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Familial Alzheimer's disease

Xue-Yang Jiang, Ting-Kai Chen, Jun-Ting Zhou, Si-Yu He, Hong-Yu Yang, Yao Chen, Wei Qu, Feng Feng, Hao-Peng Sun
Designing multitarget-directed ligands (MTDLs) is considered to be a promising approach to address complex and multifactorial maladies such as Alzheimer's disease (AD). The concurrent inhibition of the two crucial AD targets, glycogen synthase kinase-3β (GSK-3β) and human acetylcholinesterase ( h AChE), might represent a breakthrough in the quest for clinical efficacy. Thus, a novel family of GSK-3β/AChE dual-target inhibitors was designed and synthesized. Among these hybrids, 2f showed the most promising profile as a nanomolar inhibitor on both h AChE (IC50 = 6...
March 8, 2018: ACS Medicinal Chemistry Letters
Jodi R Paul, Hira A Munir, Thomas van Groen, Karen L Gamble
Disruption of circadian rhythms is commonly reported in individuals with Alzheimer's disease (AD). Neurons in the primary circadian pacemaker, the suprachiasmatic nucleus (SCN), exhibit daily rhythms in spontaneous neuronal activity which are important for maintaining circadian behavioral rhythms. Disruption of SCN neuronal activity has been reported in animal models of other neurodegenerative disorders; however, the effect of AD on SCN neurophysiology remains unknown. In this study we examined circadian behavioral and electrophysiological changes in a mouse model of AD, using male mice from the Tg-SwDI line which expresses human amyloid precursor protein with the familial Swedish (K670N/M671L), Dutch (E693Q), Iowa (D694N) mutations...
March 11, 2018: Neurobiology of Disease
Jennifer L Etnier, William B Karper, Jeffrey D Labban, Aaron T Piepmeier, Chia-Hao Shih, William N Dudley, Vincent C Henrich, Laurie Wideman
Background: Alzheimer's disease is a progressive disease that degrades cognitive functioning and ultimately results in death. Currently, there is no cure for Alzheimer's disease and, hence, the identification of preventative strategies is important. Physical activity (PA) is a behavioral intervention that holds promise with respect to delaying the onset of Alzheimer's disease. Purpose: The purpose of this study was to explore the differential cognitive benefits achieved in response to PA as a function of a person's genetic risk for AD...
February 5, 2018: Annals of Behavioral Medicine: a Publication of the Society of Behavioral Medicine
V Hepnarova, J Korabecny, L Matouskova, P Jost, L Muckova, M Hrabinova, N Vykoukalova, M Kerhartova, T Kucera, R Dolezal, E Nepovimova, K Spilovska, E Mezeiova, N L Pham, D Jun, F Staud, D Kaping, K Kuca, O Soukup
Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line...
March 2, 2018: European Journal of Medicinal Chemistry
Subodh Kumar, P Hemachandra Reddy
A non-invasive and early-detectable peripheral biomarker is urgently needed for Alzheimer's disease (AD). The present study is a step forward to verify the biomarker properties of human microRNA-455-3p (Hsa-miR-455-3p) in AD patients. Our previous findings on mild cognitive impaired subjects, AD patients and AD cells and mouse models unveiled the miR-455-3p as a potential peripheral biomarker for AD. In the current study, we verified the differential expression of miR-455-3p in postmortem AD brains obtained from NIH NeuroBioBank, and fibroblasts and B-lymphocytes from both familial and sporadic AD patients from Coriell Cell Repository of National Institutes on Aging...
2018: Frontiers in Aging Neuroscience
Nicole R Fowler, C Elizabeth Shaaban, Alexia M Torke, Kathleen A Lane, Samir Saba, Amber E Barnato
Background: The decision to implant a cardiac device in a person with Alzheimer's disease or related dementia requires considering the possible trade-offs of quality of life (QOL) and quantity of life. This study measured the decision-making experience of patients with and without cognitive impairment (CI) who received a cardiac device and their family members who were involved in the decision. Methods and Results: Semi-structured interviews and questionnaires were administered with 15 patient-family member dyads...
2018: Cardiol Cardiovasc Med
Agnieszka Zagorska, Anna Partyka, Adam Bucki, Alicja Gawalska, Anna Czopek, Maciej Pawlowski
BACKGROUND: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. OBJECTIVE: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery...
