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Find video protocols related to scientific articles indexed in Pubmed.
Plant-Based Nutraceutical Interventions against Cognitive Impairment and Dementia: Meta-Analytic Evidence of Efficacy of a Standardized Gingko biloba Extract.
J. Alzheimers Dis.
PUBLISHED: 10-30-2014
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Among nutraceuticals and nutritional bioactive compounds, the standardized Ginkgo biloba extract EGb 761 is the most extensively clinically tested herbal-based substance for cognitive impairment, dementia, and Alzheimer's disease (AD). In the last three years, notwithstanding negative meta-analytic findings and the discouraging results of preventive trials against AD, some randomized controlled trials focusing particularly on dementia, AD, and mild cognitive impairment (MCI) subgroups with neuropsychiatric symptoms (NPS) and some recent meta-analyses have suggested a renowned role for EGb 761 for cognitive impairment and dementia. Meta-analytic findings suggested overall benefits of EGb 761 for stabilizing or slowing decline in cognition of subjects with cognitive impairment and dementia. The safety and tolerability of EGb 761 appeared to be excellent at different doses. Subgroup analyses showed that these clinical benefits of EGb 761 were mainly associated with the 240 mg/day dose, and also confirmed in the AD subgroup. More importantly, one of these meta-analyses showed clinical benefits in cognition, behavior, functional status, and global clinical change of EGb 761 at a dose of 240 mg/day in the treatment of patients with dementia, AD, and MCI with NPS. The inclusion of the recent randomized controlled trials focusing on dementia, AD, and MCI subgroups with NPS may partly explain the conflicting results of these recent meta-analyses and previous pooled findings.
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Mediterranean diet and cognitive decline. A lesson from the whole-diet approach: what challenges lie ahead?
J. Alzheimers Dis.
PUBLISHED: 10-22-2014
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Higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micronutrients, and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. The findings from prospective studies and very recent systematic reviews and meta-analyses suggested that adherence to the MeDi fulfilling the whole-diet approach may affect not only the risk of Alzheimer's disease, but also of predementia syndromes and their progression to overt dementia. However, some concerns exist regarding how these instruments have been developed for measuring adherence to the MeDi, suggesting a better qualitative and quantitative selection of the individual dietary components and/or food groups to improve their reliability.
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Efficacy and safety studies of gantenerumab in patients with Alzheimer's disease.
Expert Rev Neurother
PUBLISHED: 08-01-2014
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Among active and passive anti-?-amyloid (A?) immunotherapies for Alzheimer's disease (AD), bapineuzumab and solanezumab, two humanized monoclonal antibodies, failed to show significant clinical benefits in mild-to-moderate AD patients in large Phase III clinical trials. Another ongoing Phase III trial of solanezumab aims to confirm positive findings in mild AD patients. Gantenerumab is the first fully human anti-A? monoclonal antibody directed to both N-terminal and central regions of A?. A 6-month PET study in 16 AD patients showed that gantenerumab treatment dose-dependently reduced brain A? deposition, possibly stimulating microglial-mediated phagocytosis. Two ongoing Phase III trials of gantenerumab in patients with prodromal or mild dementia due to AD will determine if any reduction in brain A? levels will translate into clinical benefits. An ongoing secondary prevention trial of gantenerumab in presymptomatic subjects with genetic mutations for autosomal-dominant AD will verify the utility of anti-A? monoclonal antibodies as prevention therapy.
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Amyloid-directed monoclonal antibodies for the treatment of Alzheimer's disease: the point of no return?
Expert Opin Biol Ther
PUBLISHED: 06-30-2014
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Two humanized monoclonal antibodies, bapineuzumab and solanezumab, directed against the N terminus and mid-region of ?-amyloid (A?), respectively, were recently tested in large, long-term Phase III trials in patients with mild-to-moderate Alzheimer's disease (AD).
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Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: the way forward.
Expert Rev Clin Immunol
PUBLISHED: 02-04-2014
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Both active and passive anti-?-amyloid (A?) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain A? deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of A?, were disappointing. Also solanezumab, directed at the mid-region of A?, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active A? vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-A? immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-A? immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the A? cascade hypothesis of AD.
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Is there still any hope for amyloid-based immunotherapy for Alzheimer's disease?
Curr Opin Psychiatry
PUBLISHED: 01-22-2014
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We reviewed clinical trials on active and passive anti-?-amyloid (A?) immunotherapy for the treatment of Alzheimer's disease with a particular focus on monoclonal antibodies against A?.
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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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Advances in the identification of ?-secretase inhibitors for the treatment of Alzheimers disease.
Expert Opin Drug Discov
PUBLISHED: 12-14-2011
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In an attempt of altering the natural history of Alzheimers disease (AD), several compounds have been developed with the aim of inhibiting ?-secretase, the enzymatic complex generating ?-amyloid (A?) peptides (A?(1 - 40) and A?(1 - 42)), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiological cascade of AD.
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Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging.
Age (Dordr)
PUBLISHED: 06-14-2011
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Midlife elevated blood pressure and hypertension contribute to the development of Alzheimers disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS-ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16-1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39-8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 -0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08-0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a "class" was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.
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Apolipoprotein E genotypes and neuropsychiatric symptoms and syndromes in late-onset Alzheimers disease.
Ageing Res. Rev.
