bluuebunny/crossref_metadata_2025 huggingface dataset:
Reliability, validity, and feasibility of a smartphone‐based cognitive assessment for preclinical Alzheimer disease
Authors: Nicosia Jessica , Aschenbrenner Andrew J. , Balota David A. , Sliwinski Martin J. , Tahan Marisol , Adams Sarah , Stout Sarah Holtz , Wilks Hannah M , Gordon Brian A. , Benzinger Tammie L.S. , Fagan Anne M. , Xiong Chengjie , Bateman Randall J. , Morris John C , Hassenstab Jason J.
Published: June 2023

Background

Smartphone‐based ecological momentary assessments (EMA) have the potential to capture subtle changes in cognition associated with preclinical Alzheimer disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on EMA principles and administers brief tests of associative memory, processing speed, and working memory ∼4 times per day over 7 consecutive days. Participants perform these 7‐day cycles every ∼6 months, longitudinally. ARC was designed to be performed unsupervised, on participants’ personal devices, and in their everyday environments in order to increase accessibility, testing, and reliability.

Method

We evaluated the reliability, validity, and feasibility of ARC in a large, well‐characterized sample of cognitively normal older adults (ages 65‐97) and individuals with very mild dementia (ages 61‐88). Participants completed at least one 7‐day cycle of ARC testing along with conventional cognitive assessments. Most participants also had cerebrospinal fluid, amyloid and tau PET, and structural MRI data available. The reliability, validity, and feasibility of ARC as an unsupervised, high‐frequency cognitive assessment tool using participants’ personal smartphones was tested by examining (1) between‐subjects and test‐retest reliability, (2) correlations with age, conventional cognitive measures, and AD‐related biomarkers, and (3) adherence and attrition rates of older adults with varying technology familiarity.

Result

First, ARC tasks demonstrated good reliability such that between‐person reliability across the 7‐day cycle and test‐retest reliabilities at 6‐month and 1‐year follow‐ups all exceeded intraclass correlations of 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures. Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, high adherence rates and low attrition rates indicated that ARC was feasible and, to some extent, enjoyable, for older adult participants.

Conclusion

Ultimately, these results suggest that ARC is a reliable and valid measure of cognition in older adults at risk for AD and is a feasible tool for assessing subtle cognitive changes associated with the earliest stages of AD.
The relationship between emotion and cognition in cognitively healthy cohort: Using NIH toolbox emotion battery
Authors: Umucu Emre , Van Hulle Carol A. , Fischer Barbara L. , Wyman Mary F. , Lee Beatrice , Zuelsdorff Megan , Salazar Hector , Simó Carola A. Ferrer , Carlsson Cynthia M. , Johnson Sterling C. , Asthana Sanjay , Gleason Carey E.
Published: June 2023

Background

The NIH Toolbox was designed to provide brief, reliable, and valid measures of neurological and behavioral functions. Emotion assessment using the NIH Toolbox Emotion Battery has recently received significant attention given emerging evidence that emotional health is predictive of physical health and overall well‐being. The purpose of this study is to examine whether the modified emotion toolbox model is associated with cognition in sample of cognitively healthy adults.

Method

Participants were 529 enrollees in the Wisconsin ADRC who had normal cognition. The majority of participants were female (65.8%) and White (78.3%). Average age was 63.69 (SD = 8.37). NIH Toolbox Emotion Battery factors and a measure of executive function, Trail Making Test (TMT) Parts A & B were examined using SEM. To evaluate the overall goodness‐of‐fit, we used the following criteria: χ2 nonsignificant, χ2/df between1‐3, comparative fit index (CFI)>0.95, Tucker–Lewis index (TLI)>0.95, standardized root mean square residual (SRMR)<0.05, and the root mean square error of approximation (RMSEA)<0.08.

Result

The initial SEM results indicated a non‐acceptable fit for the data: χ2(51,N = 529) = 275.99, p<.01 (should be not significant), χ2/df = 5.41 (<3), CFI = 0.92(>.95), TLI = 0.90 (>.95), SRMR = 0.05, and RMSEA = 0.09 (<.08), 90% confidence interval (CI) = [0.08, 0.10] based on previously reported goodness‐of‐fit criteria. Based on modification indices, conceptually and statistically meaningful correlated error terms were added to the model (e,g., proximity between emotional support and friendship; emotional support and instrumental support; stress and sadness). After correlating some error terms based on theoretical background and modification indices, the modified SEM results indicated an acceptable fit for the data: χ2/df = 2.52 (<3), CFI = 0.98, TLI = 0.97, SRMR = 0.03 and RMSEA = 0.05, 90% confidence interval (CI) = [0.04,0.06].

Conclusion

Our modified model using the NIH Toolbox Emotion Battery had an acceptable fit for the data in a cognitively healthy cohort. Although we did not include all emotion toolbox variables, our modified model still had a great fit to the data. We specifically found that positive emotions including social satisfaction measures were correlated with cognition. We did not find any correlation between negative affect and cognition, which could be due to limited sample size. Measuring and identifying positive and negative emotions are important in clinical and research practice.
Amyloid on autopsy in the oldest‐old may be associated with sleep duration thirty years earlier: The 90+ Study
Authors: Melikyan Zarui A. , Mander Bryce A , Greenia Dana E. , Fletcher Evan M , Decarli Charles , Montine Thomas J. , Bukhari Syed A. , Paganini‐Hill Annlia , Kawas Claudia H. , Corrada María M. M.
Published: June 2023

Background

Amyloid production and clearance from the brain are thought to be related to sleep duration. The association between brain amyloid accumulation and self‐reported sleep duration has been mostly established in cross‐sectional studies using PET. Our aim is to examine the longitudinal association between amyloid in the oldest‐old (90+ years), measured on autopsy and PET, with sleep duration self‐reported ∼30 years earlier.

