bluuebunny/crossref_metadata_2025 huggingface dataset:
Life’s Simple 7 Relates to Better Cognitive and Brain Health in Individuals with Autosomal Dominant Frontotemporal Dementia
Authors: VandeBunte Anna M , Kramer Joel H. , Casaletto Kaitlin B. , Paolillo Emily W. , Saloner Rowan , Lee Hyunwoo , Hsiung Ging‐Yuek Robin , Staffaroni Adam M. , Lee Shannon Y. , Tartaglia Carmela , Heuer Hilary W. , Boeve Brad F. , Boxer Adam L. , Rosen Howard J.
Published: December 2023

Background

Cardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life’s Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD.

Method

243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD.

Result

Mutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913)

Conclusion

Better cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD.
Development and Comparison of a Novel Mid‐Region Directed p‐Tau 181 Assay with Tau Positron Emission Tomography in Alzheimer’s Disease
Authors: Tagai Kenji , Tatebe Harutsugu , Matsuura Sayo , Zhang Hong , Kokubo Naomi , Matsuoka Kiwamu , Endo Hironobu , Oyama Asaka , Hirata Kosei , Shinotoh Hitoshi , Kataoka Yuko , Matsumoto Hideki , Oya Masaki , Kurose Shin , Takahata Keisuke , Ichihashi Masanori , Kubota Manabu , Seki Chie , Shimada Hitoshi , Takado Yuhei , Kawamura Kazunori , Zhang Ming‐Rong , Higuchi Makoto , Tokuda Takahiko
Published: December 2023

Background

Several blood‐based phosphorylated tau (p‐tau) assays that focus on the N‐terminus have been developed and established as non‐invasive biomarkers for detecting Alzheimer’s disease (AD) pathologies from their early stages. However, the p‐tau measured by these assays may not necessarily reflect the accumulation of tau lesions in the brain due to correlation with Aβ burden. Therefore, there remains a significant unmet need to develop blood‐based tau biomarkers that are interchangeable with tau deposits in the brain.

Methods

We have devised a novel Simoa assay that can detect N‐ and C‐terminally truncated fragment of p‐tau181 in plasma (QST assay), utilizing an antibody against the mid‐region of tau protein for capture, and an antibody AT270 for detection. The plasma p‐tau181 was measured with both the QST assay and a conventional p‐tau181 Simoa assay (Quanterix) in 164 subjects, including 40 cognitively normal (CN) individuals, 48 with AD continuum, 50 with progressive supranuclear palsy, and 26 with other frontotemporal lobar degeneration, who underwent Aβ (11C‐PiB) and tau (18F‐PM‐PBB3, Florzorotau) positron emission tomography (PET) scans. Subsequently, we conducted a head‐to‐head comparison of p‐tau181 assays in correlation with the imaging biomarker and cognitive dysfunction.

Results

QST p‐tau assay demonstrated inferior performance compared to the Quanterix assay in the qualification of Aβ PET (QST assay: AUC = 0.771, Quanterix assay: AUC = 0.867). Neither assay showed a significant correlation with Aβ PET accumulation in the AD group. Meanwhile, the QST assay exhibited excellent correlations with tau PET accumulation in regions indicative of AD including temporal cortex and neocortex (p<0.0005), whereas the Quanterix assay demonstrated non‐linear correlations with tracer binding. In trajectories from CN to AD continuum, the QST assay exhibited a linear association, as well as tau PET accumulation, while the Quanterix assay exhibited a sigmoidal curve association.

