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https://www.readbyqxmd.com/read/28334939/association-between-tau-deposition-and-antecedent-amyloid-%C3%AE-accumulation-rates-in-normal-and-early-symptomatic-individuals
#1
Duygu Tosun, Susan Landau, Paul S Aisen, Ronald C Petersen, Mark Mintun, William Jagust, Michael W Weiner
A long-term goal of our field is to determine the sequence of pathological events, which ultimately lead to cognitive decline and dementia. In this study, we first assessed the patterns of brain tau tangle accumulation (measured with the positron emission tomography tracer 18F-AV-1451) associated with well-established Alzheimer's disease factors in a cohort including cognitively healthy elderly individuals and individuals at early symptomatic stages of Alzheimer's disease. We then explored highly associated patterns of greater 18F-AV-1451 binding and increased annualized change in cortical amyloid-β plaques measured as florbetapir positron emission tomography binding antecedent to 18F-AV-1451 positron emission tomography scans, and to what extent these multimodal pattern associations explained the variance in cognitive performance and clinical outcome measures, independently and jointly...
March 17, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28334857/co-cultures-with-stem-cell-derived-human-sensory-neurons-reveal-regulators-of-peripheral-myelination
#2
Alex J Clark, Malte S Kaller, Jorge Galino, Hugh J Willison, Simon Rinaldi, David L H Bennett
Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1...
February 15, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28331953/value-of-fdg-pet-scans-of-non-demented-patients-in-predicting-rates-of-future-cognitive-and-functional-decline
#3
Nare Torosyan, Kelsey Mason, Magnus Dahlbom, Daniel H S Silverman
PURPOSE: The aim of this study was to examine the value of fluorodeoxyglucose (FDG) positron emission tomography (PET) in predicting subsequent rates of functional and cognitive decline among subjects considered cognitively normal (CN) or clinically diagnosed with mild cognitive impairment (MCI). METHODS: Analyses of 276 subjects, 92 CN subjects and 184 with MCI, who were enrolled in the Alzheimer's Disease Neuroimaging Initiative, were conducted. Functional decline was assessed using scores on the Functional Activities Questionnaire (FAQ) obtained over a period of 36 months, while cognitive decline was determined using the Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE) scores...
March 22, 2017: European Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/28329165/four-genome-wide-association-studies-identify-new-extreme-longevity-variants
#4
Paola Sebastiani, Anastasia Gurinovich, Harold Bae, Stacy Andersen, Alberto Malovini, Gil Atzmon, Francesco Villa, Aldi T Kraja, Danny Ben-Avraham, Nir Barzilai, Annibale Puca, Thomas T Perls
The search for the genetic determinants of extreme human longevity has been challenged by the phenotype's rarity and its nonspecific definition by investigators. To address these issues, we established a consortium of four studies of extreme longevity that contributed 2,070 individuals who survived to the oldest one percentile of survival for the 1900 U.S. birth year cohort. We conducted various analyses to discover longevity-associated variants (LAV) and characterized those LAVs that differentiate survival to extreme age at death (eSAVs) from those LAVs that become more frequent in centenarians because of mortality selection (eg, survival to younger years)...
March 15, 2017: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/28326602/synthesis-characterization-and-evaluation-of-difluoropyrido-4-3-b-indoles-as-potential-agents-for-acetylcholinesterase-and-antiamnesic-activity
#5
Malavalli Madaiah, Bidarur K Jayanna, Arakere S Manu, Maralekere K Prashanth, Hosakere D Revanasiddappa, Bantal Veeresh
Acetylcholinesterase (AChE) inhibitors are currently the most widely prescribed drugs for Alzheimer's disease. The high potential of indole compounds in medicinal chemistry led us to discover a novel series of fluoroindole compounds. The synthesis and pharmacological analysis of the difluoropyrido[4,3-b]indoles 11-34 are described. Compounds 11-34 were tested for AChE inhibition activity using a rat brain homogenate. Compounds 25-29 display a promising in vitro profile with an IC50 value range of 46-51.6 nM and show significant protective effect on scopolamine-induced amnesia...
