bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and pharmacologic proteasome augmentation ameliorates Alzheimer’s disease‐like symptom and pathology progression through increased turnover of amyloid precursor protein machinery
Authors: Pickering Andrew 
Published: December 2020

AbstractBackgroundThe proteasome has key roles in neuronal proteostasis, including removal of misfolded or oxidized proteins, presynaptic protein turnover, as well as synaptic efficacy and plasticity. Proteasome dysfunction is a prominent feature of Alzheimer’s disease (AD). Artificial impairment of proteasome function can mimic many neurodegenerative phenotypes.MethodsWe created transgenic mice and flies as well as novel proteasome activating drugs to examine whether proteasome augmentation can reduce AD like symptoms in animal models of the disease.ResultsWe report that manipulation of proteasome activity can influence the rate of AD‐like progression. We show that augmentation of proteasome function in fly and cell culture models of AD delays mortality, cell death, and AD‐like cognitive deficits. We developed a transgenic mouse with neuronal‐specific proteasome overexpression which, when crossed with a mouse model of AD, reduced mortality and diminished AD‐like cognitive deficits. To establish translational relevance, we developed a set of novel proteasome‐activating peptidomimetics based on modifications of proteasome binding fragments derived from the viral protein HIV‐1 Tat. These agonists stably penetrate the blood‐brain‐barrier and enhance 20S as well as 26S proteasome activity. We show that treatment with these agonists protects against cell death in a cell culture model of AD as well as both cognitive decline and mortality in fly and mouse models of AD. The protective effects observed from proteasome overexpression in our models appear to be driven at least in part by increased turnover of the amyloid precursor protein (APP) and β‐secretase enzyme (BACE1) by the proteasome.ConclusionWe conclude that the proteasome plays an important role in AD‐like progression. Furthermore augmentation of proteasome function is protective against AD‐like pathogenesis in diverse models of the disease, potentially representing a new therapeutic target for treatment of AD.
Big data and dementia in New Zealand
Authors: Yates Susan , Rodriguez Claudia Rivera , Martinez‐Ruiz Adrian , Coomarasamy Christin , Whittington Rosie , Krishnamurthi Rita , Cheung Gary , Kerse Ngaire , Cullum Sarah 
Published: December 2020

AbstractBackgroundResearch is increasingly looking at how routinely collected health and social care data can be used to influence policy and service design, however the accuracy of such data in New Zealand is not known. Estimates suggest there are 62,000 people living with dementia in NZ, projected to reach 170,000 by 2050, however these figures are extrapolated from overseas prevalence data and do not take into account a variety of factors including NZ’s unique demography, specifically Māori and Pacific Islanders who are at higher risk of dementia. Ideally, we would conduct a NZ based dementia prevalence study to obtain accurate data in all the major NZ ethnic groups, however the time and cost required to do this could be prohibitive. The use of routinely collected data may provide a cost‐effective alternative or parallel process to assess and monitor dementia in NZ, as well as examine other characteristics which potentially modify the risk of dementia and adverse outcomes. It is unclear whether routinely collected data is a good proxy‐measure, given approximately a third of people with dementia never receive a specialist diagnosis, dementia coding is poor even for those who are diagnosed, and there are inequities in how non‐European’s access services.MethodA small‐scale dementia prevalence study is currently being completed in two geographic areas of South Auckland. Interviews are being completed by bi‐cultural bi‐lingual interviewers in a number of different ethnic groups including Asian, Maori, NZ European, and Pacific Islanders. Routinely collected health and social care data for the same geographic areas are also being collected.ResultData collection is due to be completed in the first half of 2019, following which the sensitivity and positive predictive value of the routinely collected dataset will be assessed.ConclusionRoutinely collected data can be a rich source of information, particularly in populations which are little researched or where further information is needed. In NZ little is known about the extent of dementia, and whether this differs across the major ethnic groups. It is hoped that this research will provide a starting point for robust collection of dementia healthcare information in NZ.
Anemia and the risk of dementia in the oldest‐old: The Monzino 80‐plus population‐based study
Authors: Lucca Ugo , Tettamanti Mauro , Riva Emma , Mandelli Sara , Forloni Gianluigi , Galbussera Alessia A. 
Published: December 2020

