bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma phospho‐tau predicts differences in white matter microstructural complexity and cognition in non‐demented older adults
Authors: Bender Andrew R. , Dubois Kelly N. , Grabinski Tessa , Peltier Scott , Giordani Bruno , Paulson Henry L. , Kanaan Nicholas M , Hampstead Benjamin M.
Published: December 2022

Background

White matter (WM) measures from diffusion magnetic resonance imaging (dMRI) are sensitive to Alzheimer’s disease (AD) pathology and cognitive impairment. Whereas most extant dMRI studies focused on uniformly‐oriented WM fiber tracts, variations in crossing fiber regions also show sensitivity to mild cognitive impairment (MCI) and AD diagnoses. Such crossing fiber alterations may reflect differential disease effects on constituent fibers, suggesting that quantifying crossing fibers may provide unique markers of early WM changes and neurocognitive risk in AD and MCI. Although few methods exist for quantifying crossing fibers, recent findings show older age is associated with increased microstructural complexity (CX) a novel method to characterize in crossing fibers. The present study evaluated CX in relation to variation in plasma AD biomarkers and cognitive performance in older adults without dementia.

Method

Data from 48 participants included clinical evaluation, neuropsychological assessment, dMRI neuroimaging and venipuncture. SIMOA assays quantified the AD plasma biomarkers Aβ42, Aβ40, and tau phosphorylated at threonine181 (pTau‐181). Participants were clinically characterized as cognitively normal (n=19) or with MCI (amnestic: n=18; non‐amnestic: n=11). Diagnostic groups did not differ with respect to years of age and education, systolic and diastolic blood pressure, proportions of men and women, proportions of APOE ε4 allele carriers, or plasma biomarker levels. Processing of dMRI data followed the MRtrix fixel‐based analysis (FBA) framework to estimate voxelwise CX data for all participants.

Result

Voxelwise regression of whole‐brain CX on pTau‐181 levels revealed a significant positive effect in the dorsal cingulum bundle and adjacent corpus callosum. Post hoc regression of mean CX sampled from significant voxels on pTau‐181 showed greater pTau‐181 level strongly predicts higher CX in this region (partial‐R=0.579, p<0.001), even while controlling for age, education, and Montreal Cognitive Assessment (MoCA) score. Path analysis linking pTau‐181 and cognition showed elevated circulating pTau‐181 levels strongly predict increased white matter complexity in mid‐cingulum bundle, which in turn predicts reduced cognitive performance on measures of working memory, list learning, and semantic fluency.

Conclusion

Microstructural complexity in crossing fiber WM regions provides a sensitive marker of early WM alterations associated with elevated plasma phospho‐tau and cognitive decrements in non‐demented older adults.
A new LC‐MS/MS assay for the quantification of Aβ40 and Aβ42 in plasma: validation and clinical performance
Authors: Weber Darren M , Kim Jueun C , Goldman Scott , Racke Michael K , Clarke Nigel J
Published: December 2022

Background

Early detection of Alzheimer’s disease (AD) represents an unmet clinical need. Cerebrospinal fluid (CSF) biomarkers can potentially fulfil this need, but specimen collection is invasive. Blood‐derived biomarkers are preferable, and several studies have shown an association between the Aβ42/40 ratio and amyloid PET status. However, blood diagnostic tests for AD are challenging due to interlaboratory differences in analytical techniques and preanalytical handling. Here we describe the development and validation of a LC‐MS/MS assay to quantify Aβ40 and Aβ42 from plasma and assess clinical performance.

Method

Aβ40 and 42 peptides were simultaneously immunoprecipitated prior to protein digestion and LC‐MS/MS analysis. Blood collection studies were conducted to determine the optimal specimen type, tube type, and storage conditions. Clinical validation studies were performed in a cohort of 209 clinically assessed individuals with PET data (67 cognitively normal, 66 with early MCI, 37 with late MCI, and 39 with AD).

Result

Both Aβ40 and 42 showed a linear measurement range of 10‐2500 pg/mL, with R2 values ≥0.99. Assay precision ranged from 2.6‐9.0% for Aβ40, Aβ42, and Aβ42/40. Plasma specimens were stable for up to 5 freeze‐thaw cycles, 6 hours at room temperature, 5 days refrigerated, at least 32 days frozen and 9 months at ultra‐low temperature. Compared to other tube types, blood collected in K2EDTA tubes had an average analyte response that was 1.6‐fold higher for both Aβ40 and 42 (range 1.4‐4.0 fold). Peptide recovery was higher in plasma than in serum (1.2‐1.4 fold higher for Aβ40 and 42). Variation in the internal standard signal, a measure of overall assay variability, was <10% for K2EDTA compared to >20% for other tube types (range 24.6‐33.3%). The test accurately differentiated PET‐positive from PET‐negative individuals (AUROC=0.862 95% CI 0.814‐0.910). At the Aβ42/40 cut‐point of 0.160, the assay has a sensitivity of 71% and specificity of 89% for detecting PET‐positivity, which is suggestive of AD.

Conclusion

We optimized the analytical performance of an LC‐MS/MS assay for plasma Aβ40 and Aβ42. Preanalytical factors, including specimen collection tube types, were key for reproducible and accurate quantification. Performance characteristics were similar to those reported in the literature using CSF specimens.
Longitudinal analysis of auditory dysfunction in Alzheimer’s disease mice 5xFAD
Authors: Na Daxiang
Published: December 2022

Background

There is no cure for AD at this moment. All available therapies require accurate diagnosis and staging of AD to ensure proper strategy. Current diagnosis methods rely on high‐cost technologies with radioactive agents, and those are not necessarily included in regular health screenings. Thus, a low‐cost, non‐invasive approach of AD analysis is in great need. The comorbidity between Alzheimer’s disease and hearing loss has been shown to be significant. Beyond hearing loss, AD patients also showed auditory processing disorders. However, it remains unclear if auditory deficits can be a good biomarker for AD analysis, especially for early stages.