Conclusions

We have developed a new p‐tau181 assay directly correlated with tau PET accumulation. This quantitative system serves as a promising surrogate marker for tau lesions in the AD brain, which facilitate screening and monitoring of tau deposits in various settings, including developing disease‐modifying therapeutics.
Functional connectivity of the frontoparietal control network is positively associated with cognition, independent of amyloid and tau burden, in the A4 study
Authors: Boyle Rory , Shirzadi Zahra , Coughlan Gillian T , Properzi Michael J , Chhatwal Jasmeer P. , Buckley Rachel F. , Sperling Reisa A. , Schultz Aaron P.
Published: December 2023

Background

The Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) study is the first secondary prevention trial of an anti‐amyloid therapy, solanezumab, in cognitively unimpaired older adults with elevated amyloid‐beta (Ab)‐PET burden. The inclusion of resting‐state functional connectivity MRI (fcMRI) as a secondary outcome measure is a novelty for clinical trials. Despite promising longitudinal findings, there is mixed evidence for cross‐sectional associations between functional connectivity in the default mode (DMN) and frontoparietal control (FPCN) networks, with Ab, tau, and cognition. Here, in a large cross‐sectional sample, we investigate these associations and assess whether fcMRI accounts for variability in cognition that is not attributable to Ab or tau.

Method

1,641 participants from A4 and the LEARN observational arm with fcMRI passed quality control and had complete data for sociodemographics, cognition, and Ab (Florbetapir)‐PET (Table 1). A subset had tau (Flortaucipir)‐PET (n = 420). Within‐network connectivity estimates of the default mode (DMN) and left and right frontoparietal control networks (FPCN) were obtained using template‐based rotation (Fig. 1).

Using hierarchical regressions, we examined the independent associations of functional connectivity with Ab burden (mean cortical standardized uptake value [SUVr]), tau burden (mean of inferior temporal and entorhinal SUVrs), and cognition (Preclinical Alzheimer’s Cognitive Composite), independent of covariates (age, sex, education level, head motion, scanner and, where applicable, Ab and/or tau burden).

Result

Ab and tau burden were not independently associated with DMN or right FPCN connectivity. Higher tau was associated with reduced left FPCN connectivity, independent of Ab. Stronger left and right FPCN connectivity were associated with better cognition, independent of Ab and tau (Table 2). This association was stronger for the left FPCN.

Conclusion

FPCN functional connectivity is associated with better cognition, independent of Ab and tau burden. This association was strongest in the left FPCN and supports evidence that implicates FPCN connectivity in cognitive reserve and resilience. While this association is robust, weak effect sizes suggest that functional connectivity explains a limited amount of variability in cognition after accounting for covariates and AD pathology. Future release of the A4 study longitudinal data will enable quantification of the added value of fcMRI in AD clinical trials.
Enrollment and Scientific Progress of the Multisite SuperAging Research Initiative
Authors: Rogalski Emily J , Huentelman Matthew J , Roberts Angela C , McIlroy William , Van Ooteghem Karen , Finger Elizabeth , Lim Andrew , Okonkwo Ozioma , Goldstein Felicia C , Martersteck Adam , Parrish Todd , Scholtens Denise , Gill Nathan Pruneau , Tull Mary Beth , Pina Yasmin , Dorn Megan , Carolan Padraig , Zemlock Debby , Eldes Fatima , Amador Gabriella , Mather Molly A , Engelmeyer Janessa , Weintraub Sandra , Geula Changiz , Mesulam Marsel , Maher Amanda Cook
Published: December 2023

Background

The SuperAging Research Initiative is a multisite consortium focused on identifying factors promoting extraordinary cognitive aging. The designation of SuperAger is reserved for individuals age 80+ who have episodic memory capacity that would be considered at least average for those 2‐3 decades younger. The presence of such outliers raises questions of fundamental importance to the neurobiology of brain aging, resilience, resistance, and avoidance of cognitive decline caused by Alzheimer’s disease. The original study of SuperAgers emerged at Northwestern and helped establish the phenotype. The SuperAging Research Initiative was established in 2021 and is focused on increasing minority representation and expanding deep phenotyping of this unique population.

Methods

Harmonized data collection has been initiated across the five sites including behavioral, health, biologic, genetic, environmental, socioeconomic, psychosocial, neuroanatomic, and neuropathologic factors. Here we summarize the initial recruitment progress and baseline characteristics of the current cohort.