Method

We analyzed data on 289 individuals with one‐time report of their usual nocturnal sleep duration as part of Leisure World Cohort Study (LWCS) in the early 1980s, and brain autopsy or 18F‐florbetapir (amyloid) PET between 2004 and 2021 with The 90+ Study. Sleep duration was analyzed as continuous and categorical variables (<7(short), 7‐8(optimal, reference) and >8 hours(long)). National Institute on Aging Alzheimer Association (NIA‐AA) amyloid (A) and neuritic (C) plaque scores were dichotomized as negative (0‐1, reference) and positive (2‐3). Standardized uptake value ratio (SUVr) for the posterior cingulate/precuneuswas analyzed as continuous and binary (SUVr <0.76 vs. ≥0.76) variables. We analyzed sleep duration, as predictor, in relation to amyloid on autopsy (A and C scores) and PET (SUVr), as outcomes, using multiple logistic and multiple linear regressions, controlling for age, sex, education, positive items from the Zung depression scale, and time between sleep report and PET or autopsy.

Result

Sleep was reported on average at 68 years, autopsy was done ∼29 years and PET was done ∼32 years later (Table 1). Long sleep, compared to optimal sleep, was associated with 67% decrease in the odds of being NIA‐AA A positive (Table 2). Although PET amyloid results were not significant, they suggest that every hour increase in sleep duration may be associated with 0.01 unit decrese in SUVr and with 11% lower odds of being PET amyloid positive (Table 3). PET amyloid by sleep group analysis was underpowered and not done.

Conclusion

In this group of oldest‐old individuals, long, compared to optimal, sleep duration self‐reported 29 years earlier is associated with lower odds of amyloid deposition on autopsy. One of the plausible mechanisms is that longer sleep duration may support greater amyloid clearance and decreased production.
A community‐based study of reporting demographic and clinical information concordance between informant and cognitively impaired participants
Authors: Khan Noreen , Lewandowski‐Romps Lisa , Heeringa Steven G , Briceno Emily M , Longoria Ruth , Garcia Nelda M , Morgenstern Lewis B
Published: June 2023

Background

We studied concordance between informants’ and cognitively impaired participants’ reporting of demographic and clinical information in a community‐based cohort study.

Method

As part of the community‐based Brain Attack Surveillance in Corpus Christi‐Cognitive (BASIC‐C) project, households in Nueces County, Texas, USA, were randomly identified. Participants ≥ age 65 were recruited using door‐to‐door (5/1/2018‐3/15/2020) and phone (04/20/2020‐current) recruitment. Individuals with possible cognitive impairment were identified using the Montreal Cognitive Assessment (MoCA) during door‐to‐door recruitment and Telephone Montreal Cognitive Assessment (T‐MoCA) during phone recruitment. Participants who scored ≤25 and ≤18 on the MoCA and T‐MoCA respectively were eligible for participation. Named informants and participants both answered questions regarding the participant’s demographics and health status. Models were generated to examine the predictors that influence concordance between informant and participant answers. Predictors in the model included participants’ age, gender, ethnicity, degree of cognitive function (estimated by MoCA/T‐MoCA score), and relationship to informant.

Result

Table 1 provides the concordance between participant and informant answers. Overall concordance was high. Female participants were two and a half times more likely to have concordant answers about date of birth with informants than non‐spouses and male participants, and spouses were three and a half times more likely to agree with participants on date of birth than non‐spouses. (Table 2). Degree of cognitive function of the study participant also showed a large effect on concordance based on the question of whether the participant was diagnosed with dementia (p < .001) (Table 4). Other relationships in comparison to child, including other family member and friend/neighbor/other, were associated with concordance of answers to participant educational attainment and high blood pressure diagnosis (Table 3 and 5). Questions about participant diagnosis of diabetes, heart disease, stroke, and alcohol consumption, had no significant predictors. Ethnicity was not a significant predictor for any question.

Conclusion

Though most of our concordance rates were >80%, in studies that ask demographic and health history questions of cognitively impaired participants, the gold standard for “true” information remains uncertain. Our results, along with future research, may indicate that in these scenarios, studies should consider supplementing participant responses with informant contributions.
Association of Objective and Subjective Sleep Duration and Diurnal Cortisol Rhythm among Community‐Dwelling People Living with Dementia
Authors: Dong Fanghong , McPhillips Miranda Varrasse , Hodgson Nancy A
Published: June 2023

Background

Evidence has shown that both short and long sleep duration have adverse effects on cognitive health in older adults. Although changes in sleep duration have been linked with alterations in the hypothalamic‐pituitary‐adrenal axis, research on the association between sleep duration and various components of diurnal cortisol rhythm is inconsistent. In addition, limited research has examined this association in community‐dwelling people living with dementia. The aim of this study is to examine the association of objective and subjective sleep duration and cortisol rhythm indicators in a community‐dwelling population living with dementia.

