bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking molecular abnormalities to balance deficits using a zebrafish model for tauopathies
Authors: Zhu Yunlu , Leary Paige , Bai Qing , Burton Edward A , Schoppik David 
Published: December 2022

AbstractBackgroundThe ability to maintain balance is an evolutionarily‐conserved behavior that is frequently disrupted found in patients with neurodegenerative diseases. One of the most prominent balance disorders is found in patients with progressive supranuclear palsy (PSP), a primary tauopathy pathologically characterized by tau over‐representation in the brainstem vestibulospinal (VS) nucleus, where they frequently exhibit accidental‐backward falls starting from the early stage of the disease. Although pathological features of PSP correlate well with its clinical phenotype, how tau aggregation affects neuronal and circuit functions, which eventually leads to behavioral deficits, remains unclear.MethodTo dissect disease mechanisms across molecular, cellular, circuitry, and behavioral levels, we generated tau fish by expressing human 0N/4R‐Tau in zebrafish VS nucleus. Tau expression and phosphorylation were validated using immunohistochemistry staining with PHF‐1 antibody. To examine the effect of tau on balance behavior, we measured postural control of free‐swimming tau fish and compared to that of tau‐negative siblings. Moreover, we tested response of VS neurons to nose‐down and nose‐up tilt stimulus using 2‐photon calcium imaging.ResultTtau‐expressing zebrafish exhibit impaired balance control while maintaining normal locomotor ability. Interestingly, we did not observe any neuronal death in the VS nucleus. Functional imaging of the VS nucleus shows impaired directional tuning in tau‐expressing neurons in response to tilt stimulus. We also found ectopic accumulation of acidic organelles in the cell bodies of tau‐positive neurons, suggesting abnormal lysosomal function.ConclusionOur results demonstrate how molecular abnormalities disrupt specific behavior in tauopathies before neurodegeneration appeared.
Facilitators and Barriers of Social Participation of Older Adults: Systematic Review of Qualitative Studies
Authors: Lee Hamin , Park Hae Yean , Lim Young Myoung , Park Sun Ha , Kim Mi Kyeong 
Published: December 2022

AbstractBackgroundAs the population of older adults is increasing, the number of older adults exposed to vulnerability of social isolation is also growing. It has been reported that maintaining regular level of social participation in old age is closely related to health, well‐being and cognitive benefits. Previous studies on factors that affect older adults’ social participation have mainly focused on logistical barriers. However logistical barrier alone is not sufficient to understand the factors of older adults’ social participation. The purpose of this study is to systematically examine the facilitators and barriers of older adults’ social participation, and to present basic data that comprehensively consider the individual, environmental and social contexts to promote the older adults’ social participation.MethodThrough PubMed, Embase, Cochrane, data from 2012 to 2022 was collected. The main keyword search terms were ‘elderly’, ‘older adults’, social participation’, ‘engagement’, ‘motiv*’, ‘barrier’, ‘facilitat*’. 7 articles that satisfy the inclusion criteria were selected for analysis.ResultIn the results, the activities the older adults are participating were related to religious activities, volunteering, socilaizing, leisure and ICT. The factors promoting and hindering social pariticpation of the older adults were analyzed. The analyzed factors were assorted into ‘personal/ internal factors’, ‘environmental facotrs’, ‘social network factors’. Facilitators included the desire for belongness, the desire to give back to society, interest, and interaction with a special person. Barriers included environmental accessibility, uniteresting activities, fear, lack of ability to maintain social relationships, and economic difficulties. Factors that either facilitated or hindered social participation included socioeconomic status, infrastructure accessibility, presense of supporters, religion and ethnicity. The results of this study emphasize that not only logistical factors, but also motivation, desire, social context of older adults’ can promote or inhibit their social participation.ConclusionAs ageing population increases, the number of older adults who are vulnerable to social isolation is also increasing. To prevent this, a broad understanding of what promotes and inhibits the participation of the older adults is needed. In this study, facilitators and barriers of older adults social participation were comprehensively identified.
Bioequivalence and safety comparison of once‐weekly donepezil transdermal system with oral donepezil: results of a phase 1 pharmacokinetic study in healthy volunteers
Authors: Tariot Pierre N. , Braeckman Rene , Oh Charles 
Published: December 2022