Results

We will present the organizational structure, progress, and baseline characteristics of the cohort to date. The SuperAging Research Initiative includes three Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology) and two Research Projects. Enrollment (target, n = 500) has commenced across four U.S. Sites located in Illinois, Wisconsin, Michigan, and Georgia, and a Canadian Site in Southwest Ontario, with a focus on enrollment of Black SuperAgers and Cognitively Average Elderly Controls with similar demographics. Project 1 uses state‐of‐the‐art wearable technology to obtain quantitative measurements of daily life including, sleep, physical activity, autonomic responsivity, and social engagement to determine whether SuperAgers have relatively preserved physiologic and behavioral ‘complexity’ compared to Controls. Project 2 focuses on transcriptomic, genetic, and protein profiling to examine central and peripheral immune and inflammatory system parameters of SuperAgers.

Conclusions

By identifying factors contributing to superior memory performance in old age, outcomes may help isolate modifiable factors that promote healthspan and perhaps also prevent age‐related brain diseases such as Alzheimer’s disease.
Familial relatedness in genetic frontotemporal dementia cohorts: findings from the international Frontotemporal Dementia Prevention Initiative
Authors: Ramos Eliana Marisa , Mirza Saira S. , Wojta Kevin , Yang Zhongan , Paterson Andrew D. , Rogaeva Ekaterina , Brushaber Danielle , Foroud Tatiana M. , Forsberg Leah K. , Heuer Hilary W. , Russell Lucy L. , Lago Argentina Lario , Rademakers Rosa , Boeve Brad F. , Rosen Howard J. , Rohrer Jonathan D. , Boxer Adam L. , Masellis Mario , Geschwind Daniel H. ,   GENFI and ALLFTD consortia
Published: December 2023

Background

Given the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large‐scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses.

Methods

Genome‐wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy‐Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two‐stage approach, to calculate pairwise identity‐by‐descent (IBD) estimates and KING coefficients, followed by family‐network identification and pedigree reconstruction using PRIMUS.

Results

First, we calculated IBD estimates among all participants by restricting pairs to those with estimates>0.1875 (up to second‐degree relatives). Overall, we identified a total of 292 second‐degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD‐causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi‐site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry‐based analysis among participants with estimated European ancestry, using the KING‐robust algorithm.

Conclusions

These lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies.
Causal Associations Between Plasma Protein Levels and Alzheimer Disease
Authors: Guen Yann Le , Belloy Michael E , Kasireddy Nandita , He Zihuai , Greicius Michael D
Published: December 2023

Background

The aim of this study was to infer causal relationships between protein levels measured in blood and the risk of late‐onset Alzheimer disease (AD).

Method

Two‐sample Mendelian randomization (MR) was used to infer the causal effect of protein levels on AD risk. Summary statistics from genome‐wide association studies (GWAS) for 4,907 SomaScan aptamers (measuring 4,719 proteins) from Ferkingstad et al. (2021) in 35,559 Icelanders (average age = 55±17years), and for AD GWAS from Bellenguez et al. (2022). Instruments for exposures were selected at p < 5×10−8 and p < 5×10−6 thresholds respectively for the main and sensitivity analyses. Instruments were pruned for linkage disequilibrium (r2 < 0.0001) to ensure selection of independent instruments. Because APOE is highly pleiotropic and exposure effect size is hypothesized by MR not to be larger than the outcome (Steiger filtering), thus variants within ±1MB from APOE were removed in the MR‐analysis. Two tests were considered: Inverse‐Variance‐Weighted and Weighted‐Median, which allows robust MR estimates even when some invalid instruments are included.

Result

Among known AD‐GWAS genes, TREM2, PILRA, ACE, CR1, and BIN1 protein levels were associated with AD. Proteins without prior AD‐GWAS links were also found to be associated with AD including: PPBP, NRP2, AZGP2, and TNFSF13B/BAFF (Figures 1&2). Interestingly, APOE and KLOTHO levels were not associated with AD (Figures 3&4), though increased APOE level significantly associated with increase AD risk when including cis‐APOE variants at p < 5×10−6 (Figure 5).