Method

Participants in the Healthy Patterns Sleep Study (NCT03682185) provided three saliva samples at wakening, 30 minutes after waking, and bedtime on two consecutive days. Diurnal cortisol rhythm indicators included waking cortisol, cortisol awaking response, diurnal cortisol slope, and bedtime cortisol. Objective sleep duration was measured by averaging actigraphy over three days, and subjective sleep duration was assessed by a single item from the Pittsburgh Sleep Quality Index. The average daily total sleep duration was grouped into three categories: ≤5 (short), ≥9 (long), and >5 & <9 (normal). 195 participants with valid cortisol and sleep data were used for analysis.

Result

Approximately 60% (objective) or 45% (subjective) of the participants maintained seven to eight hours of sleep. Normal and long objective and subjective sleep duration preserved an intact diurnal cortisol rhythm. Short objective sleep duration, however, was associated with higher waking cortisol (p = 0.016) and diminished cortisol awaking response (p = 0.049), compared to normal sleep. No significance was found using subjective short sleep duration.

Conclusion

This cross‐sectional study showed that objective short sleep duration was associated with disrupted cortisol rhythm. The findings suggest that neuroendocrine disturbance could be one mechanism linking sleep and dementia risk. Future studies are needed to confirm these findings using more sampling points in the morning. Additionally future research needs to consider the confounding sociodemographic and clinical characteristics such as race and dementia severity in a larger sample.
Sex differences in plasma phosphorylated‐tau181 vary between older adults with and without mild cognitive impairment
Authors: Tucker Miwa , Kramer Joel H. , Casaletto Kaitlin B. , Gontrum Eva Q. , Lago Argentina Lario , Rojas Julio C. , Saloner Rowan , Chan Brandon
Published: June 2023

Background

Women exhibit higher tau pathology than men on central nervous system biomarkers of tau (e.g., PET imaging, CSF), particularly among APOE4 carriers and those with symptomatic Alzheimer’s disease (AD). The purpose of this study was to determine if these sex differences were detectible using a novel plasma biomarker of tau pathology in non‐demented adults.

Method

Plasma phosphorylated‐tau181 (P‐tau181)was assayed (Quanterix Simoa) in 132 cognitively unimpaired individuals (CU; 61 men, 71 women) and 43 individuals with mild cognitive impairment (MCI; 28 men, 15 women)who underwent florbetapir PET imaging. Controlling for age, linear regression examined plasma P‐tau181 as a function of sex, diagnosis, and their interaction. To determine whether sex‐differences in plasma P‐tau181 were influenced by amyloid pathology, results were compared before and after accounting for APOE4 genotype and Aβ‐PET positivity.

Result

The sex by diagnosis interaction on plasma P‐tau181 was statistically significant (β = 0.19; p = .044), and this effect strengthened after covarying for APOE4 and Aβ‐PET (β = 0.23; p = .006). In MCI, women exhibited higher mean plasma P‐tau181 concentrations than men (3.59 pg/ml vs. 3.06 pg/ml; Cohen’s d = 0.70; p = 0.032). In CU, women trended towards lower mean pTau concentrations than men (1.90 pg/ml vs. 2.28 pg/ml; Cohen’s d = ‐0.33; p = 0.064).

Conclusion

Results demonstrate greater tau burden, as measured with plasma P‐tau181, in women than men with MCI, consistent with prior studies using CSF P‐tau181 and tau‐PET imaging. In contrast, women without cognitive symptoms had the lowest levels of plasma P‐tau181, suggesting elevated plasma P‐tau181 may be particularly sensitive to cognitive impairment in women. Statistical adjustment for APOE4 and Aβ‐PET did not account for, but instead magnified, the sex by diagnosis interaction on plasma P‐tau181, suggesting factors beyond amyloid (e.g., sex hormones) may mediate diagnostic‐dependent patterns of sex‐differences in plasma P‐tau181 and could help clarify mechanisms that predispose women to tau pathology.
Repeat RNA structure and protein interactions influence RAN translation and neurodegenerative phenotypes in models of FTD and ALS
Authors: Malik Indranil , Swaminathan Harish , Rouskin Silvi , Todd Peter K.
Published: June 2023

Background

The most common genetic cause of Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) is an intronic GGGGCC hexanucleotide repeat expansion in C9orf72 (C9FTD/ALS). Transcribed GGGGCC repeat RNAs sequester RNA‐binding proteins (RBPs) into nuclear and cytoplasmic foci, which inhibits their normal functions. GGGGCC repeat RNAs also support translation of toxic repeat peptides through a process known as repeat associated non‐AUG (RAN) translation. Here we sought to understand how repeat RNA secondary structure and RBP engagements that occur during RNA transcription, processing, and trafficking influence GGGGCC RAN translation and repeat elicited toxicity, with a goal of identifying novel therapeutic targets.

Method

We developed a cellular RNA‐capture methodology coupled to mass spectrometry to identify GGGGCC repeat RNA‐interacting proteins within specific cellular compartments. In parallel, we used chemical approaches to probe GGGGCC repeat RNA secondary structures inside cells and RAN translation assays to determine whether repeat RNA secondary structures and/or interacting RBPs influence RAN translation efficiency. We employed Drosophila and neuronal models of repeat expansions to evaluate potential RBPs as disease modifiers.