AbstractBackgroundOral donepezil, a reversible acetylcholinesterase inhibitor, is a widely prescribed treatment for dementia of the Alzheimer type. Dose escalation of oral donepezil can result in gastrointestinal distress, leading to treatment discontinuation, which emphasizes the need for a transdermal system (TDS). Donepezil TDS (Adlarity®) was recently approved for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type.MethodsAn open‐label, randomized, crossover, 3‐period trial (NCT04617782) with healthy volunteers (aged 18‐55 years) was conducted to assess bioequivalence of once‐weekly 10‐mg/d and 5‐mg/d donepezil TDS with once‐daily 10‐mg oral donepezil. All participants received 5‐mg/d donepezil TDS during the 5‐week Period 1, followed by 10‐mg/d TDS or 10‐mg/d oral donepezil in the 5‐week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state in Week 5 of each treatment. Safety and tolerability were also evaluated.ResultsOf 60 participants enrolled, all received 5‐mg/d TDS, 55 received 10‐mg/d TDS, and 56 received oral donepezil. At steady state, adjusted geometric mean ratio (GMR; % [90% CI]) of TDS to oral donepezil for maximum plasma concentration and area under the plasma concentration versus time curve (0‐168 h) were 88.7 (81.7‐96.2) and 108.6 (100.5‐117.4) for 10‐mg/d and 86.1 (79.8‐92.9) and 105.3 (97.6‐113.6) for 5‐mg/d TDS (dose normalized). The 90% CIs for the GMRs were generally within the accepted 80%–125% range for establishing bioequivalence. Adverse events (AEs) were reported in 80% of participants—53.3% for the 5‐mg/d TDS, 54.5% for the 10‐mg/d TDS, and 57.1% for oral donepezil. Except for abdominal pain (5.5% vs 1.8%), fewer gastrointestinal AEs were reported with 10‐mg/d TDS than oral donepezil (constipation, 5.5% vs 17.9%; nausea 1.8% vs 30.4%; diarrhea 3.6% vs 12.5%), respectively. There were also fewer AEs of dizziness (3.6% vs 19.6%) and no incidence of somnolence (0 vs 10.7%) reported with TDS. No serious AEs, AEs leading to treatment discontinuation, or deaths were reported.ConclusionBoth donepezil TDS strengths were bioequivalent to oral donepezil on a milligram‐per‐day basis. The safety profile of donepezil TDS supports its use in treating dementia of the Alzheimer type.
Common vaccines and the risk of dementia: a population‐based study
Authors: Douros Antonios , Ante Zharmaine , Suissa Samy , Brassard Paul 
Published: December 2022

AbstractBackgroundThe growing evidence for an infectious etiology of dementia supports the investigation of immunization as a preventative intervention. Prior observational studies suggesting that common vaccines are associated with an up to 60% decreased risk of dementia had several methodological limitations. Thus, to provide evidence for this question, we assessed in a large population whether common vaccines are associated with a decreased risk of dementia.MethodWe conducted a population‐based cohort study with a nested case‐control analysis using the Gold and Aurum datasets from the United Kingdom’s Clinical Practice Research Datalink (CPRD). The study cohort included all dementia‐free individuals aged ≥50 years enrolled in the CPRD between January 1988 and December 2018, and followed until March 2021. Each case of dementia identified during follow‐up was matched on sex, age, cohort entry date, duration of follow‐up, and CPRD dataset with up to four controls randomly selected via risk‐set sampling. Conditional logistic regression yielded confounder‐adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of dementia associated with exposure to common vaccines (influenza, pneumonia, shingles, tetanus, diphtheria or pertussis) >2 years before the index date compared to no exposure to these vaccines during the study period. In sensitivity analyses, we applied a longer lag period (10 years) and used active comparators (participation in screening programs for breast and prostate cancer) to account for detection bias.ResultOur study cohort included 13,383,431 dementia‐free individuals aged ≥50 years, including 212,562 who developed dementia over a mean 10‐year follow‐up (mean age 70 years; 62% female). Exposure to common vaccines was associated with an increased risk of dementia (OR, 1.38; 95% CI, 1.36‐1.40), compared with no exposure, driven mostly by immunization for influenza (OR, 1.39; 95% CI, 1.37‐1.41). Applying a longer lag period (OR, 1.22; 95% CI, 1.20‐1.24) and using active comparators (versus breast cancer screening: OR, 1.34; 95% CI, 1.26‐1.42 / versus prostate cancer screening: OR, 1.22; 95% CI, 1.14‐1.31) slightly attenuated the risk increase.ConclusionOur large population‐based study showed no decreased risk of dementia associated with exposure to common vaccines. The observed increase in the risk is likely a result of detection bias.
Investigating the binding of high molecular weight tau to LRP1
Authors: Cooper Joanna M , Lathuiliere Aurelien , Dickson John , Glynn Calina , Fan Zhanyun , Donahue Cameron , Migliorini Mary , Hyman Bradley T. , Strickland Dudley K 
Published: December 2022

