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In addition, both microglial and astrocyte gene expression patterns consistent with neurodegeneration were seen in PS mice expressing different forms of ApoE. These results show that ApoE4 can drive increased tau-mediated neurodegeneration.
ApoE is also abundantly expressed in peripheral tissues including liver where it mediates plasma lipid metabolism. APOE4 carriers have increased risk for hypercholesterolemia and atherosclerosis. To address apoE isoform-dependent functions in CNS and periphery, we developed cell type-specific and inducible apoE mouse models. More interesting, expression of apoE4 prior to amyloid deposition had a greater impact on amyloid pathology than that during the rapid growth period.
When apoE isoforms were expressed exclusively in the periphery in the Apoe-knockout background, apoE4 inhibited synaptic functions, impaired cognition, and was associated with compromised blood-brain barrier integrity and vascular functions. These results provide mechanistic insights as to how apoE4 increases the risk for AD and how we can develop apoE isoform-specific strategies for AD prevention and therapy.
Peters , K. Luther , S.
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Yet their interdependence remains partly unclear. For pairwise correlations between amyloid species and tTAU Pearson correlation coefficients were calculated.
Conclusion Neurodegener Dis ;17 suppl 1 — Page Downloaded by: Marizzoni , C. Ferrari , J. Jovicich , D. Albani , C. Babiloni , M. Didic , G. Forloni , J. Molinuevo , F. Nobili , 8 9 10 11 12,13 14 15 L. Parnetti , P. Payoux , P. Rossini , P. Soricelli , M. Tsolaki , P. Visser , 16,17 18 19 1,20 J. Wiltfang , R.
Bordet , O. Blin , G. Baseline analysis. Longitudinal analysis. Linear Mixed Model for repeated measures to study the association between CSF status and time on clinical and biomarker values. Results Neurodegener Dis ;17 suppl 1 — Page Downloaded by: Conclusion Neurodegener Dis ;17 suppl 1 — Page Downloaded by: Goldhardt , T.
Grimmer , H. Alexopoulos , V. Magdolen , E. KLK6 was highly expressed in the nervous system, positively associated with age, increased in brain tissue and in CSF and associated with pTau levels.
In this study, we aimed at elucidating the suitability of KLK6, 8, and 10, to distinguish between NC and patients with probable AD and explored associations with AD biomarkers.
APOE, and lifestyle, e. Most recently we have found that low-grade infections, e. Genetic susceptibility factors have been elucidated over the past decade using genome-wide association studies GWAS and more recently by follow up with whole genome sequencing WGS and whole exome sequencing WES.
Many of the more recently identified AD genes are involved in innate immunity, e. To study CD33 and other innate immune-related AD genes, we have incorporated microglia into our 3D neural cultures while also utilizing classic transgenic mouse models. Aspects of all these studies will be covered. This approach has successfully discovered several causal genes for the major clinical subtypes i. Alzheimer disease and frontotemporal dementia. Knowledge of these genes has provided fundamental insights in the disease mechanisms that are underlying neurodegenerative dementia that became cornerstones in potential pharmaceutical interventions.
However, mutations in the known genes associated with early-onset dementia EOD explain only a minor fraction of the patients and families.
Continued interest in EOD genetics is warranted since recent studies using massive parallel sequencing, demonstrated that rare genetic variants might contribute to our further understanding of the molecular disease mechanisms behind EOD.
Clinical studies have indicated that EOD is highly heterogeneous with a substantial fraction of patients in whom the disease is unrelated to previous identified biological pathways. Further, many EOD patients have been excluded from genetic studies since their clinical phenotype was atypical and did not fit the de strict diagnostic entities.
Nonetheless, several of those atypical EOD patients have a positive family history of dementia and some belong to large families. We showed that mutations in known causal genes can be found in patients with diagnostic unclassified EOD. Also, mutations are found in genes that were associated with late-onset dementia e.
In extended families, we used exome sequencing and identified rare genetic variants in genes that had not yet been associated with EOD.
Chiba-Falek , L. Tagliafierro , M. Lutz , A. It has been suggested that changes, even subtle, in the expression levels of wild-type genes in the brain can, over years, lead to neurodegenerative diseases.
Moreover, differences in gene expression profiles between brain tissues from neurodegenerative disease patients compared to healthy controls have been reported. In particular, we focus on noncoding variants and their cis-regulatory effects on gene expression using a comprehensive strategy that combines multiple-level approaches. The tool is a searchable, annotated database of SSVs, with associated customizable scoring software that is designed to evaluate and prioritize SSVs that are most likely to have significant biological effects and impact on disease risk.
Collectively, the innovative approaches we developed represent a cohesive strategy for discovering potentially functional and causal variants within candidate risk-genes associated with AD-PD spectrum disorders. Pattamatta , L. Nguyen , Y. Liu , B. Perez , O. Bardhi , A. Yachnis , L. An emerging theme is that coding and non-coding expansion mutations are bidirectionally expressed, producing two mutant RNAs and up to six mutant RAN proteins.
