bluuebunny/crossref_metadata_2025_split huggingface dataset:
Motor dysfunction as a marker for mild cognitive impairment and Alzheimer’s disease
Authors: Koppelmans Vincent , Weisenbach Sara , Duff Kevin M , Ruitenberg Marit FL 
Published: December 2020

AbstractBackgroundMild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) are associated with motor impairments that can precede cognitive symptoms by several years. While prior studies suggest that such motor impairments may be an early disease marker and predict AD progression, most only included a single motor measure. Here, we tested the hypothesis that a broad motor assessment can distinguish MCI and AD from healthy controls (HC).MethodTo identify which measures jointly have the strongest predictive power we developed a comprehensive test battery assessing hand grip force, finger tapping speed (single and dual synchronized/alternating), Archimedes spiral and Trail Making Test drawing, and motor sequence learning. HC and MCI individuals additionally completed a 6‐meter walking test, timed up‐and‐go test, and Romberg balance test.ResultSo far 10 patients with amnestic MCI (70±5y; 5 males), 10 patients with AD (75±6y; 4 males), and 13 HC (69±6y; 5 males) completed the battery. We observed a pattern of mild to moderate motor deficits across motor domains in MCI patients compared to HC, including grip force, finger tapping and walking speed (medium‐to‐large effect sizes; eta2=0.08‐0.16). AD patients showed deficits in simple reaction time and drawing speed (large effect sizes; eta2=0.18‐0.2) compared to HC.ConclusionOur findings suggest that specific motor measures could be used as novel, inexpensive, non‐invasive biomarkers for dementia. If these cross‐sectional motor differences persist with larger samples, then it will be important to examine them longitudinally.
Social network structure and dementing processes
Authors: Zhang Yun , Natale Ginny , Clouston Sean 
Published: December 2020

AbstractBackgroundHow are components of individual social relationships associated with the dementing process? We examined associations between social network structure on incidence of mild cognitive impairment (MCI) and conversion to probable dementia, and on mortality rate.MethodWe utilized six waves of a nationally representative cohort of residents aged over 65 years and older in the United States (2011‐2016; National Health and Aging Trends Study; NHATS). Respondents were categorized into normal cognition, MCI, or probable dementia. Four‐status multi‐state survival models (MSMs) were used to provide multivariable‐adjusted measures, fit with a misclassification matrix, assessed effects of social network structure on the dementing process.ResultEligible NHATS participants (N=6,078) were mostly female (58.42%), and the majority were Non‐Hispanic white (68.99%). At baseline, the average age was 77.49±7.79 years and respondents reported an average number of 1.93 ±1.31 members of their social networks. In multivariable‐adjusted MSMs accounting for age, sex, education and race/ethnicity, having larger social networks was associated with lower hazards of conversion from MCI to probable dementia (adjusted Hazard Ratio (aHR): 0.82; 95%C.I.=[0.67‐0.99]). Having at least one friend within social network was associated with lower hazards of conversion from MCI to dementia (aHR=0.48 [0.33‐0.71]) but was associated with higher risk of mortality in the MCI group (aHR=2.58 [1.47‐4.51]). Finally, participants with at least one college graduate in their social network reported lower incidence of dementia (aHR=0.37 [0.26‐0.51]).ConclusionOur study is one of the first studies exploring effects of social network structure on the dementing process in a nationally representative prospective cohort of older adults. We found that having at least one friend, a larger social network, or having a college graduate within social network was associated with lower risk of MCI or conversion to dementia. We also reveal substantial disparities in cognitive dementing by education and race/ethnicity as well as clustering risks for low‐educated families.
Reading of the speedometer value in elderly drivers with cognitive impairments: A comparison of analog and digital speedometer
Authors: Peng Zhouyuan , Kinoshita Ayae , Shimosaka Momoyo , Miyamoto Masakazu , Kuzuya Akira 
Published: December 2020

