bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Anthropometry Measures between Urban and Rural Aging Cohort in India
Authors: M Amitha C , L Abhishek M , Stezin Albert , Hameed Shafeeq K Shahul , Malo Palash Kumar , M Divya N , Partha Ajith , Menon Meenakshi , Narayanasamy Rajitha , R Meghana , Velavarajan Goutham , Diwakar Latha , Kommaddi Reddy Peera , Singh Sadhana , Arvind Prathima , HS Sunitha , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: December 2023

Background

Anthropometric characteristics of individuals and populations are simple and strong predictors of nutrition, future ill health, functional impairment and mortality (WHO‐TRS 854). Our objective was to observe differences in various anthropometric measurements between urban and rural aging participants in India. The Tata Longitudinal Study of Aging (TLSA) and Srinivaspura Aging Neurosenescence and COGnition (SANSCOG) study are ongoing, large‐scale, prospective, population‐based cohort studies in urban and rural India respectively (Sundarakumar J et.al 2020).

Method

A cross‐sectional comparative study that included 1089 urban and 4913 rural participants of both the genders aged 45 years and above were selected from ongoing TLSA and SANSCOG studies. Anthropometric measurements such as Height, Weight, Waist circumference, Hip circumference, Waist‐Hip ratio, Waist‐Height ratio, Body fat and Visceral fat of both the groups were obtained through a structured clinical protocol by trained physicians and nurses and Tanita body composition analyzer. Chi‐square and Mann Whitney U tests were used to analyze the results as the data was not normally distributed.

Result

Urban participants were older and had more years of education. The proportion of males and females did not differ between both cohorts as shown in Table 1. Mann‐Whitney U test was conducted to determine whether there was a difference in various anthropometric measures between Urban and Rural cohorts. The results indicate significant difference between the groups as shown in Table 2.

Conclusion

Urban participants were observed to have comparatively high range of anthropometric measurements compared to rural participants. This difference may be because mean age of rural cohort was less where they mostly engage in more physically demanding occupation such as farming while their urban counterparts were elder and may engage in sedentary occupation.
Investigating how telephone‐based mindfulness training impacts family conflict and communication for rural African American dementia caregivers
Authors: Shafer Jennifer Suzanne , Harr Elondra , Roth Isabel , Faurot Kim
Published: December 2023

Background

Older African Americans (AA) are disproportionately affected by Alzheimer’s disease and related dementias (ADRD). In turn, AA ADRD caregivers are more likely to provide in‐home care while being less likely to use respite services as compared to White caregivers. Caregiving for people with ADRD is associated with considerable physical, financial, and emotional strain (Alzheimer’s Association, 2022). Mindfulness‐based interventions (MBI) can be effective at addressing these issues for ADRD caregivers and have been found to be culturally acceptable for AA caregivers (Woods‐Giscombé et al., 2014). However, few studies have tested targeted MBI on rural AA caregivers. As part of a broader study, we investigated the effects of a telephone‐delivered MBI on AA ADRD caregiver burden and relevant secondary outcomes for both caregiving team members. The purpose of this study is to explore how mindfulness training impacts family conflict within the informal caregiving team.

Method

Primary caregivers and care partners of people with dementia participated in an eight‐week MBSR training program consisting of eight telephone‐delivered, instructor‐led classes and one virtual retreat. Post‐participation interviews with study participants (n = 51) were analyzed using Atlas.ti to assign descriptive meaning to sections of the data. After all codes were finalized, a detailed codebook was created, which included each code, its definition, and an example quote, along with any comments.

Result

Our analysis revealed four key themes illustrating how the mindfulness intervention served to positively impact family conflict and communication among participating caregivers. Mindfulness training: 1) is helpful in resolving present family conflict; 2) provides tools for future conflict resolution; 3) helps the caregiver feel more present/in control despite family conflict; and 4) enriches already positive family connections.