Method

5xFAD animals were bred in CBA/B6 hybrid background to compensate the hearing loss deficits in C57/B6 strain and only F1 animals were used in this study. The auditory features were monitored by Auditory Brainstem Response (ABR) test and Distortion Product Otoacoustic Emission (DPOAE) test at 3, 6, 9 and 12‐month‐old, which correlate to young ‐ middle age of human lifespan. Their anti‐masking ability was evaluated by masking ABR and notched noise ABR in 3 and 12‐month‐old animals. Fluorescent immunostaining was performed to evaluate anatomical change in cochlea.

Result

AD animals showed accelerated age‐related hearing loss comparing to their WT littermates. The ABR threshold showed significant change at lower frequencies first, then extended to all testing frequencies. DPOAE threshold did not show significant change at any testing frequency. Aged AD animals showed significantly higher threshold increase in masking ABR and notched‐noise ABR. In addition to the increased hearing threshold, ABR waveform abnormalities were also observed in the AD animals. Longitudinal analysis revealed that ABR waveform abnormalities develop along with the progression of AD. Those abnormalities suggest auditory neuropathy and auditory processing deficits in AD animals. Histology analysis showed no significant change in synapse number or efference morphology.

Conclusion

Auditory dysfunction is a possible outcome of AD, and more likely reflecting the anatomical changes in central nervous system rather than periphery. Auditory dysfunction is a good candidate as a biomarker for AD progression at early stages.
Applying Data‐Independent Acquisition Mass Spectrometry on Cerebrospinal Fluid Samples from a Neurology Clinic for Biomarker Discovery in Alzheimer’s Disease
Authors: de Geus Matthijs B , Leslie Shannon N , Ramirez Christopher E. , Trombetta Bianca A. , Wang Weiwei , Lam Tukiet , Gotti Clarisse , Roux‐Dalvai Florence , Droit Arnaud , Nairn Angus C , Arnold Steven E. , Carlyle Becky C.
Published: December 2022

Background

Diagnosis of Alzheimer’s disease (AD) primarily relies on cognitive assessments combined with imaging and limited fluid biomarkers. These biomarkers do not correlate with cognitive prognosis. Analysis of larger sets of biomarkers could improve diagnosis and prognosis of AD and differentiate between comorbid pathophysiologies, and measure treatment efficacy. Here, we report analysis of a Data‐independent Acquisition (DIA) mass‐spectrometry method used to simultaneously quantify hundreds of proteins in a large‐scale patient cohort. We aim to define markers that are able to stratify and diagnose AD in this clinically complex cohort.

Method

Samples from 408 patients spanning various dementia diagnoses were collected from the Massachusetts General Hospital Lumbar Puncture clinic. The patient cohort consisted of ATN‐verified cognitively‐unimpaired (n = 81), mild‐cognitive impairment from AD (n = 116), mild‐cognitive impairment from other causes (n = 78), dementia from AD (n = 65) and dementia from other causes (n = 31). Samples were analyzed on an Orbitrap Fusion using a DIA method and raw files were searched using Scaffold‐DIA.

Result

Analyses of the method’s technical performance showed a median intrabatch CV of 24.7% which decreased to 17.5% after filtering for peptides expressed in 95% of all samples. The mean interbatch CV was 73.7% which reduced to 28.8% after ComBat batch‐correction. After filtering for missing values and selecting only the peptides with a mean intrabatch CV below 25%, our dataset consists of 1761 unique peptide sequences belonging to 516 proteins.

To determine the differential abundance of peptides we fit a linear regression model to the data. 572 peptides were found to be differentially abundant across all diagnoses compared to AD (padj < 0.05). 11 of these peptides belonging to 5 proteins (PKM, ALDOA, GUAD, BASP1 and CH3L1) were differentially abundant between AD and all non‐AD diagnoses, suggesting specificity for AD. PKM and ALDOA, are involved in regulation of balance between glycolysis and oxidative phosphorylation, potentially indicating a shift in brain metabolism in AD.

Conclusion

Technically robust unbiased mass‐spectrometry can highlight novel AD specific biomarkers which may reflect pathophysiological processes key to AD progression.
Supporting decision making among people living with dementia: Developing a DCE tool
Authors: Turner Anne M , Miller Lyndsey M. , Asirot Mary Grace , Sharma Rashmi
Published: December 2022

Background

Persons living with dementia (PLWD) face many decisions about transitioning to more supportive care as their disease progresses, but are often left out of the decision‐making process. The Decision‐Making in Alzheimer’s Research (DMAR) project is developing a tool, informed by stakeholder input, that uses images, story‐telling, and discrete choice experiments (DCEs) to unpack the preferences of PLWD about transitions in supportive care and facilitate their inclusion in the decision‐making process. This study describes the development and design of the DMAR tool.

Method

We conducted in‐depth interviews between September 2020 and December 2021 with 24 PLWD, 37 caregivers, and 18 direct care staff or providers to understand decisions that PLWD encounter as they transition to supportive care, and the related decision‐making factors. We recorded, transcribed, coded, and analyzed interviews for key themes and factors. We then used heat maps to determine the four key factors for making decisions about obtaining more supportive care.

