APP/PS1 mice at any age, contrary to previous reports using maze-based learning and memory tasks. We hypothesized that daily and long-term touchscreen training may have inadvertently acted as a cognitive enhancer. When touchscreen-tested mice were assessed on the Morris water maze, they showed improved task acquisition compared to naïve APP/PS1 mice and wild-type (WT) littermate controls. In addition, we show that touchscreen-trained WT and APP/PS1 mice show increased cell proliferation and immature neuron numbers in the dentate gyrus compared to behaviorally naïve WT and APP/PS1 mice. This result indicates that the touchscreen testing paradigm could improve cognitive performance, and/or mask an impairment, in experimental mouse models. This touchscreen-induced cognitive enhancement may involve increased neurogenesis, and possibly other forms of cellular plasticity. This is the first study to show increased numbers of proliferating cells and immature neurons in the hippocampus following touchscreen testing, and that touchscreen training can improve cognitive performance in maze-based spatial navigation tasks. This potential for touchscreen testing to induce cognitive enhancement, or other phenotypic shifts, in preclinical models should be considered in study design. Furthermore, touchscreen-mediated cognitive enhancement could have therapeutic implications for cognitive disorders.
Identification, Synthesis, Conformation and Activity of an Insulin-like Peptide from a Sea Anemone
The role of insulin and insulin-like peptides (ILPs) in vertebrate animals is well studied. Numerous ILPs are also found in invertebrates, although there is uncertainty as to the function and role of many of these peptides. We have identified transcripts with similarity to the insulin family in the tentacle transcriptomes of the sea anemone Oulactis sp. (Actiniaria: Actiniidae). The translated transcripts showed that these insulin-like peptides have highly conserved A- and B-chains among individuals of this species, as well as other Anthozoa. An Oulactis sp. ILP sequence (IlO1_i1) was synthesized using Fmoc solid-phase peptide synthesis of the individual chains, followed by regioselective disulfide bond formation of the intra-A and two interchain disulfide bonds. Bioactivity studies of IlO1_i1 were conducted on human insulin and insulin-like growth factor receptors, and on voltage-gated potassium, sodium, and calcium channels. IlO1_i1 did not bind to the insulin or insulin-like growth factor receptors, but showed weak activity against KV1.2, 1.3, 3.1, and 11.1 (hERG) channels, as well as NaV1.4 channels. Further functional studies are required to determine the role of this peptide in the sea anemone.
The oligodendrocyte-enriched orphan G protein-coupled receptor Gpr62 is dispensable for central nervous system myelination
BACKGROUND: Myelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction. Establishing the proper pattern of myelin in neural circuits requires communicative axo-glial interactions, however, the molecular interactions that occur between oligodendrocytes and axons during developmental myelination and myelin maintenance remain to be fully elucidated. Our previous work identified G protein-coupled receptor 62 (Gpr62), an uncharacterized orphan g-protein coupled receptor, as being selectively expressed by mature oligodendrocytes within the CNS, suggesting a potential role in myelination or axoglial interactions. However, no studies to date have assessed the functional requirement for Gpr62 in oligodendrocyte development or CNS myelination. METHODS: To address this, we generated a knockout mouse strain lacking the Gpr62 gene. We assessed CNS myelination during both postnatal development and adulthood using immunohistochemistry, electron microscopy and western blot. In addition, we utilized AAV-mediated expression of a tagged Gpr62 in oligodendrocytes to determine the subcellular localization of the protein in vivo. RESULTS: We find that virally expressed Gpr62 protein is selectively expressed on the adaxonal myelin layer, suggestive of a potential role for Gpr62 in axo-myelinic signaling. Nevertheless, Gpr62 knockout mice display normal oligodendrocyte numbers and apparently normal myelination within the CNS during both postnatal development and adulthood. CONCLUSIONS: We conclude that in spite of being well-placed to mediate neuronal-oligodendrocyte communications, Gpr62 is overall dispensable for CNS myelination.