PUBLISHED: 05-29-2011
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Neuropsychiatric symptoms (NPS) in dementia, previously denominated as behavioural and psychological symptoms of dementia, are often more distressing, impairing, and costly than cognitive symptoms, representing a major health burden for older adults. These symptoms are common features of Alzheimers disease (AD), and are one of the major risk factors for institutionalization. There is a high prevalence of neuropsychiatric disturbances in patients with AD, including depression, anxiety, apathy, psychosis, aggression, and agitation. At present, the role of the apolipoprotein E (APOE) genotypes in the development of NPS or neuropsychiatric syndromes/endophenotypes in AD patients is unclear. In this article, we summarized the findings of the studies of NPS and neuropsychiatric syndromes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between the APOE polymorphism and NPS in late-onset AD, other studies reported a significant association between the APOE ?4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. However, current cumulative evidence coming from the few existing longitudinal studies shows no association of APOE genotypes with NPS as a whole in AD. Some negative studies that focused on the distribution of APOE genotypes between AD patients with or without NPS further emphasized the importance of sub-grouping NPS in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, possible lack of statistical power to detect associations in the negative studies, and small sample sizes generating false positives that cannot be consistently replicated. Finally, many reviewed studies were cross-sectional, whereas it would be of paramount importance to evaluate the risk for incident NPS in relation to the APOE genotype in prospectively followed cohorts of AD patients. In fact, identifying predisposing genetic risk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromes or symptoms in AD, so optimizing possible therapeutic options.
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Diet and Alzheimers disease risk factors or prevention: the current evidence.
Expert Rev Neurother
PUBLISHED: 05-05-2011
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Preventing or postponing the onset of Alzheimers disease (AD) and delaying or slowing its progression would lead to a consequent improvement of health status and quality of life in older age. Elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA; in particular, n-3 PUFA) and a reduced risk of cognitive decline and dementia. Poorer cognitive function and an increased risk of vascular dementia (VaD) were found to be associated with a lower consumption of milk or dairy products. However, the consumption of whole-fat dairy products may be associated with cognitive decline in the elderly. Light-to-moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for VaD, cognitive decline and predementia syndromes, the current evidence is only suggestive of a protective effect. The limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supports a protective role of these macronutrients against cognitive decline, dementia and AD. Only recently, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micro- and macro-nutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD and a decreased all-cause mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk of AD, but also of predementia syndromes and their progression to overt dementia. Based on the current evidence concerning these factors, no definitive dietary recommendations are possible. However, following dietary advice for lowering the risk of cardiovascular and metabolic disorders, high levels of consumption of fats from fish, vegetable oils, nonstarchy vegetables, low glycemic index fruits and a diet low in foods with added sugars and with moderate wine intake should be encouraged. Hopefully this will open new opportunities for the prevention and management of dementia and AD.
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Anti-?-amyloid immunotherapy for Alzheimers disease: focus on bapineuzumab.
Curr Alzheimer Res
PUBLISHED: 04-20-2011
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Recent advances in our understanding of the neurobiology of Alzheimers disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain ?-amyloid (A?) via anti-A? antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-A? immunotherapies of clearing A? deposits from the brain of the AD patients. An active anti-A? vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active A? vaccines and passive A? immunotherapies have been developed and are under clinical investigation with the aim of accelerating A? clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-A? monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce A? burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on bapineuzumab will tell us if passive anti-A? immunization is able to alter the course if this devastating disease.
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Monoclonal antibodies against ?-amyloid (A?) for the treatment of Alzheimers disease: the A? target at a crossroads.
Expert Opin Biol Ther
PUBLISHED: 04-19-2011
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Several second-generation active ?-amyloid (A?) vaccines and passive A? immunotherapies are under clinical investigation with the aim of boosting A? clearance from the brain of the Alzheimers disease (AD) patients. However, the preliminary cognitive efficacy of bapineuzumab, a humanized anti-A? monoclonal antibody, appears uncertain. Moreover, the occurrence of vasogenic edema and, more rarely, brain microhemorrhages, especially in apolipoprotein E ?4 carriers, have led to abandoning of the highest dose of the drug. Solanezumab, another humanized anti-A? monoclonal antibody, was shown to neutralize soluble A? oligomers, which is believed to be the more neurotoxic A? species. Phase II studies showed a good safety profile of solanezumab while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. However, the preliminary equivocal cognitive results obtained with bapineuzumab as well as the detrimental cognitive effects observed with semagacestat, a potent ?-secretase inhibitor, raise the possibility that targeting A? may not be clinically efficacious in AD. The results of four ongoing large Phase III trials on bapineuzumab and two Phase III trials on solanezumab will tell us if passive anti-A? immunization is able to alter the course of this devastating disease, and if A? is still a viable target for anti-AD drugs.
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Frailty syndrome and all-cause mortality in demented patients: the Italian Longitudinal Study on Aging.
Age (Dordr)
PUBLISHED: 03-28-2011
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Cognition has already been considered as a component of frailty, and it has been demonstrated that it is associated with adverse health outcomes. We estimated the prevalence of frailty syndrome in an Italian older population and its predictive role on all-cause mortality and disability in nondemented subjects and in demented patients. We evaluated 2,581 individuals recruited from the Italian Longitudinal Study on Aging, a population-based sample of 5,632 subjects, aged 65-84 years old. Participants received identical baseline evaluation at the 1st survey (1992-1993) and were followed at 2nd (1995-1996) and 3rd survey (2000-2001). A phenotype of frailty according to partially modified measurement of Cardiovascular Health Study criteria was operationalized. The overall prevalence of frailty syndrome in this population-based study was 7.6% (95% confidence interval (CI) 6.55-8.57). Frail individuals noncomorbid or nondisable were 9.1% and 39.3%, respectively, confirming an overlap but not concordance in the co-occurrence among these conditions. Frailty was associated with a significantly increased risk of all-cause mortality over a 3-year follow-up (hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.52-2.60) and over a 7-year follow-up (HR 1.74, 95% CI 1.44-2.16), but with significant increased risk of disability only over a 3-year follow-up (HR 1.32, 95% CI 1.06-1.86 over a 3-year follow-up and HR 1.16, 95% CI 0.88-1.56 over a 7-year follow-up). Frail demented patients were at higher risk of all-cause mortality over 3- (HR 3.33, 95% CI 1.28-8.29) and 7-year follow-up periods (HR 1.89, 95% CI 1.10-3.44), but not of disability. Frailty syndrome was a short-term predictor of disability in nondemented older subjects and short- and long-term predictor of all-cause mortality in nondemented and demented patients.
