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Find video protocols related to scientific articles indexed in Pubmed.
The partial volume effect in the quantification of 1H magnetic resonance spectroscopy in Alzheimer's disease and aging.
J. Alzheimers Dis.
PUBLISHED: 06-15-2014
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1H-MRS variability increases due to normal aging and also as a result of atrophy in grey and white matter caused by neurodegeneration. In this work, an automatic process was developed to integrate data from spectra and high-resolution anatomical images to quantify metabolites, taking into account tissue partial volumes within the voxel of interest avoiding additional spectra acquisitions required for partial volume correction. To evaluate this method, we use a cohort of 135 subjects (47 male and 88 female, aged between 57 and 99 years) classified into 4 groups: 38 healthy participants, 20 amnesic mild cognitive impairment patients, 22 multi-domain mild cognitive impairment patients, and 55 Alzheimer's disease patients. Our findings suggest that knowing the voxel composition of white and grey matter and cerebrospinal fluid is necessary to avoid partial volume variations in a single-voxel study and to decrease part of the variability found in metabolites quantification, particularly in those studies involving elder patients and neurodegenerative diseases. The proposed method facilitates the use of 1H-MRS techniques in statistical studies in Alzheimer's disease, because it provides more accurate quantitative measurements, reduces the inter-subject variability, and improves statistical results when performing group comparisons.
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Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.
Valentina Escott-Price, Celine Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L Destefano, Jean-Charles Lambert, Carla A Ibrahim-Verbaas, Adam C Naj, Rebecca Sims, Gyungah Jun, Joshua C Bis, Gary W Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A Thornton-Wells, Nicola Denning, Albert V Smith, Vincent Chouraki, Charlene Thomas, M Arfan Ikram, Diana Zelenika, Badri N Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L Dunstan, Maria Vronskaya, , Andrew D Johnson, Agustin Ruíz, Marie-Therese Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L Fitzpatrick, Joseph D Buxbaum, Dominique Campion, Paul K Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L Lopez, Philip L De Jager, Vincent Deramecourt, Janet A Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M Goate, Nathalie Fiévet, Matthew J Huentelman, Michael Gill, Kristelle Brown, M Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B Larson, Amanda J Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimón, Alberto Lleó, Anthony Bayer, Debby W Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G Younkin, Eliecer Coto, Kara L Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J Owen, Kelley M Faber, Palmi V Jonsson, Onofre Combarros, Michael C O'Donovan, Laura B Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H Mosley, David A Bennett, Tamara B Harris, Laura Fratiglioni, Clive Holmes, Renée F A G de Bruijn, Peter Passmore, Thomas J Montine, Karolien Bettens, Jerome I Rotter, Alexis Brice, Kevin Morgan, Tatiana M Foroud, Walter A Kukull, Didier Hannequin, John F Powell, Michael A Nalls, Karen Ritchie, Kathryn L Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R Martin, Reinhold Schmidt, Dan Rujescu, Jean-Francois Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M Nöthen, Caroline Graff, Bruce M Psaty, Jonathan L Haines, Mark Lathrop, Margaret A Pericak-Vance, Lenore J Launer, Christine Van Broeckhoven, Lindsay A Farrer, Cornelia M van Duijn, Alfredo Ramírez, Sudha Seshadri, Gerard D Schellenberg, Philippe Amouyel, Julie Williams.
PLoS ONE
PUBLISHED: 01-01-2014
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Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
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Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimers disease and frontotemporal dementia.
Neurobiol. Aging
PUBLISHED: 05-08-2013
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A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimers disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3172 AD and 682 FTD patients and 2169 healthy controls from Spain. We found that 0.6% of AD patients carried this variant compared to 0.1% of controls (odds ratio [OR] = 4.12, 95% confidence interval [CI] = 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR = 4.11, 95% CI = 2.99-5.68, p = 5.27×10(-18)). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk, and suggest that this rare genetic variant is not related to FTD.
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Machine learning and social network analysis applied to Alzheimers disease biomarkers.
