bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA‐Binding Proteins Musashi and Tau Aggresome in Alzheimer’s disease
Authors: Montalbano Mauro , Aday Abbigael , Jerez Cynthia , Fung Leiana , Kayed Rakez 
Published: December 2023

AbstractBackgroundTauopathies, such as Alzheimer’s disease (AD), are characterized by the accumulation of toxic tau oligomers in the brain and accumulation of proteinaceous inclusions stored in cellular structures called aggresomes. Recent studies suggest that AD also exhibits pathology related to RNA binding proteins (RBPs), including Musashi proteins. Our lab has previously discovered that Musashi 1 (MSI1) and Musashi 2 (MSI2) aggregate in human AD brains and we have also visualized co‐localization with tau oligomers, suggesting toxic direct crosstalk between tau and MSI proteins. With this discovery and the growing evidence indicating MSI proteins as contributors to AD pathology, through their loss of functions it is crucial to elucidate how the interactions between misfolded tau and MSI influence tau aggregation and perhaps formation of cellular aggresomes.MethodIn this study, we characterize which tau oligomeric species, including phosphorylated and ubiquitinated ones, interact with MSI within the human AD brain (Braak Stage V‐VI). We investigate the deposition and cellular location of MSI and tau aggregates in AD and age‐matched control human cortical brain tissues by biochemical, immunohistochemistry and co‐immunofluorescence assays. Using high‐resolution microscopy and imaging analysis we measured the differences in size and morphology of MSI/tau co‐aggregates.ResultInvestigation of these co‐aggregates showed specific accumulation in neurons as well as in glial cells (astrocytes and microglia). We performed biochemical assays using commercial and in‐house antibodies to qualitatively investigate MSI1, MSI2, and tau across in AD brains. Co‐IF was performed to investigate the spatial and quantitative distribution of MSI1, MSI2, and tau aggregates. MSI/tau aggregate morphological characterization was conducted to profile their size and shape in AD cortices.ConclusionFor the first time, we show that the presence and quantity of tau oligomeric species and MSI co‐aggregates vary across the AD brains, showing inter‐subjects’ variability in size and deposition density. We also identify that tau conformers with MSI1 and MSI2 form different co‐aggregates in size and morphology quantifying their colocalization in high‐resolution 3D imaging. Further investigations are warranted to determine the temporal and regional distribution of these tau species in association with MSI proteins as well as the mechanisms underlying their aggregation.
Lessons from Covid‐19: A narrative and reflective practice review of non‐pharmacological treatments for agitation in Alzheimer’s dementia, in a time of social distancing
Authors: Ablett Annie , De Souza Stephen , Glass Rachel 
Published: December 2023

AbstractBackgroundAgitation as a behavioural and psychological symptom of dementia is common and distressing for patients and their carers. There are several non‐pharmacological approaches to managing agitation in Alzheimer’s Dementia (AD). Many of these require close interactions with the patient. However, social distancing during the coronavirus pandemic has made many of these interventions impractical. As busy clinicians working on a psychiatric unit managing AD patients with agitation, we wished to explore what we could offer in a time of social distancing. Our study sought to review the literature looking at the non‐pharmacological management of agitation in dementia and reflect on this as clinicians working amid a pandemic. While the pandemic recedes, this review and reflection still offers guidance for the management of agitation in AD whilst reducing the risk of disease transmission. The review would help to keep our most vulnerable safe during future outbreaks of infectious disease.MethodWe conducted a systematic review of the literature to identify non‐pharmacological treatments for the management of agitation in Alzheimer’s disease related dementia. Specifically, we sought evidence related to treatment in inpatient and care facilities. We appraised the evidence about these treatments. We then went on to use practitioner reflection on this evidence to consider the practicalities of implementation during the social distancing restrictions of the Covid‐19 pandemic.ResultMyriad non‐pharmacological therapies exist to help treat agitation in individuals with AD. Of these the evidence suggests music therapies and caregiver education interventions reduced agitation most significantly. We found that the most effective methods tailor treatment to the individual’s preferences and needs and use active engagement in therapies. Non‐group activities and those which do not involve shared equipment are most easily implementable during Covid‐19.ConclusionInterventions which are individually tailored to the patient and involve an active element to them are most effective, however those with an active element are less easily used during a pandemic. Given the evidence base and practicalities of implementation, our review suggests music therapy for those with agitation in AD.