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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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Therapeutic intervention for Alzheimers disease with ?-secretase inhibitors: still a viable option?
Expert Opin Investig Drugs
PUBLISHED: 01-11-2011
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Compounds that inhibit or modulate ?-secretase, the pivotal enzyme which generates ?-amyloid (A?), are potential therapeutics for Alzheimers disease (AD).
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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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Bapineuzumab: anti-?-amyloid monoclonal antibodies for the treatment of Alzheimers disease.
Immunotherapy
PUBLISHED: 11-25-2010
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In the last decade, new therapeutic approaches targeting ?-amyloid (A?) have been discovered and developed with the hope of modifying the natural history of Alzheimers disease (AD). The most revolutionary of these approaches consists in the removal of brain A? via anti-A? antibodies. After an active vaccine (AN1792) was discontinued in 2002 due to occurrence of meningoencephalitis in approximately 6% of patients, several other second-generation active A? vaccines and passive A? immunotherapies have been developed and are under clinical investigation with the aim of accelerating A? clearance from the brain of AD patients. The most advanced of these immunological approaches is bapineuzumab, which is composed of humanized anti-A? monoclonal antibodies that has been tested in two Phase II trials. Bapineuzumab has been shown to reduce A? burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ?4 carriers, and vasogenic edema may limit its clinical use. The results of four ongoing large Phase III trials on bapineuzumab will provide answers regarding whether passive anti-A? immunization is able to alter the course of this devastating disease.
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Effect of intrathecal baclofen, botulinum toxin type A and a rehabilitation programme on locomotor function after spinal cord injury: a case report.
J Rehabil Med
PUBLISHED: 09-30-2010
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A few studies have reported the use of botulinum toxin injections after spinal cord injury, as this is the gold standard to treat focal spasticity. We report such a case here.
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Polymorphisms in glutathione S-transferase omega-1 gene and increased risk of sporadic Alzheimer disease.
Rejuvenation Res
PUBLISHED: 09-06-2010
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Previous studies examining the association between the glutathione S-transferase omega-1 (GSTO1) single-nucleotide polymorphisms (SNPs) and Alzheimer disease (AD) have yielded conflicting results. Furthermore, an effect of GSTO1 rs4925 on the age-at-onset (AAO) of AD was found in different studies on sporadic and familial AD cases, but with contrasting findings. A total sample of 103 AD patients, and 157 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotyped for the apolipoprotein E (APOE) polymorphism and the GSTO1 rs4925 and rs1804834 SNPs. Furthermore, we performed a haplotype analysis on these two SNPs on the GSTO1 locus and evaluated the possibility of interaction with APOE. Significant differences were observed in rs4925 genotype distribution between AD patients and age- and sex-matched healthy controls. Both the C/A (odds ratio [OR]?= 3.116; 95% confidence interval [CI], 1.749-5.550) and the A/A (OR = 10.802; 95% CI, 3.605-32.128) genotypes resulted in an association with AD. A higher frequency of the allele A was observed in AD patients than in age- and sex-matched controls (OR = 3.789; 95% CI, 2.442-5.878). No significant differences were observed in the rs1804834 genotype or allele frequencies between AD patients and controls. No significant influence of the GSTO1 genotypes on the AAO was observed. No significant interaction was found among the GSTO1 SNPs and APOE. In both AD and controls, no important linkage disequilibrium (LD) was observed among the markers investigated. Whereas the C-A haplotype appeared to be protective against AD (OR = 0.303; 95% CI, 0.204-0.451), the A-A haplotype appeared to be at increased risk for AD (OR = 4.014,; 95% CI, 2.528-6.382). Our findings supported a role of the GSTO1 rs4925 SNP in the risk of sporadic AD in southern Italy, suggesting that this and other variants of the GSTO1 gene could be implicated in AD pathogenesis.
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Effect of botulinum toxin type A, motor imagery and motor observation on motor function of hemiparetic upper limb after stroke.
Brain Inj
PUBLISHED: 06-24-2010
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In rehabilitation settings, motor imagery, motor observation and mirror therapy serve as techniques for the recovery of paretic upper limb in patients with movement disorders after stroke, whereas botulinum toxin type A (BTX-A) offers the best treatment for focal spasticity.
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REVIEW: ?-Secretase inhibitors for the treatment of Alzheimers disease: The current state.
CNS Neurosci Ther
PUBLISHED: 06-16-2010
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Drugs currently used for the treatment of Alzheimers disease (AD) partially stabilize patients symptoms without modifying disease progression. Brain accumulation of oligomeric species of ?-amyloid (A?) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being spent to identify drugs able to interfere with proteases regulating A? formation from amyloid precursor protein (APP). This article briefly reviews the profile of ?-secretase inhibitors, compounds that inhibit ?-secretase, the pivotal enzyme that generates A?, and that have reached the clinic.
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Polymorphism C in the serotonin transporter gene in depression-free elderly patients with vascular dementia.
Dement Geriatr Cogn Disord
PUBLISHED: 05-26-2010
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Genotypes of the solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) have been variously associated with depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding their association with severe dementia, in particular with vascular dementia (VaD).
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Metabolic-cognitive syndrome: a cross-talk between metabolic syndrome and Alzheimers disease.
Ageing Res. Rev.