March 22, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28325166/color-perception-differentiates-alzheimer-s-disease-ad-from-vascular-dementia-vad-patients
#6
N A Arnaoutoglou, M Arnaoutoglou, P Nemtsas, V Costa, S J Baloyannis, K P Ebmeier
BACKGROUND: Alzheimer's Disease (AD) and Vascular Dementia (VaD) are the most common causes of dementia in older people. Both diseases appear to have similar clinical symptoms, such as deficits in attention and executive function, but specific cognitive domains are affected. Current cohort studies have shown a close relationship between αβ deposits and age-related macular degeneration (Johnson et al., 2002; Ratnayaka et al., 2015). Additionally, a close link between the thinning of the retinal nerve fiber (RNFL) and AD patients has been described, while it has been proposed that AD patients suffer from a non-specific type of color blindness (Pache et al...
March 22, 2017: International Psychogeriatrics
https://www.readbyqxmd.com/read/28323831/genetic-assessment-of-age-associated-alzheimer-disease-risk-development-and-validation-of-a-polygenic-hazard-score
#7
Rahul S Desikan, Chun Chieh Fan, Yunpeng Wang, Andrew J Schork, Howard J Cabral, L Adrienne Cupples, Wesley K Thompson, Lilah Besser, Walter A Kukull, Dominic Holland, Chi-Hua Chen, James B Brewer, David S Karow, Karolina Kauppi, Aree Witoelar, Celeste M Karch, Luke W Bonham, Jennifer S Yokoyama, Howard J Rosen, Bruce L Miller, William P Dillon, David M Wilson, Christopher P Hess, Margaret Pericak-Vance, Jonathan L Haines, Lindsay A Farrer, Richard Mayeux, John Hardy, Alison M Goate, Bradley T Hyman, Gerard D Schellenberg, Linda K McEvoy, Ole A Andreassen, Anders M Dale
BACKGROUND: Identifying individuals at risk for developing Alzheimer disease (AD) is of utmost importance. Although genetic studies have identified AD-associated SNPs in APOE and other genes, genetic information has not been integrated into an epidemiological framework for risk prediction. METHODS AND FINDINGS: Using genotype data from 17,008 AD cases and 37,154 controls from the International Genomics of Alzheimer's Project (IGAP Stage 1), we identified AD-associated SNPs (at p < 10-5)...
March 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28323681/predictors-that-a-diagnosis-of-mild-cognitive-impairment-will-remain-stable-3-years-later
#8
Matthew A Clem, Ryan P Holliday, Seema Pandya, Linda S Hynan, Laura H Lacritz, Fu L Woon
BACKGROUND AND OBJECTIVE: In half to two thirds of patients who are diagnosed with mild cognitive impairment (MCI), the diagnosis neither converts to dementia nor reverts to normal cognition; however, little is known about predictors of MCI stability. Our study aimed to identify those predictors. METHODS: We obtained 3-year longitudinal data from the National Alzheimer's Coordinating Center Uniform Data Set for patients with a baseline diagnosis of MCI. To predict MCI stability, we used the patients' baseline data to conduct three logistic regression models: demographics, global function, and neuropsychological performance...
March 2017: Cognitive and Behavioral Neurology: Official Journal of the Society for Behavioral and Cognitive Neurology
https://www.readbyqxmd.com/read/28322283/susceptibility-to-neurofibrillary-tangles-role-of-the-ptprd-locus-and-limited-pleiotropy-with-other-neuropathologies
#9
L B Chibnik, C C White, S Mukherjee, T Raj, L Yu, E B Larson, T J Montine, C D Keene, J Sonnen, J A Schneider, P K Crane, J M Shulman, D A Bennett, P L De Jager
Tauopathies, including Alzheimer's disease (AD) and other neurodegenerative conditions, are defined by a pathological hallmark: neurofibrillary tangles (NFTs). NFT accumulation is thought to be closely linked to cognitive decline in AD. Here, we perform a genome-wide association study for NFT pathologic burden and report the association of the PTPRD locus (rs560380, P=3.8 × 10(-8)) in 909 prospective autopsies. The association is replicated in an independent data set of 369 autopsies. The association of PTPRD with NFT is not dependent on the accumulation of amyloid pathology...
March 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28322204/cognitive-decline-associated-with-pathological-burden-in-primary-age-related-tauopathy
#10
Kyra S Jefferson-George, David A Wolk, Edward B Lee, Corey T McMillan
INTRODUCTION: Primary age-related tauopathy (PART) is a neuropathological diagnosis characterized by tau neurofibrillary tangles (NFTs) in the absence of amyloid plaque pathology. Although most individuals over 50 years of age have evidence of NFTs, the clinical and cognitive consequences of PART are not known. METHODS: We evaluated 226 neuropathologically confirmed PART cases from the National Alzheimer's Coordinating Center database who participated in a total of 846 longitudinal neuropsychological assessments from the Alzheimer's Disease Center program's Uniform Data Set...