Result

Our RNA structural studies revealed that GGGGCC repeat RNAs form primarily hairpin structures, rather than G‐quadruplex structures, in cells. Folding repat RNAs into such hairpins supports RAN translation whereas folding repeat RNAs into g‐quadruplex structures strongly inhibits their translation. We identified multiple RBPs enriching in the nuclear fraction of GGGGCC RNA‐interactome, including hnRNPH1 and SR (serine/arginine‐rich domain) proteins, which are known components of the nuclear foci found in C9FTD/ALS patient cells. Our comparative analysis found that lowering SR protein expression or modifying its phosphorylation modified toxicity in Drosophila models of multiple repeat expansion disorders. Currently we are investigating how repeat RNA structures influence RBP interactions and whether structure dependent RBP interactions selectively modulate RAN translation.

Conclusion

We present a comprehensive approach to evaluate the roles of repeat RNA secondary structures and critical RBPs in RNA toxicity underlying dementia‐associated repeat expansion disorders.
Partnering with hospital providers to facilitate handoff for persons with dementia in the acute care setting
Authors: Jeune Vanessa
Published: June 2023

Objectives

Individuals with Alzheimer’s disease and related dementias cannot verbalize their care needs during transitions of care (TOC) and rely on their home caregivers (HCs) for advocacy. The lack of communication between clinicians in one setting and HCs can lead to detrimental health outcomes for the length of stay. With the assistance of Family Nurse Consultants (FNCs), a standardized care needs communication tool (SCNCT) for support persons of persons with dementia (PWD) was implemented to enhance the ability of the support person to communicate care needs during TOC.

Method

Participants of the project included FNCs who assessed the needs of the PWD enrolled in a specialized adult daycare center. After obtaining IRB approval, pre‐ and post‐educational 5‐point Likert scale surveys were administered to capture if a gap exists in communication care needs for cognitively impaired individuals and if the tool can help bridge that gap. A PowerPoint presentation was utilized for training the FNCs on the SCNCT. Participants were informed to anticipate another survey within thirty days of follow‐up training.

Results

Descriptive statistics were utilized to analyze the Likert scale questions for all surveys. Only the last question of the 30‐day post‐implementation survey yielded scale data. Eight FNCs completed the pre‐survey and another survey post‐presentation. Seven of them responded to the survey 30‐day post‐project implementation. The tool was new to the FNCs, and the output generated a utilization rate of 43%. Moreover, HCs who were offered the tool benefited from that time of preparation for their loved ones. There was also a statistically significant improvement in FNCs' perception of the value and usefulness of the tool after they were introduced to it. The results of the two‐tailed Wilcoxon signed‐rank test conducted to investigate the pre‐ and post‐survey scores were significant based on p = .039.

Conclusion

The project did not demonstrate the HCs' involvement with the tool due to limitations associated with the COVID 19 pandemic, yet the results showed promising due to the champions' perceived value. Nonetheless, the project findings revealed that HCs could be crucial members to strengthen TOC for the cognitively impaired individual using the SCNCT.
Progress of CNS aggregated protein degradation therapeutics from APRINOIA’s small molecule discovery platform
Authors: Lin Yih‐Shyan , Tempest Paul , Jang Ming‐Kuei , Tai Chin‐Yin , Wu Meng‐Fang , Li Chung‐Lin , Ma Haou‐Tzong , Lai Yen‐Ting
Published: June 2023

Background

The hallmark of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), is an accumulation of protein aggregates, which lead to neurotoxicity and dysfunction. Small molecule therapeutics that can remove pathological aggregates are highly desired for both diseases.

Method

Our small molecule discovery platform consists of our proprietary small molecule collection, unique PET imaging biomarkers and cryoEM structures. Our proprietary collection of CNS‐focused aggregated protein binding agents, previously developed by APRINOIA to map the structure‐activity relationship of its tau PET tracer programs, is selectively coupled with agents designed to hijack cellular quality‐control systems which facilitate aggregation clearance. We have developed a screening funnel to interrogate the ability of our small molecules to affect clearance of protein aggregates.

Result

Therapeutic compounds developed have been shown to bind to intracellular tau aggregates in fluorescence assays. Furthermore, we have identified compounds that show proteosome dependent elimination of aSyn aggregates in the ReNcell VM neuronal model. PK studies show that these compounds can cross the BBB. In vivo studies with rTg4510 mice show that a single dose of our degraders can affect reduction of tau protein.

Conclusion

APRINOIA’s small molecule discovery platform has produced lead compounds capable of degrading protein aggregates in cellular assays and in vivo models. Further development is ongoing.
Plasma amyloid‐β oligomerization tendency predicts amyloid PET positivity
Authors: Pyun Jung‐Min , Yu Ji Sun , Lee Ryan , Shim Kyu Hwan , Youn Young Chul , Ryoo Nayoung , Han Sang‐Won , Park Young Ho , Kang Sungmin , An Seong Soo , Kim SangYun
Published: June 2023

Background

Among other emerging amyloid‐targeting blood‐based biomarkers, Multimer Detection System‐Oligomeric Amyloid‐β (MDS‐OAβ) measures dynamic changes in concentration of oligomeric amyloid‐β (OAβ), which is considered the main pathogenic culprit of Alzheimer’s disease (AD), in plasma after spiking with synthetic amyloid‐β (Aβ). We aimed to investigate predictability of MDS‐OAβ on amyloid Positron Emission Tomography (PET) positivity.