PUBLISHED: 04-21-2010
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A growing body of epidemiological evidence suggested that metabolic syndrome (MetS) and Mets components (impaired glucose tolerance, abdominal or central obesity, hypertension, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol) may be important in the development of age-related cognitive decline (ARCD), mild cognitive impairment (MCI), vascular dementia, and Alzheimers disease (AD). These suggestions proposed in these patients the presence of a "metabolic-cognitive syndrome", i.e. a MetS plus cognitive impairment of degenerative or vascular origin. This could represent a pathophysiological model in which to study in depth the mechanisms linking MetS and MetS components with dementia, particularly AD, and predementia syndromes (ARCD or MCI), suggesting a possible integrating view of the MetS components and their influence on cognitive decline. In the present article, we discussed the role of these factors in the development of cognitive decline and dementia, including underlying mechanisms, supporting their influence on ?-amyloid peptide metabolism and tau protein hyperphosphorylation, the principal neuropathological hallmarks of AD. In the next future, trials could then be undertaken to determine if modifications of these MetS components including inflammation, another factor probably related to MetS, could lower risk of developing cognitive decline. Future research aimed at identifying mechanisms that underlie comorbid associations of MetS components will not only provide important insights into the causes and interdependencies of predementia and dementia syndromes, but will also inspire novel strategies for treating and preventing cognitive disorders.
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Prevalence of aging-associated cognitive decline in an Italian elderly population: results from cross-sectional phase of Italian PRoject on Epidemiology of Alzheimers disease (IPREA).
Aging Clin Exp Res
PUBLISHED: 04-09-2010
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The prevalence of the preclinical phase of dementia varies greatly, according to the diagnostic criteria and assessment procedures applied. The purpose of this study was to estimate the prevalence of cognitive impairment according to the Aging-Associated Cognitive Decline (AACD) diagnostic criteria in an Italian elderly population.
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Effectiveness of botulinum toxin type A treatment of neck pain related to nocturnal bruxism: a case report.
J Chiropr Med
PUBLISHED: 03-18-2010
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This case report describes a patient with nocturnal bruxism and related neck pain treated with botulinum toxin type A (BTX-A).
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Are NSAIDs useful to treat Alzheimers disease or mild cognitive impairment?
Front Aging Neurosci
PUBLISHED: 02-24-2010
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Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect subjects carrying one or more epsilon4 allele of the apolipoprotein E (APOE epsilon4) against the onset of Alzheimers disease (AD). The biological mechanism of this protection is not completely understood and may involve the anti-inflammatory properties of NSAIDs or their ability of interfering with the beta-amyloid (Abeta) cascade. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and cyclooxygenase-2 (COX-2) selective inhibitors in mild-to-moderate AD patients produced negative results. A secondary prevention study with rofecoxib, a COX-2 selective inhibitor, in patients with mild cognitive impairment was also negative. A primary prevention study (ADAPT trial) of naproxen (a non-selective COX inhibitor) and celecoxib (a COX-2 selective inhibitor) in cognitively normal elderly subjects with a family history of AD was prematurely interrupted for safety reasons after a median period of treatment of 2 years. Although both drugs did not reduce the incidence of dementia after 2 years of treatment, a 4-year follow-up assessment surprisingly revealed that subjects previously exposed to naproxen were protected from the onset of AD by 67% compared to placebo. Thus, it could be hypothesized that the chronic use of NSAIDs may be beneficial only in the very early stages of the AD process in coincidence of initial Abeta deposition, microglia activation and consequent release of pro-inflammatory mediators. When the Abeta deposition process is already started, NSAIDs are no longer effective and may even be detrimental because of their inhibitory activity on chronically activated microglia that on long-term may mediate Abeta clearance. The research community should conduct long-term trials with NSAIDs in cognitively normal APOE epsilon4 carriers.
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Late-life depression, mild cognitive impairment, and dementia: possible continuum?
Am J Geriatr Psychiatry
PUBLISHED: 01-28-2010
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Clinical and epidemiologic research has focused on the identification of risk factors that may be modified in predementia syndromes, at a preclinical and early clinical stage of dementing disorders, with specific attention to the role of depression. Our goal was to provide an overview of these studies and more specifically to describe the prevalence and incidence of depression in individuals with mild cognitive impairment (MCI), the possible impact of depressive symptoms on incident MCI, or its progression to dementia and the possible mechanisms behind the observed associations. Prevalence and incidence of depressive symptoms or syndromes in MCI vary as a result of different diagnostic criteria and different sampling and assessment procedures. The prevalence of depression in individuals with MCI was higher in hospital-based studies (median: 44.3%, range: 9%-83%) than in population-based studies (median: 15.7%, range: 3%-63%), reflecting different referral patterns and selection criteria. Incidence of depressive symptoms varied from 11.7 to 26.6/100 person-years in hospital-based and population-based studies. For depressed normal subjects and depressed patients with MCI, the findings on increased risk of incident MCI or its progression to dementia were conflicting. These contrasting findings suggested that the length of the follow-up period, the study design, the sample population, and methodological differences may be central for detecting an association between baseline depression and subsequent development of MCI or its progression to dementia. Assuming that MCI may be the earliest identifiable clinical stage of dementia, depressive symptoms may be an early manifestation rather than a risk factor for dementia and Alzheimer disease, arguing that the underlying neuropathological condition that causes MCI or dementia also causes depressive symptoms. In this scenario, at least in certain subsets of elderly patients, late-life depression, MCI, and dementia could represent a possible clinical continuum.
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The APOE polymorphism in Alzheimers disease patients with neuropsychiatric symptoms and syndromes.
Int J Geriatr Psychiatry
PUBLISHED: 01-27-2010
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Neuropsychiatric symptoms (NPS) are a common feature of Alzheimers disease (AD), resulting in particular AD endophenotypes. The common AD genetic risk factor apolipoprotein E (APOE) has been suggested underlying these AD endophenotypes.
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Apolipoprotein E-related all-cause mortality in hospitalized elderly patients.