Result

Decisions and roles in decision‐making differ depending on the stage of dementia. However, even persons with very early dementia had difficulty discussing plans regarding more supportive care. Early decision‐making centered on obtaining support around instrumental activities of daily living. Decisions to bring more supportive care into the home or seek supportive care outside the home were mentioned primarily by caregivers and staff members. Overall, the four most commonly mentioned factors influencing decision‐making were level of function, quality of life, out of pocket costs, and amount of supportive care

Conclusion

These four factors will be incorporated into a DCE tool to identify the relative importance of identified factors in making decisions regarding transitions to more supportive care. In this roundtable, we will further discuss plans to develop an electronically administered DCE tool to track the consistency of preferences of PLWD and their caregivers over time. We will also describe challenges encountered when eliciting preferences of PLWD, the role of technology in decision‐making, and creative methods, such as story‐telling and images, to enhance discussions with PLWD regarding supportive care.
Withdrawn: Glycine transporter 1 (GlyT1) is a novel therapeutic target for Alzheimer’s disease
Authors: Yoo Miran , Kim Seong Muk , Lee Juho , Kim Hye‐Ju , Park Seong Jeong
Published: December 2022

Withdrawal: Miran Yoo, Seong Muk Kim, Juho Lee, Hye‐Ju Kim, Seong Jeong Park “Glycine transporter 1 (GlyT1) is a novel therapeutic target for Alzheimer's disease” Alzheimer's & Dementia, Volume 18, Supplemental Issue 10.

The above abstract, published online on 20th December 2022, on Wiley Online Library (https://alz‐journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.064468) has been withdrawn by agreement between the authors, the Senior Director of Scientific Programs and Outreach, Claire Sexton, the Director of Scientific Programs at the Alzheimer's Association, Ozama Ismail, and John Wiley & Sons Inc. The abstract has been withdrawn at the authors’ request because the authors did not have Amyloid Solution's authorization to publish the information contained in it.
Dementia prediction in the general population using clinically accessible variables: a proof‐of‐concept study using machine learning. The AGES‐Reykjavik Study
Authors: Twait Emma L. , Navarro Constanza L. Andaur , Gudnason Vilmundur , Launer Lenore J. , Geerlings Mirjam I.
Published: December 2022

Background

Early identification of dementia is crucial for prompt intervention and better outcomes for high‐risk individuals in the general population. The use of machine learning in dementia prediction has allowed for highly accurate models that could aid in early classification; however, they have focused on expensive predictors. Exploring predictors that are more accessible is crucial for the possible widespread use of machine learning models in clinical practice.

Method

Data from 4,793 individuals without dementia or mild cognitive impairment at baseline were included from the population‐based AGES‐Reykjavik Study. Cognitive, biometric, and MRI assessments (total: 64 variables) were collected at baseline, with follow‐up of incident dementia diagnoses for a maximum of 12 years. Elastic net regression, random forest, support vector machine, Naïve Bayes, logistic regression, and elastic net Cox regression (for time‐to‐event analysis) were explored as possible algorithms. Model 1 was fit using all variables, model 2 after feature selection using the Boruta package, and model 3 without neuroimaging markers (clinically accessible model). Ten‐fold cross‐validation, repeated ten times, was implemented during training. Upsampling was used to account for imbalanced data. Tuning parameters were optimized for recalibration automatically using the caret package.

Result

During training, the Model 2 elastic net regression had the highest AUC [0.78; 95% CI: 0.76‐0.80], sensitivity [72; 95% CI: 68‐75], and specificity [72; 95% CI: 70‐73]. For Model 3, excluding MRI markers, the AUC remained high [AUC 0.75; 95% CI: 0.73‐0.77]. Similar results were found in our test data for Model 3 [AUC 0.74; 95% CI: 0.71‐0.77]; thus, the risk of overfitting was low. Time‐to‐event analysis using elastic net Cox models showed similar discrimination [c‐statistic 0.79] during testing. The most important variables based on Boruta selection included the Activities of Daily Living, presence of APOE e4 allele, memory functioning, and sex.

Conclusion

Supervised machine learning could be used to identify individuals at high‐risk for dementia in the general population using easily accessible variables. As dementia becomes a leading problem in developing countries, this clinically accessible model could be explored for use in these areas for better identification of individuals at risk in the community. Further external validation is needed.
Plasma glial fibrillary acidic protein, neurofilament light, phosphorylated‐tau‐181 and amyloid β42/40 as prognostic biomarkers for clinical progression to dementia in individuals with subjective cognitive decline and mild cognitive impairment
Authors: Honey Madison I. J. , Verberk Inge M.W. , Gouda Mariam , Hussainali Zulaiga , Kroeze Lior A. , van Leeuwenstijn Mardou , Mank Arenda , Trieu Calvin , Wilson David , Pijnenburg Yolande A.L. , van der Flier Wiesje M. , van Harten Argonde C. , Teunissen Charlotte E.
Published: December 2022

Background

Blood‐based biomarkers can provide a non‐invasive and accessible way to identify neurodegenerative diseases before the clinical onset of dementia. Our study aimed to examine whether levels of phosphorylated‐tau‐181 (pTau181), amyloid beta1‐42/1‐40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are associated with risk of developing dementia in a memory clinic population of individuals with either subjective cognitive decline (SCD) or mild cognitive impairment (MCI).