Conclusion

Our study informs the directionality of association between certain plasma protein levels and AD risk, and prioritizes candidate proteins to be considered for AD drug development.
Contactless fall detection with radio frequency sensors for the aging population
Authors: Khan Arshia A , Johnson Brian B , Snyder Kristine
Published: December 2023

Background

Falls remain a primary concern for People with Dementia (PwD) living in long‐term care facilities (LTCFs) despite many prevention and intervention methods that have tried. Current fall detection monitoring systems use wearable or vision‐based sensors. The problem is research has shown that many seniors will not consistently wear a device on their body or allow cameras in their living space because of privacy concerns that severely limit the technology user acceptance. The current standard of care is self‐report or eyewitness and therefore fall events are often undetected and underreported due to human error. Hence, we are proposing a solution to address this unmet need with a novel fall management system engineered with radio frequency (RF) sensors that do not require an individual to wear or interact with a device.

Method

Six healthy participants simulated three types of falls, medial and lateral, anterior and posterior, and collapse in the Dementia and Elderly Care Robotics and Sensing (DECRS) Lab, University of Minnesota Duluth. The sensor was installed in the lab as it would be in the resident room of an LCTF. The simulated room included a bed, chair, and mattress on the floor to protect the participants.

Result

Our study found that the contactless fall detection and activity system identified falls at overall sensitivity rate of 89% with a specificity of 100% in 748 tests and activity was identified at 90%. Our system identified “medial and lateral” falls with a 92% sensitivity, “anterior and posterior” falls with a 91% sensitivity, and “collapse” falls with a 75% sensitivity.

Conclusion

Contactless sensing holds tremendous potential for monitoring individuals living with AD/ADRD and the elderly population for aging in place. LTCFs that are short staffed could benefit by utilizing tools that augment the capabilities of nurses with a continuous collection of patient‐generated health data (PGHD) and a notification system that is integrated with existing workflows and only send alerts for potential events that would require immediate attention.
Humanoid Mobile Robots and wearable sensors improve the quality of care and address worker shortages in nursing homes
Authors: Khan Arshia A
Published: December 2023

Background

Technology has been identified as a solution to address the growing healthcare worker shortages(Harp, 2023). Humanoid robots have great potential to help augment care in elderly and people affected with dementia (Khan & Anwar, 2020; Joseph et.al, 2018).

Humanoid robots and wearable sensors were deployed in eight nursing homes to help address healthcare worker shortages and augment care of elderly and people affected with dementia. The resident satisfaction and quality of life annual survey conducted by the Minnesota Department of Human Services revealed an improved satisfaction and quality of life in the domain of activities in the nursing homes that deployed robots when compared to the nursing homes that did not deploy the robots. The pre and post data gathered revealed that the residents felt happier, more cared for, less tired and less frustrated after interacting with the robots. The staff feedback indicates that the staff had time to address their chores while the robots engaged teh residents.

Method

Two humanoid robots and ten wearable sensors per facility were deployed in 8 different nursing homes. The robots were programmed to address the domains of physical, emotional/social and cognitive wellbeing. Four forms of data ‐ 1) nursing home resident satisfaction and quality of life data gathered by the Minnesota Department of Human Services; 2) pre and post surveys conducted before and after interactions with the robots; 3) weekly feedback was from the healthcare staff and wearable sensor data.

Result

The nursing home resident satisfaction and quality of life data gathered annually by the Minnesota Department of Human Services revealed improvement in the satisfaction and the quality of life domain of activities in the nursing homes that deployed humanoid robots versus the nursing homes that did not deploy humanoid robots. The pre and post surveys conducted before and after the interactions with the robots showed 17.4% improvement in their happiness, 4.3% more cared for,10% less tired and 14.5% less frustrated after engaging in the activities with humanoid robots.

