Neuroscience Next 2020 Abstracts
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Abstract
Julie Ottoy1,2 Min Su Kang2 Jeroen Verhaeghe1 Sigrid Stroobants1,3 Jenna Stevenson2 Nesrine Rahmouni2 Daniel Chartrand4 Gassan Massarweh4 Jean-Paul Soucy4 Serge Gauthier2 Pedro Rosa-Neto2 Steven Staelens1 1Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium 2Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montréal, QC, Canada 3University Hospital of Antwerp, Antwerp, Belgium 4Montreal Neurological Institute, Montréal, QC, Canada Correspondence Julie Ottoy, Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium. Email: [email protected] Abstract Background The standardized uptake value ratio (SUVR) has been widely applied in anti-Aβ trials of Alzheimer’s disease. However, the method is prone to bias from variation in plasma clearance and cerebral blood flow. For more accurate Aβ quantification, the distribution volume ratio (DVR) can be applied, but requires a long dynamic scan. In addition, both SUVR and DVR require selection of a reference region, which may suffer from Aβ (e.g. mutation-carriers). Here, we suggest an alternative tissue-to-plasma ratio method based on bolus-plus-constant-infusion (B/I) PET. Method Five PSEN1-carriers (MMSE 26.4±3) underwent 90-min [18F]-AV45-PET with continuous intravenous tracer infusion. 90-min continuous sampling, 10 arterial, and 6 venous samples were taken to determine individual metabolite-corrected plasma inputs and calculation of the ‘gold standard’, full-kinetic VT,2TCM and graphical VT,Logan. Additionally, VT using bolus-plus-constant-infusion was determined as the equilibriumratio (55-75min) of tracer concentration in tissue to the average of 3 metabolite-corrected arterial or venous plasma samples (Ctissue/Cplasma=VT,B/I). Last, DVR was calculated using cerebellar grey (CB-DVR), subcortical white matter (WM-DVR), or pons (pons-DVR) as the reference. The plasma free fraction (Fp) was determined in both arterial and venous blood. Result Bolus-plus-constant-infusion PET demonstrated true equilibrium with low rate of [18F]-AV45 concentration change (e.g., Cparietal 2.0±1.4%, CCB: 3.1±3.4%, and Cplasma: 5.6±3.5% change/20min). At 55min post-injection, the arterial parent fraction stabilized at 31±2% and VT,B/I corresponded well to the full-kinetic VT,2TCM and VT,Logan (average cortical difference: 2.9±0.8 and 3.3±0.7%, respectively) (Fig.1). Tracer concentrations remained 32±10% lower in venous compared to arterial plasma. Fp (9±2%) did not differ between arterial and venous blood. When using tissue reference, CB-DVRB/I underestimated VT,B/I patterns due to the presence of cerebellar Aβ (Fig.2). In contrast, WM-DVRB/I and pons-DVRB/I were positively correlated to VT,B/I (Fig.2). The WM-DVRB/I showed +6.2±1.3 and the pons-DVRB/I showed +6.9±1.2% difference compared to the full-kinetic DVR2TCM. Conclusion 20-min static B/I-PET with an arterial sample is sufficient to reproduce the full-kinetic VT,2TCM. Further investigation is needed to understand arterial-venous [18F]-AV45 concentration differences to replace arterial by venous samples. In the presence of a suitable reference region, the B/I method can be applied to calculate DVR using a static scan and without blood data. Gabriela Lopes Martins Suélyn Koerich Giovanni Freitas Gomes André Zeni Salgado Antônio Carlos Pinheiro Oliveira Helton José Reis Universidade Federal de Minas Gerais, Belo Horizonte, Brazil Correspondence Gabriela Lopes Martins, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Email: [email protected] Abstract Background Alzheimer's disease (AD) is the largest cause of dementia in the world, characterized by behavioral changes, cognitive impairment and progressive loss of memory. Despite its relevance, the pathophysiological mechanisms of the disease are still not well understood and the use of animal models may help to understand the neurodegenerative and neurocognitive changes that occur in AD. Thus, the aim of this study was evaluate the anxiety-related behavior of a double transgenic mouse model for Alzheimer's Disease, the APP/PS1, which overexpress the amyloid precursor protein (APP) and the presenilin-1 (PS1) protein. Methods The elevated plus maze test was performed on APP/PS1 (n = 7) and wild type (WT, n = 7) mice at 8 and 10 months of age. Total time (in seconds) in open and closed arms was evaluated, and the results were expressed as mean and standard deviation. All statistical tests were two-tailed and a significance level of p < 0.05 was set. Statistical analyses were performed using GraphPad Prism 6.01. The Committee for the Care and Use of Laboratory Animals of the Federal University