bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunological response to dual Aβ/Tau vaccine PRX123 surrogate and effects on brain amyloid plaques in rapidly depositing transgenic animal model
Authors: Tourino Clara , Trumble Alyssa , Louie LeeAnn , Barbour Robin M. , Kinney Gene G. , Campbell Brian , Zago Wagner M. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is defined by hallmark features including Aβ plaque deposits and tau tangles throughout the brain. Clinical evidence demonstrates that N‐terminal anti‐Aβ antibodies capable of robustly reducing Aβ plaques in the brains of AD patients can slow cognitive decline. In addition, preclinical evidence indicates that antibodies binding MTBR‐tau can prevent cell to cell transmission, potentially suppressing the pathogenic spatiotemporal spread of tau. Because both Aβ and tau are involved in the etiology and progression of AD, it is hypothesized that simultaneously disrupting these pathologic processes may provide additional therapeutic benefit compared to removal of Aβ plaques alone. Vaccine approaches targeting both Aβ and tau may be advantageous in treating early AD by generating long‐term polyclonal responses capable of disease‐modifying effects that could prevent or delay the clinical manifestation of AD onset. PRX123 is a dual Aβ/tau peptide vaccine against the N‐terminus of Aβ and MTBR‐tau that was demonstrated in preclinical studies to generate robust immunogenic responses, simultaneously producing antibodies that promote clearance of Aβ plaques and neutralization of MTBR‐tau in vitro. The following study was conducted to evaluate the in vivo efficacy of preclinical surrogate PRX123 (PRX123s) in a transgenic mouse model expressing human amyloid precursor protein and with aggressively high Aβ pathology.MethodsAPP/PS1 (Thy1‐hAPP*V717I/Thy1‐hPS1*A246E) transgenic mice were vaccinated with PRX123s beginning at 3.5 months old for 6 months.ResultsPRX123s generated robust antibody titers capable of binding structural features indicative of Aβ plaques and tau tangles in post‐mortem AD brain tissue at concentrations expected to be reached in the brain (0.3% of plasma concentrations). Immunohistochemical analysis of brain tissue from vaccinated APP/PS1 mice demonstrated significant reduction in cortical Aβ plaques compared to a nonsense peptide control group. The clearance was similar to the treatment with a plaque‐clearing N‐terminal monoclonal antibody, used as positive control.ConclusionsTogether these data demonstrate that PRX123 may be capable of generating high‐quality antibody responses to clear Aβ plaques at brain exposures which may be achievable in patients and support the continued development of PRX123—a dual Aβ‐tau conjugated linear peptide vaccine designed to treat and/or prevent Alzheimer’s disease.
A multi‐class deep learning model to estimate brain age while addressing systematic bias of regression to the mean
Authors: Shah Jay , Luo Ji , Sohankar Javad , Reiman Eric M. , Chen Kewei , Su Yi , Li Baoxin , Wu Teresa 
Published: December 2023

AbstractBackgroundAge‐related changes in human brain may contribute to the development of age‐related neurodegenerative diseases. It may be possible to estimate “brain age” from magnetic resonance imaging (MRI) and the difference between a person’s brain and chronological age, ∆age, reflecting whether a person’s brain has been aging faster or slower than their chronological age. Deep Learning Models typically regress age on imaging features, leading to systematic biases associated with regression to the mean (RTM), including overestimation of brain age in younger persons and underestimation in older persons. We estimate brain age from a person’s MRI as a multi‐class classification problem and developed deep learning model to estimate brain age free from RTM bias.MethodTwo 3D ResNet‐18 models were implemented: regression and multi‐class classification. We transform the task of predicting age as continuous variable to predicting probabilities of discrete age values where age is discretized to closest integer values. Both models were trained on 7,372 T1‐weighted MRI scans of 5,848 cognitively normal participants (age: 8‐95 years) from public data sources (IXI, ICBM, ABIDE, NACC and OASIS). We create train, validation, and test set in ratio 80:10:10 with matching age distribution. Mean squared error is used as loss function in training regression model. Whereas in the classification model, we introduce two loss terms in addition to standard cross‐entropy loss: (1) minimizing the difference between mean (∑c∗pc) of expected age and the actual age, and (2) minimizing variance (∑(c‐mean)2∗pc), where pc is probability sample belonging to class c.ResultThe regression model achieved MAE = 3.93 years and R2 = 0.90 on unseen test set whereas classification model achieved MAE = 2.41 and R2 = 0.96 on same test set. We observe significant decrease in systematic bias using the classification model ‐ for younger (age<30) and older (age>70) subsets, average ∆age improved from 3.17 to 0.2, and from ‐2.49 to ‐0.97 respectively (Figure1).ConclusionOur proposed classification model with improved loss function to predict brain age from imaging features eliminates systemic bias present in traditional regression approaches and also improves performance by a significant margin. This model can be used more reliably to study age‐related alterations in brain and AD‐related deviations from natural aging.