Higher Coffee Consumption Is Associated With Slower Cognitive Decline and Less Cerebral A beta-Amyloid Accumulation Over 126 Months: Data From the Australian Imaging, Biomarkers, and Lifestyle Study
(FRONTIERS MEDIA SA, 2021-11-19)
Background: Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer's disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations. Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over 126 months. In a subset of individuals, we also investigated the relationship between habitual coffee intake and cerebral Aβ-amyloid accumulation (n = 60) and brain volumes (n = 51) over 126 months. Results: Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown reliably to measure the first signs of cognitive decline in at-risk cognitively normal populations), and lower likelihood of transitioning to mild cognitive impairment or AD status, over 126 months. Higher baseline coffee consumption was also associated with slower Aβ-amyloid accumulation over 126 months, and lower risk of progressing to "moderate," "high," or "very high" Aβ-amyloid burden status over the same time-period. There were no associations between coffee intake and atrophy in total gray matter, white matter, or hippocampal volume. Discussion: Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption potentially reducing cognitive decline by slowing cerebral Aβ-amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate whether coffee intake could be incorporated as a modifiable lifestyle factor aimed at delaying AD onset.
Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-11-01)
Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.
Hippocampal neurogenesis mediates sex-specific effects of social isolation and exercise on fear extinction in adolescence
(ELSEVIER SCIENCE INC, 2021-11-01)
Impaired extinction of conditioned fear is associated with anxiety disorders. Common lifestyle factors, like isolation stress and exercise, may alter the ability to extinguish fear. However, the effect of and interplay between these factors on adolescent fear extinction, and the relevant underlying neural mechanisms are unknown. Here we examined the effects of periadolescent social isolation and physical activity on adolescent fear extinction in rats and explored neurogenesis as a potential mechanism. Isolation stress impaired extinction recall in male adolescents, an effect prevented by exercise. Extinction recall in female adolescents was unaffected by isolation stress. However, exercise disrupted extinction recall in isolated females. Extinction recall in isolated females was positively correlated to the number of immature neurons in the ventral hippocampus, suggesting that exercise affected extinction recall via neurogenesis in females. Pharmacologically suppressing cellular proliferation in isolated adolescents using temozolomide blocked the effect of exercise on extinction recall in both sexes. Together, these findings highlight sex-specific outcomes of isolation stress and exercise on adolescent brain and behavior, and highlights neurogenesis as a potential mechanism underlying lifestyle effects on adolescent fear extinction.
Fixel-based Analysis of Diffusion MRI: Methods, Applications, Challenges and Opportunities
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-11-01)
Diffusion MRI has provided the neuroimaging community with a powerful tool to acquire in-vivo data sensitive to microstructural features of white matter, up to 3 orders of magnitude smaller than typical voxel sizes. The key to extracting such valuable information lies in complex modelling techniques, which form the link between the rich diffusion MRI data and various metrics related to the microstructural organization. Over time, increasingly advanced techniques have been developed, up to the point where some diffusion MRI models can now provide access to properties specific to individual fibre populations in each voxel in the presence of multiple "crossing" fibre pathways. While highly valuable, such fibre-specific information poses unique challenges for typical image processing pipelines and statistical analysis. In this work, we review the "Fixel-Based Analysis" (FBA) framework, which implements bespoke solutions to this end. It has recently seen a stark increase in adoption for studies of both typical (healthy) populations as well as a wide range of clinical populations. We describe the main concepts related to Fixel-Based Analyses, as well as the methods and specific steps involved in a state-of-the-art FBA pipeline, with a focus on providing researchers with practical advice on how to interpret results. We also include an overview of the scope of all current FBA studies, categorized across a broad range of neuro-scientific domains, listing key design choices and summarizing their main results and conclusions. Finally, we critically discuss several aspects and challenges involved with the FBA framework, and outline some directions and future opportunities.
Age of Onset and Its Related Factors in Cocaine or Methamphetamine Use in Adults from the United States: Results from NHANES 2005-2018
Cocaine and methamphetamine are widely used illicit psychostimulants worldwide, with steadily increasing global markets that may impact on the frequency of use. Importantly, their use typically begins in youth. This is a particular concern because there is a link between the early age of first substance use and severity of substance use disorder later in life. The aim of the present study was therefore to investigate trends in prevalence, frequency, and age of onset of cocaine or methamphetamine use between 2005 and 2018 in the United States, using the nationally representative NHANES datasets. Factors associated with the ages of cocaine or methamphetamine use onset were also identified. From 2005 to 2018, prevalence and frequencies of cocaine or methamphetamine use increased, while age of onset remained relatively stable (~20 years of age). Annual household income, use of other substances, and intravenous drug use were identified as factors associated with early onset cocaine or methamphetamine use. These factors have important implications toward developing new prevention programs to reduce psychostimulant use.
