bluuebunny/crossref_metadata_2025 huggingface dataset:
History of preoperative COVID‐19 infection and postoperative cognitive change among older adults undergoing major elective surgeries
Authors: Sanborn Victoria , Enos Sara J , Tremont Geoffrey , Bedrosian Hannah E , Dousis Hunter M , Daiello Lori A
Published: December 2023

Background

Emerging evidence suggests that recovery from COVID‐19 infection may be associated with cognitive decline and possibly, incident dementia. Older adults undergoing major surgeries are at heightened risk for postoperative delirium and delayed cognitive recovery; however, it is unknown whether preoperative COVID‐19 infection is associated with worse perioperative cognitive outcomes. Therefore, the objective of this study was to investigate relationships between history of preoperative COVID‐19 infection and cognitive change following major elective surgery.

Method

The study population consisted of cognitively normal adults, ≥ 65years, enrolled in the Cognitive Recovery After Elective Surgery (CREATES) study, an ongoing investigation of BBB function and perioperative cognition. Participants who completed preoperative baseline and 2‐month postoperative assessments were included in the analyses. Cognitive performance (global function (MoCA) and age‐ and education‐adjusted letter fluency, category fluency, learning, memory) at baseline was compared with 2‐month postoperative test results in the entire sample and among those with/without preoperative COVID‐19. Between‐group differences were analyzed using independent samples t‐tests, chi‐square analyses, and repeated measures ANOVAs.

Result

A total of 34 participants (mean age, 75 [SD] 4.9 years; 83% White; 54% orthopedic surgery) were included. Of these, 10 reported a preoperative, non‐hospitalized COVID‐19 infection and 24 did not have preoperative COVID‐19. No cases of postoperative delirium were observed. In the full sample, there was evidence of cognitive improvement in letter fluency (F = 5.53, p = 0.03, η2 = 0.18) and memory (F = 4.42, p = 0.04, η2 = 0.12), relative to preoperative baseline. On the MoCA, a global cognitive measure, 86% scored within normal range (MoCA ≥ 26) 2 months after surgery. COVID sub‐groups did not differ on baseline demographics, family history, medical, or cognitive variables (all p’s<0.5). There was no effect of time on change in cognitive test scores (all p’s<0.05) at the 2‐month postoperative assessment.

Conclusion

In this modest sample of older surgical patients, history of preoperative COVID‐19 infection was not associated with cognitive decline after surgery; however, postoperative improvement on some cognitive tests was observed in the full sample. Future research in larger populations including biomarkers of neuroinflammation is needed to determine whether older adults with history of COVID‐19 infection are at additional risk of cognitive decline following surgery.
Early metformin initiation was not associated with incident dementia: a population‐based cohort study
Authors: Wu Che‐Yuan , Wang Christa , Saskin Refik , Swardfager Walter
Published: December 2023

Background

Metformin is the first‐line pharmacotherapy for type 2 diabetes. Although metformin was previously suggested to prevent dementia, most existing epidemiologic studies did not adequately address immortal time bias or confounding due to disease severity. We aim to determine the association of metformin with dementia risk using various bias mitigation strategies.

Method

This population‐based retrospective cohort study utilized data housed at ICES (https://www.ices.on.ca/). Using a validated algorithm for diabetes (Specificity = 99.1%, PPV = 91.4%), residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered the cohort. We excluded potential type 1 diabetes or advanced diabetes cases by excluding people with insulin as the first received glucose‐lowering medication. To select people at an early disease stage who could either initiate metformin or start lifestyle interventions alone, we excluded people with hemoglobin A1c <6.5% or ≥8.0% or estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2. Using a landmark analysis to address immortal time bias, the exposure was classified into “metformin monotherapy initiation within 180 days after new diabetes diagnosis” or “no glucose‐lowering medications within 180 days”. To mitigate reverse causality, a 1‐year lag period was applied to the end of the 180‐day landmark period, and therefore follow‐up started 1.5 year after cohort entry. Incident dementia was ascertained using a validated algorithm for Alzheimer’s disease and related dementias (Sensitivity = 79.3%, Specificity = 99.1%). Adjusted hazard ratios (aHR) and confidence intervals (CI) were obtained from propensity‐score weighted Cox proportional hazard models.