Method

A total of 96 subjects who visited Seoul National University Bundang Hospital for medical check‐up complaining of cognitive decline and had undergone extensive medical assessment were recruited. Amyloid statuses were dichotomized into positive or negative based on visual assessment of amyloid PET. Plasma OAβ concentration was measured by MDS‐OAβ. In the previous validation study, 0.78ng/ml was established as the cut‐off value and the plasma OAβ concentration higher than or equal to the cut‐off value was defined MDS‐OAβ positive.

Result

MDS‐OAβ positivity could discriminate amyloid PET positivity with the AUC value of 0.855 (95% CI 0.776–0.933). Adding MDS‐OAβ positivity to prediction models including age, MMSE score, and APOE ε4 status improved the performance up to the AUC value of 0.926 (95% CI 0.871–0.980).

Conclusion

The Aβ oligomerization tendency in plasma could predict amyloid PET positivity with high performance, and when it is combined with age, MMSE score, and APOE ε4 status, the predictability was improved substantially. This suggests the potential of MDS‐OAβ as a useful initial stage test in clinical and research field of AD.
Narrative design for dementia care: Arranging the built environment of care homes to aid communication
Authors: Minetou Loukia , Minetou Loukia , Hennessy Catherine , Ward Richard , Quirke Martin
Published: June 2023

Background

The built environment has been shown to have significant potential to improve the quality of life and contribute to the well‐being of persons living with dementia. Persons with dementia in residential care suffer from isolation as it is difficult for staff and family members to find common routes of communication when the disease progresses. Within dementia care there is an urgent need to further facilitate communication especially with people living with late stage dementia. Storytelling has been effectively used in art therapy and art interventions for people affected by dementia to enhance communication, social connectivity and well‐being.

This presentation explores the possibilities of incorporating a novel type of environmental design in care homes that would enhance narrative agency in residents with dementia thus allowing residents, caregivers and staff members to communicate through storytelling.

Methods

Drawing on interdisciplinary research, the primary focus of the presentation is a case study examining the implementation of storytelling design in residential care settings. The case study reports on the co‐creation of a space focused on offering lived experiences for residents with dementia in a London care home highlighting design elements that trigger storytelling and stimulate imagination. Such elements include sensory wall surfaces, furniture, soft furnishings, configuration of space and inclusion of technology. The presentation explores whether this type of design could provide routes of communication between residents, staff and family members thus improving the quality of life of people living with dementia.

Results

Based on this case study example, the presentation discusses the value and impact of appropriate storytelling design on the wellbeing of people with dementia and their carers, and future avenues for improving the physical environment in care homes based on narrative design possibilities.

Conclusion

There is a possibility for a significant impact of narrative design to communication, social connectivity and well‐being of people living with dementia.
Tau deficiency protects human neurons from Abeta‐induced reduction of network activity
Authors: Bachmann Sarah , Kabbani Aghyad Al , Bell Michael , Kluge Lena , Klimek Jennifer , Zempel Hans
Published: June 2023

Background

One hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau‐isoforms are expressed, originating from alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms differ in the number of N‐terminal inserts (0, 1, or 2N) and the C‐terminal repeat number (3 or 4R). Recent results from murine neurons highlight that the six human‐specific isoforms are differentially localized within neurons and influence microtubule dynamics in an isoform‐specific manner. In this study, we generated a human neuronal model system to further characterize the human‐specific Tau‐isoforms under basic and pathological conditions.

Method

We successfully generated three Tau KO hiPSC cell lines derived from Ngn2‐WTC11 cells using CRISPR/Cas9 and characterized the generated cell lines using genetic, biochemical and microscopy‐based methods.

Result

No difference between Tau KO and WT hiPSCs was observed in the capability of neuronal differentiation or neuronal morphology. Interestingly, Tau KO neurons were shown to be resistant to an Abeta‐induced reduction of network activity. Initial results from re‐expressed Tau‐isoforms in these neurons support the differential localization of the isoforms observed previously. Further experiments will investigate the isoform‐specific role of Tau regarding microtubule dynamics, axonal branching, and synapse formation under basal and pathological conditions.

Conclusion

Tau KO hiPSCs are a versatile tool to study basic as well as pathological functions of Tau. Expected results will provide a major understanding of Tau function and help identifying potential therapeutic targets for the treatment of AD and related neurodegenerative diseases.
The Addenbrooke’s Cognitive Examination–Revised (ACE‐R) in the diagnosis of Alzheimer’s disease: A new logarithm using Mokken scaling analysis
Authors: Amaral‐Carvalho Viviane , Silva Thais Bento Lima , Mariano Luciano Inácio , Souza Leonardo Cruz de , Guimarães Henrique Cerqueira , Bahia Valeria S , Nitrini Ricardo , Barbosa Maira Tonidandel , Yassuda Monica Sanches , Caramelli Paulo
Published: June 2023

Background

The ACE‐R is an accurate and brief cognitive battery for the detection of mild dementia, especially for the discrimination between Alzheimer’s disease (AD) and frontotemporal dementia. The aim of this study was to develop a new logarithm based on discriminative items of the ACE‐R combined with relevant demographic characteristics that may interfere on cognition.

Method

The ACE‐R was administered to 102 patients with mild dementia due to probable AD and 161 controls from two Brazilian research centers. All individuals were submitted to the Mattis Dementia Rating Scale (DRS) and the ACE‐R. The performance of the patients was compared and analyzed. Mokken scaling analysis was applied to identify the latent trait on the AD Group. Multivariate logistic regression and ROC curve analysis were carried out.