AbstractBackgroundHemoglobin concentration tends to decline and prevalence of anemia to increase with age. In recent years anemia has been repeatedly linked to a number of adverse outcomes. Anemia has also been proposed as a potential risk factor for cognitive impairment and dementia. Chronic reduction of oxygen supply to the brain could account for this association. However, evidence from prospective population‐based cohorts is very limited. Aim of the present study was to investigate the association of anemia with prevalent and incident dementia among the oldest‐old participants in the Monzino 80‐plus study.MethodConsent to blood sampling was obtained in 1,115 participants in a door‐to‐door, prospective population‐based study on the prevalence and incidence of dementia among 80‐years and older residents in the province of Varese, Italy. Anemia was defined according to WHO criteria as a hemoglobin concentration <120 g/L in women and <130 g/L in men. Diagnosis of dementia fulfilled DSM‐IV criteria. Potential confounders included in "fully”‐adjusted models: age, sex, education, smoking history, alcohol consumption, hospital admission during the previous year, history of diabetes, hypertension, myocardial infarction, heart failure, respiratory failure, renal failure, stroke, TIA, parkinsonism, cancer.ResultParticipants were 90.3 (5.6) years old on average, 74.5% women, and had a mean (SD) 5.1 (2.5) years of education. 374 subjects (33.5%) were anemic. Mean hemoglobin concentration decreased and prevalence of anemia increased with age (both p<0.0001). Anemic oldest‐old had a lower mean MMSE score (18.3 ± 9.1) than non anemic (20.8 ± 8.0; fully‐adjusted p=0.0130). In univariate analysis, anemia status was significantly associated with increased odds of having dementia (OR: 1.62; 95%CI: 1.26‐2.08; p=0.0002). When adjusted for confounders, this cross‐sectional association was marginally non significant (fully‐adjusted OR: 1.339; 95%CI: 0.999‐1.794; p=0.0508). Over a 15‐year follow‐up period 318 subjects were diagnosed with dementia out of 614 participants without at baseline. Oldest‐old with anemia did not have a significantly increased risk of incident dementia with respect to those without (univariate analysis, HR: 1.12; 95%CI: 0.85‐1.46; p=0.4306).ConclusionIn the present prospective population‐based study in the oldest‐old, anemia was not significantly associated with an increased risk of developing dementia.
Using cohort data to emulate lifestyle interventions: Long‐term beneficial effects of initiating physical activity on cognitive decline and dementia
Authors: Leist Anja , Terrera Graciela Muniz , Solomon Alina 
Published: December 2020

AbstractBackgroundIntervention studies have shown beneficial short‐term effects of physical activity on cognitive decline and reduced risk of dementia. However, randomized controlled trial data of lifestyle interventions over long time spans are not available due to lack of resources, feasibility or ethical reasons. Drawing from the principles of emulating a ‘target trial’, which apply design principles of randomized trials to the analysis of observational data, cohort data of a large European survey were analyzed to understand the long‐term effects of physical activity changes.MethodBiennial assessments of the economic, social, and health situation of respondents aged 50 and older came from the Survey of Health, Ageing and Retirement in Europe (2004‐2017). Cognitive functioning (immediate recall, delayed recall, and verbal fluency) and self‐reported diagnosis of dementia were assessed at each follow‐up. The target trial included sedentary respondents at t1 who, at follow‐up (t2), stayed sedentary (“control group”) or newly reported vigorous physical activity more often than once a week (initiators, “treatment group”). Inclusion and exclusion criteria were implemented as close as possible to those of the FINGER trial. Inverse‐probability weighting accounted for the probability of initiating physical activity with a large set of predictor variables. Selecting respondents aged 50‐85 years old who met the target trial inclusion and exclusion criteria, assessments of cognitive functioning and self‐reported diagnosis of dementia were available for 8,781 respondents at t3 (on average 3.02 years later), 3,858 respondents at t4 (5.84 years), and 2,304 respondents at t5 (7.72 years). A total of 304 respondents reported a diagnosis of dementia.ResultInitiators of vigorous physical activity had higher cognitive functioning at two follow‐ups compared to non‐initiators (t3: “average treatment effect on the treated”, ATET=0.059, CI: 0.028, 0.090), which remained significant after implementing inclusion and exclusion criteria. Initiators had lower risk of dementia compared to non‐initiators at all three follow‐ups (t3: ATET=‐0.009, CI: ‐0.015, ‐0.005, relative risk decrease ‐46.7%), remaining significant after implementing inclusion and exclusion criteria.ConclusionEmulating a target trial showed long‐term benefits of initiating physical activity for cognitive functioning and dementia risk. Multidomain interventions related to nutrition, social, cognitive activities etc. can be similarly emulated.
Alzheimer‐like glucose hypometabolism predicts subsequent dementia in amyloid‐negative mild cognitive impairment
Authors: Malotaux Vincent , Dricot Laurence , Quenon Lisa , Ivanoiu Adrian , Lhommel Renaud , Hanseeuw Bernard 
Published: December 2020