Conclusion

Humanoid robots and wearable sensors have proved to help improve the quality of life of elderly.
Amyloid‐dependent tau phosphorylation drives faster accumulation of tau aggregates in female
Authors: Wang Yi‐Ting , Therriault Joseph , Servaes Stijn , Tissot Cécile , Rahmouni Nesrine , Arias Jaime Fernandez , Benedet Andrea Lessa , Mathotaarachchi Sulantha , Stevenson Jenna , Ashton Nicholas J. , Karikari Thomas K , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro
Published: December 2023

Background

The high prevalence of Alzheimer’s dementia in females have long puzzled researchers in the field. Despite similar amyloid levels, females show higher load of neurofibrillary tangles (NFTs). Previous literature proposed that amyloid‐β (Aβ) and phosphorylated tau (p‐tau) synergism accelerates biomarker abnormalities. However, it remains to be answered whether this synergism is the driving force behind faster tau progression in females. The overarching goal of the study wa to investigate whether amyloid‐β aggregates differentially impose tau hyperphosphorylation and neurofibrillary tangles formation in a sex‐specific manner.

Method

In this longitudinal study, we assessed 287 participants from TRIAD cohort at McGill University Research Centre for Studies in Aging. Cerebral Aβ and tau deposition were assessed with positron emission tomography (PET) radiotracers [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240, respectively. Cerebrospinal fluid (CSF) p‐tau181 and p‐tau217 were also measured (analysed at the Clinical Neurochemistry Laboratory at the University of Gothenburg, Sweden). Regression and voxel‐based models with interaction terms were used to evaluate baseline tau load and NFT accumulation rate as a function of sex and baseline biomarkers (Aβ and p‐tau).

Result

We identified sex difference in the relationships between CSF p‐tau, Aβ and NFT (Fig 1). Specifically, voxelwise analyses demonstrated that female presented stronger positive correlations between CSF p‐tau and AD core biomarkers (Aβ and NFT). Furthermore, we discovered that Aβ and CSF ptau181 interactively potentiated tau accumulation in females but not males (Fig 2, Table 1). Together, the present results support that Aβ load imposes higher tau aggregation in females.

Conclusion

Aβ‐dependent tau phosphorylation was the key driver for faster NFT accumulation observed in female.
A mobile application (chatbot) to automate delivery of sleep‐dependent memory tasks
Authors: Lam Aaron Kin Fu , D'Rozario Angela , Bradford Dana , Ireland David , Fripp Jurgen , Simonetti Simone , Mills Peta , Naismith Sharon L
Published: December 2023

Background

Prior work has shown that sleep is critical for memory through a process called sleep‐dependent memory (SDM). However, SDM appears to diminish with age, and may be further compromised in those with mild cognitive impairment (MCI) and dementia. Typically, studies examining SDM have been small, often restricted by the need for administration in the sleep laboratory. Consequently, understanding of SDM decrements in MCI has been limited, hindering targeted developments of treatments for SDM. We aimed to develop an app‐based ‘chatbot’ for measuring SDM, allowing data to be obtained at scale and in response to treatments without the need for sleep laboratory attendance.

Method

An initial prototype of the chatbot was developed for Android and iOS utilising a 32‐item word‐pair task demonstrated to be suitable for people with MCI. The task delivery included pre‐sleep learning and memory and post‐sleep recall. To reduce content‐specific practice effects, an alternative word‐pair list was included for repeat testing.

Co‐design focus group methodologies were used to ascertain usability and acceptability for older people with MCI who attended a memory clinic. Participants (N = 11) attended one of two 90‐minute focus groups in which semi‐structured questions probed technology use and gathered feedback for app improvement.

Results

Participant feedback validated that core useability and content features of the chatbot were appropriately developed for the specific use of older adults at risk of dementia. Participants were comfortable with the chatbot obtaining demographics and habitual sleep and wake times and providing notifications for completing the task pre‐ and post‐sleep. No negative feedback was received on the layout of the instructions for the test or delivery of the word‐pairs task. Suggested improvements included ability to defer testing and customise notifications, and provision of performance feedback or rewards for compliance. This information was used to further develop the chatbot.