Prevalence and type of subjective cognitive concerns among participants at baseline and their relationship to cognition and other factors
Authors: Farias Sarah Tomaszewski , Chan Michelle L , York Michelle , Sachs Bonnie C. , Cummings Tiffany , Krueger Kristin R , Hartman Elizabeth , Lee Athene KW , Whitmer Rachel A. , Leng Xiaoyan , Snyder Heather M , Baker Laura D , Papp Kathryn V. ,   the U.S. POINTER Neuropsychology Team for the U.S. POINTER Study Group
Published: December 2023

AbstractBackgroundThe U.S. POINTER study is a phase 3, multicenter, 2‐year randomized controlled trial (RCT) of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Inclusion criteria included specific risk factors (e.g., family history of dementia, vascular risk factors) but not subjective cognitive concerns (SCCs). However, SCCs are likely to be common in this group of at‐risk individuals. U.S. POINTER provides a unique opportunity to evaluate the prevalence of SCCs and their demographic and clinical correlates in an at‐risk group.MethodsRecruitment for the U.S. POINTER study is still ongoing, and the following is based on a partial sample. The sample includes 1811 U.S. POINTER participants with complete baseline data (collected by December 2022), mean age = 68.2y (SD = 5.2), 73.5% are female, 70.2% have18+ years education, and 29.3% are from underrepresented groups. SCCs were measured by the brief 12‐item Everyday Cognition (ECog) questionnaire which includes two items in each of 6 domains: everyday memory, language, visuospatial abilities, planning, organization and divided attention. Responses on the ECog range from 0 = no change/better compared to baseline, 1 = questionably/inconsistently worse, 2 = consistently a little worse, 3 = much worse. Neuropsychological performance was measured using a global composite and episodic memory, executive functioning, and processing speed composites. Other variables included demographics, depression (Geriatric Depression Scale total score; GDS) and sleep (Insomnia severity index (ISI)) and vascular disease burden index.ResultsThirty‐five percent of the cohort endorsed having a subjective complaint on the ECog (score ≥2 on any item). The most frequent complaint was “Remembering where I have placed objects” (23%). SCCs did not differ by age, sex or education. ECog‐12 Total were related to insomnia and depression (p<.0001). After adjusting for age, sex, education, vascular risk burden, GDS and ISI, greater SCC (ECog‐12 Total) was still associated with the global composite and all three domains (ps < 0.003).ConclusionsSCCs, particularly everyday memory complaints, were relatively common in this at‐risk cohort. While SCCs were related to depression and sleep, they were also independently associated with slightly worse cognitive function.
Implementation of cognitive screening in primary care: DIGITAL‐ Indiana University Health System and Indiana University – A Davos Alzheimer’s Collaborative flagship site program
Authors: Swartzell Kristen L , Willis Deanna R , Hammers Dustin B. , Brosch Jared R. , Murray James F , Fowler Nicole R 
Published: December 2023

AbstractBackgroundWith the emergence of novel therapeutics, the importance of early identification of people at risk of developing Alzheimer’s disease is more critical than ever. Most asymptomatic at‐risk individuals are primary care patients, who often have limited access to specialty care. Therefore, development of feasible, acceptable, and scalable ways to identify early cognitive impairment in the primary care setting is essential. The DAVOS Alzheimer’s Collaborative DIGITAL Demonstration Project was conducted to understand the feasibility, acceptability, and implementation of digital cognitive screening in primary care.MethodsPatients ≥65 years presenting for any issue to one of six Indiana University Health primary care sites between June and December 2022 were asked to complete the Linus Health Digital Clock and Recall (DCR™) cognitive assessment screening tool. Scores on the DCR™ range 0‐5, with 0‐1 categorized as cognitively impaired, 2‐3 as likely cognitively unimpaired, and 4‐5 as cognitively unimpaired. Data regarding number of DCR™ screening attempts that were refused, incomplete, or completed was collected. This pragmatic demonstration project allowed patients to be approached multiple times and complete the screening multiple times within the project time frame. Patients first completed screening test results were analyzed using descriptive statistics.ResultsOver the 7‐month project, 3,343 screening attempts were made. The screening test was refused by patients (54.6%) 1,825 times and was attempted but incomplete 64 (1.9%) times. 1,454 (43%) screenings were completed, which represents 1,405 unique patients. Among these, 172 (12%) scored positive for cognitive impairment, 506 (36%) scored likely cognitively impaired, 628 (45%) scored cognitively unimpaired, and 99 (7%) results were unanalyzable.ConclusionsUsing the DCR™, cognitive screening was successfully completed in nearly half of the primary care patients approached, regardless of their presenting concern, with 48% scoring either impaired or likely impaired. This cognitive screening approach appears to have utility in developing early detection for cognitive impairment in primary care, which will be an initial step towards identifying patients who could benefit from disease‐modifying therapeutics.