Curr Top Med Chem
PUBLISHED: 01-25-2013
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Due to the fact that the number of deaths due Alzheimer is increasing, the scientists have a strong interest in early stage diagnostic of this disease. Alzheimers patients show different kind of brain alterations, such as morphological, biochemical, functional, etc. Currently, using magnetic resonance imaging techniques is possible to obtain a huge amount of biomarkers; being difficult to appraise which of them can explain more properly how the pathology evolves instead of the normal ageing. Machine Learning methods facilitate an efficient analysis of complex data and can be used to discover which biomarkers are more informative. Moreover, automatic models can learn from historical data to suggest the diagnostic of new patients. Social Network Analysis (SNA) views social relationships in terms of network theory consisting of nodes and connections. The resulting graph-based structures are often very complex; there can be many kinds of connections between the nodes. SNA has emerged as a key technique in modern sociology. It has also gained a significant following in medicine, anthropology, biology, information science, etc., and has become a popular topic of speculation and study. This paper presents a review of machine learning and SNA techniques and then, a new approach to analyze the magnetic resonance imaging biomarkers with these techniques, obtaining relevant relationships that can explain the different phenotypes in dementia, in particular, different stages of Alzheimers disease.
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Rare variants in calcium homeostasis modulator 1 (CALHM1) found in early onset Alzheimers disease patients alter calcium homeostasis.
PLoS ONE
PUBLISHED: 01-01-2013
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Calcium signaling in the brain is fundamental to the learning and memory process and there is evidence to suggest that its dysfunction is involved in the pathological pathways underlying Alzheimers disease (AD). Recently, the calcium hypothesis of AD has received support with the identification of the non-selective Ca(2+)-permeable channel CALHM1. A genetic polymorphism (p. P86L) in CALHM1 reduces plasma membrane Ca(2+) permeability and is associated with an earlier age-at-onset of AD. To investigate the role of CALHM1 variants in early-onset AD (EOAD), we sequenced all CALHM1 coding regions in three independent series comprising 284 EOAD patients and 326 controls. Two missense mutations in patients (p.G330D and p.R154H) and one (p.A213T) in a control individual were identified. Calcium imaging analyses revealed that while the mutation found in a control (p.A213T) behaved as wild-type CALHM1 (CALHM1-WT), a complete abolishment of the Ca(2+) influx was associated with the mutations found in EOAD patients (p.G330D and p.R154H). Notably, the previously reported p. P86L mutation was associated with an intermediate Ca(2+) influx between the CALHM1-WT and the p.G330D and p.R154H mutations. Since neither expression of wild-type nor mutant CALHM1 affected amyloid ß-peptide (Aß) production or Aß-mediated cellular toxicity, we conclude that rare genetic variants in CALHM1 lead to Ca(2+) dysregulation and may contribute to the risk of EOAD through a mechanism independent from the classical Aß cascade.
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Genetic variation in the tau protein phosphatase-2A pathway is not associated with Alzheimers disease risk.
BMC Res Notes
PUBLISHED: 06-01-2011
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Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in AD brain is the result of upregulation of tau kinases and downregulation of tau phosphatases.
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Genetic cross-interaction between APOE and PRNP in sporadic Alzheimers and Creutzfeldt-Jakob diseases.
PLoS ONE
PUBLISHED: 03-25-2011
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Alzheimers disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ?4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ?4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF?=?3.59, p?=?0.027), and sCJD (SF?=?7.26, p?=?0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD.
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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimers disease.
Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean-Charles Lambert, Minerva M Carrasquillo, Richard Abraham, Marian L Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Nicola Jones, Alexandra Stretton, Charlene Thomas, Alex Richards, Dobril Ivanov, Caroline Widdowson, Jade Chapman, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K Lupton, Carol Brayne, David C Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kristelle S Brown, Peter A Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A David Smith, Helen Beaumont, Donald Warden, Gordon Wilcock, Seth Love, Patrick G Kehoe, Nigel M Hooper, Emma R L C Vardy, John Hardy, Simon Mead, Nick C Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Eckart Rüther, Britta Schürmann, Reiner Heun, Heike Kölsch, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, John Gallacher, Michael Hüll, Dan Rujescu, Ina Giegling, Alison M Goate, John S K Kauwe, Carlos Cruchaga, Petra Nowotny, John C Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter P De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas J Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis Deloukas, Ammar Al-Chalabi, Christopher E Shaw, Magda Tsolaki, Andrew B Singleton, Rita Guerreiro, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Karl-Heinz Jöckel, Norman Klopp, H-Erich Wichmann, V Shane Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Zbigniew K Wszolek, Dennis W Dickson, Neill R Graff-Radford, Ronald C Petersen, , Cornelia M van Duijn, Monique M B Breteler, M Arfan Ikram, Anita L Destefano, Annette L Fitzpatrick, Oscar Lopez, Lenore J Launer, Sudha Seshadri, Claudine Berr, Dominique Campion, Jacques Epelbaum, Jean-Francois Dartigues, Christophe Tzourio, Annick Alpérovitch, Mark Lathrop, Thomas M Feulner, Patricia Friedrich, Caterina Riehle, Michael Krawczak, Stefan Schreiber, Manuel Mayhaus, S Nicolhaus, Stefan Wagenpfeil, Stacy Steinberg, Hreinn Stefansson, Kari Stefansson, Jón Snaedal, Sigurbjorn Bjornsson, Palmi V Jonsson, Vincent Chouraki, Benjamin Genier-Boley, Mikko Hiltunen, Hilkka Soininen, Onofre Combarros, Diana Zelenika, Marc Delepine, María J Bullido, Florence Pasquier, Ignacio Mateo, Ana Frank-García, Elisa Porcellini, Olivier Hanon, Eliecer Coto, Victoria Alvarez, Paolo Bosco, Gabriele Siciliano, Michelangelo Mancuso, Francesco Panza, Vincenzo Solfrizzi, Benedetta Nacmias, Sandro Sorbi, Paola Bossù, Paola Piccardi, Beatrice Arosio, Giorgio Annoni, Davide Seripa, Alberto Pilotto, Elio Scarpini, Daniela Galimberti, Alexis Brice, Didier Hannequin, Federico Licastro, Lesley Jones, Peter A Holmans, Thorlakur Jonsson, Matthias Riemenschneider, Kevin Morgan, Steven G Younkin, Michael J Owen, Michael O'Donovan, Philippe Amouyel, Julie Williams.
Nat. Genet.
PUBLISHED: 03-10-2011
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We sought to identify new susceptibility loci for Alzheimers disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimers Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ? 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimers disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).
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Genetic variation in APOE cluster region and Alzheimers disease risk.
Neurobiol. Aging
PUBLISHED: 01-10-2011
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We report the fine mapping/sequencing results of promoter and regulatory regions of APOE cluster genes (APOE, APOC1, APOC4, APOC2, and TOMM40) in Alzheimers disease (AD) risk as well as in the progression from mild cognitive impairment (MCI) to AD. Long-range sequencing in 29 MCI subjects who progressed to dementia revealed 7 novel variants. Two potentially relevant novel variants and 34 single nucleotide polymorphisms (SNPs) were genotyped in a large sample of AD, MCI, and control subjects (n = 1453). Globally, very little association signal was observed in our sample in the absence of APOE ?4. Rs5158 (APOC4 intron 1) and rs10413089 (3 to APOC2) showed a trend toward an increase in AD risk independently from APOE ?4 associated risk though it did not survive multiple test correction (uncorrected p = 0.0099 and 0.01, respectively). Interestingly, rs10413089 showed a similar effect in an independent series. The analysis of the discovery sample showed an association of TOMM40 single nucleotide polymorphisms with progression from MCI stage to AD (rs59007384 and rs11556510), as well as with a shorter time to progression from MCI status to AD (rs10119), though these results could not be replicated in independent series. Further studies are needed to investigate the role of APOE cluster variants in AD risk.
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Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.
Neurobiol. Aging
PUBLISHED: 01-08-2011
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Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimers disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.
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Decline of executive processes affects identification of emotional facial expression in aging.