Result

Mean ± SD total scores in the ACE‐R were 70.2 ± 10.8 in AD and 85.1 ± 8.2 in controls. AD Mokken ACE‐R (AMokACE‐R) comprises 12 items measuring the same latent concept. Logistic regression with cross‐validation pointed that AMokACE‐R + Years of education + ACE‐R items Orientation (time) and Memory (name and address recall) share importance as independent variables (p<0.05). The proposed logarithm reached an area under the curve of 0.968, with 93% sensitivity, 94% specificity, 90% PPV and 95% NPV.

Conclusion

The new logarithm using the ACE‐R items achieved high diagnostic accuracy in identifying mild AD versus controls. Furthermore, the final ROC curves showed the superiority of the model proposed in relation to the analysis of the subscales individually, as the literature previously reported. Further analysis in larger samples, with biomarkers or pathological confirmation, are necessary to confirm these findings.
Patients with Alzheimer’s disease dementia show partially resilient parietal “HUBS” modeled from resting‐state alpha electroencephalographic rhythms
Authors: Lopez Susanna , Percio Claudio Del , Lizio Roberta , Noce Giuseppe , Padovani Alessandro , Nobili Flavio Mariano , Arnaldi Dario , Famà Francesco , Moretti Davide , Soricelli Andrea , Ferri Raffaele , Buttinelli Carla , Giubilei Franco , Güntekin Bahar , Yener Görsev , Stocchi Fabrizio , Vacca Laura , Bonanni Laura , Babiloni Claudio
Published: June 2023

Background

Graph theory models a network by its nodes and connections. “Degree” hubs reflect node centrality, while “connector” hubs are those linked to several clusters of nodes. Here we compared hubs modelled from measures of interdependencies of between‐electrode resting‐state eyes‐closed electroencephalography (rsEEG) rhythms in normal old (Nold) and Alzheimer’s disease dementia (ADD) participants. As ADD is considered as a “network disease” and is typically associated with abnormal rsEEG delta (< 4 Hz) and alpha rhythms (8‐12 Hz) over associative posterior areas, we predicted abnormal posterior hubs from measures of interdependencies of those rhythms in ADD as compared to Nold participants.

Method

To report robust results, we measured interdependencies of rsEEG rhythms from delta to gamma bands (2‐40 Hz) by both bivariate linear lagged connectivity and multivariate (directional) isolated lagged effective coherence. Furthermore, we used three different definitions of “connector” hub.

Result

Convergent results showed that in both Nold and ADD groups, there were significant parietal “degree” and “connector” hubs derived from alpha rhythms. These hubs had a prominent outward “directionality” in the two groups, but that “directionality” was lower in ADD than Nold participants (Figure 1).

Conclusion

Independent methodologies and hub definitions suggest that ADD patients may be characterized by low outward “directionality” of topologically partially resilient parietal “degree” and “connector” hubs derived from rsEEG alpha rhythms. Combined use of independent methodologies in rsEEG studies may produce robust results in clinical applications in ADD patients.
Dual tasking paradigm in clinical stages of early Alzheimer’s disease
Authors: Sorinas Jennifer , Cormack Francesca K , Taptiklis Nick , Vallejo Vanessa , Snædal Jón , Jonsdottir Maria K. , Hannesdottir Kristin , Curcic Jelena
Published: June 2023

Background

In Alzheimer’s disease (AD) both motor and cognitive domains are impaired [1‐2]. However, these domains are usually assessed independently, even when performing dual‐task (DT) paradigms, the cognitive‐motor interaction (CMI) is not taken into account which may lead to misinterpretation of the patient’s global state. To date, there are no precise markers to neither detect subtle signs of pre‐clinical neurodegeneration nor accurately monitor disease progression.

Method

We have evaluated the motor and cognitive components of a DT paradigm concurrently (Figure 1). 50 participants, aged 60 to 80 years, were included in the study, distributed across four cohorts corresponding to progressive clinical stages of early AD [3]: 1) amyloid negative, cognitively healthy participants (control group), 2) amyloid positive pre‐symptomatic AD, 3) Mild Cognitive Impairment (MCI) due to AD and 4) mild AD. Two inertial measurement units (IMUs) (Physilog, GaitUp S.A.) were attached to each foot to measure gait parameters and a small microphone (Wireless GO, RØDE) was attached to the shirt to record counting. Both timing and gait features were extracted from raw data, however only conventional features, correct response rate (CRR) and gait speed, were considered for this abstract and were used to evaluate the CMI based on Plummer’s classification system [5]. Moreover two‐way ANOVA was carried out to evaluate the effect of cohort and cognitive load conditions on the CMI.

Result

Our results show that there is a significant drop in performance at both the cognitive and motor tasks while performing DT and that this drop is more pronounced as we move toward stages of greater cognitive impairment and as we increase the cognitive load of the task (Figure 2). Moreover, CMI shows a cognitive‐priority trade‐off in all cohorts (better/similar counting while slower walking), but movement toward mutual interference effect (worst counting and slower walking) when increasing cognitive load and state of cognitive decline (Figure 3).