AbstractBackgroundWith cognitive functions deteriorated, the capability to get the information of speed, one of the essential element needed to perform safe driving1, may be influenced. We aim to investigate the reading of the speedometer (SM) values in elderly driver with cognitive impairments by comparing the recognition of analog and digital SM values, and examine its correlation with cognitive functions.MethodsElderly subjects with driving experience who visited the outpatient neurology clinic in the Kyoto university hospital for cognitive complaints from July 2018 to December 2019 were investigated. Cognitive tests were carried out, as well as a test asking participants to read the speed values of analog SM and digital SM presented on the iPad within the time limit.ResultsAmong 48 participants slightly more than half of them returned their driving licenses (retired drivers) whereas 22 still hold a valid driving license (current drivers). Based on the result of Wilcoxon test, among all participants the result of reading test of digital SM had significant higher scores than analog SM (Z=‐3.996, p<0.0001). According to the Mann‐Whitney U test, there was no significantly different about their reading ability of both analog and digital SM values between current drivers and retired drivers. Additionally, the reading ability of digital SM was significantly correlated with the score of Mini‐mental state examination, block design test and clock drawing test.ConclusionsAmong elderly drivers with cognitive impairments, it was shown that digital SM was easier to read than analog SM. This newly gained information provides an innovative insight to the design of SM. Reference: Francois M, Osiurak F, Fort A, Crave P, Navarro J. Analogue versus digital speedometer: effects on distraction and usability for truck driving. European Conference on Human Centred Design for Intelligent Transport Systems; 2016‐06‐30, 2016; Loughborough, France.
Selective impairment of molecular interaction between ADP and ATP synthase by anesthetics
Authors: Liang Feng , Xie Zhongcong 
Published: December 2020

AbstractBackgroundIsoflurane, sevoflurane, and desflurane have been shown to have different neurotoxic effects. However, the underlying mechanism at the single molecular level remains unknown. Isoflurane, sevoflurane, and desflurane can differently induce mitochondrial dysfunction and ATP synthase is the critical component of mitochondrial function. We, therefore, set out to assess whether different anesthetics can selectively impair the interaction of ADP and ATP synthase at a single molecular level.MethodThe human H4‐APP cells were treated with 2% isoflurane, 4% sevoflurane, or 12% desflurane for 6 hours. The mitochondrial function was measured by using a Seahorse XFp Extracellular Flux Analyzer. Next, we employed a nanobeam technology‐based single molecular dynamic interaction detection method to determine the interaction of ADP and ATP synthase following the administration of isoflurane, sevoflurane, and desflurane. Each of resonance shifts, detected by a nanosensor, corresponded to single molecular interaction of ADP and ATP synthase. Finally, the single molecular dynamics computer simulation was used to identify the binding sites between ATP synthase and each of the anesthetics.ResultThe Seahorse XFp Extracellular Flux Analyzer demonstrated that isoflurane, but not sevoflurane or desflurane, induced mitochondrial dysfunction in the H4‐APP cells. The nanobeam technology‐based single molecular dynamic interaction detection method demonstrated that isoflurane significantly impaired the interaction of ADP and ATP synthase as evidenced by the decreased numbers of resonance shift, longer duration between the resonance shifts and decreased disassociation constant. Neither sevoflurane nor desfluraneimpaired such interaction. Mechanistically, the single molecular dynamics computer simulation study, assessing the various energy binding ability and different binding dynamic activity, demonstrated that there were 7, 1 and 2 binding sites in ATP synthase by isoflurane, sevoflurane and desflurane, respectively. Note that all of the identified 7 binding sites in ATP synthase by isoflurane are dominated binding position of amino acid related to the generation of ATP.ConclusionThese findings suggest that isoflurane has more binding sites with ATP synthase than sevoflurane or desflurane, which impairs the molecular interaction of ADP and ATP synthase, leading to the selective mitochondrial dysfunction and neurotoxicity observed following the administration of isoflurane but not sevoflurane or desflurane.
Hierarchical involvement of molecular players in human neocortex in the course of preclinical and symptomatic Alzheimer’s disease
Authors: Li Xiaohang , Tsolis Konstantinos C , Koper Marta J , Ronisz Alicja , Ospitalieri Simona , von Arnim Christine , Otto Markus , Vandenberghe Rik , Tousseyn Thomas , Scheuerle Angelika , Economou Tassos , Carpentier Sebastien , Thal Dietmar Rudolf 
Published: December 2020