March 8, 2018: Current Medicinal Chemistry
Austin T Smith
In the midst of a typical emergency medicine resident schedule packed with clinical shifts, resident scheduling, scholarly projects, conference scheduling, and family needs, I took time to visit my grandparents. They are in their 90s and because they live so far away, they had yet to meet my 1 year old daughter. Age has caught up to them over the last five years; particularly my grandfather who is in the final stages of Alzheimer's disease. He has lost the ability to recognize even his family over the last few years which has been difficult for us to experience...
March 9, 2018: Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine
Lisa Seipold, Hermann Altmeppen, Tomas Koudelka, Andreas Tholey, Petr Kasparek, Radislav Sedlacek, Michaela Schweizer, Julia Bär, Marina Mikhaylova, Markus Glatzel, Paul Saftig
A disintegrin and metalloproteinase 10 (ADAM10) plays a major role in the ectodomain shedding of important surface molecules with physiological and pathological relevance including the amyloid precursor protein (APP), the cellular prion protein, and different cadherins. Despite its therapeutic potential, there is still a considerable lack of knowledge how this protease is regulated. We have previously identified tetraspanin15 (Tspan15) as a member of the TspanC8 family to specifically associate with ADAM10...
March 8, 2018: Cellular and Molecular Life Sciences: CMLS
Doris T Zallen
PurposeApolipoprotein-E (APOE) genetic testing to estimate risk for developing late-onset Alzheimer disease is increasingly being offered without prior genetic counseling or preparation. Consumer interest continues to grow, raising the question of how best to conduct such testing.MethodsTwenty-six semistructured interviews were carried out to study the reactions of individuals who had already learned of their higher risk after APOE testing had been done because of a family history of Alzheimer disease, or from genetic tests done for other health-related or general-interest reasons...
March 8, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Ling-Yun Fan, Ya-Mei Lai, Ta-Fu Chen, Yung-Chin Hsu, Pin-Yu Chen, Kuo-Zhou Huang, Ting-Wen Cheng, Wen-Yi Isaac Tseng, Mau-Sun Hua, Ya-Fang Chen, Ming-Jang Chiu
Alzheimer's disease (AD) progresses insidiously from the preclinical stage to dementia. While people with subjective cognitive decline (SCD) have normal cognitive performance, some may be in the preclinical stage of AD. Neurofibrillary tangles appear first in the transentorhinal cortex, followed by the entorhinal cortex in the clinically silent stage of AD. We expected the earliest changes in subjects with SCD to occur in medial temporal subfields other than the hippocampal proper. These selective structural changes would affect specific memory subcomponents...
March 8, 2018: Human Brain Mapping
Alexandra C Newton
Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are "receptors" for the potent tumor-promoting phorbol esters...
April 2018: Critical Reviews in Biochemistry and Molecular Biology
Shota Suzumura, Aiko Osawa, Natsumi Maeda, Yuko Sano, Akihiko Kandori, Tomohiko Mizuguchi, Ying Yin, Izumi Kondo
AIM: We have developed a smart terminal device for screening finger function, and investigated the capability of this tool for detecting abnormalities of finger dexterity. METHODS: Finger dexterity was measured for 31 patients with Alzheimer's disease (AD group), 15 people diagnosed with mild cognitive impairment (MCI group) and 48 family members (healthy older adult group) as the control. Cognitive function was assessed using the Mini-Mental State Examination. RESULTS: There were significant differences between the AD and control group in response time, rhythm and contact duration (P ≤ 0...
March 7, 2018: Geriatrics & Gerontology International
Petros Takousis
Changes associated with neurodegeneration at the cellular level are manifestations of deregulated biochemical pathways, and typically precede neuronal loss. Incorporation of molecular markers in the diagnostic process could aid detection of early changes, prior to extensive neuronal loss, as early as the presymptomatic stages of the disorder, thus enabling improved patient stratification for targeted drug development. Such biomarkers should be sufficiently sensitive and specific to distinguish AD from other disorders with overlapping symptoms...