of Minas Gerais (UFMG) approved all experimental procedures here conducted (CEUA 374/2018). Results No significant differences were observed comparing the APP/PS1 and WT animals in relation to total time in the open arms of the labyrinth, at 8 and 10 months of age. However, APP/PS1 remained less time in the closed arms of the apparatus compared to WT animals, both at 8 months of age (77.30 s ± 28.96 vs. 50.14 s ± 27.60, p = 0.0012), and at 10 months (66.89 s ± 34.87 vs. 45.14 s ± 35.49, p = 0.026). Conclusions APP/PS1 apparently had less anxious-like behavior, once they remained less time in the closed arms of the apparatus, compared to WT group. However, this result can be attributed to a potential loss of memory in these animals, leading to a fear inhibition, which requires further investigation. Based on this, this animal model can provide a better understanding of the behavioral changes that succeed in AD, helping to elucidate the pathological processes that occur in the disease. Kaitlin McManus1 Lisa Blackmer-Raynolds2 Emma Donigan3 Melissa J Glenn3 1McLean Hospital, Belmont, MA, USA 2Emory University, Atlanta, GA, USA 3Colby College, Waterville, ME, USA Correspondence Kaitlin McManus, McLean Hospital, Belmont, MA, USA. Email: [email protected] Abstract Background The human apolipoprotein E e4 (hAPOE4) allele is the greatest known genetic risk factor for Alzheimer’s disease (AD) and is associated with numerous aspects of AD pathology. Although the hAPOE4 allele is associated with increased cognitive deficits and anxiety in AD patients (Robertson et al., 2005), healthy elderly participants (Berteau-Pavy et al., 2007), and hAPOE4 knock-in mice (Grootendorst et al., 2005; Mahely et al., 2006; Raber et al., 1998, 2000), little is known about how cognitive and affective disturbances develop throughout the lifespan. Furthermore, there exists limited published research using hAPOE4 knock-in rat models. Significant insights are possible with rats given their use as behavioral models over the last century. Thus, the goals of the present study were to 1) carefully study behavior using a hAPOE4 knock-in rat model, and 2) perform behavioral assessments throughout the lifespan. Methods To address these goals, 20 hAPOE4 knock-in (10 male) and 20 wildtype (10 male) Sprague-Dawley rats were acquired at 4 weeks of age. After a short acclimation period, behavioral tasks were conducted over 2 years. Cognitive tests included assays of object, place, and context memory along with spatial memory and attentional set shifting. Emotion-based tests included the open field and elevated plus maze. Results The results revealed sex and age-dependent effects of the hAPOE4 knock-in: hAPOE4 rats, particularly females, displayed a significant increase in anxiety behavior as they aged. hAPOE4 females displayed deficits in remembering the location of objects at two months of age, but neither sex displayed spatial memory deficits when tested on the Morris water maze a year later. At 15-18 months of age, hAPOE4 rats displayed impaired cognitive flexibility and set shifting abilities indicative of executive dysfunction. Around one year of age, hAPOE4 males displayed reduced motor capabilities and hAPOE4 females had increased lethality. Conclusions The results of the present study demonstrate that the hAPOE4 allele has measurable impacts on cognition and affect that are both sex and age dependent. This highlights the importance of in-depth longitudinal assessments in order to understand how genetic variants including the hAPOE4 allele may confer a heightened risk to AD development. Ismael Perez Jessica Cantu Tabitha Rodriguez John L VandeBerg Mario Gil University of Texas Rio Grande Valley, Brownsville, TX, USA Correspondence Ismael Perez, University of Texas Rio Grande Valley, Brownsville, TX, USA. Email: [email protected] Abstract Background Cognitive decline is part of normal aging. Neurodegenerative diseases, including Alzheimer's Disease and related dementias (ADRD), accelerate these harmful effects that impact everyday functioning. Studying the learning and memory changes that occur during aging in animals may help uncover underlying mechanisms. Commonly used animal models in aging research involve the use of rodents to study these processes. However, LaFerla and Green (2012) note major translational issues with rodent models, including lack of models of idiopathic ADRD. Our study is unique as we utilized an atypical laboratory animal model, the Monodelphis domestica, to study natural decline in cognitive abilities. Method We used habituation-dishabituation paradigm and social recognition tasks to assess cognitive ability, and age was the