Design, synthesis, and biological evaluation of Propargylated phenyl‐styryl‐pyrimidine derivatives as dual inhibitors of monoamine oxidase and acetylcholinesterase
Authors: Jangid Kailash , Devi Bharti , Kumar Vijay , Kumar Vinod 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a neurological disorder, and its etiology is not completely known. Due to its multifactorial nature different theories were proposed for its initiation and progression including amyloid cascade hypothesis; tau hypothesis; cholinergic hypothesis, excitotoxicity hypothesis, mitochondrial cascade hypothesis. Various attempts are made, aimed to intervene with different target sites including amyloid‐β peptide (Aβ), acetylcholinesterase (AChE), tau protein, monoamine oxidase (MAO), β ‐site amyloid‐Precursor protein‐cleaving Enzyme 1 (BACE‐1), free radicals and metal ions (Fe2+, Cu2+, Zn2+), in order to control the AD. Previously approved drugs are based on the one drug one biological target strategy but over the past several years multi‐target directed ligands (MTDL) strategy has gained much interest in the development of effective inhibitors for the treatment of AD.MethodBased on our previous research work on MTDLs, in the current work we report the synthesis of phenyl‐styryl‐pyrimidine derivatives designed by taking pharmacophore from previously reported molecules and evaluated the effect of extended conjugation in pyrimidine functionalization against MAO‐B and AChE inhibition. In vitro Screening of the synthesized compounds as inhibitors of the cholinesterases and MAO enzymes using Ellman’s and Amplex red assay. This study is also supported by computational tools like‐ molecular docking, molecular dynamics, pharmacokinetics properties etc.ResultCompound VKB‐3 was found to be the most potent MAO‐B inhibitor with an IC50 value of 4.93 μM. Additionally, it exhibits strong inhibition of AChE, with an IC50 value of 9.016 µM. Similarly, compound VKB‐14, displayed inhibition for MAO‐B with an IC50 of 7.265 µM and for AChE with an IC50 of 9.291 µM. In the Lineweaver‐Burk reciprocal plots, both VKB ‐3 and VKB ‐14 exhibited hyperbolic non‐competitive type inhibition. In the docking studies, VKB‐3 and VKB‐14 displayed good affinity towards AChE (‐7.095 and ‐6.767 kcal/mol) and MAO‐B (‐8.548 and ‐11.20 kcal/mol), respectively. MD simulation study suggested that the compound VKB‐14 was able to form more stable complex with both the targeted proteins.Conclusion
VKB‐14 was found as potential lead, which showed good inhibition against both AChE and MAO‐B enzymes. It can be further optimized as MTDL for the treatment of AD.
Retinal phosphorylated tau correlates with the presence of microglia in Alzheimer’s disease and primary tauopathies.