Conclusion

Nearly all caregivers described the intervention as being helpful in resolving current family conflict, and those caregivers who did not endorse present family conflict stated that the mindfulness training provided tools for alleviating future conflict should it occur. Most caregivers reported that the intervention helped them to feel more present and better able to work through conflict when family miscommunication did occur. Similarly, caregivers confirmed that mindfulness training acted to reinforce already positive family connections.
The Alzheimer multifactorial therapeutic agent E2F4DN prevents long‐term potentiation and cognitive loss and improves neuronal survival in homozygous 5xFAD mice
Authors: Sanchez‐Puelles Crisitna , Fraj Alberto , Cano‐Daganzo Vanesa , Garrido‐García Alberto , Perea Gertrudis , Frade Jose María
Published: December 2023

Background

Despite many decades of work, we still lack effective therapies against Alzheimer’s disease (AD), likely due to its complex etiology, which requires a multifactorial therapeutic approach. Among the variety of proposed etiological factors, synaptic failure has proof to be an early hallmarks of AD (Nat. Neurosci. 2016;19:443‐453), which precedes neuronal‐death (J. Neurosci. 2006;26:10129‐10140). We have recently shown, using both transgenic mice and gene therapy, that E2F4 is a multifactorial therapeutic target against AD (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐3039), likely due to its homeostatic function (Int. J. Mol. Sci. 2022;23:12093). The phosphorylation of two conserved Thr residues of E2F4 is necessary to induce cognitive loss in AD (Neurotherapeutics 2021;18:2484‐2503). Therefore, we have developed a novel therapy consisting in neuronal expression of a dominant negative form of E2F4 (E2F4DN), which cannot be phosphorylated in the conserved Thr residues (Neurotherapeutics 2021;18:2484‐2503, Mol. Neurobiol. 2022;59:3016‐3039). In this work we wanted to verify whether the expression of E2F4DN could correct AD‐associated synaptic dysfunction and neuronal loss in 5xFAD mice, a known mouse model of AD.

Method

We expressed E2F4DN (intravenous administration of AAV‐E2F4DN) in 6 weeks old control and homozygous 5xFAD mice, and stereological, electrophysiological and behavioral studies were performed at 6 months. Cell counting was achieved by unbiased stereology in the CA1 hippocampal region. Cognition was analyzed through novel‐object location and contextual fear conditioning test. Synaptic function (basal synaptic transmission, presynaptic function and long‐term potentiation (LTP)) were measured by electrophysiological recordings of field excitatory postsynaptic potentials in hippocampal CA3‐CA1 synapses. Afterwards, the mechanism underlying memory recovery was evaluated analyzing protein levels of different subunits of the synaptic receptors AMPA and NMDA.

Result

E2F4DN expression in neurons prevents neuronal death in the hippocampus (CA1) of homozygous 5xFAD mice, reaching similar values of cell number and CA1 volume to those observed in control mice. Moreover, E2F4DN prevents LTP loss leading to cognitive improvement, as 5xFAD mice treated with our therapy present a noticeable improvement hippocampal‐dependent memory. This effect correlates with the increase of key LTP regulators.

Conclusion

E2F4‐Based Gene Therapy improves neuronal survival, LTP and cognition, being a safe multifactorial approach for AD treatment.
Acoustic stimulation during sleep predicts long‐lasting increases in memory performance and beneficial amyloid response in older adults
Authors: Wunderlin Marina , Zeller Céline J. , Teunissen Charlotte E. , Nissen Christoph , Klöppel Stefan , Züst Marc Alain
Published: December 2023

Background

Phase‐locked acoustic stimulation (PLAS) during slow wave sleep (SWS) is able to boost SWS and – as a downstream effect – improve sleep‐dependent memory consolidation. Due to an assumed bi‐directional link between SWS disturbances and memory decline in aging, older adults might benefit most from interventions targeting SWS improvements.

Method

Here, 32 healthy older adults (mean age: 68.9) were allocated to an intervention or control group and completed a three‐night protocol with either real‐PLAS (intervention group) or sham‐PLAS (control group), preceded by a baseline night with sham‐PLAS and an adaptation night. Memory was assessed across the intervention and at a one‐week and three‐months follow up.

Result

PLAS consistently induced an entrainment of slow oscillations (SOs) with stimulation‐locked increases in spectral‐power bands associated with sleep (SO, delta, and spindle power) as well as a global increase of 24% in the number of SO‐coupled spindles, a proposed mechanism for memory consolidation. The individual magnitude of the PLAS‐induced increases in spectral‐power bands and SO/spindle coupling strength predicted memory performance across the intervention and up to three months post intervention in a dose‐dependent manner. PLAS‐induced increases in memory performance were further associated with a direct beneficial change in plasma amyloid levels. Importantly, all results were exclusive to the intervention group.