Predicting Post-Stroke Somatosensory Function from Resting-State Functional Connectivity: A Feasibility Study
Accumulating evidence shows that brain functional deficits may be impacted by damage to remote brain regions. Recent advances in neuroimaging suggest that stroke impairment can be better predicted based on disruption to brain networks rather than from lesion locations or volumes only. Our aim was to explore the feasibility of predicting post-stroke somatosensory function from brain functional connectivity through the application of machine learning techniques. Somatosensory impairment was measured using the Tactile Discrimination Test. Functional connectivity was employed to model the global brain function. Behavioral measures and MRI were collected at the same timepoint. Two machine learning models (linear regression and support vector regression) were chosen to predict somatosensory impairment from disrupted networks. Along with two feature pools (i.e., low-order and high-order functional connectivity, or low-order functional connectivity only) engineered, four predictive models were built and evaluated in the present study. Forty-three chronic stroke survivors participated this study. Results showed that the regression model employing both low-order and high-order functional connectivity can predict outcomes based on correlation coefficient of r = 0.54 (p = 0.0002). A machine learning predictive approach, involving high- and low-order modelling, is feasible for the prediction of residual somatosensory function in stroke patients using functional brain networks.
CaRotid Artery Filtering Technique (CRAFT): A Technique for Carotid Artery Stenting with Intrinsic Embolic Protection.
(Korean Society of Interventional Neuroradiology, 2021-11)
PURPOSE: Carotid artery stenting (CAS) is an established treatment for symptomatic carotid artery stenosis as an alternative to carotid endarterectomy. A variety of techniques and devices have been devised to minimise periprocedural stroke risk using either proximal or distal embolic protection. This study presents a method of embolic protection during CAS-the CaRotid Artery Filtering Technique (CRAFT). MATERIALS AND METHODS: The CRAFT technique employs aspects of both proximal and distal embolic protection. The CASPER RX stent (MicroVention, Tustin, CA, USA), which is a double-layered, closed-cell, micromesh nitinol stent, is deployed across the carotid artery stenosis with the assistance of a FlowGate balloon guide catheter (Stryker Neurovascular, Fremont, CA, USA). The partially deployed stent acts as a distal filter while the balloon guide is deflated midway during stent deployment to prevent distal plaque embolisation, followed by completion of stent deployment and angioplasty. RESULTS: A total of 94 patients underwent CAS using the CRAFT technique between June 2016 and March 2021. Successful stent deployment was achieved in all patients. Preliminary results demonstrated acute stent occlusion in 6 patients (6.4%) and distal embolic stroke in 5 patients (5.3%). The median procedural fluoroscopy time was 34 minutes with an interquartile range of 22 to 55 minutes. CONCLUSION: The CRAFT technique of CAS presented by this study can be applied in the treatment of symptomatic carotid artery stenosis in both emergency and elective procedure settings with a high technical success and low distal embolic stroke risk.
Role of Lipocalin-2 in Amyloid-Beta Oligomer-Induced Mouse Model of Alzheimer's Disease
Lipocalin-2 (LCN2) is an inflammatory protein with diverse functions in the brain. Although many studies have investigated the mechanism of LCN2 in brain injuries, the effect of LCN2 on amyloid-toxicity-related memory deficits in a mouse model of Alzheimer's disease (AD) has been less studied. We investigated the role of LCN2 in human AD patients using a mouse model of AD. We created an AD mouse model by injecting amyloid-beta oligomer (AβO) into the hippocampus. In this model, animals exhibited impaired learning and memory. We found LCN2 upregulation in the human brain frontal lobe, as well as a positive correlation between white matter ischemic changes and serum LCN2. We also found increased astrocytic LCN2, microglia activation, iron accumulation, and blood-brain barrier disruption in AβO-treated hippocampi. These findings suggest that LCN2 is involved in a variety of amyloid toxicity mechanisms, especially neuroinflammation and oxidative stress.