Authors: de Ruyter Frederique J. Hart , Morrema Tjado , de Boer Johannes , Verbraak Frank D. , Bouwman Femke H. , Hoozemans Jeroen 
Published: December 2023

AbstractBackgroundPhosphorylated tau (p‐tau) is a hallmark of neurodegenerative diseases such as Alzheimer’s disease (AD). We recently showed that p‐tau in the retina was increased in the plexiform layers of the retina in patients with AD and other tauopathies[1]. Microglia, the resident immune cells of the central nervous system, have also been found to be activated in the retina of patients with AD. To obtain more insight in AD related changes in the retina we investigate the correlation between p‐tau and microglia in the retina of patients with AD and non‐AD tauopathies.MethodRetinal tissue samples were obtained from post‐mortem eyes of patients with AD (n = 16), primary tauopathies (n = 7) and non‐demented controls (n = 11). Immunohistochemistry was performed to detect p‐tau Ser202/Thr205 (AT8) and microglia in activated and resting state (IBA‐1). The mean positive pixel count in the inner plexiform layer (IPL) of p‐tau and microglia were analyzed using Qupath.ResultAs previously described[1], we found increased levels of p‐tau Ser202/Thr205 in controls with Braak NFT I‐III, AD and primary tauopathies. In the current study, p‐tau Ser202/Thr205 was correlated to microglia (IBA‐1). We found a positive correlation between p‐tau Ser202/Thr205 and microglia in the inner plexiform layer of the far (rs[46] = 0.29, p < 0.05) and mid periphery of the retina (rs[42] = 0.37, p < 0.05).ConclusionOur findings show a correlation between the presence of p‐tau Ser202/Thr205 and microglia as assessed with IBA‐1 in a cohort of non‐demented controls, AD cases and non‐AD tauopathies. These results suggest that microglia play role in retinal tau pathology, and support the strong connection between microglia activation and tau pathology as observed in the brain. The results of this study may provide new insights into the pathology of AD in the retina and provide opportunities for early detection and monitoring treatment of the disease.1. Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies. Acta Neuropathol, 2023. 145(2): p. 197‐218 https://doi.org/10.1007/s00401-022-02525-1.
Data‐driven neuroanatomical subtype trajectories of primary progressive aphasia
Authors: Taylor Beatrice , Bocchetta Martina , Shand Cameron , Todd Emily G. , Chokesuwattanaskul Anthipa , Crutch Sebastian J , Rohrer Jonathan D. , Warren Jason D , Hardy Chris JD , Oxtoby Neil P 
Published: December 2023

AbstractBackgroundPrimary progressive aphasia (PPA) is an atypical neurodegenerative dementia with three main clinical variants: semantic (svPPA), non‐fluent/agrammatic (nfvPPA) and logopenic (lvPPA). While svPPA is typically associated with left anterior temporal lobe atrophy, neuroimaging findings in nfvPPA, lvPPA and PPA not otherwise specified (PPA‐nos) are more variable. We therefore applied unsupervised machine learning to one of the largest databases of PPA magnetic resonance imaging (MRI) scans ever acquired.MethodBaseline MRI scans were collected from 273 people with PPA participating in the longitudinal research programme in the Queen Square Dementia Research Centre (svPPA n = 97; nfvPPA n = 109; lvPPA n = 51; PPA‐nos n = 16). Longitudinal scans were collected from 138 participants. We used Subtype and Stage Inference (SuStaIn), a model that combines disease progression modelling with unsupervised machine learning to identify subgroups of patients following a similar trajectory. We standardised the data with respect to cognitively normal controls (n = 360). Based on clinicians’ input we chose 19 brain regions of interest to model from those generated by GIF (Cardoso et al. 2012). The model was fit using baseline data, selecting the appropriate number of subtypes using cross‐validation (Young et al. 2018).ResultCross‐validation supported four subtypes of spatiotemporal atrophy (Figure 1). Clinical variant representation per subtype assignment (1/2/3/4) was: svPPA (n = 74/15/4/4), nfvPPA (n = 3/35/21/44), lvPPA (n = 1/18/30/2) and PPA‐nos (n = 7/4/3/2) (Figure 2). Subtype 1 showed early decline in the left anterior temporal lobe and sparing of the left frontal lobe. Subtype 2 showed early decline of the left insula and sparing of the temporal pole. Subtype 3 showed initial atrophy of the left temporoparietal junction; Subtype 4 showed early atrophy in the left precentral gyrus. Statistical analysis of posterior distributions found low similarity between subtypes (Hellinger distance > 0.66) (Figure 3), validating the presence of four distinct subtypes.ConclusionWhile the data‐driven atrophy subtypes did not align perfectly with clinical variants, we found a correspondence between Subtype 1 and svPPA, the most coherent PPA variant. Subtypes 2,3 and 4 were associated with nfvPPA and lvPPA, corroborating work suggesting these diagnostic terms encompass multiple clinical phenotypes. Future work will investigate the association between clinical diagnosis, longitudinal subtype, and clinical measures.