Conclusion

We demonstrate for the first time that PLAS is associated with both long‐lasting benefits in memory and metabolite clearance in older adults, rendering PLAS a promising tool for the treatment of cognitive decline.
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

Background

Tauopathies, 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.

Method

In 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.

Result

Investigation 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.

Conclusion

For 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

Background

Agitation 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.

Method

We 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.

Result

Myriad 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.

Conclusion

Interventions 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

Background

The 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.

Methods

Recruitment 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.

Results

Thirty‐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).

Conclusions

SCCs, 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

Background

With 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.

Methods

Patients ≥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.

Results

Over 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.

Conclusions

Using 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

Background

Alzheimer’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.

Method

Based 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.

Result

Compound 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

Background

Phosphorylated 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.

Method

Retinal 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.

Result

As 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).

Conclusion

Our 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

Background

Primary 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.

Method

Baseline 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).

Result

Cross‐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.

Conclusion

While 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

Background

The 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.

Method

This 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.

Result

The 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.

Conclusion

This 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

Background

Already 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.

Method

Narrative 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.

Result

Gaps 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.

Conclusion

The 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.
A 5‐hydroxymethylation‐based clock derived from cell‐free DNA in blood reveals accelerated epigenetic aging in patients with Alzheimer’s disease
Authors: Zhang Zhou , Beadell Alana , Cui Xiao‐long , Capuano Ana W. , Bennett David A. A , He Chuan , Arvanitakis Zoe , Zhang Wei
Published: December 2023

Background

Environmental exposure and lifestyle factors can induce epigenetic aging acceleration that has been implicated in various complex diseases. Enabling technologies compatible with convenient biospecimens, e.g., 2‐3 mL of blood, will facilitate clinical application. Targeting 5‐hydroxymethylcytosines (5hmC), a stable and under‐investigated regulator in the human genome, may improve our understanding of epigenetic aging and its implications in Alzheimer’s disease (AD).

Method

Using our previously published genome‐wide 5hmC profiles derived from cell‐free DNA (cfDNA) in blood (∼1,200 healthy individuals [HEA], 48.2±10.9 yrs, 59.3% males, 2:1 randomization for training and testing) using the 5hmC‐Seal technique and next‐generation sequencing, a 5hmC‐based clock was constructed to characterize epigenetic ages (5hmC‐age). Epigenetic‐chronological age correlation, median error, and mean aging acceleration were evaluated. An independent set of cfDNA samples collected from 20 subjects (86.2±4.3 yrs, 60.0% males) with pathologically confirmed AD and 17 matched controls on chronological age, sex, and education (86.8±3.8 yrs, 58.8% males) without AD (non‐AD), from the Rush Memory and Aging Project, were employed to calibrate and examine epigenetic aging in AD.

Result

Chronological ages were found to be associated with the 5hmC modification levels of a significant proportion of genes in HEA, particularly those genes involved in immune response, inflammation, metabolism, and environmental exposure. An epigenetic clock comprised of ∼300 genes was then constructed. In HEA samples, we observed Pearson correlations of 0.88 and 0.65, median errors of 3.7 and 4.9 years, and mean aging accelerations of 0.03 and 0.57 years between chronological age and 5hmC‐age in training and testing samples, respectively, indicating that 5hmC‐age was a robust estimation of chronological age. In the independent small sample of AD and non‐AD subjects, a general acceleration of 5hmC‐ages relative to chronological ages was observed, with a calibrated mean aging acceleration of 2.55 years in persons with AD relative to non‐AD subjects.

Conclusion

The 5hmC‐Seal appears to provide a convenient tool to evaluate epigenetic aging in blood that may facilitate preventive and precision medicine. Specifically, accelerated epigenetic aging was found in AD, suggesting that epigenetic age assessed in blood may be a novel biomarker for this neurodegenerative disease. This study was supported partially by the NIH (RF1AG074549, R01AG17917).
Regional variation in diagnostic intensity of dementia among older U.S. adults: a cross‐sectional study
Authors: Bynum Julie
Published: December 2023

Background

Alzheimer’s disease and related dementias (ADRD) are known to be underdiagnosed; but little is understood about how the likelihood of obtaining a diagnosis varies across place or demographic subgroups. Using observed diagnosed cases from national billing data, we report variation by region, age, and race/ethnicity in newly diagnosed dementia cases taking into account underlying population risk.