These findings impact our fundamental understanding of gene expression and protein translation and should now be considered for a broad category of neurological disorders.
These C9-BAC mice show decreased survival, paralysis, muscle denervation, motor-neuron loss, anxiety-like behavior and cortical and hippocampal neurodegeneration in a repeat-length and expression dependent manner. RAN protein accumulation increases with age and severity of disease and TDP inclusions are found in degenerating brain regions in end-stage animals. Insights into RNA vs.
Certain up-regulated miRNAs contribute to chronic inflammation, innate-immune and synaptic disturbances in various brain cell types such neurons, astroglia, microglia, endothelial cells , thereby leading to progression of neurodegenerative diseases like sporadic Alzheimer's disease AD , prion disease PrD and age-related macular degeneration AMD. Several of these more well-studied miRNA-mediated pathogenic circuitries will be discussed in this lecture.
Lastly, our ideas on miRNA-mRNA coupling and their regulatory mechanism in the developing and aging CNS continue to evolve, and technological advancement, refinement and recent discoveries continue to contribute to our understanding of the pathogenic mechanisms that characterize these age-related neurodegenerative and neuropsychiatric disorders of the human CNS. De Jager , H. Klein , D.
Genome-wide DNA methylation and transcription profiles were available for a large subset of these samples. ATAC-seq was applied to induced forebrain neurons to measure chromatin accessibility. Results We identified 26, H3K9Ac domains which primarily occurred at promoters 15, and enhancers 8, H3K9Ac levels at promoters were positively correlated with transcription.
Furthermore, we find evidence that transcriptomic networks mediate the effect of genetic loci via mitochondrial function. Previous evidence suggests a role of mitochondrial dysfunction in early stage AD pathophysiology. Rovelet-Lecrux , K. Le Guennec , O. Quenez , G. Nicolas , D. Wallon , J. Alexander , P. Deleuze , M. Lathrop , O. Kalev , S. Mehrabian , L.
Traykov , T. Le Ber , T. Jonveaux , 13 10 4 2 C. FREX , G. Kovacs , D. Hannequin , D. Method WES data were screened for rare 1. Statistical models were adjusted for clinical or demographic factors that also differed between the groups. Sanabria Diaz , B. Draganski , L. Melie Garcia , F. Method We used graph theory and cortical thickness obtained from T1-weighted structural magnetic images to study brain network co-variance properties NPs in a longitudinal sample comprised MCI who convert into AD and non-converters.
All subjects were selected from the ADNI database. Results The co-variation patterns among anatomical regions showed the double of differences over time between carriers and non-carriers for MCI who progressed into AD. Large co-variations patterns between carries and non-carriers involved structures like superior and inferior parietal cortex, precuneus and middle frontal regions described previously as a core of highly connected brain structures.
The MCI carriers in this group showed a significant increase over time in the characteristic path length, clustering index, local efficiency, global connectivity and a global efficiency decrease.
Interestingly, this was not the case for MCI non-converters in which the same patterns of differences between groups were preserved over time.
Our findings suggest a differential genetic modulation associated with the disease progression. Waninger , C. Berka , M. Karic , A. Meghdadi , D. Salat , A. Martinos Center for Biomedical Imaging, Department of Radiology, Charlestown, USA 3 Biogen, Neurodegenerative Drug Development, Cambridge, USA Aims There is a critical unmet need for reliable, cost effective and noninvasive biomarkers to quantify cognitive defects associated with dementia at early stages and facilitate development of efficacious, disease modifying therapeutics.
Neurophysiological metrics including quantitative EEG and event-related potentials ERPs reliably measure the physiology associated with cognition and may provide sensitive metrics for early diagnosis, tracking disease progression and assessing efficacy of novel interventions for dementia. F-Measure, a combined measure of processing speed and accuracy, was used to evaluate performance. MCI patients evidenced larger and more widespread decreases in the LPC during IR with significant decreases over central, temporal, parietal and occipital regions.
Significant differences were observed in performance during IR; F-measure in the healthy group 0. Mendonca , Z. Sun , H. Lon , R. Jin , C. Locke , S. Goss , D.
Wang , W. Robieson , B.
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Method In the multicenter Ph0 non-treatment study, 26 AD subjects, 52 mild cognitive impairment MCI subjects, and 26 healthy subjects of similar age were enrolled. Subjects underwent magnetic resonance imaging MRI and amyloid positron-emission tomography PET imaging as well as 2 lumbar punctures to collect cerebrospinal fluid CSF.
The 2 studies ADNI and the Ph0 study were similar with respect to inclusion and exclusion criteria for each of the three diagnostic groups.
Ewing JA. Detecting alcoholism. The CAGE questionnaire. JAMA ; 14 : J Pneumol ; 28 4 : The hospital anxiety and depression scale. Acta Psychiatr Scand , 67 6 : The role of conceptual frameworks in epidemiological analysis: a hierarchical approach.