Reading between the lines: the association between education, literacy, and dementia in a cohort of older South African adults
Authors: Gao Sarah , Bassil Darina T. , Farrell Meagan T. 
Published: December 2023

AbstractBackgroundThe relationship between education and cognitive function in later life has been widely studied, yet it remains uncertain whether the association is due to a true protective effect of education or to test‐taking skills developed through formal education. Literacy, as an objective measure of learning, may clarify this relationship, particularly in low‐ and middle‐income countries (LMIC) where the effect of education may be influenced by school attendance and quality. This study aimed to investigate: 1) the concordance between subjective and objective literacy measures and educational attainment, and 2) the ability of literacy to predict cognitive outcomes.MethodThis study utilized data from Wave 2 of the Health and Aging in Africa: a Longitudinal Study of an INDEPTH Community in South Africa (HAALSI), a population‐based study in Agincourt, South Africa, and its dementia sub‐study (n = 559), collected in 2019‐2020 and 2018‐2019, respectively. Three measures of literacy (self‐report, short sentence reading, reading grade level test) were compared using Cohen’s kappa statistic. Multivariable seemingly unrelated regression (SUR) models were used to examine the association of literacy with cognitive test scores, adjusting for age, sex, and educational attainment. Additionally, multivariable logistic regression models were conducted to assess the independent effect of literacy on dementia risk, controlling for educational attainment.ResultThe Cohen’s kappa score between the three literacy measures was 0.615, indicating substantial agreement. The Cohen’s kappa score between the literacy measures and educational attainment was 0.608. SUR models revealed a statistically significant relationship (p‐value<0.05) between literacy and z‐standardized cognitive test scores in most tests. Literacy was associated with reduced risk of dementia beyond education, with a relative risk ratio of 0.13 (p‐value<0.001) for the literate vs. illiterate groups without education.ConclusionThis study highlights the importance of utilizing objective reading tests to measure literacy in populations, rather than relying solely on self‐reported literacy status. Results indicate that literacy is significantly associated with cognitive function, independent of educational attainment. This suggests that literacy skills acquired outside of formal education may reflect underlying protective factors, such as motivation and resilience, against dementia.
Negotiating Dementia care in networks of care: The effects of compounded disasters on social networks of care in rural Puerto Rico
Authors: de Victoria Patria C Lopez 
Published: December 2023

AbstractBackgroundAlready living through public health infrastructure cuts and austerity measures, Puerto Rico has experienced a multifaceted series of compounded disasters: hurricanes, earthquakes, and the ongoing COVID‐19 pandemic. These events have further exacerbated and disrupted the protocols and procedures employed by health and government officials in the care and support of caregivers and family members living with dementia. In the mountainous interior of the island, this has further been pronounced, where the roles and resources of healthcare professionals have been pressed and stretched. This study aims to explore the disruption to the social networks of health care professionals and social workers in the aftermath of these events.MethodNarrative interviews were carried out with 16 health care professionals and social workers who served as brokers—a link between groups, information and/or resources—to the citizens of various towns in the interior of the island of Puerto Rico. Grounded theory methodology was employed to explore changes within the network.ResultGaps in the networks of public health officials were identified, resulting in the emergence of multiple structural holes. These gaps were bridged by the local communities of health care and social workers, who were responsible for providing resources and support beyond those typically provided to the community. The bridging of these gaps—although at times limited—was crucial in order to ensure the provision of resources and support to caregivers of family members with dementia.ConclusionThe results reveal the diverse roles assumed by health care and social work professionals as intermediaries in the aftermath of compounded disasters. These findings provide insight into the necessary connections within the health care and local community that must be established to mitigate the effects of natural and human‐caused catastrophes. The understanding of the roles performed and assumed by these professionals can aid in the development of mitigation strategies that could improve the provision of resources and support to vulnerable populations of elderly living with dementia in future disaster situations.