Conclusion

To our knowledge, this is the first feasibility study assessing the CMI at preclinical and early clinical stages of AD. Our preliminary results suggest that the DT paradigm is a sensitive method to detect early signs of neurodegeneration and monitor AD progression.
Glial cell reactivity drives cognitive decline in LDLr‐/‐ mice: experimental evidences
Authors: Rodrigues Matheus Scarpatto , Farias Hemelin Resende , Schons Tainá , Machado Alessandra Gonçalves , Bast Rachel KSS , Engblom David , Budni Josiani , de Bem Andreza Fabro , de Oliveira Jade
Published: June 2023

Background

Familial hypercholesterolemia (FH) is a clinical condition characterized by increased plasma cholesterol levels, due to a mutation in the gene encoding the low‐density lipoprotein receptor (LDLr) in cells [Brown and Goldstein, 1984]. Importantly, clinical evidence indicates that FH negatively affects cognition and favors the development of neuropathologies [Ariza et al., 2016; Zambón et al, 2010], however, the mechanisms behind this relationship are still not fully understood. In this study we aimed to investigate the role of glial cell reactivity on the cognitive deficits related to the FH, as well as the possible neuroprotective effect of a pharmacological inhibitor of microglial cell activation.

Method

Firstly, male 3‐months‐old and 14‐months‐old C57BL/6 wild‐type and LDLr knockout mice (LDLr‐/‐) mice brains were prepared for the evaluation of glial cell morphology by immunofluorescence. In addition, the mice’s hippocampus was removed to measure the immune content of synaptic and tight‐junctions proteins. Moreover, male and female 6‐months‐old C57BL/6 wild‐type and LDLr‐/‐ mice were treated with minocycline (50 mg/kg) or vehicle (saline) for four weeks. Afterwards, mice were submitted to behavioral tests.

Result

Middle‐aged LDLr‐/‐ mice (14‐months‐old) exhibited increased microgliosis in hippocampus, which was correlated with morphological change of microglial cells and astrocytes in this same brain region. Also, middle‐aged LDLr‐/‐ mice presented a reduction in the immune content of synaptophysin‐1 in the hippocampus. Moreover, young adult (3‐months‐old) LDLr‐/‐ mice exhibited reduced immune content of PSD95 in the hippocampus. Finally, the administration of minocycline to 6‐months‐old LDLr‐/‐ mice ameliorated the performance of hypercholesterolemic mice in hippocampal‐dependent memory tasks, without modifying their locomotor activity and metabolic parameters.

Conclusion

Taken together, our results demonstrated that FH alters the glial cell reactivity, which was associated with changes in synaptic proteins in the hippocampus. In addition, the pharmacological modulation of microglial cell reactivity ameliorated the hippocampal‐dependent memory in LDLr‐/‐ mice, suggesting that increased glial cell reactivity is a key event for HF‐related cognitive deficits.
Clinical outcomes of amyloid and tau markers according to vascular markers
Authors: Chun Min Young , Kim Young Ju , Choe Yeongsim , Park Yu Hyun , Kim Jinhee , Kim Hee Jin , Jeong Jee Hyang , Jang Hyemin , Seo Sang Won
Published: June 2023

Background

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) aggregation [A] and tau aggregation reflecting neurofibrillary tangles [T]. These AD markers lead to neurodegeneration [N] and cognitive impairments. Recently, the ATN research framework of was presented by National Institute on Aging and Alzheimer’s Association. Cerebral small vessel disease (CSVD, [V]), which is one of most important cause of cognitive impairments, has an additive or synergistic effect on cognitive impairments with AD markers. In the present study, we investigated the frequency of ATV abnormalities in participants with varying degree of AD and CSVD markers. We also determined whether CSVD might synergistically affect cognitive decline with AD markers.

Method

We consecutively recruited 195 subjects (105 AD‐related cognitive impairment subjects, 86 subcortical vascular cognitive impairment subjects) from Samsung Medical Center. [A] and [T] positivities were determined by cut‐off values of Aβ and tau uptakes on PET using iterative outlier methods. [V] was assessed by the presence of severe white matter hyperintensity. All subjects underwent neuropsychological tests including Mini‐Mental State Exam (MMSE) and clinical dementia rating‐sum of boxes (CDR‐SOB). A linear mixed effect model was used to compare cognitive changes over time.

Result

The number of subjects of A‐T‐, A+T‐, and A+T+ groups were 16 (15.1%), 29 (27.4%), and 56 (52.8%) in the V‐ group; and 46 (51.7%), 33 (37.1%), and 8 (9.0%) in the V+ group. The linear mixed effects model analysis showed that A+/T+ were associated with worse cognitive decline, and its impact is higher in the V+ group than in the V‐ group (Figure).

Conclusion

Our findings suggested that there were interactive effects of AD markers and CSVD on cognitive decline. These findings demonstrate the importance of vascular factor management in patients with cognitive impairment and suggest that the ATV framework is useful in predicting cognitive decline in clinical practice.
Effects of APOE genotype on amyloid PET positivity according to cognitive status and ethnicity
Authors: Chun Min Young , Kim Bo‐Hyun , Kim Jinhee , Jeong Jee Hyang , Kim Hee Jin , Jang Hyemin , Seo Sang Won
Published: June 2023

Background

Among the various risk factors for Alzheimer disease (AD), apolipoprotein E (APOE) genotype ε4 is known to be a strong factor. On the other hand, ε2 is known to have a protective effect. It is not yet clear how amyloid positivity according to the APOE genotype differs by diagnostic criteria. Also, there were no studies showing the ethnic difference in the effects of APOE genotype on amyloid‐beta (Aβ) between American and Asian. The aim of this study was to investigate how Aβ positivity (Aβ+) according to APOE genotypes differs by ethnicity and cognition.

