112 research outputs found

    Análisis mediante inteligencia computacional de marcadores genéticos en pacientes colombianos con enfermedad de Alzheimer

    Get PDF
    Un objetivo principal de la genética humana es comprender la relación entre las variaciones en las secuencias de ADN y la susceptibilidad a ciertas enfermedades. En este trabajo en particular, la información genética se analiza en relación con la enfermedad de Alzheimer (EA), con el fin de mejorar su diagnóstico, prevención y tratamiento. En Colombia, esta enfermedad requiere actualmente una atención especial debido a que su incidencia ha aumentado significativamente en los últimos años. Por esta razón, este trabajo analiza un conjunto de doce marcadores genéticos o polimorfismos de nucleótido simple (SNP) en un grupo de pacientes colombianos con EA a través de un método de inducción constructiva basado en un enfoque de aprendizaje de máquina, denominado reducción de dimensión multifactorial (MDR). Además, se realizaron análisis de epistasia estadística, obteniendo la relación de sinergia entre las variables mediante la ganancia de la información de los genes relacionados con la AD, proporcionando una metodología simple para caracterizar las interacciones en los estudios de asociación genética y determinar los rasgos más importantes que describen el comportamiento de la enfermedad.Abstract. A main goal of human genetics is to understand the relationship between variations in DNA sequences and the susceptibility to certain illnesses. In this particular work, genetic information is analyzed in relation to the Alzheimer's disease (AD) in order to improve its diagnosis, prevention and treatment. In Colombia, this disease currently requires special attention because its incidence has increased significantly in recent years. Thus, this work analyzes a set of twelve genetic markers or single nucleotide polymorphisms (SNPs) in a set of colombian patients through a constructive induction method based on a machine learning approach, namely, multifactor dimensionality reduction (MDR). Also, some statistical epistasis analysis is carried out. Particularly, epistasis is obtained based on information gain from AD related genes, providing a simple methodology to characterize interactions in genetic association studies and capturing important traits that describe the behavior of the disease.Maestrí

    Detecting and tracking early neurodegeneration in familial Alzheimer’s disease

    Get PDF
    Alzheimer’s disease (AD) is recognized to have a long presymptomatic period, with initial deposition of extracellular amyloid and intracellular tau, followed by downstream neurodegeneration and cognitive decline. There is great interest in testing potential disease-modifying treatments for AD prior to the onset of symptoms, when minimal neuronal loss has occurred. To facilitate this, robust and sensitive methods are needed to identify at-risk individuals, stage their disease, and track progression. Familial Alzheimer’s disease (FAD) shares many features, clinically, radiologically, and neurophysiologically, with the more common sporadic form of disease. Carriers of autosomal dominantly inherited mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes have relatively predictable ages at symptom onset, based on family history. Study of FAD mutation carriers therefore provides the opportunity for the prospective study of asymptomatic individuals with known underlying AD pathology prior to the onset of clinical disease. The studies presented herein aim to improve the identification and characterization of early FAD neurodegenerative change and its earliest downstream cognitive effects. A multimodal approach is taken, with both presymptomatic and mildly symptomatic individuals included. Chapter one provides an introduction to AD and methods for measuring early neurodegeneration. Chapter two then outlines the general methodological approach across the different studies. Chapters three and four present results of magnetic resonance imaging studies of macrostructural (cortical thickness) and microstructural (diffusion-weighted imaging) cortical change. Chapter five reports results for a new blood-based biomarker of neurodegeneration – serum neurofilamentlight. Chapter six investigates a novel approach to presymptomatic cognitive testing – 6 assessing accelerated long-term forgetting. In all studies, significant differences between mutation carriers and non-carrier controls are detectable during the presymptomatic period. The thesis draws together these different approaches and discusses how they advance our understanding of the neurobiology of AD and their potential utility in both clinical assessment and presymptomatic therapeutic trials