AbstractBackgroundThe spread of neurofibrillary tangle (NFT) pathology across the brain is a hallmark of Alzheimer’s disease (AD) and is thought to be driven by the cell‐to‐cell transport of seed competent tau protein. LRP1 is a receptor for tau that mediates tau uptake, degradation, and seeding of intracellular tau aggregation. We previously found that LRP1 binds recombinantly produced 2N4R tau with high affinity, and that phosphorylation on tau reduces its affinity for LRP1. However, it is unknown if LRP1 interacts with the soluble HMW forms of tau that drive tau seeding, and here we investigate LRP1 binding to HMW phospho‐mimetic tau or HMW tau isolated from AD patient brains.MethodWe recombinantly produced tau containing mutations to mimic phosphorylation patterns of high‐molecular weight (D20Q3) or low molecular weight (D8Q2) tau found in AD brains. Next, we measured their ability to bind purified LRP1 binding via surface plasmon resonance (SPR) and determined the ability of LRP1 expressed in cells to mediate 125I‐labeled tau internalization. We also investigate the binding of HMW pathogenic forms of tau as well as LMW forms of tau isolated by size exclusion chromatography from AD patient brain extracts to LRP1 using a novel SPR capture assay.ResultWe found that D20Q3 and D8Q2 tau bind LRP1 much weaker (Kd = 1249nM & Kd = 388nM, respectively) than unmodified 2N4R tau (Kd = 20nM). 125I‐labeled tau uptake assays indicate reduced uptake for both D20Q3 and D8Q2 tau compared to 2N4R tau. Finally, preliminary results demonstrate that LRP1 is able to bind pathogenic forms of HMW tau isolated from AD patient brains, although there appears to be variability from different patients and LRP1 may bind HMW tau weaker than LMW tau. Studies are underway to determine the affinity of these forms for LRP1.ConclusionOur results demonstrate that LRP1 binds pathogenic forms of tau, with significant variation seen between patients. Future studies will investigate if the affinity of these forms correlate with their ability to promote tau seeding.
An oligomer‐directed Aβ antibody decreases synaptotoxic oligomeric Aβ in brain and improves behavioral abnormality in humanized APP knock‐in mice
Authors: Liu Lei , Lawton Trebor L , Liu Wen , Cai Yuqi , Meunier Angela , Lauro Bianca , Jin Shanxue , Selkoe Dennis J 
Published: December 2022