Age (Dordr)
PUBLISHED: 01-08-2010
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The most common apolipoprotein E (APOE) allelic variation is implicated in many age-related diseases and human longevity with controversial findings. We investigated the effect of APOE gene polymorphism on all-cause mortality in elderly patients taking into consideration the functional disability, cognitive impairment, malnutrition, and the occurrence of common age-related diseases. APOE genotypes were determined in 2,124 geriatric hospitalized patients (46.5% men and 53.5% women; mean age, 78.2 +/- 7.1 years; range, 65-100 years). At hospital admission, all patients underwent a comprehensive geriatric assessment to evaluate functional disability, cognitive status, nutritional status, and comorbidity. The main and secondary diagnoses at hospital discharge were also recorded. Mortality status was evaluated in all patients after a maximum follow-up of 5 years (range, from 1.26 to 5.23 years; median, 2.86 years). During the study period, 671 patients died (32.0%). At hospital admission, these patients showed a significant higher prevalence of cardiovascular diseases (56.3% vs 53.4%; p = 0.007), neoplasias (32.3% vs 13.7%; p < 0.001), and lower prevalence of neurodegenerative diseases (17.7% vs 20.7%; p < 0.001) than survived patients. Moreover, they also showed an higher prevalence of disability (52.0% vs 25.6%; p < 0.001), cognitive impairment (31.0% vs 18.8%; p < 0.001), and malnutrition (74.0% vs 46.1%; p < 0.001) than survived patients. In the overall study population, the APOE epsilon2 allele was significantly associated to neurodegenerative diseases (odds ratio = 0.59; 95% confidence interval (CI), 0.37-0.94). No significant association between the APOE polymorphism and disability, malnutrition, co-morbidity status, and with all-cause mortality was observed. In patients with cardiovascular diseases, however, a decreased risk of all-cause mortality was found in the epsilon2 allele carriers (hazard ratio = 0.56; 95% CI, 0.36-0.88). In this population, APOE allele variants might play a role on cardiovascular disease-related mortality.
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All-cause mortality and competing risks of fatal and nonfatal vascular events in the Italian longitudinal study on aging: impact of lipoprotein(a).
Rejuvenation Res
PUBLISHED: 12-18-2009
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Among possible determinants of vascular events, the role of high lipoprotein(a) (Lp[a]) serum levels represents a still uncertain independent risk factor in elderly populations. Moreover, the cumulative incidence of nonfatal vascular events due to high Lp(a) serum levels is conditioned by the competing risk of death from any causes that are a function of age. After a 6.3-year median follow up, we tested the competing risks of all-cause mortality, cumulative fatal-nonfatal stroke events, cumulative fatal-nonfatal coronary artery disease (CAD) events, and nonfatal stroke or CAD events due to high Lp(a) serum levels in a population-based, prospective study conducted in one of the eight centers of the Italian Longitudinal Study on Aging (ILSA), Casamassima, Bari, Italy. Of 704 elderly individuals (65-84 years), 372 (169 women and 203 men) agreed to participate in the study. As compared with those in the lowest Lp(a) tertile serum levels, subjects in the highest tertile (>20 mg/dL) had a higher partially adjusted risk of nonfatal CAD (hazard ratio, 4.19; 95% confidence interval [CI], 1.36-12.94) and nonfatal stroke (hazard ratio, 3.38; 95% CI, 1.00-11.56). Compared with those in the lowest tertile, subjects in the highest tertile had a higher fully adjusted risk of nonfatal CAD (hazard ratio, 3.41; 95% CI, 1.08-10.78). Finally, overall no statistically significant association was found between Lp(a) and the risk of all-cause mortality, cumulative fatal-nonfatal stroke, and cumulative fatal-nonfatal CAD events. In our population, Lp(a) was not a significant independent predictor of stroke and death from all causes, but it was an independent predictor of nonfatal CAD. Finally competing risk, conditioning the timing and occurrence of vascular events in our study population, could be a correct approach for evaluating the role of Lp(a) lipoprotein in vascular disease among elderly people.
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Metabolic syndrome and the risk of vascular dementia: the Italian Longitudinal Study on Ageing.
J. Neurol. Neurosurg. Psychiatr.
PUBLISHED: 12-03-2009
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The authors investigated the relationship of metabolic syndrome (MetS) and its individual components with incident dementia in a prospective population-based study with a 3.5-year follow-up.
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Botulinum toxin type A in the treatment of painful adductor muscle contracture after total hip arthroplasty.
Orthopedics
PUBLISHED: 10-15-2009
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Painful adductor muscle contracture is an important cause of failure during rehabilitation following total hip arthroplasty (THA). Adductor muscle contracture may be caused by postoperative muscle retractions, adhesive capsulitis, postoperative leg-length inequalities caused by implant failure, or preexisting hip pathologies. A 34-year-old woman experienced a persistent painful contracture into the left adductor magnus muscle after THA. She had no leg-length inequalities and, according to the Medical Research Council scale (grades 0-5), muscle strength of the quadriceps was 5/5 for the right side and 3/5 for the left. The degree of functionality according to the Harris hip score (HHS) was 16/100 in the left hip. The pain level, measured with the visual analog scale (VAS), was 7/10. The patient was unable to fully adhere to the rehabilitation program and walked with a limp during the stance phase of gait. After 7 days of treatment with injections of botulinum toxin type A into the left adductor magnus muscle (dose, 150 UM) and subsequent rehabilitation, a great reduction of painful contracture was observed (VAS score, 2/10). The procedure was well tolerated and no adverse effects were noted. After 20 days, hip articular range of motion and gait had improved (HHS score, 75/100). The clinical effects of botulinum toxin type A were present at 2-month follow-up. This treatment may be a viable alternative for the management of painful adductor muscle contracture after THA, without significant side effects.
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Alpha-2-macroglobulin gene, oxidized low-density lipoprotein receptor-1 locus, and sporadic Alzheimers disease.
Neurobiol. Aging
PUBLISHED: 10-10-2009
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A total sample of 169 AD patients, and 264 age- and sex-matched unrelated caregivers from Apulia, southern Italy, were genotypized for alpha-2-macroglobulin (A2M) Val1000/Ile single-nucleotide polymorphism (SNP) (rs669), apolipoprotein E (APOE), and SNPs (+1073 and +1071) in the oxidized low-density lipoprotein receptor-1 (OLR1) gene on chromosome 12. A2M allele and genotype frequencies were similar between AD patients and controls, also after stratification for late onset (>/=70 years) and early onset (<70 years) or APOE varepsilon4 status. However, there was evidence in support of LD between the OLR1+1071, the OLR1+1073, and the rs669 SNPs, with T-C-A haplotype being associated with significant increased risk of AD in both the whole sample and when we stratified according to early and late onset AD subjects, with the allelic association with AD predominantly from the OLR1+1073 SNP, further supporting the role of OLR1 as a candidate risk gene for sporadic AD.