AbstractBackgroundPatients with mild cognitive impairment (MCI) are at‐risk of progression to Alzheimer’s dementia (AD), particularly if they have elevated amyloid (Aβ), the hallmark pathology of AD. However, a proportion of Aβ‐negative MCI also progress to dementia in clinical practice. We sought to investigate (1) whether subthreshold Aβ load, brain metabolism, or atrophy could predict progression to dementia in patients with Aβ‐negative MCI, and (2) whether the regional pattern was distinct from patients with Aβ‐positive MCI.MethodSeventy‐nine older adults underwent [18F]‐FDG‐PET to estimate their brain metabolism, [18F]‐Flutemetamol‐PET to assess their Aβ load, and 3D‐T1 MRI. Aβ load was expressed in Centiloids and a threshold of 43 corresponding to visual assessment was used to define Aβ positivity. FDG data were expressed as Standardized Uptake Value ratios (SUVr) scaled on pons with partial volume correction. MRI‐PET co‐registration was performed with PetSurfer. Eight Aβ‐negative MCI progressed to dementia after four years. We compared their FDG and thicknesses maps to 25 Aβ‐negative normal older adults, 31 Aβ‐negative stable MCI, and 15 Aβ‐positive MCI who also progressed to AD dementia after four years. Demographics and follow‐up durations are provided in Table1.ResultSubthreshold Aβ did not predict progression to dementia among Aβ‐negative MCI (p=0.81). Vertex‐wise analyses highlighted temporo‐parietal hypometabolism in the Aβ‐negative MCI who progressed to dementia, compared to stable Aβ‐negative controls (Fig. 1), and to a lesser extent compared to stable Aβ‐negative MCI patients (Fig. 2). However, their cerebral metabolism was similar to the one observed in Aβ‐positive MCI (Fig.3). Finally, the regional pattern of cortical thinning in progressive Aβ‐negative MCI was less typical of AD (Fig.4). Adjusting for age, sex, e4 status, or Aβ did not modify these observations.ConclusionTemporoparietal FDG predicts subsequent dementia in Aβ‐negative MCI patients, suggesting a close association with clinical progression. The FDG regional pattern is however not specific of Aβ pathophysiology.
Assessment of SORL1 rare variants segregation in Alzheimer disease families and in vitro models suggests diverse penetrance and oligogenic inheritance
Authors: Nicolas Gaël , Schramm Catherine , Miguel Laetitia , Lacour Morgane , Rousseau Stéphane , Wallon David , Charbonnier Camille , Zarea Aline , Campion Dominique , Rovelet‐Lecrux Anne , Lecourtois Magalie 
Published: December 2020