Advancing Brain Health Equity in Puerto Rico: Highlights of the First “Puerto Rico Alzheimer’s Disease and Related Dementias Research Symposium”
Authors: Arroyo‐Miranda Mirna L 
Published: December 2023

AbstractBackgroundADRD is a major public health concern in Puerto Rico (PR) due, in part, to a rapidly aging population with high cardiovascular risk and admixed genetics. Although ADRD research has been slowly growing, systemic barriers, such as mass migration of scientists and socioeconomic inequalities, make research efforts increasingly difficult in the island. Compared to other Hispanic/Latinos in U.S. mainland, Puerto Rican Hispanic/Latinos in the territory remain less represented in ADRD research. Therefore, we held the first “Puerto Rico Alzheimer’s Disease and Related Dementias Research Symposium” in February 2023 with the aims of 1) enhancing knowledge, skills, and intellectual support for ADRD researchers, and 2) developing a blueprint for ADRD research policy.MethodApproximately 120 participants attended the 2‐day symposium in Ponce, PR. We held sessions showcasing local ADRD research, plenary sessions covering topics on grant and manuscript writing skills, building collaborations, applying research for advocacy, and the role of academia in ADRD research. In facilitated group discussions, participants identified challenges to advancing brain health research in PR in terms of goals, investigator support, dissemination, and public policy, as well as potential solutions. Emerging themes and next steps were considered during a plenary discussion at the end of symposium.ResultAcademic‐institutional barriers (e.g., lack of full‐time positions, career development opportunities, and mentoring) were identified as major challenges to research production in PR. Investigator‐level barriers identified were lack of research tools, skills and strategies, information on funding opportunities, and connections with potential collaborators. Policy‐level barriers identified were inadequate access to existing ADRD data sources, reduced monetary resources for infrastructure and human capital, and shifting priorities with changes in government.ConclusionAs ongoing goal, participants resolved to build the “Puerto Rico ADRD Research Consortium,” to address identified needs and challenges. ADRD public health efforts should be geared towards promoting a research culture: reducing the “brain drain,” creating and leveraging existing data sources, increasing ADRD research education and advocacy, and fostering partnerships among ADRD stakeholders to maintain a pipeline of innovative research. This research culture will potentially lead to advancing transformative brain health equity initiatives in PR.
The Japan‐multimodal intervention trial for prevention of dementia (J‐MINT): a multi‐center, randomized, 18‐month controlled trial
Authors: Arai Hidenori , Sugimoto Taiki , Akatsu Hiroyasu , Doi Takehiko , Fujiwara Yoshinori , Hirakawa Akihiro , Kinoshita Fumie , Kuzuya Masafumi , Lee Sangyoon , Matsuo Koichiro , Michikawa Makoto , Ogawa Susumu , Otsuka Rei , Sato Kenji , Shimada Hiroyuki , Suzuki Hiroko , Suzuki Hiroyuki , Takechi Hajime , Takeda Shinya , Umegaki Hiroyuki , Wakayama Satomu , Sakurai Takashi ,   J‐MINT study group
Published: December 2023

AbstractBackgroundThe Japan‐multimodal intervention trial for prevention of dementia (J‐MINT) aimed to examine the efficacy of the multi‐domain intervention in the prevention of cognitive decline in older adults at high risk of dementia.MethodThe J‐MINT is an 18‐month, multi‐centered, randomized controlled trial. Participants aged 65‐85 years with mild cognitive deficits were recruited and randomized into multi‐domain intervention (management of vascular risk factors, group‐based physical exercise, nutritional counseling, and cognitive training) and control groups (health‐related information in writing every 2 months) at a 1:1 allocation ratio using the dynamic allocation method. The primary outcome was a change from baseline to 18‐month follow‐up in a composite Z score combining several neuropsychological tests, which include tests of global cognitive function (MMSE); memory (Logical memory I and II subset of the Wechsler Memory Scale‐Revised and the Free and Cued Selective Reminding Test); attention (Digit Span); executive function/processing speed (Trail Making Test, Digit Symbol Substitution Test, and Letter word fluency test).ResultBetween November 26, 2019, and December 28, 2020, 1677 participants were screened and 531 were randomly assigned to the multi‐domain intervention group (n = 265) or control group (n = 266). Four hundred and three (75.9%) participants completed the trial. The full analysis set included 433 patients who received the intervention program/health‐related information at least once. In the primary efficacy analysis, there were no significant differences in the change of composite Z score between the intervention group and the control group (mean difference 0.047 [95% CI ‐0.029 to 0.124]). In the analysis for each neuropsychological test, the score of the letter word fluency test in the intervention group significantly improved by a mean of 0.827 (95% CI = 0.356 to 1.298) points, whereas the mean difference between the intervention group and control group was not significant (mean difference 0.625 [95% CI ‐0.039 to 1.289]). In subgroup analyses, the intervention effect on composite Z score was significant among older adults with the apolipoprotein‐E (APOE) ε4 allele (mean difference 0.164 [95% CI 0.011 to 0.317]).ConclusionThe multi‐domain intervention showed significant efficacy for the prevention of cognitive decline among Japanese older adults with the APOE ε4 allele.