Result

Compared to no or delayed metformin initiation (N = 22,369; 1,768 events; 117,414 person‐years), metformin initiation within 180 days (N = 12,331; 978 events; 65,761 person‐years) showed no association (aHR [95% CI] = 1.047 [0.956‐1.147]) with dementia risk over mean follow‐up of 5.28 years. The sensitivity analysis with a 1‐year landmark period also showed no association (aHR [95% CI] = 1.040 [0.942‐1.148]) when comparing metformin initiation within 1 year (N = 13,902; 1,047 events; 68,404 person‐years) to no or delayed initiation (N = 19,078; 1,433 events; 91,917 person‐years).

Conclusion

Early metformin initiation was not associated with a lower dementia risk. The present study does not support metformin as a drug to prevent dementia.
Locus coeruleus hyperactivity in middle age may be associated with better cognitive performance
Authors: Riley Elizabeth , Swallow Khena , Anderson Adam , De Rosa Eve
Published: December 2023

Background

Measuring the health of the locus coeruleus (LC), the brainstem site of the first cellular damage in Alzheimer’s Disease (AD) pathogenesis, is of particular interest for early diagnosis. In both rodents and humans (Elman 2017; Kelberman 2023; Malatt 2022; Weinshenker 2008), increased tonic firing rates have been noted in middle age. This occurs prior to the hypoactivity and reduced functional and structural connectivity associated with cognitive aging (Jacobs 2015; Kelberman 2022; Langley 2022; Prokopiou 2022) . Understanding the mechanism or function behind LC hyperactivity in middle age may be key to identifying individuals on pathological aging trajectories.

Method

Participants (29 younger, 18 middle‐aged, 24 older) performed a dual attention task in the scanner with multi‐echo fMRI and concurrent pupillometry. Cognition was assessed with NIH Toolbox Cognitive Battery (Fluid Composite) and sorted into high (>50th percentile) or low (<50th) categories. Age groupings were determined by a pupillary behavior data analysis.

Results

Pupil (Fig. 1): using a linear mixed effects model to predict the dynamic range‐normalized pupillary response area under the curve (AUC) from age group and trial type, there was a significant effect of age and significant age*trial type interactions. Middle‐aged adults had larger responses than other groups. Using a model to predict AUC from cognitive category and trial type, there was a significant interaction between cognitive category and trial type, with the high cognitive group having larger target and distractor responses.

Blood‐Oxygen‐Level‐Dependent (BOLD) (Fig. 2): using a linear mixed effects model to predict LC BOLD response from age group and trial type, there was no significant effect of age but a significant age*trial type interaction. Middle‐aged adults had larger distractor responses and older adults had smaller target responses. Using a model to predict BOLD response from cognitive category and trial type, there was no significant effect of category, but there was a significant interaction between category and trial type, with the high cognitive group having larger target and distractor responses.

Conclusions

Elevated LC BOLD and pupillary responses to target trials in middle age are associated with better cognitive performance. LC hyperactivity may be adaptive in middle age.
URBAn Native Elders: Risk and Protective Factors for Alzheimer’s Disease and Related Dementias ‐ Overview and Methods
Authors: Nelson Lonnie A , Mednansky Sage W. , Pham‐Lake Camille , Bryne Charlotte , Jones Jacob , Valenzuela Yenny Gabriela , Rivas Rhiannon , Cuellar‐Rocha Priscilla , West Cynthia , Lee Sunny T. , Ali Tauqeer , Collier Ann , Mortenson Ryan , Suchy‐Dicey Astrid M , Muller Clemma , Buchwald Dedra
Published: December 2023

Background

Over 86% of American Indian and Alaska Native elders live in urban metropolitan areas, yet the extant epidemiological data on cognition and aging in this racial and ethnic population has been collected in reservation communities and may have limited generalizability to the larger population. Multi‐faceted, high quality data are needed to assess risk and protective factors in this underserved and understudied population.