Method

We recruited 4,203 Korean subjects from multi‐centers in South Korea and 1,069 subjects from Alzheimer’s Disease Neuroimaging Initiative database. All subjects underwent neuropsychological tests, APOE genotype tests, and amyloid PET (FMM/FBB/AV45) scans. Subjects with the ε2/ε4 genotype were excluded due to the opposing effects of the ε4 and ε2 alleles. The degree of influence on amyloid positivity by each factor was analyzed by logistic regression.

Result

The frequency of Aβ+ in normal cognition (NC) group was higher in ADNI than in Korean group (p <0.001). Amnestic mild cognitive impairment and AD dementia (ADD) groups showed no difference in the frequency of Aβ+ between ADNI and Korean groups. Relative to APOE ε3/ε3 group, APOE ε4 carriers showed higher frequent Aβ+ regardless of cognitive status and ethnicity (Figure). ADNI and Korean groups showed APOE ε2 carriers less frequent Aβ+ in ADD but not in NC relative to APOE ε3/ε3 group.

Conclusion

Our findings suggested that there were no differences in effects of APOE ε4 genotype on Aβ+ between European and Korean. These findings will be helpful in predicting amyloid positivity and AD intervention according to APOE genotype and ethnicity.
Clinical outcomes of conversion to amyloid‐beta positivity in amyloid‐beta negative elderly
Authors: Kim Jun Pyo , Chun Min Young , Jeong Jee Hyang , Jang Hyemin , Seo Sang Won
Published: June 2023

Background

Early detection of amyloid beta (Aβ) accumulation has become important as Aβ accumulation begins before clinical symptoms appear. Previous longitudinal studies of Aβ‐negative (Aβ‐) people have shown that some of them convert to amyloid‐positive (Aβ+) and others remain amyloid‐negative. The clinical effects of conversion to Aβ+ have not been extensively investigated, yet. The aim of the study is to investigate the longitudinal cognitive changes according to conversion to Aβ+.

Method

We recruited subjects from 62 Korean subjects from Samsung Medical Center and 275 the Alzheimer’s Disease Neuroimaging Initiative database that were followed for more than three years. All subjects were amyloid PET negative and showed normal cognitive function at baseline. They were followed for more than three years and underwent amyloid PET and clinical dementia rating‐sum of boxes (CDR‐SOB). Longitudinal cognition changes according to conversion to Aβ+ were analyzed using a linear mixed effect model.

Result

Twelve (4.4%) of Aβ‐ ADNI participants and three (4.8%) of Aβ‐ Korean participants were converted to Aβ+. The ADNI and Korean subjects showed that CDR‐SOB was significantly deteriorated in the converter group than in the non‐converter group (p = 0.034 for ADNI; p = 0.022 for Korean).

Conclusion

Our findings revealed that conversion to Aβ+ predicted worse clinical outcomes, suggesting that it is important to recognize potential candidates for primary prevention of AD.
Promoting patient‐centered‐care through a virtual reality medical school curriculum focused on dementia and end‐of‐life in the COVID Era
Authors: Negris Olivia R , Balas Johanna S. , Phelps Emily Broman , Washington Erin , Brennan Ann , Volgman Annabelle Santos , Fleischman Debra A , Aggarwal Neelum T.
Published: June 2023

Background

The COVID pandemic has brought death and dying to the forefront, contributing to the already high levels of physician burnout. Furthermore, there is a negative correlation between physician burnout and empathy. Due to time constraints of clinical rotations in traditional medical education, there are often shortcomings in students’ understanding of how to best manage and communicate with chronically or terminally ill patients. This study implements a distributive model of a virtual reality (VR)‐based curriculum, utilizing vignettes that portray a Latinx woman, Beatriz, with Alzheimer’s disease, and a veteran, Clay, with cancer transitioning to hospice from a first‐person perspective.

Method

Medical and premedical students in Chicago were recruited (N = 12, 75% female, 58% White, 58% M2) and engaged in a self‐directed VR‐based curriculum, including Embodied Labs modules and corresponding lectures from expert physicians. Lecture content time was 2 hours 40 minutes and VR module time was 35 minutes, which students completed at their own pace prior to a Zoom group discussion. Participants completed a series of pre‐ and post‐surveys.

Result

Preliminary qualitative analysis reveals participant‐perceived increased competencies in the following themes: medical knowledge and preparedness (100%), compassion and empathy (67%), communication and patience (50%), emotional connection and advocacy (50%), and family values and comfort (42%) after program completion. Moreover, 11/12 participant reflections either directly stated the value of this experience for their professional development or explicitly highlighted its utility within medical school curricula. Additional qualitative content analyses and quantitative statistics on the changes in pre‐ and post‐survey measures are forthcoming.

Conclusion

Burnout and reduced patient‐centered‐care have been identified as barriers to empathic delivery of care in the COVID era. Utilizing VR to develop a medical curriculum fosters increased compassion and empathy in the context of dementia and end‐of‐life care. This multi‐dimensional curriculum can be scaled and implemented virtually to mitigate the impact of burnout on empathy in trainees caring for patients during the pandemic. Future aims include formally integrating this model into a medical curriculum, targeting students early in their career before they are overwhelmed with burnout, and broadening content to include trainees from diverse medical professional programs and institutions.