AbstractBackground
SORL1 rare (allele frequency <1%) loss‐of‐function (LOF) and missense predicted damaging (Mis3) variants have first been identified in early‐onset Alzheimer disease (EOAD, onset before 66 years) patients with a positive family history. However, segregation data in families are still missing to assess the actual pattern of inheritance. Since then, we and others have shown an increased burden of SORL1 rare LOF and Mis3 variants in EOAD patients, whatever the family history, and in late onset AD patients, with a lower effect size. In addition, although the interpretation of the biological effect of LOF variants is rather straightforward, no formal evidence of a functional effect of Mis3 variants can be inferred from bioinformatics predictions only.MethodWe gathered data from French families with a rare LOF or Mis3 variant and developed a cellular model to assess the role of SORL1 missense variants.ResultWe studied 20 families with a LOF variant (mean age at onset (AAO) in probands, 55.4 years, range: [48‐65]). Seventeen showed a positive family history. Mean AAO in affected relatives was 66.3 (range: [50‐80]). One patient carried two LOF compound heterozygous variants. DNA was available in 18 relatives: 5/6 affected relatives carried the familial variant (AAO = [61‐78]) while 3/12 unaffected were also carriers, aged 42, 71 and 95, respectively. Strikingly, 57% affected carriers were APOE4+ including one homozygous, who was also a carrier of a LOF rare ABCA7 risk variant.We developed a functional assay using CRISPR/Cas9 introduction of variants in iPSCs. We succeeded in introducing a homozygous LOF variant showing increased levels of Aβ in the supernatant. We are now inducing neuronal differentiation and introducing missense variants to better sort missense variants for penetrance studies and understand mechanisms. Interestingly, in one family with a Mis3 variant associated with increased Aβ secretion, the proband was APOE4+ and carried a LOF rare ABCA7 risk variant. Additional families and variants are currently being studied.ConclusionOur data support incomplete penetrance and oligogenic determinism in SORL1 families, making genetic counseling difficult. The development of cellular models will help us understand how and which missense variants result in reduced SORL1 functions.
Left amygdala volume moderates the relationship between nocturnal high‐frequency heart rate variability and verbal memory retention in older adults with amnestic mild cognitive impairment
Authors: Kong Shawn Dexiao , Hoyos Camilla M , Phillips Craig L , McKinnon Andrew C , Palmer Jake R , Duffy Shantel L , Mowszowski Loren , Lin Pinghsiu , Gordon Christopher J , Naismith Sharon L 
Published: December 2020

AbstractBackgroundNocturnal high‐frequency heart rate variability (HF‐HRV), an indicator of parasympathetic tone, is decreased in older adults with amnestic mild cognitive impairment (aMCI) during slow wave sleep. However, it is unclear whether or how this parasympathetic dysfunction relates to early cognitive decline. We therefore aimed to explore associations between nocturnal HF‐HRV during slow wave sleep and verbal memory retention in older adults at risk for dementia, and whether this relationship is related to amygdala volume, a sub‐cortical brain region linked to both verbal memory and parasympathetic modulation.MethodOlder adults attending a memory clinic for cognitive concerns (n=313, mean age 67 years, SD 8.51) completed medical and neuropsychological assessments (including Rey Auditory Verbal Learning Test to assess verbal memory retention). Participants were classified by clinical consensus as aMCI (n=99), non‐amnestic mild cognitive impairment (naMCI; n=134), or subjective cognitive impairment (SCI; n=80). Participants also underwent overnight polysomnography with continuous heart rate recordings. Power spectral analysis of HF‐HRV was analysed for slow wave sleep periods. T1‐weighted magnetic resonance imaging was performed in a sub‐set of participants (n=210) and amygdala (left and right) volumes were derived. All statistical analyses were adjusted for known confounders (age, education).ResultA significant association between lower slow wave sleep HF‐HRV and poorer verbal memory retention was evident in aMCI group (r=0.393, p=0.004) only, (SCI: r=‐0.092, p=0.464; naMCI: r=0.038, p=0.759). Multiple regression analysis (R2=0.440; p<0.001) revealed poorer verbal memory retention in the aMCI group was predicted by reduced HF‐HRV (7.5%), older age (6.3%), and lower levels of education (6.8%). While left amygdala volume (3%) did not independently predict verbal memory retention, a significant interaction indicated that those with larger left amygdala volumes and greater HF‐HRV had superior verbal memory retention (HF_HRV*left amygdala; 7.1%).ConclusionSpecific to older adults with aMCI, our data showed that parasympathetic modulation during slow wave sleep, particularly for those with larger amygdala volume, may play a key role in memory consolidation. Given that older adults with aMCI are at greater risk of developing dementia due to Alzheimer’s disease, reduced nocturnal parasympathetic activity may be an early marker of cognitive decline in Alzheimer’s disease.
Tau passive immunotherapy efficacy is modulated by antibody Fc domain
Authors: Nisbet Rebecca M. , Brici David , Götz Jürgen 
Published: December 2020