Method

We intend to collect medical history, lifestyle and behavioral history, neurocognitive battery, anthropometric measures, blood and urine samples, cranial 3T MRI, rsfMRI, and wrist actigraphy data from 1200 urban‐dwelling Native elders (age 55 and older) across 5 major metropolitan areas: Anchorage, AK; Seattle, WA; San Bernardino, CA; Phoenix, AZ; and Oklahoma City, OK. This initial cohort will be the first in a NIA‐funded longitudinal cohort study to evaluate the brain and cognitive health of this population as they advance in age.

Result

Originally funded in the summer of 2019, data collection was initially delayed due to the pandemic, but was initiated at one site (Phoenix) in the summer of 2021 and is now underway at all 5 field sites, with a total of 260 participants enrolled as of the time of this writing.

Conclusion

This study represents the largest effort to characterize the cognition and brain health of a generalizable sample of urban‐dwelling American Indian and Alaska Native elders to date.
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

Background

Alzheimer’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.

Methods

APP/PS1 (Thy1‐hAPP*V717I/Thy1‐hPS1*A246E) transgenic mice were vaccinated with PRX123s beginning at 3.5 months old for 6 months.

Results

PRX123s 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.

Conclusions

Together 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

Background

Age‐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.

Method

Two 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.

Result

The 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).

Conclusion

Our 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

Background

ADRD 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.

Method

Approximately 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.

Result

Academic‐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.

Conclusion

As 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

Background

The 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.

Method

The 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).

Result

Between 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]).

Conclusion

The 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

Background

We 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.

Method

We 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.

Result

According 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.

Conclusion

The 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

Background

Fastball 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).

Method

All 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.

Result

A 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.

Conclusion

These 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

Background

Caregivers 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.

Methods

In 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.

Results

We 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.

Conclusion

Our 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

Background

In 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.

Method

We 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+.

Result

The 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.

Conclusion

The 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

Background

Some 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.

Method

We 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.

Result

Table 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).

Conclusion

Different combinations of plasma biomarkers can improve the accuracy to detect Ab‐pathology in cognitively unimpaired individuals and facilitate preclinical AD trials recruitment.
Optimal combination of CSF phosphorylated‐tau forms to predict Alzheimer’s disease pathological burden as measured by PET
Authors: Collij Lyduine E. , Gobom Johan , Janelidze Shorena , Ossenkoppele Rik , Smith Ruben , Strandberg Olof , Stomrud Erik , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Zetterberg Henrik , Blennow Kaj , Hansson Oskar
Published: December 2023

Background

Recently, we demonstrated the sensitivity of a novel CSF mass spectrometer‐based assay, which enabled the assessment of multiple phospho‐tau (pTau) forms (pT181, pS199, pS202, pT205, pT217, pT231, and pS396) and two non‐phosphorylated peptides. Initial results suggested that there may be disease associated differences across pTau species. Here, we aimed to investigate the associations between these CSF pTau forms and Alzheimer’s disease (AD) core pathologies as measured by PET.

Methods

We included 352 participants from the BioFINDER‐2 cohort with available CSF mass‐spectrometry quantification and who underwent [18F]flutemetamol and [18F]RO948 PET to assess amyloid‐β (Aβ) and tau burden, respectively (Table1). Aβ burden was determined globally and in an early accumulating region (precuneus). Tau burden was determined for a temporal meta‐ROI and Braak stages (I‐II, III‐IV, V‐VI). The ratio of tau phosphorylated to non‐phosphorylated peptides was additionally determined for pS199, pS202, pT205, pT217. CSF pTau‐forms (ratio‐)levels were log‐transformed. To assess the contribution of Aβ and tau burden on pTau‐forms (ratio‐)levels, we ran multivariable linear regression models including both Aβ and tau PET measures as independent variables, covarying for age and sex. Next, we determined the parsimonious model (i.e. minimal number of predictors within 2 Akaike points of optimal model) of pTau‐forms (ratio‐)levels using R package MuMIn to predict Aβ and tau PET burden in the different ROIs.