The effect of microglia activation on cerebral injury induced by conditional Tpk knockout in brain neurons of adult mice and the mechanism exploration
Authors: Zhao Ruoqi , Jin Boru , Zhong Chunjiu , Sang Shaoming 
Published: December 2023

AbstractBackgroundWe previously designed and constructed the neuronal Tpk conditional knockout mouse model, which can simulate various pathophysiological changes of Alzheimer’s disease (AD). The objective of this study was to explore the effect and mechanism of microglia activation induced by the conditioned neuronal Tpk knockout on neuronal injury.MethodWe selected the 3‐month‐old CaMKII‐CreERT2/+
; Tpkfl/fl
(Tpk‐cKO) and negative control mice Tpkfl/f
(Control) from the same nest. The mice were given CSF1R inhibitor (PLX3397)respectively during the whole stage (the 2nd∼10th weeks after induction), the late stage (the 6th∼10th weeks after induction), and the early stage (the 2nd∼6th weeks after induction) to eliminate microglia during whole/early/late stage. Besides, the single‐cell RNA sequencing (scRNA‐seq) analysis was performed at different time courses.ResultAccording to scRNA‐seq analysis, Microglia can be divided into different subgroups, which have different functions and proportions, and their pseudotime states were quite distinct. Among them, microglia subgroup 5 was highly distributed in the early pseudotime state playing the role of immune regulation and neuroprotection, while subgroup 6 was mainly distributed in the late pseudotime state contributing to phagocytosis damage. Therefore, when microglia were eliminated for the whole period, the protective effect of microglia was completely lost leading to more cerebral injury. Eliminating microglia at the early stage, the cerebral injury was alleviated because the repopulated microglia was still in the early pseudotime state performing immunomodulatory and neuroprotective functions. Eliminating microglia at late stage can also mitigate the cerebral injury, mainly because it not only has received the immunomodulatory and neuroprotective effects in the early stage, but also reduce the phagocytic damage in the late stage.ConclusionThe overall effect and mechanism of microglia activation induced by neuronal Tpk conditional knockout on cerebral injury are distinct in different stages, which is associated with the function and proportion of microglia clusters. The major effect of microglia at the early stage was immunoregulation and neuroprotection induced by cluster 5, and the general effect of the late stage was phagocytic damage mainly provided by cluster 6.