March 16, 2017: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/28317487/impact-of-cytokines-and-chemokines-on-alzheimer-s-disease-neuropathological-hallmarks
#11
Catarina Domingues, Odete A B da Cruz E Silva, Ana Gabriela Henriques
Alzheimer's disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by aggregates of β-amyloid peptides, which deposit as senile plaques, and of TAU protein, which forms neurofibrillary tangles. It is now widely accepted that neuroinflammation is implicated in AD pathogenesis. Indeed, inflammatory mediators, such as cytokines and chemokines (chemotactic cytokines) can impact on the Alzheimer´s amyloid precursor protein by affecting its expression levels and amyloidogenic processing and/or β-amyloid aggregation...
March 17, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28315680/selenoprotein-s-is-required-for-clearance-of-c99-through-endoplasmic-reticulum-associated-degradation
#12
Jun Ki Jang, Ki Jun Park, Jea Hwang Lee, Kwan Young Ko, Seongman Kang, Ick Young Kim
Amyloid beta precursor protein (APP) is normally cleaved by α-secretase, but can also be cleaved by β-secretase (BACE1) to produce C99 fragments in the endoplasmic reticulum (ER) membrane. C99 is subsequently cleaved to amyloid β (Aβ), the aggregation of which is known to cause Alzheimer's disease. Therefore, C99 removing is for preventing the disease. Selenoprotein S (SelS) is an ER membrane protein participating in endoplasmic reticulum-associated degradation (ERAD), one of the stages in resolving ER stress of misfolded proteins accumulated in the ER...
March 15, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28315462/implications-of-cerebrovascular-atp-binding-cassette-transporter-g1-abcg1-and-apolipoprotein-m-in-cholesterol-transport-at-the-blood-brain-barrier
#13
Alexandra Carmen Kober, Anil Paul Chirackal Manavalan, Carmen Tam-Amersdorfer, Andreas Holmér, Ahmed Saeed, Elham Fanaee Danesh, Martina Zandl, Nicole Maria Albrecher, Ingemar Björkhem, Gerhard M Kostner, Björn Dahlbäck, Ute Panzenboeck
Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain...
March 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28315450/phospholipid-oxidation-and-carotenoid-supplementation-in-alzheimer-s-disease-patients
#14
O S Ademowo, H K I Dias, I Milic, A Devitt, R Moran, R Mulcahy, A N Howard, J M Nolan, H R Griffiths
Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterised by decline of memory, cognitive function and changes in behaviour. Generic markers of lipid peroxidation are increased in AD, therefore reactive oxygen species have been suggested to be involved in the aetiology of cognitive decline. Carotenoids are depleted in AD serum, therefore we have compared serum lipid oxidation between AD and age-matched control subjects before and after carotenoid supplementation. The novel oxidised phospholipid biomarker 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) was analysed using electrospray ionization tandem mass spectrometry (MS) with multiple reaction monitoring (MRM), 8-isoprostane (IsoP) was measured by ELISA and ferric reducing antioxidant potential (FRAP) was measured by a colorimetric assay...