2018: Methods in Molecular Biology
Mohammad Faruq Abd Rachman Isnadi, Voon Kin Chin, Roslaini Abd Majid, Tze Yan Lee, Maizaton Atmadini Abdullah, Ramatu Bello Omenesa, Zaid Osamah Ibraheem, Rusliza Basir
Interleukin-33 (IL-33) is an IL-1 family member, which exhibits both pro- and anti-inflammatory properties solely based on the type of the disease itself. Generally, IL-33 is expressed by both endothelial and epithelial cells and mediates its function based on the interaction with various receptors, mainly with ST2 variants. IL-33 is a potent inducer for the Th2 immune response which includes defence mechanism in brain diseases. Thus, in this paper, we review the biological features of IL-33 and the critical roles of IL-33/ST2 pathway in selected neurological disorders including Alzheimer's disease, multiple sclerosis, and malaria infection to discuss the involvement of IL-33/ST2 pathway during these brain diseases and its potential as future immunotherapeutic agents or for intervention purposes...
2018: Mediators of Inflammation
John Grundy, Kon Mouzakis, Rajesh Vasa, Andrew Cain, Maheswaree Curumsing, Mohamed Abdelrazek, Niroshine Fernando
By the 2050, it is estimated that the proportion of people over the age of 80 will have risen from 3.9% to 9.1% of population of Organisation for Economic Cooperation and Development countries. A large proportion of these people will need significant help to manage various chronic illnesses, including dementia, heart disease, diabetes, limited physical movement and many others. Current approaches typically focus on acute episodes of illness and are not well designed to provide adequately for daily living care support...
2018: Studies in Health Technology and Informatics
Xulong Wang, Vivek M Philip, Guruprasad Ananda, Charles C White, Ankit Malhotra, Paul J Michalski, Krishna R Murthy Karuturi, Sumana R Chintalapudi, Casey Acklin, Michael Sasner, David A Bennett, Philip L De Jager, Gareth R Howell, Gregory W Carter
Recent technical and methodological advances have greatly enhanced genome-wide association studies (GWAS). The advent of low-cost whole-genome sequencing facilitates high-resolution variant identification, and the development of linear mixed models (LMM) allows improved identification of putatively causal variants. While essential for correcting false positive associations due to sample relatedness and population stratification, LMMs have commonly been restricted to quantitative variables. However, phenotypic traits in association studies are often categorical, coded as binary case-control or ordered variables describing disease stages...
March 5, 2018: Genetics
Sarah Iribarren, Samantha Stonbraker, Niurka Suero-Tejeda, Maribel Granja, José A Luchsinger, Mary Mittelman, Suzanne Bakken, Robert J Lucero
PURPOSE: To identify the information and communication needs of Hispanic family caregivers for individuals with Alzheimer's Disease and Related Dementias (ADRD) and the manner in which online tools may meet those needs. METHODS: We conducted 11 participatory design sessions with 10 English- and 14 Spanish-speaking urban-dwelling Hispanic family caregivers and gathered data using a survey, collage assemblage, and audio and video recordings. Four investigators analyzed transcripts of audio recordings with a coding framework informed by several conceptual models...
March 5, 2018: Informatics for Health & Social Care
Morgane Cam, Emilie Durieu, Marion Bodin, Antigoni Manousopoulou, Svenja Koslowski, Natalia Vasylieva, Bogdan Barnych, Bruce D Hammock, Bettina Bohl, Philipp Koch, Chiori Omori, Kazuo Yamamoto, Saori Hata, Toshiharu Suzuki, Frank Karg, Patrick Gizzi, Vesna Erakovic-Haber, Vlatka Bencetic Mihaljevic, Branka Tavcar, Erik Portelius, Josef Pannee, Kaj Blennow, Henrik Zetterberg, Spiros D Garbis, Pierrick Auvray, Hermeto Gerber, Jeremy Fraering, Patrick C Fraering, Laurent Meijer
Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown...
February 28, 2018: Journal of Alzheimer's Disease: JAD
Anne Bourbonnais, Francine Ducharme, Philippe Landreville, Cécile Michaud, Marie-Andrée Gauthier, Marie-Hélène Lavallée
Few studies have been conducted on strategies to promote the implementation of complex interventions in nursing homes (NHs). This article presents a pilot study intended to assess the strategies that would enable the optimal implementation of a complex intervention approach in NHs based on the meanings of screams of older people living with Alzheimer's disease. An action research approach was used with 19 formal and family caregivers from five NHs. Focus groups and individual interviews were held to assess different implementation strategies...
March 1, 2018: Journal of Applied Gerontology: the Official Journal of the Southern Gerontological Society
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