AbstractBackgroundProteomic profile changes have been reported in the brains from individuals having Alzheimer’s disease. However, it is not yet clear whether they represent a continuous process from mild to severe changes, or whether the proteins become involved step‐by‐step in a hierarchal manner. Additionally, in previous studies, cases with initial Aβ plaque and NFT pathology were considered as controls, and brain homogenates were not separated into distinct fractions. Therefore, there is a gap of knowledge regarding the initial steps of AD pathogenesis and the spatial resolution of the respective protein changes in terms of subcellular distribution.MethodWe analyzed soluble, dispersible (insoluble proteins and vesicles in mixtures with the intra‐/extracellular fluid), membrane‐associated (SDS‐soluble), and plaque‐associated (formic‐acid‐soluble) fractions of brain homogenates from 19 control cases without AD pathology, 17 pathologically preclinical AD (p‐preAD), and 17 symptomatic AD (symAD) cases by label‐free liquid chromatography coupled to tandem mass spectrometry. Proteomic changes and related pathways involved in p‐preAD and symAD were determined by integrated analyses combining quantitative proteomics, neuropathological measurements, regression analysis, and gene ontology overrepresentation tests.ResultThree hierarchical classes of proteins, namely early‐ and late‐responding proteins and gradually changing proteins were identified across control, p‐preAD and symAD samples. Additionally, five proteins exhibited reduced abundance in the soluble fraction accompanied by increase in the membrane‐associated fraction between symAD and the group of p‐preAD + control cases, suggesting pathological alterations in their functions. Gene ontology analysis showed that the synaptic vesicle cycle and other endocytosis‐related pathways were overrepresented by early‐responding and gradually changing proteins, whereas caspase‐mediated cleavage of cytoskeletal proteins were enriched in the late‐responding protein class.ConclusionWe identified an apparent hierarchy of key proteins in the human brain during AD pathogenesis, from which the early responding proteins point to pathways that are not yet a main focus in AD research. This hierarchy of proteome change in the neocortex clearly distinguished the preclinical phase from the symptomatic phase and identified the synaptic vesicle cycle as a likely primary affected function in AD initiation. Our results may open new roads for therapies by intervening on those key proteins and their respective pathways.
Gender dimorphism in serotonin dopamine and norepinephrine neurons of isodendritc core in postmortem human and nonhuman primate control subjects
Authors: Reddy Arubala P , Sawant Neha , Bunquin Lloyd S , Reddy Hemachandra 
Published: December 2020

AbstractBackgroundComorbidity of depression in bMets, NPSs and NDDs is resource demanding clinical area considering treatment challenges and patient care. NPSs represent prodromal symptoms of dementia results of neurobiological changes in specific subcortical region. Dynamic cascade of Aβ shifts from nonamyloidogenic is implicated in early cognitive impairment and depressive symptoms. Serotonergic system is implicated in Aβ pathology and NE is important to compensatory in Aβ degradation. Although the role of DA is not investigated in AD pathology. Overall neuromodulation in IDC of midbrain is imperative and intriguing aspect of monoaminergic association in AD and other NDDs pathology.Here we present genetic dimorphism of key area of the brain (5HT: dorsal raphe, DA:substantia nigra, Noradrenaline: locus ceruleous).Method4males and 4 females midbrain of control subject were collected from Neurobiobank (NIH) and ONPRC. Brain sections were collected 20‐micron sections on cover glass plain slides. 4mm tissue punches were used to collect RNA from tissues. Enough tissues used to generate 10ug‐20 ug average quality RNA. 4ug RNA from Raphe, substantia nigra and locus ceruleous was isolated using trizol isolation and sent to UTSW microarray core. The RNA was hybridized to Clariom D Human chip and CEL chip data obtained from UTSW core. CEL files were uploaded in Transcriptome Analysis Console (TAC4.0). Statistically significant data in Excel file is uploaded in Ingenuity Pathway analysis software to find biological pathways dominate female and male brains. Microarray analysis of adult serotonin neurons in human and NHP dorsal raphe, Substantia nigra and Locus ceruleous (DR/SN/LC) Chip has expression of 500.000 known and unknown RNA species transcript encoding 135,000 RNAResultHuman DR/SNC/LC have 6643/13475/9194 number of probe set and 850/896//501 pathways, and Rhesus DR/SNC/LC have 7261/2157/1938 probe sets and 872/218/198 pathways altered respectively with one or more genes. Major dominated pathways: electron transport chain. Oxidative phosphorylation, miRNA, mitochondria dysfunction, apoptosis signaling, will be presented in the posterConclusionMajor energy metabolism pathway dominates in all three area in male DR/SN/LC area clearly state female brain having lower energy metabolism may results in reduce homeostasis in Isodendritc core midbrain area. Although compensatory mechanism may still yet investigate.
Tau acetylation at K280 is critical for propagation and an antibody targeting it prevents in vivo tau propagation
Authors: Yoon Seung‐Yong , Song Halim , Kim Na‐Young , Kim Dong‐Hou 
Published: December 2020

