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Benjamin Lam, Aun Khan, Julia Keith, Ekaterina Rogaeva, Juan Bilbao, Peter St George-Hyslop, Mahdi Ghani, Morris Freedman, Donald T Stuss, Tiffany Chow, Sandra E Black, Mario Masellis
INTRODUCTION: Corticobasal syndrome (CBS) resulting from genetic Alzheimer's disease (AD) has been described only once. Whether familial CBS-AD is a distinct clinical entity with its own imaging signature remains unknown. METHODS: Four individuals with CBS from two families underwent detailed assessment. For two individuals, regional atrophy and hypoperfusion were compared to autopsy-confirmed typical late-onset AD and corticobasal degeneration, as well as genetically proven PSEN1 cases with an amnestic presentation...
October 12, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Philip S J Weston, Jennifer M Nicholas, Manja Lehmann, Natalie S Ryan, Yuying Liang, Kirsty Macpherson, Marc Modat, Martin N Rossor, Jonathan M Schott, Sebastien Ourselin, Nick C Fox
OBJECTIVE: To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration. METHODS: We recruited 43 FAD mutation carriers-36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)-and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2...
October 12, 2016: Neurology
Laura Borrello, Chiara Cupidi, Valentina Laganà, Maria Anfossi, Maria Elena Conidi, Nicoletta Smirne, Maria Taverniti, Roberto Guarasci, Amalia Cecilia Bruni
The rebuilding of the N family, a large Italian kindred affected by early-onset autosomal dominant Alzheimer's disease (AD), provided an important contribution to the discovery of Presenilin 1 (PSEN1), the main gene responsible for familial AD. This pedigree was identified with the help of medical records from the archives of the Psychiatric Hospital of Girifalco, Italy. The clinical record of Angela R., an ancestor of the N family, dating back to 1904, showed a clinical picture of Angela R., consistent with a diagnosis of non-amnestic probable AD, matching the "dysexecutive" phenotype described in her descendants...
October 11, 2016: Journal of Neurology
Aitana Sogorb-Esteve, María-Salud García-Ayllón, Juan Fortea, Raquel Sánchez-Valle, Alberto Lleó, José-Luis Molinuevo, Javier Sáez-Valero
BACKGROUND: Presenilin-1 (PS1), the active component of the intramembrane γ-secretase complex, can be detected as soluble heteromeric aggregates in cerebrospinal fluid (CSF). The aim of this study was to examine the different soluble PS1 complexes in the lumbar CSF (CSF-PS1) of individuals with Alzheimer's disease (AD), particularly in both symptomatic and asymptomatic genetically determined AD, in order to evaluate their potential as early biomarkers. METHODS: Western blotting, differential centrifugation and co-immunoprecipitation served to determine and characterize CSF-PS1 complexes...
September 29, 2016: Molecular Neurodegeneration
Teng Jiang, Ying-Dong Zhang, Qing Gao, Jun-Shan Zhou, Xi-Chen Zhu, Huan Lu, Jian-Quan Shi, Lan Tan, Qi Chen, Jin-Tai Yu
As the most common type of neurodegenerative disease, Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730(G), an intronic variant of TREM1, is associated with an increased Aβ neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear...
November 2016: Acta Neuropathologica
Waseem K Raja, Alison E Mungenast, Yuan-Ta Lin, Tak Ko, Fatema Abdurrob, Jinsoo Seo, Li-Huei Tsai
The dismal success rate of clinical trials for Alzheimer's disease (AD) motivates us to develop model systems of AD pathology that have higher predictive validity. The advent of induced pluripotent stem cells (iPSCs) allows us to model pathology and study disease mechanisms directly in human neural cells from healthy individual as well as AD patients. However, two-dimensional culture systems do not recapitulate the complexity of neural tissue, and phenotypes such as extracellular protein aggregation are difficult to observe...