Method

Among a 20% random sample of fee‐for‐service Medicare beneficiaries, we identified those who received a new ADRD diagnosis in 2019 using billing data. The rate of new ADRD diagnosis was estimated overall and by Hospital Referral Region (HRR) and stratified by age category (65‐74, 75‐84, ≥85) and by race/ethnicity. A measure of ADRD diagnosis intensity across HRRs was calculated as the observed‐to‐expected ratio (O:E ratio) of new cases; expected new ADRD cases for each HRR were estimated using Poisson regression adjusted for regional measures of education, population health (diabetes, obesity, and smoking), and diagnostic intensity for chronic illness. Among older Americans, the probability of receiving an ADRD diagnosis was estimated according to regional ADRD diagnosis intensity.

Result

3.0% (143,029 of 4,842,034) of older adults received a new ADRD diagnosis in 2019 and ranged from 1.7‐5.4% across HRRs (Figure 1). The unadjusted mean ADRD diagnosis rate was 2.9 per 100 and differed by age (age ≥ 85 = 8.8/100, 75‐84 = 3.4/100, and 65‐74 = 1.0/100, p<.001) and race (White = 2.9/100, Black 3.4/100, and Hispanic 2.8/100, p<.001). Variability across HRRs was largest among the youngest age category, Black, and Latino groups. In adjusted analyses, all the regional characteristics explained 33% of the variation in new ADRD diagnosis (pseudo‐R2 = 0.33). Adjusted for regional characteristics, the ADRD diagnosis intensity (i.e., O:E ratio) varied from 0.7 to 1.4 across HRRs overall (Figure 2) and was most variable among the youngest age category (65‐74), Black, and Latino groups. These groups also had the greatest difference in the likelihood of diagnosis if residing in low versus high ADRD diagnosis intensity (Figure 3).

Conclusion

The likelihood of receiving an ADRD diagnosis varies across the U.S., particularly among those 65‐74 years of age, and Black, and Latino groups.
Temporal lobe function during memory encoding in older individuals prior to the onset of cognitive impairment
Authors: Beason‐Held Lori L , Shafer Andrea T , Calcagno Nicole , Kitner‐Triolo Melissa , Resnick Susan M.
Published: December 2023

Background

Previous studies have shown that resting state brain function begins to change in the years leading up to the development of cognitive impairment. This study examines temporal lobe function during memory encoding approximately 2.5 years before the onset of cognitive impairment in Baltimore Longitudinal Study of Aging (BLSA) participants.

Methods

BLSA participants with subsequent memory impairment (Subsequently Impaired (SI), n = 22, mean age = 83.6, time to impairment = 2.5 ± 1.1 SD years post‐scan) and age, sex, and education matched cognitively normal participants (Cognitively Normal (CN), n = 64, mean age = 84.9) performed a face‐scene encoding task during fMRI scanning. Group differences in task performance and brain activation patterns were examined during encoding trials they later remembered, and trials they later forgot during the recognition phase of the task.

Results

The SI group performed more poorly than the CN group during the recognition phase of the task. Both CN and SI activated the occipitotemporal visual pathway during memory encoding. Yet relative to CN participants, the SI group showed decreased activation of the hippocampus, entorhinal cortex, parahippocampal gyrus, and fusiform gyrus during encoding of face‐scene pairs. This decreased activation was seen during both encoding of pairs they later remembered and pairs they forgot during recognition.

Conclusions

Both memory dysfunction and decreased temporal lobe activity during encoding begin before the onset of clinically evident cognitive impairment. In the SI group, the decreased temporal lobe activation was seen regardless of whether they later remembered or forgot the face‐scene pairs during the recognition task. This suggests that those who go on to develop impairment have an overall weaker functional response in temporal lobe regions during memory encoding. Further examination of the functional connectivity of these regions may help to determine if differences in brain network characteristics are related to subsequently remembered or forgotten visual stimuli during encoding.