Results

In the whole cohort, all CSF pTau‐forms peptide concentrations, except for pS396, were associated with both Aβ and tau PET burden, though to different extents (Figure1). pT217 and pT231 were more strongly associated with Aβ, while pS199 and pT205 were more strongly associated with tau. In Aβ‐positive subjects (Figure1C/D), the association with tau increased across pTau‐forms. For the multivariable parsimonious models, pTau217 consistently showed the strongest contribution to predicting amyloid and tau burden across ROIs (Table2&3). pT231 was also selected when early amyloid burden was assessed. pT205 was only selected to predict tau burden in early ROIs when corrected for the non‐phosphorylated peptide (Table3). In addition, sex significantly contributed to predicting tau‐PET burden across ROIs.

Conclusion

We provide further evidence that measurement of multiple phosphorylated‐tau species could be used to track AD disease progression.
Seizures exacerbate tau spread in the 5XFAD mouse model
Authors: Barbour Aaron J , Hoag Keegan , Li Xiaofan , Zebrowitz Sydney E , Lee Virginia M. M.‐Y. , Talos Delia M , Jensen Frances E
Published: December 2023

Background

Central to the progression of Alzheimer’s disease (AD) is the spread of pathological tau along neuronal connections. This aspect of pathological progression can be recapitulated in WT mice by intracerebral injection of human AD brain derived tau lysate (AD‐tau). AD‐tau spread is enhanced in the amyloidosis mouse model, five times familial AD (5XFAD), suggesting that tau propagation is facilitated by β‐amyloid (Aβ) plaques. Once assumed to simply be a biproduct of Aβ‐induced hyperexcitability, a bidirectional relationship between seizures and AD progression has been established. Our lab has demonstrated worsened tau and Aβ pathology and cognitive deficits in AD patients with seizure history and in seizure‐kindled 5XFAD mice. Thus, we hypothesized that seizures would exacerbate the spread of AD‐tau in the 5XFAD mouse model and that 5XFAD mice would show increased seizure susceptibility and related neuronal activity.

Method

To investigate seizure‐pathology interactions, we crossed the 5XFAD mouse model with targeted recombination in active populations (TRAP; 5X‐TRAP) mice to permanently label seizure‐activated neurons. We injected AD‐tau unilaterally into the hippocampus and overlying cortex (1 µg/site) at 3 months of age in 5X‐TRAP and WT‐TRAP littermates. Seizures were induced with pentylenetetrazol (PTZ) kindling 2‐3 weeks following surgery and seizure‐activated neurons were labeled (tdTomato) on the final day of kindling via 4‐hydroxytamoxifen administration (50 mg/kg). Mice were euthanized three months post AD‐tau injection and immunohistochemistry for phospho‐tau (AT8) was performed.

Result

We found that kindled 5X‐TRAP mice show increased pathological tau (% AT8 coverage) in the dentate gyrus (DG) and CA1 contralateral to injection site compared to non‐kindled mice (p<0.05). We also found a trend towards elevated AT8 in the ipsilateral DG across seizure kindled groups (p = 0.083) and that 5X‐TRAP mice showed increased AT8 in the ipsilateral CA1 compared to WT‐TRAP (p<0.05). Further, we found a trend towards increased seizure susceptibility (0.059) in 5X‐TRAP mice and significantly increased seizure activated neurons (tdTomato+) in the DG of kindled 5X‐TRAP mice compared to WT‐TRAP (p<0.05).