Method

From the Amsterdam Dementia Cohort we included 311 individuals with SCD (age 61±9 years, n=128 (41%) female, MMSE 29±1) and 252 with MCI (age 65±7 years, n=89 (35%) female, MMSE 27±2), who had annual follow‐up visits for re‐evaluation of diagnosis (average follow‐up duration: 2.7±1.7 years.) Baseline plasma biomarkers were measured using Simoa and the associations of the Z‐transformed biomarker concentrations with incident dementia were evaluated using Cox regression models adjusted for age, sex, baseline diagnosis and the interaction between baseline diagnosis (SCD/MCI) and the biomarker concentration. The markers were first evaluated individually and then simultaneously in a combined model. We stratified results for baseline diagnosis when the biomarker*diagnosis interaction was significant.

Result

During follow‐up, 94 individuals developed dementia (14 with SCD, 80 with MCI at baseline, 86 Alzheimer’s Disease, 8 other forms of dementia; average time to progression: 2.8±1.8 years). We found an interaction between baseline diagnosis and NfL for incident dementia (p=0.03). No other interactions were found. In the total set, both high baseline pTau181 (hazard ratio (HR)=3.4 (95%CI: 1.3–9.0); figure 1A), and high baseline GFAP (HR=5.5 (95%CI: 1.6–18.6); figure 1B) were associated with increased risk of dementia, but the association with Aβ42/40 was not significant (HR=0.4 (95%CI: 0.2–1.1)). NfL had no significant association with increased dementia incident risk in both SCD subset (HR=1.8, (95%CI: 0.9‐3.6)) and the MCI subset (HR= 1.3, (95%CI: 1.0–1.6)). When we simultaneously entered all biomarkers, pTau181 and GFAP remained significantly associated with incident dementia (table 1.)

Conclusion

Our results suggest that plasma GFAP and pTau181 have prognostic value to predict dementia in individuals presenting at a memory clinic.
Discovery of [18F]ACI‐12589, a Novel and Promising PET‐Tracer for Alpha‐Synuclein
Authors: Capotosti Francesca , Vokali Efthymia , Molette Jerome , Ravache Myriam , Delgado Christophe , Kocher Jacqueline , Pittet Laure , Vallet Coralie , Serra Andreia , Piorkowska Kasia , Dimitrakopoulos Ioannis K , Luthi‐Carter Ruth , Tsika Elpida , Touilloux Tanja , Hliva Valerie , Smith Ruben , Hansson Oskar , Streffer Johannes , Pfeifer Andrea , Kosco‐Vilbois Marie
Published: December 2022

Background

Parkinson’s disease (PD) and other synucleinopathies such as Multiple System Atrophy (MSA) involve a progressive accumulation of a‐synuclein (a‐syn) inclusions that correlates with disease stage and clinical manifestations. The development of a PET agent capable of imaging a‐syn inclusions would significantly aid in differential diagnosis, staging, and monitoring possible benefits of candidate therapeutic agents targeting a‐syn. Due to the generally lower pathologic burden of a‐syn inclusions relative to other brain proteinopathies, a reliable a‐syn PET tracer must display high binding affinity and selectivity for its intended target.

Method

Using our proprietary Morphomer® library of low‐molecular weight and conformation‐specific ligands, compounds with good affinity and target occupancy were identified. We then iteratively performed medicinal chemistry optimization cycles to further improve on‐target binding properties and selectivity based on radiobinding and classical and high‐resolution autoradiography results. Optimized compounds were then assessed further for off‐target activities and evaluated for their brain pharmacokinetic properties in non‐human primates (NHPs). The clinical candidate [18F]ACI‐12589 was subsequently advanced through preclinical assessment prior to evaluation in a clinically diverse set of synucleinopathy subjects and controls.

Result

Promising chemical scaffolds with high‐affinity binding to pathological a‐syn in tissue homogenates and sections have been optimized. Particularly, ACI‐12589 demonstrated improved target occupancy on different synucleinopathy samples, including PD and MSA, with a binding pattern aligning closely with the distribution of pathological a‐syn. Moreover, ACI‐12589 demonstrated selectivity for a‐syn versus other potential amyloid pathologies including amyloid‐beta, Tau, and TDP‐43. In NHPs [18F]ACI‐12589 revealed good brain uptake, homogenous distribution and fast washout. Initial results from the ongoing clinical trials confirm favorable pharmacokinetic parameters in patients, including rapid signal equilibration, potentially allowing short scan times. Moreover, initial clinical data in MSA patients indicate that [18F]ACI‐12589 uptake occurs in brain areas affected by the disease process based on clinical manifestations.

Conclusion

[18F]ACI‐12589 displays preclinical and clinical characteristics deemed necessary to become a reliable PET radiotracer for the imaging of a‐syn inclusions. Interestingly, ex‐vivo data from different synucleinopathy tissues is in accordance with the promising clinical data in MSA that will be presented by R. Smith et al. at this conference.
The Emory‐Sage‐SGC TREAT‐AD Center: Tool and probe development for emerging targets in Alzheimer’s Disease
Authors: Leal Karina , Axtman Alison D. , Betarbet Ranjita , Brennan Paul E , Carter Gregory W , Frye Stephen V. , Fu Haian , Greenwood Anna K , Longo Frank M. , Pearce Kenneth H. , Edwards Aled M , Levey Allan I. ,   the TREAT‐AD Consortium
Published: December 2022

Background

Alzheimer’s disease is the most common form of dementia and there is currently no effective therapy for either treatment or prevention. With repeated failure in DRUG DEVELOPMENT across industry and demonstrated heterogeneity in biological and genetic components of the disease, there is a need to evaluate a broad range of therapeutic hypotheses for target prioritization. The Emory‐Sage‐SGC TREAT‐AD Center (https://treatad.org) is generating and openly distributing validated experimental tools necessary to test target predictions generated through sequence‐based characterization of human disease state. We believe that these tools and reagents, including chemical and biological probes that target the multifaceted dysregulation in the brains of AD patients will advance the discovery of potential drug targets for AD.