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Beyond the neurotransmitter-focused approach in treating Alzheimers disease: drugs targeting beta-amyloid and tau protein.
Aging Clin Exp Res
PUBLISHED: 08-27-2009
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Drugs currently used to treat Alzheimers Disease (AD) have limited therapeutic value and do not affect the main neuropathological hallmarks of the disease, i.e., senile plaques and neurofibrillar tangles. Senile plaques are mainly formed of beta-amyloid (Abeta), a 42-aminoacid peptide. Neurofibrillar tangles are composed of paired helical filaments of hyperphosphorylated tau protein. New, potentially disease-modifying, therapeutic approaches are targeting Abeta and tau protein. Drugs directed against Abeta include active and passive immunization, that have been found to accelerate Abeta clearance from the brain. The most developmentally advanced monoclonal antibody directly targeting Abeta is bapineuzumab, now being studied in a large Phase III clinical trial. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. The discovery of inhibitors of beta-secretase, the enzyme that regulates the first step of the amyloidogenic metabolism of APP, has been revealed to be particularly difficult due to inherent medicinal chemistry problems, and only one compound (CTS-21166) has reached clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates Abeta, have been identified, the most advanced being LY-450139 (semagacestat), now in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed, and one of them, EHT-0202, has recently entered Phase II testing. Potent inhibitors of Abeta aggregation have also been identified, and one of such compounds, PBT-2, has provided encouraging neuropsychological results in a recently completed Phase II study. Therapeutic approaches directed against tau protein include inhibitors of glycogen synthase kinase- 3 (GSK-3), the enzyme responsible for tau phosphorylation and tau protein aggregation inhibitors. NP-12, a promising GSK-3 inhibitor, is being tested in a Phase II study, and methylthioninium chloride, a tau protein aggregation inhibitor, has given initial encouraging results in a 50-week study. With all these approaches on their way, the hope for disease-modifying therapy in this devastating disease may become a reality in the next 5 years.
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Dietary fatty acids and predementia syndromes.
ScientificWorldJournal
PUBLISHED: 08-26-2009
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An increasing body of epidemiological evidence suggests that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD). Furthermore, a reduction of risk for cognitive decline and mild cognitive impairment (MCI) has been found in population samples with elevated fish consumption, and high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimers disease (AD) subgroups, MCI patients, and cognitively unimpaired non-APOE epsilon4 carriers. These data, together with epidemiological evidence, support the idea that n-3 PUFA may play a role in maintaining adequate cognitive functioning in predementia syndromes, but not when the AD process has already taken over. Therefore, at present, no definitive dietary recommendations on fish and unsaturated fatty acids consumption, or lower intake of saturated fat, in relation to the risk for dementia and cognitive decline are possible.
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Interleukin 6-174 G/C promoter and variable number of tandem repeats (VNTR) gene polymorphisms in sporadic Alzheimers disease.
Prog. Neuropsychopharmacol. Biol. Psychiatry
PUBLISHED: 08-07-2009
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Previous studies examining the association between the interleukin 6 (IL-6)-174 C/G polymorphism and Alzheimers disease (AD) have yielded conflicting results. Furthermore, the C allele of the IL-6 variable number of tandem repeats (VNTR) polymorphism was associated with a delayed onset and a decreased risk of AD.
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Disease-modifying approach to the treatment of Alzheimers disease: from alpha-secretase activators to gamma-secretase inhibitors and modulators.
Drugs Aging
PUBLISHED: 08-07-2009
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In the last decade, advances in understanding the neurobiology of Alzheimers disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e. senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of beta-amyloid (A beta) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with proteases regulating A beta formation from amyloid precursor protein (APP). Compounds that stimulate alpha-secretase, the enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of beta-secretase (memapsin-2, beta-amyloid cleaving enzyme-1 [BACE-1]), the enzyme that regulates the first step of amyloidogenic APP metabolism, has proved to be particularly difficult because of inherent medicinal chemistry issues and only one compound (CTS-21166) has proceeded to clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates A beta, have been identified, the most advanced being LY-450139 (semagacestat), presently in phase III clinical development. There has been considerable disappointment over the failure of a phase III study of tarenflurbil, a compound believed to modulate the activity of gamma-secretase, after encouraging phase II findings. Nevertheless, other promising gamma-secretase modulators are being developed and are approaching clinical testing. All these therapeutic approaches increase the hope of slowing the rate of decline in patients with AD and modifying the natural history of this devastating disease within the next 5 years.
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Botulinum toxin type A in the treatment of focal hand dystonia after surgical treatment for thumb duplication.
Orthopedics
PUBLISHED: 07-29-2009
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Dystonia is a set of disorders characterized by abnormal postures and unwanted muscle spasms that interfere with motor performance. Focal dystonias, the most common, affect just 1 body part. A 25-year-old woman had a focal hand dystonia with pain and muscle spasms in the right hand after surgical treatment for thumb duplication. According to Wassels classification, she was type II, with duplication of the distal phalanx. She had undergone Bilhaut-Cloquet surgery to remove a radial supernumerary thumb. During repetitive movements, she reported pain and muscle cramping in the right thumb and wrist. Force was rated, according to the Medical Research Council scale, from grades 0 to 5, and the patient had a score of 4. No sign of joint instability was found in her hand, and normal active and passive range of motion were found for interphalangeal or metacarpophalangeal joints of right thumb. However, right thenar muscle hypoplasia was found. Repetitive activity acted as an environmental trigger for the reconstructed thumb on thenar muscle hypoplasia as residual anatomical modification. Surface electromyography showed movements suggestive of dystonia. After 5 days of treatment with botulinum toxin type A, with both the flexor pollicis longus and the abductor pollicis brevis of right hand injected with a dose of 20 microM each, the patient reported a regression of most signs and symptoms. Two-month follow-up revealed that clinical effects of botulinum toxin type A were still present.