2016: PloS One
Steffan K Soosman, Nelly Joseph-Mathurin, Meredith N Braskie, Yvette M Bordelon, David Wharton, Maria Casado, Giovanni Coppola, Holly McCallum, Marc Nuwer, Pedro Coutin-Churchman, Liana G Apostolova, Tammie Benzinger, John M Ringman
The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP...
August 8, 2016: Neurobiology of Aging
Laura Caberlotto, Luca Marchetti, Mario Lauria, Marco Scotti, Silvia Parolo
Among the genetic factors known to increase the risk of late onset Alzheimer's diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer's disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer's disease...
2016: Scientific Reports
Alma Delia Campos-Parra, Alejandra Padua-Bracho, Abraham Pedroza-Torres, Gabriela Figueroa-González, Jorge Fernández-Retana, Oliver Millan-Catalan, Oscar Peralta-Zaragoza, David Cantú de León, Luis A Herrera, Carlos Pérez-Plasencia
OBJECTIVE: The objective of the present study was to provide genomic and transcriptomic information that may improve clinical outcomes for locally advanced cervical cancer (LACC) patients by searching for therapeutic targets or potential biomarkers through the analysis of significantly altered signaling pathways in LACC. METHODS: Microarray-based transcriptome profiling of 89 tumor samples from women with LACC was performed. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, significantly over-expressed genes in LACC were identified; these genes were validated by quantitative reverse transcription-polymerase chain reaction in an independent cohort, and the protein expression data were obtained from the Human Protein Atlas...
August 28, 2016: Gynecologic Oncology
Saeid Taheri, Jin Yu, Hong Zhu, Mark S Kindy
BACKGROUND: Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer's disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear. OBJECTIVE: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβand CBF) and CBF, exacerbates cognitive decline, and increases the propensity to AD...
October 4, 2016: Journal of Alzheimer's Disease: JAD
Parvaneh Daneshmand, Kioomars Saliminejad, Marzieh Dehghan Shasaltaneh, Koorosh Kamali, Gholam Hossein Riazi, Reza Nazari, Pedram Azimzadeh, Hamid Reza Khorram Khorshid
BACKGROUND: Sporadic Alzheimer's Disease (SAD) is caused by genetic risk factors, aging and oxidative stresses. The herbal extract of Rosa canina (R. canina), Tanacetum vulgare (T. vulgare) and Urtica dioica (U. dioica) has a beneficial role in aging, as an anti-inflammatory and anti-oxidative agent. In this study, the neuroprotective effects of this herbal extract in the rat model of SAD was investigated. METHODS: The rats were divided into control, sham, model, herbal extract -treated and ethanol-treated groups...
July 2016: Avicenna Journal of Medical Biotechnology
Csilla Nemes, Eszter Varga, Zsuzsanna Táncos, István Bock, Barbara Francz, Julianna Kobolák, András Dinnyés
No abstract text is available yet for this article.
May 24, 2016: Stem Cell Research
Jannik E Jakobsen, Marianne G Johansen, Mette Schmidt, Ying Liu, Rong Li, Henrik Callesen, Margarita Melnikova, Mette Habekost, Carmela Matrone, Yvonne Bouter, Thomas A Bayer, Anders Lade Nielsen, Monika Duthie, Paul E Fraser, Ida E Holm, Arne Lund Jørgensen
Mutations in the amyloid-β protein precursor gene (AβPP), the presenilin 1 gene (PSEN1) or the presenilin 2 gene (PSEN2) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer's disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I) mutation and three copies of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw) double-mutation...