Curr Aging Sci
PUBLISHED: 01-06-2011
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The current study examined the hypothesis that old people have a selective deficit in the identification of emotional facial expressions (EFEs) when the task conditions require the mechanism of the central executive. We have used a Dual Task (DT) paradigm to assess the role of visuo-spatial interference of working memory when processing emotional faces under two conditions: DT at encoding and DT at retrieval. Previous studies have revealed a loss of the ability to identify specific emotional facial expressions (EFEs) in old age. This has been consistently associated with a decline of the ability to coordinate the performance of two tasks concurrently. Working memory is usually tested using DT paradigms. Regarding to aging, there is evidence that with DT performance during encoding the costs are substantial. In contrast, the introduction of a secondary task after the primary task (i.e. at retrieval), had less detrimental effects on primary task performance in either younger or older adults. Our results demonstrate that aging is associated with higher DT costs when EFEs are identified concurrently with a visuo-spatial task. In contrast, there was not a significant age-related decline when the two tasks were presented sequentially. This suggests a deficit of the central executive rather than visuo-spatial memory deficits. The current data provide further support for the hypothesis that emotional processing is "top-down" controlled, and suggest that the deficits in emotional processing of old people depend, above all, on specific cognitive impairment.
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Clinical progression of moderate-to-severe Alzheimers disease and caregiver burden: a 12-month multicenter prospective observational study.
Int Psychogeriatr
PUBLISHED: 09-20-2010
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Prospective studies on the clinical progression of Alzheimers disease (AD) and its relationship to caregiver burden are needed to improve illness management and use of resources.
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IGF-I gene variability is associated with an increased risk for AD.
Neurobiol. Aging
PUBLISHED: 03-18-2010
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Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain, is involved in the pathogenesis of Alzheimers disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (A?) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals. Genetic analysis indicated different distribution of genotypes of 1 single nucleotide polymorphism, and 1 extended haplotype in the AD population compared with healthy control subjects. In particular, the frequency of rs972936 GG genotype was significantly greater in AD patients than in control subjects (63% vs. 55%). The rs972936 GG genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype, and with enhanced circulating levels of IGF-I. These findings suggest that polymorphisms within the IGF-I gene could infer greater risk for AD through their effect on IGF-I levels, and confirm the physiological role IGF-I in the pathogenesis of AD.
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Citicoline, use in cognitive decline: vascular and degenerative.
J. Neurol. Sci.
PUBLISHED: 03-16-2010
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CDP-choline has been widespread used in humans for decades as a treatment for many types of cognitive impairment. Despite this, its mechanism of action still remains unclear, but several experimental models in acute cerebral ischaemia suggest that it could have a brain repair action. Due to the lack of significant adverse effects and its high tolerability, there has been a growing interest for this molecule in recent years. In this article, a review of the most significant published clinical trials in cognitive decline has been made. A few Citicoline trials have studied its effects at medium and long-term on vascular cognitive impairment and Alzheimers disease. Results show that Citicoline seems to have beneficial impact on several cognitive domains, but the methodological heterogeneity of the these studies makes it difficult to draw conclusions about these effects. New trials with a greater number of patients, uniform diagnostic criteria for inclusion and standardized neuropsychological assessment are needed to evidence with much more consistency Citicoline efficacy upon cognitive disorders. The use of new neuroimaging procedures in current trials could be of great interest.
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Caspase-1 genetic variation is not associated with Alzheimers disease risk.
BMC Med. Genet.
PUBLISHED: 02-25-2010
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Interleukin (IL)-1beta is a potent proinflammatory cytokine markedly overexpressed in the brains of patients with Alzheimers disease (AD), and also involved in development of atherosclerosis and coronary artery disease. Caspase-1 (CASP1), formerly called IL-1beta converting enzyme (ICE), mediates the cleavage of the inactive precursor of IL-1beta into the biologically active form. CASP1 genetic variation (G+7/in6A, rs501192) has been associated with susceptibility to myocardial infarction and cardiovascular death risk. We examined the contribution of this gene to the susceptibility for AD.