AbstractBackgroundThere is strong evidence that soluble oligomers of amyloid beta protein (oAβ) help initiate the pathogenic cascade of Alzheimer’s disease (AD), which suggests therapeutic strategies targeting oAβ over monomeric or fibrillar Aβ. A new antibody, 71A1, is 1∼00‐fold more sensitive for oAβ than synthetic monomers. The material that 71A1 specifically immunoprecipitates from AD soluble brain extracts impairs synaptic function as much as does the full extract. In accord, pre‐incubating brain extracts with 71A1 neutralizes its synaptotoxicity. 71A1 has potentially unique activities against disease‐relevant oAβ, making it a novel candidate for treating AD.Methods15 mg/kg 71A1 or anti‐KLH (negative control) was administered i.p. to 45 humanized APP knock‐in mice (APPNLGF/NLGF) weekly from 8 to 20 weeks of age. Cognition was assessed by spontaneous alternation (Y‐maze). Brains were harvested at age 21‐wk for biochemical, electrophysiological and immunohistochemical analyses. Diffusible (“soaking”) extracts of the brains were prepared to measure monomeric and oligomeric Aβ using homebrew ultra‐sensitive assays. Aliquots of the same soaking extracts were used to treat wild‐type mouse hippocampal slices and measure long‐term potentiation (LTP) to assess synaptotoxicity in the APPNLGF/NLGF brains post‐treatment.Results71A1 recognized oAβ and neutralized its synaptotoxicity in APPNLGF/NLGF mouse brain extracts. 71A1 effectively treated male APPNLGF/NLGF mice, which improved cognition significantly. The antibody reduced brain Aβ (1‐42) and oAβ levels with a trend toward statistical significance. Mouse brains with less oAβ had less synaptotoxicity as assessed by LTP.ConclusionsThese results demonstrate 71A1 is an oligomer‐preferring monoclonal antibody as a therapeutic candidate for AD, decreasing brain oAβ and oAβ‐induced synaptotoxicity. We believe this provides the first proof‐of‐concept mouse trial using an antibody that has been carefully characterized as oAβ‐preferring. We observed 1) a correlation between oAβ concentration and its synaptotoxicity; and 2) that 71A1 ameliorated aspects of cognitive impairment in APPNLGF/NLGF mice by targeting oAβ.
Spatial‐temporal subtypes of amyloid deposition show distinct baseline and longitudinal cognitive profiles
Authors: Mastenbroek Sophie E , Salvadó Gemma , Alves Isadora Lopes , Wottschel Viktor , den Braber Anouk , Visser Pieter Jelle , Gispert Juan Domingo , Hansson Oskar , Barkhof Frederik , Ossenkoppele Rik , Collij Lyduine E. 
Published: December 2022

AbstractBackgroundWe recently identified three distinct spatial‐temporal trajectories of amyloid deposition through the application of a machine‐learning model (i.e., Subtype and Stage Inference [SuStaIn]) to amyloid positron emission tomography (PET) data. These included Frontal, Parietal, and Occipital subtypes, defined by the earliest regions to show abnormality. The current study aimed to determine whether these subtypes of amyloid accumulation hold value in predicting baseline and longitudinal cognitive functioning in addition to a validated measure of global amyloid burden, i.e. Centiloid (CL) units.MethodThe Frontal, Parietal, and Occipital subtypes were applied to the amyloid‐PET standard uptake value ratios (SUVr) of 2,510 subjects from 3 cohorts (ADNI, EMIF‐AD, OASIS‐3). Of these, 570 subjects with a high subtype probability assignment (>50%), assigned stage ≥ 1, and available cognition were included in the analyses. Subtypes were compared on global cognition and several cognitive domains including memory, attention, executive functioning, language, and visuospatial functioning. To assess whether subtype assignment added to baseline CL in predicting baseline and longitudinal cognition (range follow‐up=0.4‐11 years), linear models (predictors: subtype and CL) and linear mixed models (predictors: subtype*time and CL*time) were performed, respectively. All models were adjusted for baseline age, sex, education, and baseline cognitive stage.ResultParticipant characteristics are shown in Table‐1. The majority was assigned to the Frontal subtype (57%), followed by Occipital (22%) and Parietal (20%). After adjusting for baseline CL, the Occipital subtype showed lower baseline language scores than the Parietal subtype (β=‐0.34, p=.046) (Fig‐1A) and lower baseline attention scores than both Frontal (β=‐0.39, p=.047) and Parietal (β=‐0.73, p=.002) subtypes (Fig‐1B, Table‐2). In addition, the Occipital subtype declined faster over time on global cognition (Fig‐2A) and language (Fig‐2B) as compared to the Frontal (βglobal cognition=‐0.35, pglobal cognition=.007; βlanguage=‐0.10, planguage=.015) and Parietal (βglobal cognition=‐0.50, pglobal cognition=.002; βlanguage=‐0.13, planguage=.015) subtypes.ConclusionOur results show the added value of amyloid subtype assignment on top of CL measures on baseline and longitudinal cognition. Specifically, the Occipital subtype was associated with lower baseline performance and showed faster rates of cognitive decline. These findings suggest that subtype assignment based on amyloid PET might improve prognosis and patient stratification in clinical trials.
The CUL3 adaptor protein SPOP plays a role in tauopathy mechanisms
Authors: Eck Randall , Kraemer Brian C 
Published: December 2022