Conclusion

Overall, our data further indicate a bidirectional relationship between seizures and AD. We also demonstrate that seizures facilitate the spread of pathological tau, thus suggesting that targeting seizure activity may slow AD progression.
A brain‐seeded fibril amplification models the aggregation process of tau in Alzheimer’s disease for drug discovery
Authors: Santambrogio Alessia , Metrick Michael , Löhr Thomas , Horne Robert , Vendruscolo Michele
Published: December 2023

Background

The microtubule‐associated protein tau is implicated in the development of a class of diverse neurodegenerative disorders, referred to as tauopathies, with symptoms of dementia and parkinsonism. Tauopathies comprise more than 20 clinicopathological entities, including Alzheimer’s disease, which accounts for 70% of dementia cases worldwide. In combination with clinical diagnosis and neuropathology, the reconstruction of different tau filaments by cryogenic electron microscopy (cryo‐EM) further points to the presence of distinct tau folds. The knowledge of these disease‐specific aggregate conformers provides a platform for the establishment of novel diagnostic methods and more tailored therapeutic approaches.

Method

In order to investigate this problem, this project aims to selectively amplify tau in vitro from human brain homogenates affected by Alzheimer’s disease (AD) and Pick’s diseases (PiD). Kinetic analysis for drug discovery for the specific process of tau aggregation that takes place in Alzheimer’s disease was performed.

Result

Strain discrimination was achieved, with a significant acceleration relative to the off‐target control, suggesting formation of two different fibril structures. Cryo‐EM was performed to confirm whether the in vitro AD‐like tau aggregates resembled those extracted from brains.We identify specific tau aggregation inhibitors, through in silico docking to binding sites on the surface of the cryo‐EM structure of tau fibrils adopting an AD fold.

Conclusion

The application of this line of research is illustrated by a study of the aggregation kinetics of AD‐like tau fibrils, and of its potential in drug discovery. In perspective, the approach that we present offer novel opportunities for the systematic in vitro study of the tau aggregation process as it may happen in the human brain.

References

(WHO), W. H. O. et al. (2019). Dementia fact sheet.

Alzheimer’s disease facts and figures. Alzheimer’s and Dementia
18, 700‐789 (2022).

Chia, S. et al. Structure‐Based Discovery of Small‐Molecule Inhibitors of the Autocatalytic Proliferation of alpha‐Synuclein Aggregates. Mol Pharm (2022).
Safety, Pharmacokinetics and Immunogenicity of Single and Multiple Ascending Doses of the Anti‐Tau Therapeutic Antibody E2814: A Phase 1, First‐In‐Human (FIH) Study in Healthy Subjects
Authors: Rawal Sumit , Yagi Takuya , Boyd Peter , Aluri Jagadeesh , Wildsmith Kristin R , Reyderman Larisa
Published: December 2023

Background

E2814 is an anti‐tau therapeutic monoclonal antibody (mAb) which is being developed as a potential disease‐modifying therapy for Alzheimer’s disease (AD). E2814 inhibits the propagation of pathological tau species by binding to the microtubule binding region (MTBR). This study evaluated safety, pharmacokinetics (PK), and immunogenicity of single and multiple doses of E2814.

Methods

This randomized, placebo‐controlled study evaluated 5 single ascending doses (SAD) and 4 multiple ascending doses (MAD) in healthy subjects. Subjects (n = 8/cohort) received single or multiple (every 4 weeks) 1‐hour IV infusions of E2814 (or placebo). Safety was evaluated through a review of adverse events (AE), clinical laboratory test results, physical examination, electrocardiogram results, and vital signs. Serial blood and CSF samples for measurement of serum and CSF E2814 concentrations by a validated electrochemiluminescence (ECL) assay were obtained at prespecified time‐points. The serum PK parameters were estimated using non‐compartmental analysis. Anti‐drug antibodies (ADA) in serum were measured by a validated ECL assay.