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Acoustic analysis of swallowing sounds: a new technique for assessing dysphagia.
J Rehabil Med
PUBLISHED: 07-01-2009
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To perform acoustic analysis of swallowing sounds, using a microphone and a notebook computer system, in healthy subjects and patients with dysphagia affected by neurological diseases, testing the positive/negative predictive value of a pathological pattern of swallowing sounds for penetration/aspiration.
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Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimers disease.
Ageing Res. Rev.
PUBLISHED: 06-05-2009
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The genetic epidemiology of sporadic Alzheimers disease (SAD) remains a very active area of research,making it one of the most prolifically published areas in medicine and biology. Numerous putative candidate genes have been proposed. However, with the exception of apolipoprotein E (APOE), the only confirmed genetic risk factor for SAD, all the other data appear to be not consistent. Nevertheless, the genetic risk for SAD attributable to the APOE gene in the general population is 20-0%, providing a strong evidence for the existence of additional genetic risk factors. The first part of the present article was dedicated to non-APOE genetics of SAD, reviewing chromosomes-by-chromosomes the available data concerning the major candidate genes. The second part of this article focused on some recently discovered aspects of the APOE polymorphism and their implications for SAD. An attempt to identify the future directions for non-APOE genetic research in SAD was also discussed.
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Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms.
Ageing Res. Rev.
PUBLISHED: 06-04-2009
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Drugs currently used in the treatment of cognitive impairment and dementia have a very limited therapeutic value, suggesting the necessity to potentially individualize new strategies able to prevent and to slow down the progression of predementia and dementia syndromes. An increasing body of epidemiological evidence suggested that elevated saturated fatty acids (SFA) could have negative effects on age-related cognitive decline (ARCD) and mild cognitive impairment (MCI). Furthermore, a clear reduction of risk for cognitive decline has been found in population samples with elevated fish consumption, high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), particularly n-3 PUFA. Epidemiological findings demonstrated that high PUFA intake appeared to have borderline non-significant trend for a protective effect against the development of MCI. Several hypotheses could explain the association between dietary unsaturated fatty acids and cognitive functioning, including mechanisms through the co-presence of antioxidant compounds in food groups rich in fatty acids, via atherosclerosis and thrombosis, inflammation, accumulation of b-amyloid, or via an effect in maintaining the structural integrity of neuronal membranes, determining the fluidity of synaptosomal membranes that thereby regulate neuronal transmission. However, recent findings from clinical trials with n-3 PUFA supplementation showed efficacy on depressive symptoms only in non-apolipoprotein E (APOE) epsilon4 carriers, and on cognitive symptoms only in very mild Alzheimers disease (AD) subgroups, MCI patients, and cognitively unimpaired subjects non-APOE epsilon4 carriers. These data together with epidemiological evidence support a possible role of fatty acid intake in maintaining adequate cognitive functioning and possibly for the prevention and management of cognitive decline and dementia, but not when the AD process has already taken over.
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Short-term effects of high-intensity laser therapy versus ultrasound therapy in the treatment of people with subacromial impingement syndrome: a randomized clinical trial.
Phys Ther
PUBLISHED: 05-29-2009
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Subacromial impingement syndrome (SAIS) is a painful condition resulting from the entrapment of anatomical structures between the anteroinferior corner of the acromion and the greater tuberosity of the humerus.
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Polyunsaturated fatty acid and S-adenosylmethionine supplementation in predementia syndromes and Alzheimers disease: a review.
ScientificWorldJournal
PUBLISHED: 05-27-2009
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A growing body of evidence indicates that nutritional supplements can improve cognition; however, which supplements are effective remains controversial. In this review article, we focus on dietary supplementation suggested for predementia syndromes and Alzheimers disease (AD), with particular emphasis on S-adenosylmethionine (SAM) and polyunsaturated fatty acids (PUFA). Very recent findings confirmed that SAM can exert a direct effect on glutathione S-transferase (GST) activity. AD is accompanied by reduced GST activity, diminished SAM, and increased S-adenosylhomocysteine (SAH), the downstream metabolic product resulting from SAM-mediated transmethylation reactions, when deprived of folate. Therefore, these findings underscored the critical role of SAM in maintenance of neuronal health, suggesting a possible role of SAM as a neuroprotective dietary supplement for AD patients. In fact, very recent studies on early-stage AD patients and moderate- to late-stage AD patients were conducted with a nutriceutical supplementation that included SAM, with promising results. Given recent findings from randomized clinical trials (RCTs) in which n-3 PUFA supplementation was effective only in very mild AD subgroups or mild cognitive impairment (MCI), we suggest future intervention trials using measures of dietary supplementation (dietary n-3 PUFA and SAM plus B vitamin supplementation) to determine if such supplements will reduce the risk for cognitive decline in very mild AD and MCI. Therefore, key supplements are not necessarily working in isolation and the most profound impact, or in some cases the only impact, is noted very early in the course of AD, suggesting that nutriceutical supplements may bolster pharmacological approaches well past the window where supplements can work on their own. Recommendations regarding future research on the effects of SAM or n-3 PUFA supplementation on predementia syndromes and very mild AD include properly designed RCTs that are sufficiently powered and with an adequate length (e.g., 3-5 years of follow-up).
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Role of biphosphonates and lymphatic drainage type Leduc in the complex regional pain syndrome (shoulder-hand syndrome).
Pain Med
PUBLISHED: 02-19-2009
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Complex regional pain syndrome (CRPS) is a clinical entity that has been termed in numerous ways in the last years. Clinically, CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings.
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Vascular factors predict polyneuropathy in a non-diabetic elderly population.
