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H Li, C L Lv, C S Yang, D F Wei, K W Chen, S W Li, Z J Zhang
BACKGROUND AND PURPOSE: SORL1 rs1699102 is associated with the risk of late-onset Alzheimer's disease. However, the effects of this single nucleotide polymorphism on cognition and brain structure during normal aging are unclear. This study aimed to examine the effects of the rs1699102 polymorphism on age-related cognitive decline and cortical gray matter reduction in the Chinese Han population. METHODS: A total of 780 non-demented adults completed a battery of neuropsychological tests...
October 25, 2016: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
S Moriguchi, T Ishizuka, Y Yabuki, N Shioda, Y Sasaki, H Tagashira, H Yawo, J Z Yeh, H Sakagami, T Narahashi, K Fukunaga
Here, we report a novel target of the drug memantine, ATP-sensitive K(+) (KATP) channels, potentially relevant to memory improvement. We confirmed that memantine antagonizes memory impairment in Alzheimer's model APP23 mice. Memantine increased CaMKII activity in the APP23 mouse hippocampus, and memantine-induced enhancement of hippocampal long-term potentiation (LTP) and CaMKII activity was totally abolished by treatment with pinacidil, a specific opener of KATP channels. Memantine also inhibited Kir6.1 and Kir6...
October 25, 2016: Molecular Psychiatry
G Kaur, M Pawlik, S E Gandy, M E Ehrlich, J F Smiley, E Levy
Recent data suggest that intraneuronal accumulation of metabolites of the amyloid-β-precursor protein (APP) is neurotoxic. We observed that transgenic mice overexpressing in neurons a human APP gene harboring the APP(E693Q) (Dutch) mutation have intraneuronal lysosomal accumulation of APP carboxylterminal fragments (APP-CTFs) and oligomeric amyloid β (oAβ) but no histological evidence of amyloid deposition. Morphometric quantification using the lysosomal marker protein 2 (LAMP-2) immunolabeling showed higher neuronal lysosomal counts in brain of 12-months-old APP(E693Q) as compared with age-matched non-transgenic littermates, and western blots showed increased lysosomal proteins including LAMP-2, cathepsin D and LC3...
October 25, 2016: Molecular Psychiatry
Lauren L Drogos, Stephanie J Gill, Amanda V Tyndall, Jill K Raneri, Jillian S Parboosingh, Aileen Naef, Kyle D Guild, Gail Eskes, Patrick J Hanly, Marc J Poulin
BACKGROUND: It has been estimated that the prevalence of Alzheimer disease (AD) and related dementias will triple by 2035, unless effective interventions or treatments are found for the neurodegenerative disease. Understanding sleep changes as a marker for both AD risk and progression is a burgeoning area of investigation. Specifically, there is emerging evidence that both sleep disturbances and the APOE ε4 allele are associated with increased dementia risk. Previous research has suggested that in AD, individuals carrying the APOE ε4 allele have decreased sleep quality compared to individuals without the APOE ε4 allele...
October 25, 2016: Neurology
Natalie S Ryan, Jennifer M Nicholas, Philip S J Weston, Yuying Liang, Tammaryn Lashley, Rita Guerreiro, Gary Adamson, Janna Kenny, Jon Beck, Lucia Chavez-Gutierrez, Bart de Strooper, Tamas Revesz, Janice Holton, Simon Mead, Martin N Rossor, Nick C Fox
BACKGROUND: The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). METHODS: We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK...
October 21, 2016: Lancet Neurology
Mengxuan Tang, Davis C Ryman, Eric McDade, Mateusz S Jasielec, Virginia D Buckles, Nigel J Cairns, Anne M Fagan, Alison Goate, Daniel S Marcus, Chengjie Xiong, Ricardo F Allegri, Jasmeer P Chhatwal, Adrian Danek, Martin R Farlow, Nick C Fox, Bernardino Ghetti, Neill R Graff-Radford, Christopher Laske, Ralph N Martins, Colin L Masters, Richard P Mayeux, John M Ringman, Martin N Rossor, Stephen P Salloway, Peter R Schofield, John C Morris, Randall J Bateman
BACKGROUND: Autosomal dominant familial Alzheimer's disease (ADAD) is a rare disorder with non-amnestic neurological symptoms in some clinical presentations. We aimed to compile and compare data from symptomatic participants in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) with those reported in the literature to estimate the prevalences of non-amnestic neurological symptoms in participants with ADAD. METHODS: We prospectively collected data from the DIAN-OBS database, which recruited participants from study centres in the USA, Europe, and Australia, between Feb 29, 2008, and July 1, 2014...
October 21, 2016: Lancet Neurology
Imelda S Barber, Anne Braae, Naomi Clement, Tulsi Patel, Tamar Guetta-Baranes, Keeley Brookes, Christopher Medway, Sally Chappell, Rita Guerreiro, Jose Bras, Dena Hernandez, Andrew Singleton, John Hardy, David M Mann, Kevin Morgan
We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD...