Method

The Emory‐Sage‐SGC TREAT‐AD Center uses integrated computational approaches to identify target predictions from a set of prioritized therapeutic hypotheses. Emerging AD targets derived from systems biology studies within the Accelerating Medicines Partnership in AD (AMP‐AD) consortium and additional NIA‐supported AD consortia were mapped to 15 biological domains (BDs) and prioritized based on an unbiased bioinformatic assessment across multiple lines of evidence for overall AD‐risk. Targets are then evaluated to identify a set of experimental reagents necessary for hypothesis testing, termed a “target enablement package (TEP).

Result

Within these 15 biological domains, we prioritized more than 30 targets for target enabling package (TEP) development. TEPs include expression constructs, knockout cell lines, assays, antibody validation, and crystal structures. All reagents are developed to meet established quality criteria. For a subset of tractable targets (MSN, SYK, SFRP1, SDC4 and CAPN2), chemical probe development is underway to provide tools to test these therapeutic hypotheses in cellular and animal systems. TREAT‐AD investigators place all data, knowledge, reagents, and tools into the open domain with no intellectual property claims.

Conclusion

The open drug discovery approach of TREAT‐AD is aimed to de‐risk potential AD therapeutics to catalyze robust and independent evaluation of a diverse portfolio of promising yet untested AD therapeutic hypotheses. All data, protocols, reagent sets, and chemical tools will be made widely available on the AD Knowledge Portal. For more information see www.treatad.org.
Potent protein biomarker for Alzheimer’s disease based on translational research
Authors: Dey Sharmistha
Published: December 2022

Background

Alzheimer's disease (AD) is an accelerating neurodegenerative disorder. Dysfunction of mitochondria and oxidative stress contributes to the pathogenesis of AD. Sirtuins play a role in this pathway and can be a potential marker to study neurodegenerative changes

Method

This study evaluated serum levels of all seven sirtuins (SIRT1 – SIRT7) proteins in three study groups: AD, Mild Cognitive Impairment (MCI), and Geriatric Control (GC) by Surface Plasmon Resonance (SPR) technique. Further, it was validated by the Western blot experiment. ROC analysis was performed to differentiate the study group based on the concentration of serum SIRT proteins

Result

Out of seven sirtuins, serum SIRT1, SIRT3, and SIRT6 levels (mean+SD) were significantly decreased in AD (1.65±0.56, 3.15±0.28, 3.36±0.32ng/µl); compared to MCI (2.17±0.39, 3.60±0.51, 3.73±0.48ng/µl) and GC (2.84±0.47, 4.55±0.48, 4.65±0.55ng/µl). ROC analysis showed the cut‐off value with high sensitivity and specificity for cognitive impairment (AD and MCI). The concentration declined significantly with the disease progression. No specific difference was observed in case of other SIRTS between the study groups.

Conclusion

This study reveals an inverse relation of serum SIRT1, SIRT3, and SIRT6 concentration with AD. ROC analysis showed that these serum proteins have greater accuracy in diagnosing of AD. This is the first report of estimation of all seven serum sirtuins and the clinical relevance of SIRT3 and SIRT6 as serum protein markers for AD.
Language and Immigrant Status Differences in Neuropsychological Performance among Middle Eastern and North African Older Adults in Detroit
Authors: Morris Emily P. , Cooper Jasmine , Tarraf Wassim , Brauer Simon , Antonucci Toni C , Ajrouch Kristine J , Zahodne Laura B.
Published: December 2022

Background

Despite being one of the fastest growing ethnic groups in the U.S., little is known regarding neuropsychological testing among Middle Eastern and North African (MENA) older adults. This study aimed to examine the effects of language of test administration (i.e., English or Arabic) and immigrant status on neuropsychological performance among MENA older adults.

Method

Participants were from the Detroit Area Wellness Network‐COVID Study and were included if they identified as MENA and did not have dementia (N = 199). Participants completed questionnaires and brief neuropsychological tests (i.e., CERAD word list, animal fluency) over the phone. Participants were coded into three groups: U.S. born, tested in English (n = 35); foreign born, tested in English (n = 93); and foreign born, tested in Arabic (n = 71). A series of regressions with foreign‐born participants tested in English as the reference group examined group differences in animal fluency, immediate memory, and delayed memory across minimally adjusted (i.e., age, sex/gender), education‐adjusted (i.e., age, sex/gender, education), and fully adjusted (i.e., age, sex/gender, education, marital status, homeownership) models.

Result

Compared to both English testing groups, foreign‐born participants tested in Arabic were more likely to be married, were less likely to own homes, and had less education. Foreign‐born participants tested in English had less education than U.S.‐born participants tested in English but did not differ on other covariates. In minimally adjusted models, there were language differences in animal fluency, but not episodic memory, such that foreign‐born participants tested in Arabic performed worse than foreign‐born participants tested in English. This language difference was eliminated after adjusting for education. Performance differences as a function of immigrant status were identified for all cognitive measures, such that foreign‐born participants tested in English performed worse than U.S.‐born participants tested in English. These differences were attenuated but not eliminated in adjusted models.

Conclusion

These results support the comparability of neuropsychological tests administered in English versus Arabic, as language differences were limited and explained by education. Future studies should examine modifiable contributors to cognitive differences between U.S.‐ and foreign‐born MENA older adults, such as educational quality and immigrant stress.
Exploring facilitators and barriers to the implementation of routine delirium screening by nurses in acute geriatric wards: A survey using the theoretical domains framework
Authors: Wee Natalie Jian‐Ting , Siew Jozhi , Yap Philip Lin Kiat , Cheong Chin Yee
Published: December 2022

Background

The aim of this study was to assess barriers and facilitators to the performance of routine delirium screening by nurses in the inpatient acute geriatric wards of a tertiary general hospital.