major biological variable in our study. Animals were divided into three age groups: young adults (postnatal day [PND] 100-200 days, n=7), adults (PND 201-365 days, n=7), and older adults (PND > 365, n=6). We tested the hypothesis that increased age is associated with deficits in olfactory-based memories of social and non-social stimuli. Result Factorial repeated measures ANOVA, with trials, biological sex, and age as factors, were performed to investigate group differences in learning performance. There was no effect of age on performance in the habituation-dishabituation task. There was a significant effect of age (F=3.173, p<0.05) and an interaction (F= 4.444, p< 0.05) for the social recognition task. Younger adults had higher investigation levels and both young adults and adults habituated and dishabituated to social stimuli. The older animals only habituated and were non-responsive to a novel stimulus animal. We recently reported sex differences in social behavior in this species (Gil et al., 2019), and there were trends toward a sex difference in memory performance in the present study, although these were not statistically significant due to low sample size. Conclusion The results of the present student indicate that Monodelphis may be used as a model for studying the biology of age-related deficits in social memory. We are currently comparing the brains of young adults and older adults, and our long-term goal is to develop the Monodelphis domestica as an animal model of idiopathic ADRD. Rebecca A. Rusnak1 Lary C. Walker2,3,4 Anthony Chan2,3,5 Jessica Raper2,3 1Emory University College of Arts and Sciences, Atlanta, GA, USA 2Emory University School of Medicine, Atlanta, GA, USA 3Yerkes National Primate Research Center, Atlanta, GA, USA 4Department of Neurology and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA 5Laney Graduate School, Atlanta, GA, USA Correspondence Rebecca A. Rusnak, Emory University College of Arts and Sciences, Atlanta, GA, USA. Email: [email protected] Abstract Background Although the most notable clinical symptom of AD is cognitive decline, neuropsychiatric symptoms such as agitation, irritability, and aberrant/stereotypic motor behavior also have been reported. The β-amyloid peptide (Aβ) is a key contributor to AD pathology, making Aβ and its precursor (β-APP) the target of many studies of AD. Overexpression of human-type β-APP induces Aβ plaque formation and cerebral β-amyloid angiopathy in transgenic rodent models, but the full phenotype of AD has not been demonstrated in any nonhuman species. Unlike rodents, nonhuman primates (NHPs) primarily use their visual system and complex neuronal circuitry to process environmental stimuli, and they are biologically closer to humans; NHPs thus present a unique opportunity to develop an animal model of AD with greater translational potential. Methods The current study used a β-APP-transgenic monkey model to seek evidence of early neuropsychiatric symptoms similar to those that occur in AD. We prepared a β-APP gene construct with Swedish (KM670/671NL) and Indiana (V717F) mutations regulated by the human polyubiquitin promoter. Three β-APP-transgenic rhesus macaques (2 females and 1 male) were produced by lentiviral transfer of the transgene into rhesus oocytes, followed by in vitro fertilization and embryo transfer. The two female monkeys expressed mutant β-APP in all tested body cells, whereas the male was a transgene-mosaic. Behavioral reactivity to an acute stressor was examined in the transgenic monkeys and five wild-type controls (3 females and 2 males) during early adulthood (5-6 years old). Results The wild-type controls exhibited increased freezing when faced with a mild threat, whereas the β-APP monkeys lacked this species-typical response. Instead, β-APP monkeys exhibited increased repetitive/stereotypic behaviors compared to controls. β-APP monkeys also expressed increased aggressive behavior when no stimulus was present, indicative of increased irritability (defined as a mood state predisposing to anger and overt hostility). Conclusions Overall, the current findings are congruent with contemporary clinical literature which highlights the significance of neuropsychiatric symptoms in predicting progression to mild cognitive impairment and eventual AD dementia. The NHP model thus might be useful for detecting early, complex behavioral features that have been linked to AD in humans. Jitendra Kumar Sinha1,2 Shampa Ghosh2 Manchala Raghunath2 1Amity University UP, Noida, India 2ICMR - National Institute of Nutrition, Hyderabad, India Correspondence Jitendra Kumar Sinha, Amity University UP, Noida, India. Email: [email protected] Abstract