Conclusion

The SDM chatbot app will now undergo further clinical and psychometric testing to determine how performance changes in relation to, rest‐activity rhythms, clinical features, and sleep and dementia biomarkers.
Reproductive span as a modifier of the association between AD biomarkers and cognitive decline in cognitively unimpaired women
Authors: Milà‐Alomà Marta , Brodu Margot M Casals , Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Escalante Armand González , Brinkmalm Ann , Kvartsberg Hlin , Shekari Mahnaz , Arenaza‐Urquijo Eider M , Fuentes‐Julian Sherezade , Deulofeu Carme , Grau‐Rivera Oriol , Kollmorgen Gwendlyn , Carboni Margherita , Ferretti Maria Teresa , Gispert Juan Domingo , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc
Published: December 2023

Background

Estrogens exert neuroprotective effects and regulate cognitive functioning and memory, and reduction of estrogen levels during menopause is proposed as a contributor to the increased risk for Alzheimer´s disease (AD) observed in women. However, previous results on the effects of estrogen exposure on AD biomarkers and risk of cognitive decline are conflicting.

We aimed to study whether reproductive span, as a proxy of endogenous estrogen exposure, influences AD‐related biomarkers and their association with cognitive change in cognitively unimpaired (CU) women.

Method

We studied 125 CU women with CSF biomarkers, amyloid PET (Centiloids), and longitudinal cognitive measures (3 years’ follow‐up) (Table 1). CSF biomarkers were measured with Roche NeuroToolKit, Elecsys® immunoassays, or IP‐MS. We used longitudinal change in PACC and in a memory composite as cognitive outcomes. Reproductive span was calculated by subtracting the age at menarche from the age at menopause. ANCOVA models adjusted by age, education, and time between visits were used to test the main effect of reproductive span on biomarkers (baseline and longitudinal change), and the interaction between reproductive span and biomarkers with cognitive change as the outcome.

Result

Reproductive span was not associated with baseline levels or longitudinal change of AD biomarkers. Reproductive span modified the association of Aβ PET Centiloids with change in PACC, and the association of Centiloids, CSF p‐tau181, SNAP‐25, synaptotagmin‐1, and ɑ‐Synuclein with change in the Memory Composite (Figure 1). Specifically, higher baseline levels of these biomarkers were associated with cognitive decline only in women with a shorter reproductive span. Reproductive span also modified the association between longitudinal change in CSF sTREM2, IL‐6, and NfL and cognitive change. In women with a shorter reproductive span, increases in these biomarkers were associated with greater memory declines. In women with a longer reproductive span, an increase in CSF sTREM2 was associated with improved memory performance at follow‐up (Figure 2).

Conclusion

In women with a shorter reproductive span, higher baseline levels of Aβ deposition and tau and synaptic CSF biomarkers are associated with a steeper decline in memory. Our results suggest that longer estrogen exposure contributes to resilience against AD‐related pathology.
Perceived social status modifies associations of plasma Alzheimer’s disease biomarkers on cognitive performance among Foreign Born Hispanic/Latinos
Authors: Diminich Erica D , Farina Mateo , Miller Joshua D , Mindt Monica Rivera , Scott Stacey B , Ailshire Jennifer , Clouston Sean A.P.
Published: December 2023

Background

Foreign born (FB) adults from Latin America are projected to account for the largest proportion of the aging immigrant population in the United States (U.S.) Migration related stressors may increase vulnerability for impairments of stress regulatory systems that are vital in maintaining brain health. We assessed how subjective social status, an individual’s perceived sense of standing in society may be associated with brain health and cognitive performance among community dwelling FB Hispanic/Latinos.

Method

Analyses included 133 FB adults (ages 22‐85) with beta‐amyloid (Aβ42, Aβ40), phosphorylated tau (p‐tau181), neurofilament light (NfL), glial fibrillary acidic protein (GFAP), cardiometabolic, sociodemographic, sociocultural data and concurrent cognitive scores, assessed with the NIH Cognition Toolbox. Participants used the McArthur Scale, a 10‐rung ladder representative of social status in the U.S., to indicate their standing relative to all others. Descriptive statistics were calculated to examine differences by perceived social status tertiles, (i.e., Low (1‐3), Average (4‐5), High (6‐10). Cross sectional multivariable linear regression models estimated the independent effects of biomarkers on outcome scores for episodic memory, processing speed, and total cognition. Model one included age, sex. Model two added education, income, employment, and health insurance. Model three adjusted for covariates in model two and included biological indicators associated with brain health (i.e., glucose, systolic blood pressure, triglycerides). Model four included nativity factors (i.e., age of migration, years of acculturation). An interaction term between plasma biomarker and perceived status examined whether perceived status modified the relationship between plasma biomarker and cognitive outcome.