AbstractBackgroundThe pathological accumulation of the microtubule binding protein tau drives age‐related neurodegeneration in a variety of disorders, collectively called tauopathies. In the most common tauopathy, Alzheimer’s disease (AD), the accumulation of pathological tau strongly correlates with cognitive decline. The underlying molecular mechanisms that drive neurodegeneration in tauopathies remain unknown and no effective disease modifying pharmacological interventions for tauopathy currently exist.MethodsWe employed classical forward genetic approaches and identified multiple loss of function alleles in the C. elegans spop‐1 gene that ameliorate tauopathy, suggesting SPOP is required for tau mediated neurodegeneration. CRISPR based genome editing methodology enabled the generation of customized SPOP‐1 loss of function and null alleles. Molecular genetics, behavioral, neuronal reporter assays, and biochemical analyses were also employed to characterize the consequences of spop‐1 loss of function on tauopathy related phenotypes in model systems.ResultsKnockout of SPOP‐1 rescues tau mediated behavioral deficits caused by neuronal dysfunction in tau transgenic C. elegans. Biochemical analysis revealed that SPOP‐1 loss of function promotes clearance of phosphorylated and total tau species from C. elegans neurons, but no change in tau transgene mRNA levels. Tau transgenic animals exhibit obvious neurodegeneration of GABAergic neurons, but loss of spop‐1 rescues neurodegeneration. While SPOP functions as an CUL3 E3 ligase adaptor protein, CUL3 function is not required for SPOP loss of function rescue of tauopathy. Genetic epistasis analysis suggests the nuclear speckle resident poly(A) RNA binding protein sut‐2 and spop‐1 function in a parallel molecular pathway.ConclusionsSPOP is a novel modifier of tauopathy phenotypes. Combined with previous findings investigating ALYREF, PARN/TOE1, SUT‐1 and SUT‐2/MSUT2, this work suggests phase‐separated nuclear speckles are an important cellular site controlling susceptibility to pathological tau. Recent work showing SPOP modification of PR dipeptides derived from C9orf72 expansion suggests common pathways may be at work in the neurodegenerative molecular mechanisms of tauopathy and repeat dipeptides.
Topographical differences in white matter hyperintensity burden and cognition in aging, MCI, and AD
Authors: Kamal Farooq , Morrison Cassandra , Zeighami Yashar , Maranzano Josefina , Dadar Mahsa 
Published: December 2022

AbstractBackgroundWhite matter hyperintensities (WMHs) are pathological changes that develop with increased age and are associated with cognitive decline. Most research on WMHs has neglected to examine regional differences and instead focuses on using a whole‐brain approach. This study examined regional WMH differences and their association with different cognition domains in normal controls (NCs), people with mild cognitive impairment (MCI), and Alzheimer’s disease (AD).Methods
We included participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Few studies using ADNI data have examined the most recent cohort, ADNI‐3. Our study included datapoints from this recently released cohort. Participants were selected from ADNI and were included if they had at least one WMH measurement and cognitive scores examining global cognition (Alzheimer’s Disease Assessment Scale‐13), executive functioning (Trail Making Test‐Part B, and memory (Rey Auditory Verbal Learning Test). MCI and AD participants were included only if they were amyloid positive. A total of 1573 participants with 7381 follow‐ups met inclusion criteria. Linear mixed‐effects models were completed to examine group differences in WMH burden and the association between WMH burden and cognition in aging, MCI, and AD.ResultsPeople with MCI and AD had increased total and regional WMH burden compared to cognitively healthy older adults. An association between WMH and cognition was observed for global cognition, executive functioning, and memory in NCs in all regions of interest. A steeper decline (stronger association between WMH and cognition) was observed in MCI compared to NCs for all cognitive domains in all regions. A steeper decline was observed in AD compared to NCs for global cognition in only the temporal region.Conclusion
Including ADNI‐3 data in this study is a novel strength to this study. These results suggest WMH burden increases from aging to AD. A strong association is observed between all cognitive domains of interest and WMH burden in healthy aging and MCI, while those with AD only had a few associations between and WMH and global cognition. These findings indicate that WMH burden is associated with changes in cognition in healthy aging and prodromal AD but not AD.