Method

Cross‐sectional surveys of nurses employed in the inpatient acute geriatric wards of a tertiary general hospital in Singapore were undertaken. Survey items were developed based on 14 domains of the Theoretical Domains Framework. Mean domain scores (range: 1‐5) were examined to identify domains representing facilitators and barriers to delirium screening. Univariate analyses were performed to investigate the relationship of each domain with self‐reported likelihood of routinely performing delirium screening for geriatric inpatients upon admission, and significant variables were entered into a multivariable regression model.

Result

112 nurses completed the surveys. Domains with the highest mean values (representing facilitators to delirium screening) were “memory, attention and decision processes” (mean: 3.14, SD 0.62), “goals” (mean: 3.08, SD 0.61), and “behavioural regulation” (mean: 2.89, SD 0.63) while “optimism” (mean: 1.88, SD 0.71), “beliefs about consequences” (mean: 2.06, SD 0.64) and “knowledge” (mean: 2.15, SD 0.63) were the lowest scoring domains (representing barriers) [Table 1]. On average, nurses neither agreed nor disagreed that delirium screening in geriatric inpatients upon admission was something that they did routinely (mean: 2.42, SD 0.83). Age, clinical grade, number of years working in the clinical grade or with a geriatric population did not affect the likelihood of routinely performing delirium screening. In the multivariable regression model, the domains that were significantly associated with increased likelihood of routinely performing delirium screening included “intentions”, “goals”, “emotions” and “reinforcement” (adjusted R2 81.68%, F(13,98) = 39.07, p < .01) [Table 2].

Conclusion

Memory, attention, decision processes, goals, and behavioural regulation strategies were found to facilitate the performance of delirium screening by nurses. Intentions, goals, emotions, and reinforcement predicted self‐reported likelihood of routinely performing delirium screening. Interventions to support routine screening of delirium for geriatric inpatients should be designed to enhance these factors and target identified barriers of knowledge, beliefs about consequences, and (lack of) optimism.
Association Analysis on Alzheimer’s Disease Sequencing Project (ADSP) 16,905 Whole‐Genome Sequence Data
Authors: Lee Wan‐Ping , Peloso Gina M , Pitsillides Achilleas N , Heard‐Costa Nancy , Wang Hui , Leung Yuk Yee , Haines Jonathan L. , DeStefano Anita L. ,   Collaboration on Alzheimer’s Disease Research (CADRE),   The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)
Published: December 2022

Background

The Alzheimer’s Disease Sequencing Project (ADSP) has released the R3 dataset of whole‐genome sequencing (WGS) from 16,905 samples collected by 17 study cohorts across three major populations including 10,651 Non‐Hispanic Whites, 3,212 Hispanics, 2,874 African Americans, and 168 others. The release also includes a callset of 206 million biallelic single nucleotide variants (SNVs), 16 million biallelic insertion/deletions (INDELs), and 28 million multiallelic variants. Leveraging this dataset, we are conducting association analysis for variants, genes, and gene sets to identify genetic risk for Alzheimer’s Disease (AD).

Method

We assembled the sample list, kept only genetically unique individuals, and removed samples with unclear AD diagnoses. Samples were further removed if they had >10 Standard Deviation (SD) on any ADSP provided quality metrics including genotype missing rate, singleton rate, heterozygous/homozygous ratio, and transition/transversion ratio. Multiallelic variants were split into biallelic variants and, after QC, merged with the biallelic callset. We filtered variants if they did not obtain the GATK “pass”, were monomporphic, has an allele balance for heterozygous (ABHet) were <0.25 or >0.75, or had a genotype missing rate >0.05. RUTH was used to perform a robust unified Hardy‐Weinberg equilibrium test. We applied GENESIS PC‐AiR to conduct principal component (PC) analysis. We are performing association analyses with two approaches: using all samples while adjusting for genetic ancestry, and within population‐specific groups defined by PC clustering (10 SD) around reference populations from the Human Genome Diversity Project. Our analytical model will adjust for sex, PCs, APOE, and technical covariates.

Result

The merged biallelic and multiallelic callset contained 223 million variants. The minor allele frequency distribution (MAF) is 88.2% MAF<0.001, 6.5% 0.001<=MAF<0.01, 2.3% 0.01<=MAF<0.05, and 3.0% MAF>=0.05. PCs within the ADSP data have been generated. We are initiating association analyses including single variant analysis (using GENESIS), gene based analyses (using SKAT‐O) and rare noncoding variant set based testing (using STAAR).

Conclusion

With this project, we will examine known and identify novel AD‐related variants. The dataset consists of participants from diverse genetic ancestry that will enable us to investigate how AD‐associated genetic risk factors differ by populations.
‘Partnering with Poise’: Alexander technique online group classes are a promising intervention to decrease loss‐of‐self and increase agency for care partners of people living with dementia
Authors: Gross Monika , Bellingham J'aime G. , Brisset Pepper , Condie Celeste L. , Lazaro Stephanie , Mello Belinda , Cohen Rajal G.
Published: December 2022

Background

Studies show 1:1 in‐person Alexander technique (AT) sessions can reduce anxiety and musculoskeletal pain with long‐term benefits [1‐4]. Care partners (CP) often experience role engulfment and loss of self [5]. AT is an embodied approach to choose functional patterns that transform disruptive stress reactions to adaptive responses, increasing confidence, self‐control, and self‐awareness. Previous in‐person group course results from 71 Parkinson’s CP showed promise with benefits retained at 12 months. COVID‐19 provided an opportunity to test synchronous online AT‐based courses for CP of people living with dementia.