September 23, 2016: Neurobiology of Aging
Nicole M Gatto, Kimberly C Paul, Janet S Sinsheimer, Jeff M Bronstein, Yvette Bordelon, Rebecca Rausch, Beate Ritz
We and others have suggested that vitamin D receptor gene (VDR) polymorphisms influence susceptibility for Parkinson's disease (PD), Alzheimer's disease (AD), mild cognitive impairment (MCI) or overall cognitive functioning. Here we examine VDR polymorphisms and cognitive decline in patients with PD. Non-Hispanic Caucasian PD patients (n=190) in the Parkinson Environment Gene (PEG) study were successfully genotyped for seven VDR polymorphisms. Cognitive function was assessed with the Mini-Mental State Exam (MMSE) at baseline and at a maximum of three follow-up exams...
November 15, 2016: Journal of the Neurological Sciences
P Tenreiro, S Rebelo, F Martins, M Santos, E D Coelho, M Almeida, A P Alves de Matos, O A B da Cruz E Silva
Synaptosomes are isolated nerve terminals. They represent an extremely attractive in vitro model system to study synaptic physiology since they preserve morphological and functional characteristics of the synapse. As such they have been used to investigate synaptic dysfunctions associated with neuropathologies like Alzheimer's disease. In the present work two simple methodologies for isolating synaptosomal-enriched fractions were compared for the first time. The starting points of both protocols were rat cortical or hippocampal homogenized tissues that underwent several differential centrifugation steps followed by a final purification of synaptosomal-enriched fractions using either a Percoll gradient or a Sucrose gradient...
October 19, 2016: Analytical Biochemistry
Jesse Mez, Jaeyoon Chung, Gyungah Jun, Joshua Kriegel, Alexandra P Bourlas, Richard Sherva, Mark W Logue, Lisa L Barnes, David A Bennett, Joseph D Buxbaum, Goldie S Byrd, Paul K Crane, Nilüfer Ertekin-Taner, Denis Evans, M Daniele Fallin, Tatiana Foroud, Alison Goate, Neill R Graff-Radford, Kathleen S Hall, M Ilyas Kamboh, Walter A Kukull, Eric B Larson, Jennifer J Manly, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Gerard D Schellenberg, Kathryn L Lunetta, Lindsay A Farrer
INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information...
October 19, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Jeffrey Cummings, Philip Scheltens, Ian McKeith, Rafael Blesa, John E Harrison, Paulo H F Bertolucci, Kenneth Rockwood, David Wilkinson, Wouter Wijker, David A Bennett, Raj C Shah
BACKGROUND: Souvenaid® (uridine monophosphate, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium), was developed to support the formation and function of neuronal membranes. OBJECTIVE: To determine effect sizes observed in clinical trials of Souvenaid and to calculate the number needed to treat to show benefit or harm. METHODS: Data from all three reported randomized controlled trials of Souvenaid in Alzheimer's disease (AD) dementia (Souvenir I, Souvenir II, and S-Connect) and an open-label extension study were included in analyses of effect size for cognitive, functional, and behavioral outcomes...
October 20, 2016: Journal of Alzheimer's Disease: JAD
Robert S C Amaral, Min Tae M Park, Gabriel A Devenyi, Vivian Lynn, Jon Pipitone, Julie Winterburn, Sofia Chavez, Mark Schira, Nancy Lobaugh, Aristotle N Voineskos, Jens C Pruessner, M Mallar Chakravarty
Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at
October 17, 2016: NeuroImage
David S Xu, Francisco Ponce
High-frequency deep brain stimulation (DBS) is a neurosurgical procedure that was introduced in the late 1980s for the treatment of movement disorders. It is a reversible, adjustable, and non-ablative therapy that has been used in over 100,000 people worldwide. The surgical procedure used to implant the DBS system, as well as the effects of chronic electrical stimulation, have been shown to be safe and effective through many clinical trials. The ability to therapeutically modulate the motor circuits of the brain in this manner has resulted in consideration of use of this surgical strategy for other neurodegenerative and neuropsychiatric disorders involving non-motor circuits, including appetite, mood, and cognition...
October 14, 2016: Current Alzheimer Research
Na Kyung Lee, Hyeong Seop Kim, Dongkyeom Yoo, Jung Won Hwang, Soo Jin Choi, Wonil Oh, Jong Wook Chang, Duk L Na
The success of stem cell therapy is highly dependent on accurate delivery of stem cells to the target site of interest. Possible ways to track the distribution of MSCs in vivo include the use of reporter genes or nanoparticles. The U.S. Food and Drug Administration (FDA) has approved ferumoxytol (Feraheme® [USA], Rienso® [UK]) as a treatment for iron deficiency anemia. Ferumoxytol is an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO) that has recently been used to track the fate of transplanted cells using magnetic resonance imaging (MRI)...