AbstractBackgroundPassive immunotherapy targeting tau is a promising strategy for the treatment of Alzheimer's disease. The proposed mechanisms of action for some tau antibodies is to engage with and clear extracellular pathogenic forms of tau, facilitated by microglial phagocytosis through antibody Fc receptor (FcR) binding. As FcR binding is mediated by the shape of the antibody Fc domain, this suggests that the antibody isotype affects the efficacy of these tau antibodies. We therefore aimed to directly compare the efficacy of a tau‐specific antibody cloned into a murine IgG1 framework, which has low‐affinity FcR binding, to that cloned into a murine IgG2a framework, which has high‐affinity FcR binding.MethodThe variable domains of our 2N‐tau specific antibody, RN2N (Nisbet et al., Brain 2017), were cloned into the murine IgG1 and IgG2a heavy chain frameworks. To investigate the ability of the two IgGs to stimulate microglial phagocytosis of recombinant tau, tau was labelled with pH‐Rodo and incubated with and without RN2N IgG, and then placed onto BV2 microglial cells. Phagocytosis was assessed by microscopy and flow cytometry. For the in vivo analysis, P301L tau transgenic pR5 mice were treated with 50 mg/kg RN2N IgG i.p. once a week for 10 weeks. Following treatment, brain pathology was assessed by western blot and immunohistochemistry.ResultAlthough the RN2N IgG1 and IgG2a had consistent binding affinities to tau, the RN2N IgG2a, which has a higher binding affinity to FcR, significantly increased the phagocytosis of extracellular tau compared to RN2N IgG1. In vivo, however, passive immunisation of pR5 mice with RN2N IgG1, but not RN2N IgG2a, reduced pathogenic tau levels in the brains of treated mice.ConclusionTaken together, our results demonstrate that although enhanced microglial activation via the RN2N IgG2a isotype increases extracellular tau phagocytosis in vitro, it is not required for antibody efficacy in vivo. This suggests that an antibody with a reduced affinity for FcRs may be beneficial in human clinical trials due to its low activation of pro‐inflammatory cytokine production. Furthermore, as RN2N‐mediated pathological tau reduction in this study was only minimal, targeting intracellular tau might be a better strategy.
Perspectives of people with dementia and family caregivers about dementia clinical research
Authors: Bouranis Nicole , Gelmon Sherril B , Lindauer Allison , Waddell Elizabeth N , Richardson Dawn M , Woo Hyeyoung 
Published: December 2020

AbstractBackgroundThe National Institute on Aging’s (NIA) national strategy to increase ADRD clinical research participation recommends continued research on identifying barriers and facilitators for ADRD study recruitment. This study builds upon its work by identifying factors affecting dementia research participation according to people with ADRD and their family caregivers in Portland, Oregon.MethodA community advisory board (CAB) comprised of clinicians, researchers, advocates, people with dementia, family caregivers, and older African Americans was established for this project. Semi‐structured dyadic interviews were conducted with individuals living with MCI or ADRD and their family caregivers, half of whom had participated in ADRD clinical research. Dyad members were interviewed separately. Interviews were audio‐recorded, coded and analyzed through thematic analysis where themes emerged from the data organically. The investigator was the single coder; the CAB interpreted findings by identifying what was most important, surprising, or missing from the interviews.ResultThere is a lack of knowledge about opportunities in the Portland area. Many interviewees were unaware of dementia studies, which was surprising as many interviewees were recruited from organizations with rich knowledge of research opportunities. One’s perceived value of ADRD research did not increase their likelihood of joining a study. Many caregivers either do not have or did not want to use limited free time to be a study partner; however, several caregivers noted that they would participate in the study if provided some sort of caregiver benefit to ease their burden, such as support, education, or respite. The number of people who avoid research because it involves taking study drugs was substantial among interviewees.ConclusionSeveral recommendations can be made based on this study. Researchers can partner with other healthcare and ADRD resource providers to share study opportunities. Study partners should be recognized as full participants who deserve compensation for their time and effort. Research organizations could develop strategies to remove or reduce the time spent and distance traveled in order to participate in research. Researchers could highlight the benefits of helping others by partnering with people with ADRD and caregivers to share the experience of participating in research.