Method

Design: Controlled feasibility trial. AT group: 14 participants (12F/2M) from 9 states; mean age 68; 72% provided 41+ hrs/wk care for family member with dementia; 13 lived with care‐receiver. Control group: 9 participants (8F/1M) from 4 states; mean age 63; 67% provided 41+ hrs/wk care; 6 lived with family care‐receiver. AT groups met 90 min/week x 10wks. Intervention: Delivered in‐home via Zoom. Embodied self‐management strategies included intentional strategies to interrupt automatic reactions and affirm centrality of the self, taught via verbal and visual instruction, activities, anatomical models/images, and demonstration videos. AT principles were embedded in everyday activities (gait, sit‐to‐stand, IADLs, etc.). Outcome Measures: Self‐report, executive function, anonymous evaluations, interviews.

Result

70% retention, 87% attendance. AT group improved executive function (Digit Span p = .003; Stroop p = .05); control group did not. AT group reported increased self‐efficacy (caregiver scale p = .08); and reduced fear (p = .004); control group did not. On 0‐10 scale, mean rating was >9 for novelty of ideas, practical tools for physical self‐management, and would recommend to a friend; and >8 for enjoyment of group interaction, practical tools for self‐management of emotions and reactions, and prevention of pain; 7.9 for feeling better prepared for CP daily challenges. Six‐month follow‐up is underway.

Conclusion

Alexander technique shows promise as a long‐term self‐management approach to reduce loss‐of‐self in CP of people living with cognitive decline. Group classes can provide cost‐effective delivery with social benefits. Online classes can increase accessibility. A full‐scale study is merited.

1.Little (2008) 2.MacPherson (2015) 3.Klein (2014) 4.Stallibrass (2002) 5.Skaff, Pearlin (1992)
Knowledge, perceptions, and feelings associated with Alzheimer’s Disease and Related Dementias among middle‐aged Latinas residing in an underserved agricultural community in California
Authors: Ambriz Elizabeth , Calderon Lucia , Deardorff Julianna , Kogut Katherine , Rojas Nadia , Torres Jacqueline M
Published: December 2022

Background

By 2060, Latinos will represent nearly one‐third of Americans and the Latino elderly population over 65 will nearly quadruple. Over the next 40 years, Latinos are projected to have the largest increase in Alzheimer’s disease and related dementia (ADRD) cases. Despite the expected number of Latinos with ADRD, knowledge gaps are particularly large for Latinas living in regions typically underrepresented in ADRDs research, such as rural and/or agricultural regions. Therefore, the goal of this study is to assess knowledge, perceptions, and feelings associated with ADRD among a sample of middle‐age Latina women.

Method

We used qualitative methods involving semi‐structured interviews to examine the knowledge, perceptions, and feelings associated with ADRD among a subsample of the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) study participants, who are Latina women residing in an underserved agricultural community entering mid‐life (mean = 47 years old). We conducted interviews with 20 Latina women and analyzed data with thematic content analysis.

Results

With regard to knowledge and perceptions about ADRD, three themes emerged: 1) Women associate ADRD with loss of memory, getting lost, losing one’s humanity; 2) They are not familiar with protective and risk factors for ADRD, including cardiovascular risk factors; 3) They believe ADRD can be prevented and want to learn how to prevent it and recognize signs and symptoms. With regard to feelings associated with ADRD, three themes emerged: 1) Fear of developing ADRD, losing independence, and not being aware of reality or who they are; 2) Sadness about how people with ADRD are treated, including those living in a nursing home; 3) A sense of powerlessness to help people with ADRD or oneself once diagnosed with ADRD.

Conclusion

Middle age represents a window of opportunity to reduce ADRD risk by raising awareness, prioritizing lifestyle changes, and create community conditions that support brain health. This study found that middle‐aged Latinas are concerned about ADRD and want to learn how to prevent ADRD and recognize signs and symptoms. More research is needed to study effective interventions to prevent ADRD among middle‐age Latinas, particularly from regions of the US often underrepresented in ADRDs research.
Sleep association between spousal caregiver and person with dementia having REM sleep behavior disorder: a case study using wearable technology
Authors: Ju Eunae , Kehoe Priscilla , Lee Jung‐Ah
Published: December 2022

Background

Rapid eye movement sleep behavior disorder (RBD) is manifested by dreams associated with recurrent abnormal behaviors during sleep including punching, running, jumping out of bed with potential injuries to partners and more often found in persons with dementia (PWD). This is significantly associated with increased caregiver’s sleep disturbances, stress, and health problems that has not been measured objectively. The purpose of this case study was to identify sleep characteristics of a spouse caregiver and dyadic sleep diary for both PWD and caregiver. Furthermore, using Wearable Internet of Things (WIOT) technology (smartring and smartphone) for the caregiver, we examined sleep parameters (e.g., resting heart rate, heart rate variability (HRV), sleep efficiency, deep sleep, REM sleep, and awake time at night) for 4 weeks.

Methods

This case study used mixed methods. A spouse caregiver (wife) and a PWD with RBD (both aged in 70s) living together were recruited. The caregiver wore the smartring 24/7 for 4 weeks. Additionally, the caregiver reported sleep diaries for herself and PWD for 4 weeks including nap time, feeling on wakening, and descriptions of their sleep experiences. At the end, the caregiver was interviewed to understand the perceived sleep experience in relation to PWD’s sleep. T‐tests were used to compare means of sleep parameters–continuous longitudinal data collected by WIOT device.