October 18, 2016: Stem Cell Reviews
Seu Ping Guiraud, Ivan Montoliu, Laeticia Da Silva, Loïc Dayon, Antonio Núñez Galindo, John Corthésy, Martin Kussmann, Francois-Pierre Martin
The methionine cycle is a key pathway contributing to the regulation of human health, with well-established involvement in cardiovascular diseases and cognitive function. Changes in one-carbon cycle metabolites have also been associated with mild cognitive decline, vascular dementia, and Alzheimer's disease. Today, there is no single analytical method to monitor both metabolites and co-factors of the methionine cycle. To address this limitation, we here report for the first time a new method for the simultaneous quantitation of 17 metabolites in the methionine cycle, which are homocysteic acid, taurine, serine, cysteine, glycine, homocysteine, riboflavin, methionine, pyridoxine, cystathionine, pyridoxamine, S-adenosylhomocysteine, S-adenosylmethionine, betaine, choline, dimethylglycine, and 5-methyltetrahydrofolic acid...
October 18, 2016: Analytical and Bioanalytical Chemistry
Jeremy J Pruzin, Julie A Schneider, Ana W Capuano, Sue E Leurgans, Lisa L Barnes, Rexford S Ahima, Steven E Arnold, David A Bennett, Zoe Arvanitakis
We examined the relationship of diabetes and hemoglobin A1C (A1C) to 2 common causes of dementia. The study included 1228 subjects who underwent annual clinical evaluations and a brain autopsy at death, as part of a Rush longitudinal cohort study of aging. A total of 433 subjects had A1C data available. Neuropathologic evaluations documented the size and location of infarcts. Modified silver stain-based Alzheimer disease (AD) measures included global and regional scores. We used regression analyses to examine associations of diabetes and A1C with overall and regional neuropathology...
October 17, 2016: Alzheimer Disease and Associated Disorders
Yoshihiro Kokubo
Hypertension is one of the strongest risk factor for cardiovascular disease. Recently, accumulating evidence also indicates that hypertension has been linked with non-cardiovascular diseases including dementia, cancer, oral health diseases and so on. In general, elderly individuals tend to have multiple diseases as getting older. Preventing of hypertension is also benefit for other diseases.In the Hisayama Study, hypertension increased the risk of vascular dementia, but were not associated with an increased risk of Alzheimer disease, and that subjects with hypertension in midlife and normotension and hypertension in late-life increased risks of incident vascular dementia...
September 2016: Journal of Hypertension
D A Bangasser, H Dong, J Carroll, Z Plona, H Ding, L Rodriguez, C McKennan, J G Csernansky, S H Seeholzer, R J Valentino
Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than in men. Corticotropin-releasing factor (CRF) orchestrates the stress response, and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1 receptor (CRF1) is sex biased whereby coupling to its GTP-binding protein, Gs, is greater in females, whereas β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing (CRF-OE) mice to test the proof of principle that when CRF is in excess, sex-biased CRF1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles...
October 18, 2016: Molecular Psychiatry
J M G van Bergen, X Li, J Hua, S J Schreiner, S C Steininger, F C Quevenco, M Wyss, A F Gietl, V Treyer, S E Leh, F Buck, R M Nitsch, K P Pruessmann, P C M van Zijl, C Hock, P G Unschuld
Quantitative Susceptibility Mapping (QSM) MRI at 7 Tesla and 11-Carbon Pittsburgh-Compound-B PET were used for investigating the relationship between brain iron and Amyloid beta (Aβ) plaque-load in a context of increased risk for Alzheimer's disease (AD), as reflected by the Apolipoprotein E ε4 (APOE-e4) allele and mild cognitive impairment (MCI) in elderly subjects. Carriers of APOE-e4 with normal cognition had higher cortical Aβ-plaque-load than non-carriers. In MCI an association between APOE-e4 and higher Aβ-plaque-load was observable both for cortical and subcortical brain-regions...
October 17, 2016: Scientific Reports
Paul S Foster, Valeria Drago, Brad J Ferguson, Patti Kelly Harrison, David W Harrison
The most frequently used measures of executive functioning are either sensitive to left frontal lobe functioning or bilateral frontal functioning. Relatively little is known about right frontal lobe contributions to executive functioning given the paucity of measures sensitive to right frontal functioning. The present investigation reports the development and initial validation of a new measure designed to be sensitive to right frontal lobe functioning, the Figure Trail Making Test (FTMT). The FTMT, the classic Trial Making Test, and the Ruff Figural Fluency Test (RFFT) were administered to 42 right-handed men...
December 2015: Brain Informatics
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