This work was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Geographic variation of prevalence of Alzheimer’s Disease and related dementias in the Central Appalachian region of the United States
Authors: Wing Jeffrey , Rajczyk Jenna , Burke James
Published: December 2023

Background

Areas within the Appalachian region may have a greater burden of under diagnosed Alzheimer’s disease and related dementias (ADRD). As rural areas have lower reported ADRD prevalence compared to urban areas in spite of lower educational attainment (which should lead to higher ADRD prevalence) this argues that the true burden of ADRD is likely underestimated in areas without adequate detection resources. There is need to understand if ADRD prevalence is truly lower in rural areas, or if this is a disease detection difference. The objective of this proposal is to assess the burden of ADRD in Central Appalachia.

Methods

Centers for Medicare and Medicaid Services Public Use Files from 2015‐2018 were used to estimate county‐level ADRD prevalence among all fee‐for‐service beneficiaries in Central Appalachia (Kentucky, North Carolina, Ohio, Tennessee, Virginia, and West Virginia). Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission’s Appalachian/non‐Appalachian designation, and by rural/urban (Rural‐Urban Continuum Codes) classification. Models were then adjusted for county‐level demographics including age, gender, Medicaid eligibility, and comorbidities (atrial fibrillation, chronic kidney disease, depression, diabetes, heart failure, hyperlipidemia, hypertension, ischemic heart disease, schizophrenia/other psychotic disorders, and stroke).

Results

The prevalence of ADRD did not vary over the time period but was higher for Appalachian counties both overall (12.0% vs. 11.6%; p = 0.001; Figure 1) and among both urban (p<0.001) and rural counties (p = 0.024; Figure 2). Urban Appalachian counties had 2‐4% higher prevalence compared to urban non‐Appalachian counties with this difference reaching statistical significance in 2017 and 2018. While a similar trend was observed in rural counties (Appalachian counties having 1‐3% higher prevalence), these yearly ratios did not reach statistical significance. After adjustment, the associations attenuated in urban counties, but over the entire study period, rural Appalachian counties had 2.2% higher prevalence than rural non‐Appalachian counties (Figure 3).

Conclusion

There is a consistent difference between Appalachian and non‐Appalachian counties, demonstrated overall and by rural status, with Appalachian counties having ADRD prevalence in the range of 1.0‐4.5% higher than non‐Appalachian counties. However, while county‐level demographics and comorbidities explained the difference in urban counties, the elevated prevalence in rural‐Appalachian counties persisted.
Design, Molecular Docking, Synthesis and Evaluation of Xanthoxylin Hybrids as Dual Inhibitors of IL‐6 and Acetylcholinesterase for Alzheimer’s Disease
Authors: Kaur Sukhvir , Bansal Yogita
Published: December 2023

Background

IL‐6 and AChE play a pivotal role in progression of AD, it is hypothesised that simultaneous inhibition of IL‐6 and AChE may prove as an effective strategy for treatment of AD. Therefore, the present study is undertaken to design novel molecules capable of acting as dual inhibitors of IL‐6 and AChE. Literature review reveals that xanthoxylin and a disubstituted amines or a carbamoyl amines are pharmacophores for IL‐6 and AChE inhibition, respectively.

Method

Xanthoxylin is coupled with various disubstituted amines or carbamoyl amines through alkyl linkers of different lengths (1‐4 carbon atoms) to design two series of 80 compounds. All designed compounds were docked into AChE to identify the best fit compounds for synthesis and evaluation of AChE inhibitory activity. The compounds showing >45% inhibition of EeAChE are selected for evaluation of IL‐6 and butyrylcholinesterase (BuChE) inhibitory activities. The compound found to be most potent against AChE, BuChE and IL‐6 inhibition was finally evaluated in vivo using STZ‐induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg).

Result

Compound K13g is found to be the most potent inhibitor of EeAChE, BuChE and IL‐6. It is further evaluated in vivo, wherein it shows dose‐dependent effects. It is observed to be less active at lower doses, but completely reversed the STZ‐induced memory deficit at 0.8 mg/kg.

Conclusion

The findings suggest that a compound having a xanthoxylin moiety connected to a piperazine ring through a three‐carbon atom chain may provide a useful template for the development of new chemical entities effective against AD.