Background Proportion of aged individuals is on the rise in the general population and most of the older people die due to non-communicable diseases like obesity. Wistar of National Institute of Nutrition obese (WNIN/Ob) rat is a novel strain developed at NIN, Hyderabad, India. These rats have significantly reduced the average lifespan of 15-18 months in contrast to 36 months in normal WNIN rats. Elucidation of various molecular and biochemical characteristics in these rats would help to establish it as an appropriate model to study the neurobiology of aging and obesity. Method Different growth characteristics were studied and the lifespan analysis was performed using OASIS software. The neuronal and glial changes were studied using Nissl staining and immunohistochemistry. Levels of oxidative stress, antioxidant enzyme activity, and extent DNA damage were studied in various brain parts. We have looked at the levels of some of the major neurotransmitters and metabolites in brain regions of WNIN/Ob rats and their age-matched normal rats using Magnetic Resonance Spectroscopy (MRS). Result The brain weights were significantly decreased and there was a 60% decrease in the total lifespan in the WNIN/Ob obese rats as compared to the lean littermates as well as WNIN normal rats. Various neuronal and glial changes were observed that are seen in the aging brain. In addition, oxidative stress levels and extent of DNA damage were observed to be significantly high in the brain of young WNIN/Ob obese rats as compared to age-matched rats and it was as high as compared to that observed in 15 months old WNIN normal rats. The levels of antioxidants enzyme activity were also significantly low in the WNIN/Ob obese rats. MRS data indicates hypo-metabolism in the brain of WNIN/Ob rats. Conclusion Onset of various degenerative features like increased oxidative stress, astrogliosis, DNA damage and decreased antioxidant levels and reduced metabolism in different brain regions of WNIN/Ob obese rats at a much younger age is a plausible cause of reduced longevity and dementia observed in this novel obese rat model. This model may be used to study the connecting link between obesity and neurological disorders where aging remains a risk factor. Lucrezia Bruno Francesca Mackenzie Mike Stolinski Kingston University, Kingston upon Thames, United Kingdom Correspondence Lucrezia Bruno, Kingston University, Kingston upon Thames, United Kingdom. Email: [email protected] Abstract Background Microglia play an important role in Alzheimer’s disease pathology, including in early stages of the disease process1. Microglial dysregulation has been associated with disturbances in the brain’s feeding and energy expenditure circuits2 showing their importance in homeostatic regulation. Defining a suitable in vitro model system to allow the investigation of microglial biology within a simulated microenvironment of healthy or diseased brain tissue is of fundamental importance. How energy substrate concentrations, oxygen levels and chemical cues can modulate microglial function could then be studied. This preliminary in vitro study investigates the effect of glucose concentrations, the main source of fuel for the brain, on microglial homeostasis. Method SIM-A9 mouse immortalised microglial cells were initially grown in DMEM/F-12 medium (17.5mM glucose) containing 10% FBS and 0.1% Penicillin/Streptomycin (Gibco, UK). After 20 hours cells were re-seeded in Neurobasal medium containing 1x B-27 supplement (Gibco, UK) and either 0mM or 1mM glucose, where 1mM simulates physiological brain glucose levels3, and were grown for 20 hours. Cell proliferation and viability was assessed over 48 hours using an Incucyte imaging system (Essen BioScience, UK) and Trypan Blue assay. Media glucose concentration and microglia activation state marker expression using PCR were also measured. Result SIM-A9 cells seeded at 7 x 105 cells/well showed minimal changes in cell proliferation and viability when maintained in 1mM glucose Neurobasal medium over 20 hours. However, maintaining cells in 0mM glucose resulted in a decrease in proliferation rate from 21 to 41 hours, even after pre-incubation in DMEM/F12. Cells maintained only in DMEM/F-12 showed continuous proliferation and minimal cell death. Changes in glucose media concentration and gene expression levels will be described. Conclusion Defining a suitable cell culture system for microglia is a fundamental step in microglial research, as until now metabolic studies on microglia have not always reflected the physiological concentrations of key metabolites in the brain. The system described shows that culturing microglial cells for 