July 14, 2016: Journal of Alzheimer's Disease: JAD
Kwangsik Nho, Emrin Horgusluoglu, Sungeun Kim, Shannon L Risacher, Dokyoon Kim, Tatiana Foroud, Paul S Aisen, Ronald C Petersen, Clifford R Jack, Leslie M Shaw, John Q Trojanowski, Michael W Weiner, Robert C Green, Arthur W Toga, Andrew J Saykin
BACKGROUND: Pathogenic mutations in PSEN1 are known to cause familial early-onset Alzheimer's disease (EOAD) but common variants in PSEN1 have not been found to strongly influence late-onset AD (LOAD). The association of rare variants in PSEN1 with LOAD-related endophenotypes has received little attention. In this study, we performed a rare variant association analysis of PSEN1 with quantitative biomarkers of LOAD using whole genome sequencing (WGS) by integrating bioinformatics and imaging informatics...
2016: BMC Medical Genomics
Yuji Kajiwara, Andrew McKenzie, Nate Dorr, Miguel A Gama Sosa, Gregory Elder, James Schmeidler, Dara L Dickstein, Ozlem Bozdagi, Bin Zhang, Joseph D Buxbaum
Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice...
August 11, 2016: Human Molecular Genetics
Şenay Görücü Yılmaz, Mehmet Emin Erdal, Aynur Avcı Özge, Mehmet Ali Sungur
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. However, biomarkers that require testing in the brain tissue pose a formidable practical barrier to AD diagnostic innovation. MicroRNAs (miRNAs) are responsible for control of gene expression at the posttranscriptional level and are essential for the function of neuronal networks and neuronal survival. miRNA expression can impact the regulation of APP (amyloid beta A4 precursor protein), PSEN1 (presenilin 1), PSEN2 (presenilin 2), and BACE1 (beta-secretase 1) genes in the brain that were previously implicated in AD pathophysiology...
August 2016: Omics: a Journal of Integrative Biology
Sara Sarroca, Patricia Molina-Martínez, Cristina Aresté, Martin Etzrodt, Pablo García de Frutos, Rosa Gasa, Anna Antonell, José Luís Molinuevo, Raquel Sánchez-Valle, Carlos A Saura, Albert Lladó, Coral Sanfeliu
Presenilin 1 (PSEN1) mutations are the main cause of monogenic Alzheimer's disease. We studied the functional effects of the mutation K239N, which shows incomplete penetrance at the age of 65 years and compared it with the more aggressive mutation E120G. We engineered stable cell lines expressing human PSEN1 wild type or with K239N or E120G mutations. Both mutations induced dysfunction of γ-secretase in the processing of amyloid-β protein precursor, leading to an increase in the amyloid β42/amyloid β40 ratio...
October 2016: Neurobiology of Aging
Aline Zarea, Camille Charbonnier, Anne Rovelet-Lecrux, Gaël Nicolas, Stéphane Rousseau, Alaina Borden, Jeremie Pariente, Isabelle Le Ber, Florence Pasquier, Maite Formaglio, Olivier Martinaud, Adeline Rollin-Sillaire, Marie Sarazin, Bernard Croisile, Claire Boutoleau-Bretonnière, Mathieu Ceccaldi, Audrey Gabelle, Ludivine Chamard, Frédéric Blanc, François Sellal, Claire Paquet, Dominique Campion, Didier Hannequin, David Wallon
OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs...
August 30, 2016: Neurology
Gregory S Day, Erik S Musiek, Catherine M Roe, Joanne Norton, Alison M Goate, Carlos Cruchaga, Nigel J Cairns, John C Morris
IMPORTANCE: The amyloid hypothesis posits that disrupted β-amyloid homeostasis initiates the pathological process resulting in Alzheimer disease (AD). Autosomal dominant AD (ADAD) has an early symptomatic onset and is caused by single-gene mutations that result in overproduction of β-amyloid 42. To the extent that sporadic late-onset AD (LOAD) also results from dysregulated β-amyloid 42, the clinical phenotypes of ADAD and LOAD should be similar when controlling for the effects of age...
September 1, 2016: JAMA Neurology
Miguel A Gama Sosa, Rita De Gasperi, Patrick R Hof, Gregory A Elder
Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1-/- embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1-/- cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1-/- cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1...
2016: Scientific Reports
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