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Genetic variations in tau-tubulin kinase-1 are linked to Alzheimers disease in a Spanish case-control cohort.
Neurobiol. Aging
PUBLISHED: 01-22-2010
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Neurofibrillary tangles, one of the characteristic neuropathological lesions found in Alzheimers disease (AD) brains, are composed of abnormally hyperphosphorylated tau protein. Tau-tubulin kinase-1 (TTBK1) is a brain-specific protein kinase involved in tau phosphorylation at AD-related sites. We examined genetic variations of TTBK1 by genotyping nine haplotype tagging SNPs (htSNPs) (rs2104142, rs2651206, rs10807287, rs7764257, rs3800294, rs1995300, rs2756173, rs6936397, and rs6458330) in a group of 645 Spanish late-onset AD patients and 738 healthy controls. Using a recessive genetic model, minor allele homozygotes for rs2651206 in intron 1 (OR=0.50, p=0.0003), rs10807287 in intron 5 (OR=0.49, p=0.0002), and rs7764257 in intron 9 (OR=0.57, p=0.023), which are in strong linkage disequilibrium, had a lower risk of developing AD than subjects homozygotes and heterozygotes for the major allele. TTBK1 is a promising new candidate tau phosphorylation-related gene for AD risk.
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A megalin polymorphism associated with promoter activity and Alzheimers disease risk.
Am. J. Med. Genet. B Neuropsychiatr. Genet.
PUBLISHED: 01-07-2010
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Elevated cerebral levels of amyloid beta-protein (Abeta) occur in Alzheimers disease (AD), yet only a few patients show evidence of increased Abeta production. This observation suggests that many, perhaps most, cases of AD are caused by faulty clearance of Abeta. Megalin, which plays an important role in mediating Abeta clearance, is an attractive candidate gene for genetic association with AD. To investigate this hypothesis, we analyzed the megalin gene in a population of 2,183 subjects. Genetic analysis indicated that the rs3755166 (G/A) polymorphism located in the megalin promoter associated with risk for AD, dependently of apolipoprotein E genotype. The rs3755166 AA genotype frequency was significantly greater in AD patients than in control subjects. Furthermore, the luciferase reporter assay indicated that the rs3755166 A variant has 20% less transcriptional activity than the rs3755166 G variant. This study provides strong evidence that this megalin polymorphism confers a greater risk for AD, and supports a biological role for megalin in the neurodegenerative processes involved in AD.
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DYRK1A genetic variants are not linked to Alzheimers disease in a Spanish case-control cohort.
BMC Med. Genet.
PUBLISHED: 07-30-2009
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As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been implicated in the abnormal hyperphosphorylation of tau in Alzheimers disease (AD) brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD.
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A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimers disease.
Aging Cell
PUBLISHED: 02-23-2009
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Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimers disease (AD), is intimately linked to aging - the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This paper reports that, in human neuronal cells, oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system leads to apoptotic cell death. Microarray analyses showed a potent activation of the cholesterol biosynthesis pathway following reductions in the cell cholesterol synthesis caused by the X-XOD treatment; furthermore, the apoptosis was reduced by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) expression with an interfering RNA. The potential importance of this mechanism in AD was investigated by genetic association, and it was found that HMGCR, a key gene in cholesterol metabolism and among those most strongly upregulated, was associated with AD risk. In summary, this work presents a human cell model prepared to mimic the effect of oxidative stress in neurons that might be useful in clarifying the mechanism involved in free radical-induced neurodegeneration. Gene expression analysis followed by genetic association studies indicates a possible link among oxidative stress, cholesterol metabolism and AD.
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A common BACE1 polymorphism is a risk factor for sporadic Creutzfeldt-Jakob disease.
PLoS ONE
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The ? site APP cleaving enzyme 1 (BACE1) is the rate-limiting ?-secretase enzyme in the amyloidogenic processing of APP and A? formation, and therefore it has a prominent role in Alzheimers disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its ?-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by A? oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimers and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, A? oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players.
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Genetic variability of the gene cluster CALHM 1-3 in sporadic Creutzfeldt-Jakob disease.
Prion
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Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.
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