    The Influence of APOE Genotype on Lipid Droplet Dynamics

    Get PDF
    Excess lipid droplet (LD) accumulation is associated with several pathological states, including neurodegenerative disorders such as Alzheimer’s disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics may contribute to the pathophysiology of AD remains unclear. Apolipoprotein E (ApoE) is a droplet-related protein with a common variant (ApoE4) that confers the largest increase in genetic risk for late-onset AD. Interestingly, ApoE4 is associated with both increased neuroinflammation and excess LD accumulation. This dissertation work seeks to quantitatively profile the lipid and protein composition of LDs between the ‘neutral’ ApoE3 and ‘risk’ ApoE4 isoforms, in order to gain insight into potential LD-driven contributions to AD pathogenesis. Targeted replacement mice expressing human ApoE3 or ApoE4 were injected with saline (control) or LPS (inflammatory stimulus) and after 24 hours, hepatic lipid droplets were isolated and droplet proteomes and lipidomes were analyzed. Quantitative proteomics showed that LD fractions from E4 mice are enriched for proteins involved in innate immunity, while E3 LDs are enriched for proteins involved in lipid ß-oxidation. Lipidomics revealed a shift in the distribution of glycerophospholipids in E4 LDs with an increase in multiple phosphatidylcholine (PC) species. There was also substantial overlap between LD proteins and AD-proteomes of human whole brain tissue. To translate these findings to the brain, primary microglia from the same strain of mice were exposed to exogenous lipid, inflammatory stimulation, necroptotic N2A cells (nN2A), or a combination of treatments to evaluate lipid droplet accumulation and impact on cell function. Microglia from ApoE4 mice accumulated more LDs at baseline, with exogenous OA, LPS stimulation, and nN2As as a percentage of E3 control across multiple experiments. E4 microglia also secreted significantly more cytokines (TNF, IL-1β, IL-10) than E3 microglia in the control, oleic acid, and nN2A treatment conditions. Interestingly, droplet inhibitors for ACAT and DGAT both decreased droplet accumulation in cells, but did not ameliorate the cytokine response. Finally, we have established a biobank of APOE genotyped peripheral blood mononuclear cells (PBMCs) from research participants. These easily accessible immune cells will serve as a highly translational model to understand LD dynamics as it relates to ApoE and AD risk. In summary, E4 cells accumulate more LDs compared to E3 under all conditions tested, while the proteomic profile of E4 LDs support the hypothesis that E4 expression increases inflammation under basal conditions. This increased LD formation in non-aged, non-diseased E4 cells may suggest preclinical dysfunction associated with the highest risk APOE genotype, and a better understanding of LD dynamics within these cells and their functional implications may provide novel targets to improve E4-related outcomes

    Análisis de conectividad funcional de la dinámica neuroenergética del TDAH = Functional Connectivity Analysis of Neuroenergetic Dynamics for ADHD

    Get PDF
    A fast and economic pilot study for measuring the neuroenergetic dynamics in an ADHD-diagnosed sample is performed. Based in a simplified connectome version, a graph theory application for neural connectivity, the performance and subjective states are linked through brain activity analysis during a behavioral attention test. ADHD is a neurobehavioral disorder related to a deficient filtering of stimuli, inefficacy performing in sustained activities and difficulties responding to unpredictable situations. There are two main strategies to evaluate this disorder: (1) behavioral tests and (2) neural biomarkers. Behavioral tests provide a criterion for classifying responses in a collection of tasks, looking for unstructured and inconsistent responses to given instructions or rules. Hyperactivity, inattention and impulsivity are some criteria analyzed. By the other hand, neural biomarkers are measurable indicators for particular states or diseases set up from EEG data. Since 2013, the theta/beta ratio was accepted as the ADHD biomarker, suggesting a misbalance of electrical brain activity. In this study, brain connectivity on sustained attention task performed by children between 7 to 13 years old from a public school. Ten participants were ADHD-diagnosed and five were selected for the control group to compare EEG signals collected with low-cost neuroheadset. Graphs show different connectivity dynamics in both groups for Theta (4-8 Hz), SMR (12-15 Hz) and Beta (15-20 Hz), indicating connectivity variations in brain regions according to the neuroenergetics theory. The connectivity in the ADHD group is reduced in lower frequencies first (Theta), then SMR and finally Beta. In contrast, the control graphs for Theta and SMR brainwaves are closer to the small-world networks and it can be noticed by comparing the measurements of the different graphs among themselves. The decay process corresponds to the bottom-up approach, where random stimuli trigger transitions from one state to the other, which is in this case the transition from attention to inattention. The declining of resources placed for disposal at the randomized SART stage might imply a limitation regulating the production of the required resources for the tasks fulfillment, as it has been reported in previous studies where other techniques are implemented

    Dementia in Parkinson’s Disease

    Get PDF
    An estimated 50% to 80% of individuals with Parkinson’s disease experience Parkinson’s disease dementia (PDD). Based on the prevalence and clinical complexity of PDD, this book provides an in-depth update on topics including epidemiology, diagnosis, and treatment. Chapters discuss non-medical therapies and examine views on end-of-life issues as well. This book is a must-read for anyone interested in PDD whether they are a patient, caregiver, or doctor