Neurol. Sci.
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We prospectively examined whether vascular factors are related to an increased incidence of Chronic Idiopathic Distal Symmetric Neuropathy (CI-DSN) in a non-diabetic elderly population. In 8 Italian municipalities, 2,512 men and women without both diabetes and CI-DSN at baseline are examined. Potential effect of vascular factors was estimated by regressing new onset CI-DSN on the occurrence of several vascular diseases and risk factors. Multivariate relative risks of CI-DSN were estimated by Cox proportional hazards models. After 3.8 (±2.4) years of follow-up, we documented 51 incident CI-DSN cases. At univariate analysis, age, comorbidity, waist circumference, leg length, peripheral artery disease, and coronary heart disease proved to increase the risk of developing CI-DSN. By multivariate analyses, only age (RR = 1.08; 95 % CI, 1.02-1.14), leg length (RR = 1.05; 95 % CI, 1.01-1.1) and peripheral artery disease (RR = 2.75; 95 % CI, 1.15-6.56) proved significant predictors of CI-DSN. Separate analyses by gender show that age is an independent predictor of CI-DSN both in men and in women, while PAD predicts the disease only in men, together with body height. Incidence of CI-DSN is higher in individuals carrying vascular conditions. In men, the presence at baseline of peripheral artery disease is associated with a threefold increase in the risk of developing CI-DSN. The incidence of neuropathy in non-diabetic individuals is associated with potentially modifiable vascular factors.
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Neuropsychiatric symptoms and functional status in Alzheimers disease and vascular dementia patients.
Curr Alzheimer Res
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Neuropsychiatric symptoms (NPS) are increasingly recognized as common in patients with dementia, both of degenerative (Alzheimers disease, AD) or vascular origin (vascular dementia, VaD). In this study, 302 demented patients, 166 with AD and 136 with VaD, were evaluated for NPS according to the Neuropsychiatric Inventory (NPI) score at the Alzheimers Evaluation Unit of Casa Sollievo della Sofferenza Hospital-IRCCS, San Giovanni Rotondo, Italy. A comprehensive geriatric assessment was also performed in all demented patients. The means of NPI scores did not differ in two groups. The overall prevalence of NPS was similar in both groups of patients (69.7% vs. 69.4%). Patients with AD had higher frequency in agitation/aggression and irritability/lability than VaD patients. Logistic analysis demonstrated a significant association between severity of the cognitive impairment and depression and eating disorders in both AD and VaD patients. The association with agitation/aggression, irritability/lability, and aberrant motor activity was found in AD only, and with apathy in VaD patients only. In both AD and VaD patients, there was a significant association between the impairment in activities of daily living (ADL) and the majority of NPI domains. A significant association was also found between the impairment of the instrumental activities of daily living (IADL) and agitation/aggression, anxiety, aberrant motor activity in AD and depression, apathy, irritability/lability, sleep disturbance and eating disorders in both AD and VaD patients. In particular, a causal mediation analysis was performed to better understand whether the relationship of NPS to functional impairment was direct or mediated by severity of cognitive dysfunction, i.e., Clinical dementia rating scale (CDR) score. Only agitation/aggression was mediated by the CDR score in affecting ADL status in VaD patients (OR: 1.12, 95% CI: 1.01-1.27). The NPI-Distress scores showed a significantly higher levels of distress in caregivers of AD than VaD. There were significant differences between AD and VaD patients with NPS, and these symptoms varied according to dementia subtype and severity and induced marked disability in ADL and IADL, increasing, prevalently, the distress of the caregivers of AD patients.
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Genetic variation in MME in relation to neprilysin protein and enzyme activity, A? levels, and Alzheimers disease risk.
Int J Mol Epidemiol Genet
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Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important ?-amyloid (A?)-degrading enzymes with regard to prevention of Alzheimers disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of A? accumulation in frontal cortex - levels of total soluble A?, oligomeric A?(1-42), and guanidine-extractable (insoluble) A? - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with A? levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.
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Alcohol consumption in mild cognitive impairment and dementia: harmful or neuroprotective?
Int J Geriatr Psychiatry
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In several longitudinal studies, light-to-moderate drinking of alcoholic beverages has been proposed as being protective against the development of age-related changes in cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimers disease, AD) or vascular origin (vascular dementia). However, contrasting findings also exist.
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Immunotherapy for Alzheimers disease: from anti-?-amyloid to tau-based immunization strategies.
Immunotherapy
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The exact mechanisms leading to Alzheimers disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular ?-amyloid (A?), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of A?. The most innovative of the pharmacological approaches was the stimulation of A? clearance from the brain of AD patients via the administration of A? antigens (active vaccination) or anti-A? antibodies (passive vaccination). Several active and passive anti-A? vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate A? and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-A? monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ?4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the A? peptide. Solanezumab, a humanized anti-A? monoclonal antibody directed against the midregion of the A? peptide, was shown to neutralize soluble A? species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-A? antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-A? drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.
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Solanezumab for the treatment of mild-to-moderate Alzheimers disease.
Expert Rev Clin Immunol
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Solanezumab (LY2062430) is a humanized monoclonal antibody that binds to the central region of ?-amyloid, a peptide believed to play a key role in the pathogenesis of Alzheimers disease (AD). Eli Lilly & Co is developing an intravenous formulation of solanezumab for the treatment of mild-to-moderate AD. Acute and subchronic treatment with solanezumab of transgenic mice attenuated or reversed memory deficits with no effects on incidence or severity of cerebral amyloid angiopathy-associated microhemorrhages, a severe side effect associated with bapineuzumab, another monoclonal antibody. Phase II studies in AD patients have shown a good safety profile with encouraging indications on cerebrospinal and plasma biomarkers. The drug is currently being investigated in Phase III trials. While there is a strong hope that solanezumab may represent the first effective passive vaccine for AD treatment, skepticism still exists on the ability of the drug to slow the rate of deterioration in patients with fully established disease.
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