Int J Epidemiol. Transtornos do humor. Nardi AE. Transtornos de ansiedade. Himmelfarb S, Murrell SA. The prevalence and correlates of anxiety symptoms in older adults. J Psychol ; 2 d Half : Symptoms of depression and anxiety during adult life: evidence for a decline in prevalence with age. Psychol Med. Almeida OP. Elderly treated in mental health emergency rooms: demographic and clinic characteristics. Rev Bras Psiquiatr ; 21 1 : Botega NJ, editor.
Cad Saude Publica ; 22 8 : J Bras Psiquiatr ; 56 1 : The role of anger in hypertensive. Psychother Psychosom ; 43 4 : Essential Hypertension: The relationship of Psychological Factors to the severity of hypertension.
J Psychosom Res ; 33 2 : Hypertension labelling, life events and psychological well-being. Psychol Med ; On the association between diabetes and mental disorders in a community sample: results from the German National Health Inteview and Examination Survey.
Diabetes Care ; Elliott A. Anxiety and HIV infection. STEP Perspect ; 98 1 : A meta-analysis on the anxiety-reducing effects of acute and chronic exercise. Outcomes and mechanisms. Sports Med ; 11 3 : Smoking increases the risk of panic: findings from a prospective community study.
Shallow-water sponges of the western Bahamas
Arch Gen Psychiatry ; 60 7 : Degenhardt L, Hall W. Make nice stitches: express authenticity Reveal t he tru e characte r within various envi ronment s of interve ntion. Accept inci dents, event s, positi ves or negati ves as pages of histor y t hat contribute to th e ric hness of a place. For exa mple, foll owing a si t e disturba nce choose interesti ng stitch ma rk s ove r scar- free plast ic surge ry.
Th e add ition of a narrati ve layer allows creatin g si t es t o go beyo nd fun ctio nality, enrichi ng user ex periences. Allow for evoluti on and mu ta ti on. Updated representations are needed to counterbalance ever-present bucolic vision s. The idea of nature must constantly be redefined. Pure surfaces and clean lines fuel the creation of patterns; site work becomes the canvas for pictorial exploration. Alterations of conventional scale transform the concepts of ergonomics, functionality, comfort, and security with relation to common components.
Encourage an ecological system approach by smartly reusing cut and fill, enhancing surface water management and merging site work into a 3D work of art. Be eccentric: explore atypical materials and techniques Question conventions and try to bring new materials and labor techniques to design projects. Seek opportunities to rethink standard assemblages and borrow methods from diverse and unexpected sources. Transform limitative realities into positive and meaningful visions.
The concept of a project is the vital gene that controls the development of the architectural design. I like to construct evolutionary outlines that explain the central concept of the project; these reveal the main components of the proposal and help to verify whether processes underway are correct or not.
For an architect who is interested in creating a pure and simple conceptual architecture, a continuous material is the perfect ingredient to achieve this goal. Thus, a straight line is a straight line, a plane is a plane, and a cube is a cube. In the House in Las Casuarinas, the nexus of the three basic axes, X, Y, and Z, is clearly defined in an architectural solution whose geometrical force can be admired from afar in the city. Nature as a background Unique situations create the opportunity for unique natural settings as a background for architectural works.
The majestic presence of Cerro Colorado hill, on the beach with the same name, helped me to envisage a club house project that would be utterly simple and have a geometry that would help to reveal the breathtaking location. In a way, the house is also a camera. Working with just a few materials and finishes helps to foreground a project's key concept. Chabuca Granda Boulevard is a test bed to explore this topic. Here, a sequence of circular plazas is configured by basic geometric forms cubes, spheres, etc.
Creating an architectural project that breaks us from the bonds of pre-defined uses for things, to encourage us to behave with greater freedom, is an important aim within our projects. And this is when artificial lighting comes into its own as a defining concept in a project.
In the Beach House in Las Arenas, the lighting design was envisaged not only to enhance the transparent or translucent planes of the project, but also to drive home the idea of the house as a floating box. The result is that the house not only seems to float towards infinity, but also has a liquid frame that dramatizes this effecl. For the Dasso Boulevard project, I designed a series of green vertical elements that, as well as acting as lighting columns, greatly increased the green spaces in the site, which hardly had garden areas.
The result is a series of green plates that create a vertical garden, which is a reference point for the entire boulevard. The Plaza del Torico project aims to insert a recognizable layer from our times into the city, while completely respecting its existing layers.In addition, we analyzed factors implicated to cause PD e.
Both full-time and part-time employees may participate in a telework arrangement. Porto Alegre: Artmed; Lecrubier Y. Arch Gen Psychiatry ; 60 7 : Neurodegener Dis ;17 suppl 1 — Page 8 Downloaded by: Interestingly, resveratrol provided protection towards alpha-synuclein dependent toxicity but had no impact on aggregation.
The employee agrees to complete all assigned work according to procedures mutually agreed upon by the employee and the supervisor.
A trial is anticipated to initiate in for the most frequent cause hexanucleotide expansion in the C9orf72 gene of both ALS and frontal temporal dementia. A meta-analysis on the anxiety-reducing effects of acute and chronic exercise.