    The effect of bright light on sleep in nursing home patients with dementia

    Get PDF
    Background: Up to 70% of nursing home patients with dementia suffer from disrupted sleep, often characterized by multiple awakenings at night and excessive daytime sleep. Sleep disruption may have negative effects on the cognition, mood, behaviour, and well-being of nursing home patients, while also representing a challenge for nursing home staff. However, few sleep scales are developed and validated specifically for the nursing home setting. Sleep problems among nursing home patients are frequently treated by medications, which are associated with severe side effects, including daytime sleepiness, and an increased risk of falls. Thus, there is a need for non-pharmacological interventions to improve sleep in this population. Bright light treatment (BLT) may represent such an intervention, providing increased light exposure aiming to impact sleep, circadian rhythmicity, mood, and/or behaviour. Light is the most important zeitgeber to the circadian system, and consequently has a significant impact on sleep-wake behaviour. Unfortunately, studies have reported low indoor light levels in nursing homes, which in combination with dementia-related neuropathology and age-related reductions in light sensitivity, are likely to contribute to sleep problems in this population. The aim of this thesis was to investigate whether increasing daytime light exposure, by means of BLT, can improve sleep in nursing home patients with dementia, and also to address methodological challenges in this field of research. Methods: Paper 1 is a systematic review of the literature, focusing on the methodological features of the included studies, in addition to their findings. Paper 2 and 3 are based on data from the DEM.LIGHT trial; a cluster-randomized placebo-controlled trial conducted in Norwegian nursing homes, including 69 patients. The intervention comprised a diurnal cycle of ambient light with a maximum of 1,000 lux and 6,000 Kelvin (K) from 10:00-15:00, administered using light emitting diode (LED) light. Before and after this interval, the light levels gradually increased/decreased in lux and K. In the placebo condition, standard light levels were maintained at 150-300 lux and approximately 3,000 K throughout the day. The intervention and placebo lights were installed in the common rooms of the included nursing home units. Outcomes were measured at baseline and at follow-up at week 8, 16, and 24. Paper 2 was a validation study of a proxy-rated sleep scale, using the baseline data from the DEM. LIGHT trial. Actigraphy was used as the reference standard. Paper 3 reported on the sleep outcomes of the trial, which were the primary outcomes. Results: Paper 1 found that there are promising, though inconsistent, results regarding the effect of BLT on sleep and circadian rhythmicity in dementia. Large heterogeneity in terms of interventions, study designs, population characteristics, and outcome measurement tools may explain some of the inconsistencies of results across studies. Paper 2 showed that the proxy-rated Sleep Disorder Inventory (SDI) had satisfactory internal consistency and convergent validity. Using actigraphy as the reference standard, the SDI was termed clinically useful, and we suggested a cut-off score of five or more as defining disrupted sleep in nursing home patients with dementia. These results should be interpreted keeping in mind that actigraphy have some important weaknesses, such as underestimating wake time. Paper 3 evaluated the effects of the BLT on sleep and found an improvement in sleep according to the SDI scores in the intervention group, as compared to the control group, from baseline to week 16 and baseline to week 24. There was no effect in terms of sleep measured by actigraphy. Conclusion: In summary, this thesis found that the evidence for an effect of BLT on sleep in nursing home patients with dementia is promising, but equivocal. Importantly, the research field faces some important methodological challenges, such as accurately measuring sleep. The SDI may represent a valid tool to measure sleep in the nursing home setting, which may be used both by researchers and by practitioners. Although the results of this thesis are not conclusive regarding the effect of BLT on sleep in nursing home patients with dementia, it may represent a step forward in understanding the potential value of BLT in this population, and may lay the ground for further investigation. The lack of an improvement on the SDI at week 8 indicates that the effect of BLT may take a long time to manifest in this population.Doktorgradsavhandlin

    Protective microglial activation in Alzheimer’s disease pathogenesis

    Get PDF
    Here it was of interest to determine the spatiotemporal relationships between Aβ, tau, and microglial pathological changes in post-mortem human AD brains by comparing differentially affected brain regions. Immunohistochemistry and fluorescence immunohistochemistry targeting Aβ, tau, and the pan-microglia marker ionised calcium binding adaptor molecule 1 (Iba1) was performed in four regions of decreasing pathological severity: inferior temporal cortex, superior frontal cortex, primary visual cortex, and primary motor cortex of ten controls, five controls with Alzheimer changes (CAc), and eight AD cases. Following a validated modified disector sampling approach, using manual and corroborative automated methods, the results showed that activated microglia predominated in the inferior temporal cortex of CAc. AD brains were characterised by increased clustering of activated microglia in the primary visual cortex and a substantial loss of clustering and ramified healthy microglia in the inferior temporal cortex. Activated microglia were found to internalise Aβ pathology but not tau pathology. Further, microglia were found to phagocytose greater quantities of pre-synapses in AD compared to both CAc and controls in a study using super-resolution microscopy. Gene amplification studies of a number of candidate genes were performed in coronal neonatal mouse brain slice cultures treated with synthetic preparations of Aβ. Findings demonstrated the upregulation of select phagocytic and anti-inflammatory markers in response to low-dose Aβ monomers. Additionally, a validation amplification study confirmed findings from an RNA-Seq study which demonstrated the upregulation of gene transcripts related to immune pathways and phagocytosis in mildly affected regions of the AD brain. Taken together, these findings are indicative of neuroprotective activation of microglia early in the pathogenesis of AD

    Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

    Get PDF
    Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40
    corecore