A passive, neural correlate of verbal fluency in Mild Cognitive Impairment using Fastball neurocognitive assessment
Authors: Alderman Sophie , Coulthard Elizabeth , Stothart George 
Published: December 2023

AbstractBackgroundFastball provides a passive and objective measure of an individual’s ability to discriminate between different visual categories using Fast Periodic Visual Stimulation and EEG. Our previous work adapted this approach to assess recognition memory in Alzheimer’s disease (Stothart et al., Brain, 2021). This research builds on previous findings by expanding the range of cognitive functions assessed to include visuo‐perceptual performance, and working with patients in an earlier stage of dementia, i.e., Mild Cognitive Impairment (MCI). The aim was to determine whether Fastball responses are sensitive to visuo‐perceptual performance in the early stages of dementia (MCI).MethodAll EEG data were collected in patients' homes using low‐cost, portable systems. Healthy older adult controls (n = 56, ACE‐III = 96 +‐ 6) and MCI patients (n = 50, ACE‐III = 82 +‐ 21) completed a battery of Fastball and neuropsychological tasks (ACE‐III, Freiburg visual acuity) designed to assess visuo‐perceptual performance. We created a letter recognition Fastball task using diffeomorphically scrambled letters as standards and whole letters as oddballs, see Figure 1.ResultA one‐way (Group; Old vs MCI) ANCOVA, controlling for basic steady state magnitude, was conducted to test for differences in oddball responses. Controls had significantly increased oddball responses compared with MCI patients (F (1,103) = 9.61, p = .003, d = 0.48). Oddball responses did not correlate with any neuropsychological measure of vision, but correlated strongly with verbal fluency performance as measured by the ACE‐III, (MCI patients (r(48) = .46, p = .001), controls (r(54) = .34, p = .01)), see Figure 2. There were no correlations between oddball responses and any other neuropsychological measure.ConclusionThese results were not anticipated as we originally hypothesised that oddball responses would correlate with visual performance. Instead, the specific relationship with verbal fluency performance indicates that the Fastball letter recognition task may provide a novel, passive correlate of verbal fluency performance in early dementia. We propose that whole letter oddball stimuli are more salient to participants with greater verbal fluency, resulting in larger oddball responses. A passive measure of verbal fluency could potentially bypass educational and linguistic confounds that can affect traditional measures of verbal fluency performance.
Typologies of caregiving: Understanding support needs of carers across four continents
Authors: Cartwright Tina J , Knight Fauzia , Ridge Damien , Loveday Catherine , Roeser Jannice , Weidner Wendy S , Halton Candida C 
Published: December 2023

AbstractBackgroundCaregivers play an essential role in supporting people living with Alzheimer’s disease globally. Cross‐country research on caregivers’ experiences of coping is a prerequisite to developing useful trans‐cultural guidelines for support organisations. While some coping strategies of caregivers globally have been identified, these are neither well understood or elaborated, nor linked effectively into carer support offerings.MethodsIn partnership with Alzheimer’s Disease International (ADI) and Roche, we conducted in‐depth qualitative interviews with photo‐elicitation with 34 caregivers from UK, US, Brazil, and South Africa to understand critical factors in coping during and after the pandemic. Inductive narrative analysis of data and participant generated images coded to dominant themes (Relationships and Caring role) were developed with input from global and national charity and industry sectors.ResultsWe uncovered four caregiving styles: Empaths used emotion‐focused strategies to construct their caring role ('put yourself in that person’s shoes’). They tended to develop strong coping skills, but needed psychosocial support and time specific information. Organisers used problem‐focused strategies and sought information and training early on ('I’m a pretty good expert now’). They developed strong narratives of organisation, advocacy and expertise. Non‐identifiers managed some aspects of the caring role but felt isolated and lacked knowledge and expertise ('do everything I can…there’s nobody else’). They sought others to manage disease related support. Reluctants struggled with unwanted caring duties ('I didn’t sign up for this’). They needed support in coming to terms with their loved one’s diagnosis and professional help with the day‐to‐day caring role.ConclusionOur findings highlight the need for tailored user‐driven support offerings, that begin with the individual carer’s experiences and needs. Our typology will be used in the communication and development of findings and best practice guidelines to inform charities and policy makers about cost effective ways of tailoring support to fit individual carer circumstances globally.
Developing a preference‐based quality of life for people living with dementia in Vietnam
Authors: Nguyen Kim Huong 
Published: December 2023

AbstractBackgroundIn Vietnam, dementia‐related quality of life is neither discussed openly nor considered in clinical and implementation trials. Subsequently, dementia care is not designed to achieve valued care that maintains or improves quality of life for Vietnamese living with dementia. In this project, we will develop a preference‐based measure to explore and quantify the quality of life priorities for people living with dementia in Vietnam.MethodWe propose a discrete choice experiment that contains two integral components. First, a series of focus groups will be conducted to explore the quality of life priorities in Vietnamese people who live with dementia. Participants will be asked to consider what quality of life means to them and discuss everyday things and activities that contribute or detract from quality of life, and to rank those activities in importance. Second, a discrete choice experiment will use such information to quantify the tradeoff between quality of life priorities. Participants will be asked to choose between scenarios that contains elements that contribute or take way their quality of life. Participant criteria are people with dementia, their family caregivers and adults aged 55+.ResultThe project will improve the knowledge and measurement of dementia‐related quality of life in Vietnam. The concrete outcomes will include: (1) the list of quality‐of‐life priorities and (2) the relative ranking of those priorities. The latter can be used to summarise quality of life rating into an index to measure quality adjusted life years – a common key outcome that enables comparison of effectiveness and cost‐effectiveness across interventions for people with dementia.ConclusionThe project outcome will enable Vietnamese people who live with dementia, for the first time, to express their quality of life priorities. This will change public awareness and discussion about dementia and appropriate care for people with dementia in the community. This will inform the quality of life data collection for trials and studies conducted in Vietnam. The instrument will enable the calculations of quality adjusted life years and the evaluation of economic values of dementia interventions.