AbstractBackgroundThe spread of tau pathology from the transentorhinal cortex to the hippocampus and neocortex in Alzheimer’s disease (AD) is explained by the prion‐like cell‐to‐cell seeding and propagation of misfolded tau aggregates. Hence, it is important to define the seeding‐ and propagation‐competent tau species and to develop targeted therapeutic antibodies.MethodVarious methods like thioflavin‐T, FRET, FACS, and in vivo stereotaxic injection of AD‐derived tau aggregate fractions were used to evaluate tau aggregation, propagation, and the efficacy of an antibody to inhibit these processes.ResultAcetylation of tau at K280 is critical for the successive tau propagation processes, including secretion, aggregation, and seeding. An antibody targeting acetylated tau at K280 effectively prevented AD‐derived insoluble tau aggregates‐induced proteopathic seeding and propagation in in vitro assays and in vivo mouse brains.ConclusionAcetylated tau at K280 is a core species of seeding and propagation, which could be a therapeutic target for AD and other tauopathies.
Subjective memory complaints: Fact or feeling?
Authors: Meynadasy Melissa A. , Hajcak Greg , Naar Sylvie , Sheffler Julia L. 
Published: December 2020

AbstractBackgroundSubjective memory complaints (SMCs) are considered a requirement for diagnosis of Mild Cognitive Impairment (MCI; Petersen, 2004). However, the evidence for a relationship between SMCs and objective cognitive impairment is mixed and often contradictory (Crumley et al., 2014; Lenehan et al., 2012; Mitchell et al., 2014; Reid & MacLullich, 2006; Roberts et al., 2009). Some research has shown that SMCs are more strongly and consistently related to psychosocial factors such as anxiety, stress, and depression (Balash et al., 2013; Dux et al., 2008; Mowla et al., 2008; Yates et al., 2017). We sought to further examine these relationships by investigating the association of SMCs with multiple objective measures of cognitive functioning as well as its association with other mood and psychosocial characteristics in a community sample of older adults.MethodSMCs were measured by the change subscale of the Metamemory in Adulthood questionnaire (Dixon et al., 1988). Objective cognitive functioning was measured with the California Verbal Learning Test, 2nd Edition (CVLT‐II) and P300 event‐related brain potential amplitude to infrequent target stimuli during a visual Go/NoGo task (i.e., indicator of allocation of attentional resources to motivationally salient stimuli). Perceived stress and psychological well‐being were measured with the NIH Toolbox Emotion Battery. Depression and Anxiety were measured with the Geriatric Depression Scale (GDS) and Geriatric Anxiety Scale (GAS), respectively.ResultsSMCs were positively associated with perceived stress, depression, and anxiety scores, p’s < .002, and negatively associated with psychological wellbeing, p = .028. However, SMCs were not associated with short or long delay verbal memory recall, p’s > .432, nor were they associated with P300 amplitude, p = .966. Further, P300 amplitude was positively related to long delay verbal memory recall, p = .018, and trending toward a significant relationship with short delay verbal recall, p = .086, supporting the use of neural markers of cognitive function to objectively assess potential cognitive impairment.ConclusionsOverall, our findings support the notion that SMCs are related to mood and psychosocial characteristics rather than objective declines in cognitive functioning, questioning the utility of SMCs as a criterion in the diagnosis of MCI.
Elder abuse in the context of dementia: Development of film resources
Authors: Antoniades Josefine , Dow Briony , Gahan Luke , Brijnath Bianca 
Published: December 2020