20 hours at 1mM glucose in Neurobasal medium following pre-incubation in DMEM/F-12 results in minimal cell death and maintains a steady proliferation state. The expression of homeostatic markers will be discussed. Eric Dyne Meghan Cawood Matthew Suzelis Min-Ho Kim Kent State University, Kent, OH, USA Correspondence Eric Dyne, Kent State University, Kent, OH, USA. Email: [email protected] Abstract Background Microglia, the brain resident phagocytic immune cells, are responsible many roles for brain homeostasis including of research has demonstrated changes are indicative of microglial activation from to such as and an opportunity to further The of this study was to changes in microglia to cues and Method human microglia were with or on a were with and then with followed by were and to a sample were an Various were and then compared using analysis software. Result microglia displayed ± major ± and an of the ± of did not significantly cell body or However, major ± and ± significantly decreased compared to of a significant increase in ± and ± and ± significantly decreased compared to of a significant increase in ± and a with ± and ± significantly decreased compared to Conclusion analysis of microglia demonstrated unique when to All of microglial and the of and the and of to investigate aspects of microglia Oliveira de of Brazil of Brazil Federal Rio Grande Brazil of Brazil Correspondence University of Brazil. Email: Abstract Background The is characterized by a decrease in the of in the female and this can be with increased This decline is associated with neurodegenerative diseases, including Alzheimer's disease AD have a with in the cognitive damage by the pathology, are has been in this due to its effect and can be used in with such as and to their This is even more when associated with animal models of such as in the are the most by AD. Method Animals were divided into experimental of or water At the of the experimental animals were to behavioral tests of maze and to open the animals underwent at for of cerebral such as and for analysis of levels and and and for analysis of and Result The results that reduced levels of and group had high levels of Results also demonstrated that of the with and long-term spatial and memories In addition, of and levels in as well as levels of in and of in and of In contrast, the effects of long-term spatial and memories as well as changes in and levels in of Conclusion In with has effects on memory and in female mice to and the AD animal model of dementia. L Research Institute, Indiana University School of Medicine, USA University School of Medicine, USA Laboratory, ME, USA Laboratory for Medicine, USA Correspondence L Research Institute, Indiana University School of Medicine, USA. Email: Abstract Background of a is known to increase the risk of Alzheimer's disease high in also increase disease cognitive deficits in AD mouse models. However, the effect of a on the and cognitive in novel models of is is that of genetic environmental risk are to develop AD. To in the Center, we have on mouse models containing of genetic risk variants in including and In addition, we have the mouse Aβ peptide that is to be more the mouse Aβ Here, we now test the effect of a high as an environmental risk factor. Methods were either a normal or a high high to models on a genetic and and female mice from strain were their at 2 months of age until months of age. were assessed using a and In addition, metabolic assays including and blood glucose, and enzyme levels as well as studies were Results in and body were observed in and also displayed significant in and body of age. in glucose, and were observed in the mice on the over the into the by the genetic and Conclusions This study to the role of age and high in the progression of in novel mouse models of These findings provide a to variants with environmental more models for Francesca John College United Kingdom College Institute of Institute, Correspondence Email: Abstract Background Neurodegenerative disorders such as Alzheimer's disease (AD) can develop making early and of progression a is a of brain activity used in clinical and laboratory the for and have its use at repeated could provide an and of brain for use in and Methods We data from a long study performed in a of older adults using a The study was approved by the and was from all were to day a for 6 a of cognitive tasks including a visual and a during in the were with and We by standard both of the and of were by without from data. These were then and the process repeated at time were calculated all Results In were participants decreased when the of Conclusions This study that it is possible to