Optimizing plasma biomarkers combinations for the detection of amyloid pathology in cognitively unimpaired individuals
Authors: Contador José , Milà‐Alomà Marta , Escalante Armand González , Ashton Nicholas J. , Shekari Mahnaz , Ortiz‐Romero Paula , Karikari Thomas K , Vanmechelen Eugeen , Day Theresa A. , Dage Jeff L. , Zetterberg Henrik , Gispert Juan Domingo , Blennow Kaj , Suárez‐Calvet Marc 
Published: December 2023

AbstractBackgroundSome Alzheimer’s disease (AD) plasma biomarkers are altered in preclinical stages. However, the optimal combination of plasma biomarkers for detecting preclinical AD has not yet been established.MethodWe investigated 361 cognitively unimpaired individuals of the ALFA+ cohort with plasma biomarkers: Aβ42/Aβ40, p‐tau181, p‐tau231, GFAP, and NfL (Simoa‐based), and p‐tau217 and t‐tau (MSD‐based). All participants had CSF Aβ42/Aβ40 levels and 328 had [18F]flutemetamol amyloid‐PET.We tested different plasma biomarkers combinations (z‐score), with sex and age, in logistic regression models, using Ab‐status (Ab‐positive defined as CSF Aβ42/Aβ40<0.071 or amyloid‐PET>12CL) as dependent variable. For each combination, we selected a “best model” (lowest AIC; BM) and a “parsimonious model” (fewer variables, ΔAIC<2, similar AUC; PM). Biomarkers with p>0.10 were removed in PM. We used DeLong tests to compare AUCs between all the possible combinations in PM and BM, PM, plasma biomarkers alone or age and sex. The statistical threshold was set at p<0.05.ResultTable 1 shows sample characteristics.When using CSF Aβ42/Aβ40 to define Ab‐status, BM included the combination of plasma Aβ42/Aβ40, GFAP, p‐tau181, p‐tau217, p‐tau231 and t‐tau (AUC = 0.85), while PM included Aβ42/Aβ40, GFAP, p‐tau217 and p‐tau231 (AUC = 0.84). Plasma Aβ42/Aβ40, GFAP and ptau231 (AUC = 0.83) or Aβ42/Aβ40, ptau217 and ptau231 (AUC = 0.83) retained similar accuracy versus BM/PM, while plasma Aβ42/Aβ40 and ptau231 (AUC = 0.82) was similar versus PM. All these biomarkers’ combinations had a significantly higher AUC than any of the plasma biomarkers alone or age and sex (Table 2).When using amyloid‐PET to define Ab‐status, BM/PM included the combination of plasma Aβ42/Aβ40, GFAP, ptau181, ptau217 and age (AUC = 0.89). Models with similar performance included: Aβ42/Aβ40, GFAP, ptau181, and ptau217 (AUC = 0.88); Aβ42/Aβ40, GFAP, ptau181 and age (AUC = 0.88); Aβ42/Aβ40, ptau181, ptau217 and age (AUC = 0.88); Aβ42/Aβ40, GFAP and ptau181 (AUC = 0.87); Aβ42/Aβ40, ptau181 and ptau217 (AUC = 0.87); Aβ42/Aβ40, GFAP and ptau217 (AUC 0.86); Aβ42/Aβ40, GFAP, ptau217 and age (AUC 0.86). All these biomarkers’ combinations had a significantly higher AUC than any of the plasma biomarkers alone or age and sex, except Aβ42/Aβ40, GFAP and ptau217 versus ptau217 alone (Table 3).ConclusionDifferent combinations of plasma biomarkers can improve the accuracy to detect Ab‐pathology in cognitively unimpaired individuals and facilitate preclinical AD trials recruitment.