AbstractBackgroundPeople with dementia are uniquely vulnerable to elder abuse, including from their family members and carers. However, when confronted with instances of elder abuse, service providers often struggle to balance the carer’s needs and the older person’s rights. Without clear and consistent messaging and training, significant discrepancies can arise in provider’s responses to elder abuse in the context of dementia. Addressing this gap, this project aimed to co‐produce with providers and the community, three short films exemplifying best‐practice responses to cases of elder abuse in the context of dementia. This paper describes the development of the elder abuse films. Using co‐production methods, two workshops were conducted with Service Providers (n = 13) and community members (n = 8) respectively. In the facilitated workshops, participants were provided with draft scripts based on real‐life scenarios covering neglect, financial and physical abuse. Following the workshops, scripts were refined and circulated to participants for further feedback. Once refined, films were developed by professional film maker (WHY Documentaries (Wollongong, NSW)), and films were circulated to Service Providers for final feedback. The final three films were launched in March, 2020 and data analytics are currently being collected. This project highlights how the use of film and media can effectively be used in educating front line providers about sensitive topics such as elder abuse in the context of dementia to improve the detection, but also the responses to abuse in community settings.
Effects of mutations in the novel FTD‐ALS gene, CYLD, on SFPQ protein
Authors: Boccanfuso Lauren , Lee Albert , Chung Roger S , Oyston Lisa J , Kwok John B , Dobson‐Stone Carol 
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders that share similar clinical and pathological hallmarks, as well as overlapping genetic aetiologies. Previously, we identified that mutations in CYLD can cause FTD‐ALS. CYLD is a lysine‐63 deubiquitinase, and the FTD‐ALS causal mutation CYLDM719V shows significantly increased deubiquitinase activity [Dobson‐Stone et al. 2020, Brain 143:783‐799]. CYLD is known to interact with the protein products of at least three established FTD and ALS genes. We sought to determine whether other FTD‐ALS proteins were influenced by modulation of CYLD.MethodWe performed mass spectrometry quantitative proteomic analysis of HEK293 lysates overexpressing wild‐type and mutant CYLD (CYLDWT & CYLDM719V), followed by western blots of total cell lysates from SH‐SY5Y and HEK293 cells overexpressing CYLDWT, CYLDM719V and the deubiquitinase‐inactive mutation CYLDD681G. Densitometry analysis was performed in Image Lab (Bio‐Rad, USA) and normalised to total protein.ResultMass spectrometry analysis indicated significant differences in expression of TIA1, MATR3, VCP and SFPQ when CYLD was overexpressed. Validation by western blot showed that overexpression of CYLD increased relative protein expression of SFPQ (2.7 fold increase for CYLDWT versus empty vector, p = 0.0048) in SH‐SY5Y cells. This is likely due to deubiquitinase activity, as CYLDD681G did not show such an increase. SFPQ is a nucleic acid binding protein that has been shown to mislocalise from the nucleus to the cytoplasm in FTD and ALS. We are currently examining whether CYLD affects subcellular localisation of SFPQ by western blot and immunofluorescent microscopy analyses.ConclusionOur study indicates that CYLD overexpression increases SFPQ protein expression via its deubiquitinase activity. However, it remains to be shown whether this mechanism is essential to the pathogenesis of FTD and ALS driven by CYLD.