March 14, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28315271/role-of-sigma-1-receptor-in-cocaine-abuse-and-neurodegenerative-disease
#15
Yu Cai, Lu Yang, Fang Niu, Ke Liao, Shilpa Buch
Sigma-1 receptors (Sig-1R) are recognized as a unique class of non-G protein-coupled intracellular protein. Sig-1R binds to its ligand such as cocaine , resulting in dissociation of Sig-1R from mitochondrion-associated ER membrane (MAM) to the endoplasmic reticulum (ER), plasma membrane, and nuclear membrane, regulating function of various proteins. Sig-1R has diverse roles in both physiological as well as in pathogenic processes. The disruption of Sig-1R pathways has been implicated as causative mechanism(s) in the development of both neurodegenerative disorders such as Alzheimer disease (AD ), Parkinson disease (PD ), amyotrophic lateral sclerosis (ALS ) and Huntington Disease (HD ) ...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28314118/in-vitro-assay-development-and-hts-of-small-molecule-human-abad-17%C3%AE-hsd10-inhibitors-as-therapeutics-in-alzheimer-s-disease
#16
Laura Aitken, Gemma Baillie, Andrew Pannifer, Angus Morrison, Philip S Jones, Terry K Smith, Stuart P McElroy, Frank J Gunn-Moore
A major hallmark of Alzheimer's disease (AD) is the formation of neurotoxic aggregates composed of the amyloid-β peptide (Aβ). Aβ has been recognized to interact with numerous proteins, resulting in pathological changes to the metabolism of patients with AD. One such mitochondrial metabolic enzyme is amyloid-binding alcohol dehydrogenase (ABAD), where altered enzyme function caused by the Aβ-ABAD interaction is known to cause mitochondrial distress and cytotoxic effects, providing a feasible therapeutic target for AD drug development...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28304092/mediation-of-cognitive-function-improvements-by-strength-gains-after-resistance-training-in-older-adults-with-mild-cognitive-impairment-outcomes-of-the-study-of-mental-and-resistance-training
#17
Yorgi Mavros, Nicola Gates, Guy C Wilson, Nidhi Jain, Jacinda Meiklejohn, Henry Brodaty, Wei Wen, Nalin Singh, Bernhard T Baune, Chao Suo, Michael K Baker, Nasim Foroughi, Yi Wang, Perminder S Sachdev, Michael Valenzuela, Maria A Fiatarone Singh
OBJECTIVES: To determine whether improvements in aerobic capacity (VO2peak ) and strength after progressive resistance training (PRT) mediate improvements in cognitive function. DESIGN: Randomized, double-blind, double-sham, controlled trial. SETTING: University research facility. PARTICIPANTS: Community-dwelling older adults (aged ≥55) with mild cognitive impairment (MCI) (N = 100). INTERVENTION: PRT and cognitive training (CT), 2 to 3 days per week for 6 months...
March 2017: Journal of the American Geriatrics Society
https://www.readbyqxmd.com/read/28302766/csf-clearance-in-alzheimer-disease-measured-with-dynamic-pet
#18
Mony J de Leon, Yi Li, Nobuyuki Okamura, Wai H Tsui, Les A Saint Louis, Lidia Glodzik, Ricardo S Osorio, Juan Fortea, Tracy Butler, Elizabeth Pirraglia, Silvia Fossati, Hee-Jin Kim, Roxana O Carare, Maiken Nedergaard, Helene Benveniste, Henry Rusinek
Evidence supporting the hypothesis that reduced cerebrospinal fluid (CSF) clearance is involved in the pathophysiology of Alzheimer's disease (AD) comes from primarily from rodent models. However, unlike rodents where predominant extra-cranial CSF egress is via olfactory nerves traversing the cribriform plate, human CSF clearance pathways are not well characterized. Using dynamic Positron Emission Tomography (PET) with (18)F-THK5117 a tracer for tau pathology, the ventricular CSF time activity was used as a biomarker for CSF clearance...
March 16, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28302722/amyloid-%C3%AE-oligomers-transiently-inhibit-amp-activated-kinase-and-cause-metabolic-defects-in-hippocampal-neurons
#19
Gisele S Seixas da Silva, Helen M Melo, Mychael V Lourenco, Natalia de M Lyra E Silva, Marcelo B de Carvalho, Soniza Alves-Leon, Jorge M de Souza, William L Klein, Wagner S da-Silva, Sergio T Ferreira, Fernanda G De Felice
AMP-activated kinase (AMPK) is a key player in energy sensing and metabolic reprogramming under cellular energy restriction. Several studies have linked impaired AMPK function to peripheral metabolic diseases such as diabetes. However, the impact of neurological disorders, such as Alzheimer disease (AD), on AMPK function and downstream effects of altered AMPK activity on neuronal metabolism have been investigated only recently. Here, we report the impact of A β oligomers (AβOs), synaptotoxins that accumulate in AD brains, on neuronal AMPK activity...
March 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28302400/substrate-and-inhibitor-specificity-of-kynurenine-monooxygenase-from-cytophaga-hutchinsonii
#20
Robert S Phillips, Andrew D Anderson, Harvey G Gentry, Osman F Güner, J Phillip Bowen
Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcat and kcat/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KI values lower than the Km for kynurenine...
March 4, 2017: Bioorganic & Medicinal Chemistry Letters
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