Results

Sleep efficiency, HRV, and awake time of the caregiver were significantly better in the nights when PWD did not have disruptive sleep behaviors compared to those nights with them (all Ps<0.05). The subjective Pittsburg‐sleep‐quality‐index(PSQI) score for the caregiver was 4 at both baseline and 4 weeks. Caregiver’s sleep diary notes showed PWD’s disruptive sleep behaviors for 8/28 days (28.6%), including bed soiling, multiple awakenings, excessive movement during sleep, aggressive behaviors – throwing out things while dreaming. In the exit interview, the caregiver expressed that RBD symptoms interrupted her sleep, however she wanted to care for PWD during the night by sleeping together.

Conclusion

This case report using WIOT objective measures found PWD’s disruptive behaviors caused the caregiver to have less sleep efficiency and greater awakenings. Subjectively using PSQI the caregiver did not acknowledge her disruption.
Microstructural changes in the white matter tracts of the brain due to mild cognitive impairment
Authors: Chandio Bramsh Q , Owens‐Walton Conor , Villalon‐Reina Julio E , Nabulsi Leila , Thomopoulos Sophia I , Guaje Javier , Garyfallidis Eleftherios , Thompson Paul M
Published: December 2022

Background

Mild cognitive impairment (MCI) is an early stage of memory loss or cognitive decline and progresses to Alzheimer’s disease at a rate of about 15% per year. It is important to study the effects of MCI on the brain. Here we present a novel along‐tract analysis of microstructural brain metrics computed from diffusion MRI. We extract, map, and visualize the profile of microstructural abnormalities on 3D models of fiber tracts, yielding fine‐scale maps of the effects of MCI.

Methods

We analyzed multi‐shell diffusion‐weighted MRI data with 127 volumes from 131 ADNI3 participants (age: 55‐91years, 74F,57M). Participants included 44 with MCI and 87 cognitively normal controls (CN). Pre‐processed using the ADNI3 dMRI protocol. We applied multi‐shell‐multi‐tissue CSD and a probabilistic particle‐filtering‐tracking to generate whole‐brain tractograms. We applied DIPY’s BUAN tractometry pipeline to extract 30 white matter tracts from all subjects and evaluate the effects of MCI on 4 DTI measures (FA, MD, RD, and AD) along the length of the tracts. BUAN applies Linear‐Mixed‐Models with DTI measures set as the response variable, group mean modeled as fixed effects term, and subject‐specific mean as random effects term.

Results

We report significant group differences between MCI and CN in 6 bundles with p‐values<0.01 and <0.001 (Fig.1). In Fig.1 and Fig2, the columns and rows show results from six bundles for four DTI measures (see Fig.2 for keywords). Fig.2 highlights areas with significant differences on the tracts with black color where for MD, p‐values<0.001 and for the rest of the 3 measures, p‐values<0.01. Fig.3 reports significant effects of MCI on the rest of the tracts and measures with p‐values<0.001. We find lower mean FA and higher mean MD, AD, and RD in the MCI, compared to the control group.

Conclusion

We applied the BUAN tractometry pipeline to map and visualize the effects of MCI on the white matter tracts of the brain. We found significant microstructural group differences in tracts where FA decreases and diffusivity measures increase in MCI participants.
Initial clinical scans using [18F]ACI‐12589, a novel α‐synuclein PET‐tracer
Authors: Smith Ruben , Capotosti Francesca , Schain Martin , Ohlsson Tomas , Touilloux Tanja , Hliva Valerie , Vokali Efthymia , Luthi‐Carter Ruth , Molette Jerome , Dimitrakopoulos Ioannis K , Jögi Jonas , Stomrud Erik , Hall Sara , Bratteby Klas , Tampio Elina , Pfeifer Andrea , Kosco‐Vilbois Marie , Streffer Johannes , Hansson Oskar
Published: December 2022

Background

To study the ability of the newly developed α‐synuclein Positron Emission Tomography (PET) tracer, [18F]ACI‐12589, created and developed by AC Immune SA, to detect α‐synuclein neuropathology in vivo, in clinically diagnosed patients with α‐synucleinopathies.

Method

We intend to scan a total of up to 50 participants with different diseases associated with α‐synuclein and age‐ and gender‐matched controls. These will include participants with Parkinson’s disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy bodies (DLB), or Parkinson’s disease caused by a duplication in the α‐synuclein gene, in addition to neurologically healthy volunteers. At the time of abstract submission, 23 participants have undergone [18F]ACI‐12589 PET scans. 20 scans consist of 0‐90 min dynamic scans with arterial blood sampling for blood input activity and metabolite analysis, two are full dynamic scans and one a 60‐90 min static scan without blood sampling. In addition, participants have undergone structural MRI, DaTscan or [18F]DOPA PET, and cognitive and motor testing (UPDRS‐III).

Result

The data are currently being processed and analyzed. Initial image analyses suggest that there is ACI‐12589 retention in brain areas affected by the disease process (such as the basal ganglia and cerebellar white matter) in participants with MSA, but also a potential age‐dependent retention in the basal ganglia and brain stem of controls.

Conclusion

We will be presenting initial promising clinical data on the novel α‐synuclein PET tracer [18F]ACI‐12589, the initial analysis of which suggests tracer binding consistent with expected patterns of α‐synuclein pathology based on clinical manifestations. Further analyses are ongoing and our updated findings will be presented at the conference.