Results

E2814 has an adequate single and multiple dose safety profile. No treatment‐emergent serious AEs, severe AEs, infusion‐related reactions, or dose limiting events were observed. There was a dose‐related increase in serum and CSF E2814 exposures. The median time to maximum E2814 concentrations in serum was 1.5 to 2 h. The half‐life of E2814 was 23 days which is typical of mAb. In SAD, serum AUC and Cmax were approximately dose proportional at lower doses and greater than dose‐proportional at higher doses. In MAD, accumulation based on Cmax and AUC was ∼1.2 and 1.3‐fold, respectively by the third dose in all dose group. The serum‐to‐CSF concentration ratio ranged between 0.1 to 0.3%. The immunogenicity to E2814 was low. In SAD, 5 subjects had transient low level ADA titers by last study day. In MAD, 1 subject had a confirmatory positive ADA at baseline prior to dose on Day 1. PK in the ADA positive subjects was comparable to that of ADA negative subjects.

Conclusion

E2814 presented an adequate safety and immunogenicity profile in healthy adults. E2814 PK was comparable to that with other mAbs. These results support further development of E2814 as a potential disease‐modifying therapy for AD.
Identification of Hippocampal and Amygdala Subfields Predictive of MoCA Scores in Patients with Dementia with Lewy Bodies
Authors: Sudhakar Tejaswi D , Levendovszky Swati Rane , Zabetian Cyrus P , Tsuang Debby W , Pillai Jagan A. , Rao Stephen M. , Oguh Odinachi , Lippa Carol , Lopez Oscar L. , Berman Sarah , Irwin David J. , Galasko Douglas R. , Litvan Irene , Marder Karen , Honig Lawrence S. , Fleisher Jori E , Galvin James E , Bozoki Andrea , Taylor Angela , Sabbagh Marwan , Wint Dylan , Cholerton Brenna , Leverenz James B , Olson Valerie
Published: December 2023

Background

Hippocampal and amygdala subfields variably affect cognitive impairment in neurodegenerative diseases. Subfields of these regions can be well segmented using modern neuroimaging tools but their role in neurodegenerative disease is under active investigation. In this study, we identified hippocampal and amygdala subregions predictive of cognitive performance and motor symptoms severity measured by MoCA (Montreal Cognitive Assessment) and MDS‐UPDRS III, respectively, in patients with dementia with Lewy Bodies (DLB).

Method

We selected all participants with probable DLB (N = 48, mean age = 71±7 years, 15% female) enrolled in the Dementia with Lewy Bodies Consortium (DLBC) as of July 2022, with concurrent measures of 3D T1 MRI sequence, MoCA, and MDS‐UPDRS III scores. We performed cortical reconstruction and volumetric segmentation of hippocampal subfields and nuclei of the amygdala using FreeSurfer (v 7.2). We used combat harmonization to account for site and scanner differences. We trained and applied a bootstrapped, bidirectional stepwise regression model of 29 predictor variables comprised of sub‐fields and mean cortical thickness against MoCA and MDS‐UPDRS III, respectively, with an 80‐20 train‐test split ratio, and 5000 repetitions, corrected for age and sex.

Result

Subfield segmentation is shown in Figure 1A. The best fitting model for MoCA included mean cortical thickness, parasubiculum, hippocampal and amygdala transition area, corticoamygdaloid transition area, and CA3 body (Figure 1B, adjusted R2 = 0.51). The best fitting model for MDS‐UPDRS III included the cortical nucleus of the amygdala and CA1 body (Figure 1C, adjusted R2 = 0.22). This model was considered a poor fit. We considered MoCA for further analysis and closely predicted scores in our 20% partitioned test sample (Figure 2A, R2 = 0.38).

Conclusion

We report model‐based selection of hippocampal and amygdala subfields to predict MoCA scores in DLB. Atrophy in these regions has been associated with global cognitive deficit in mild cognitive impairment and Alzheimer disease cohorts. The model fit for MDS‐UPDRS III scores was poor, providing evidence that these brain regions do not serve a role in motor control.