Result

Over 27.1% of FB Hispanic/Latinos reported low perceived status. Compared to those with average and high status, participants categorized as low status, reported fewer years of residence in the U.S. (P = 0.020) In multivariable adjusted models, perceived status modified associations between GFAP (P<0.001) and NfL (P<0.001) on composite scores of total cognition (P<0.001) and NfL (P<0.001) and Aβ42/40 (P<0.0001) on episodic memory and processing speed (P<0.001).

Conclusion

Perceived status among undocumented FB Hispanic/Latino adults was associated with lower scores on cognitive tasks sensitive to stress, age related decline and neurological impairments. Future studies should explore biological mechanisms through which perceived status may influence brain health and cognitive aging.
Cerebrospinal fluid metabolome‐wide association study of Alzheimer’s disease provides insight into molecular pathways
Authors: Reus Lianne M. , Boltz Toni , Francia Marcelo , Bot Merel , Loohuis Loes Olde , Teunissen Charlotte E. , Ophoff Roel , Tijms Betty , van der Lee Sven J , Visser Pieter Jelle , van der Flier Wiesje M. , Ramesh Naren
Published: December 2023

Background

Many genetic risk variants have been identified for Alzheimer’s disease (AD), but their functional consequence on molecular pathways are unclear. Quantitative trait loci (QTL) studies help elucidate the functional effect of genetic variance on (neuro)biological processes. The understanding of AD mechanisms has been limited due to the relative inaccessibility of in vivo brain tissue and its surroundings. In this study, we integrated genetic and metabolomics cerebrospinal fluid (CSF) data, to understand how AD risk variants influence neurobiological processes.

Method

We performed a genome‐wide mQTL study on 5,543 CSF metabolite levels using data from 977 subjects (age 52.7±16.6 years, 63.8%female) from the Amsterdam Dementia Cohort (n = 487; 220 controls, 87 mild cognitive impairment, 180 AD‐type dementia) and the Utrecht cohort (n = 490 controls). We measured CSF metabolites with three platforms: GC‐TOF MS (primary metabolism, 393 metabolites), CSH‐QTOF MS/MS (complex lipids, 3,532 metabolites), and HILIC‐QTOF MS/MS (biogenic amines, 1,618 metabolites). Association signals between genetic variants and CSF metabolite levels were tested using linear regression, adjusted for principal components, age, sex and site (Amsterdam/Utrecht) using a Bonferroni‐corrected genome‐wide significance threshold (5.0e−8 /754 independent CSF signals = 6.0e−11). To identify metabolites with predicted CSF levels associated with AD, we integrated metabolite summary statistics with AD summary statistics (Kunkle et al., 2019; Bellenguez et al., 2022), using a metabolome‐wide association study (MWAS) approach (FUSION software).

Result

We identified 89 genome‐wide CSF mQTLs, including 89 independent loci for 62 CSF metabolite levels. Most mQTLs were biogenic amines (81), followed by mQTLs for the primary (5) metabolism and complex lipids (3) (Figure 1). MWAS results included 24 metabolite‐AD associations with P<0.05. The strongest associations included variants proximal to the CANX gene with unannotated CSF metabolite 1.09_397.32 (PBellenguez = 2.4e−6; PKunkle = 3.4e−3), and CCDC124 variants with 8.76_225.06 (PBellenguez = 2.9e−3; PKunkle = 2.8e−5) (Figure 2).

Conclusion

We identified novel metabolite‐AD risk associations, including CANX and CCDC124 with unknown CSF metabolites. In future work we aim to identify these CSF metabolites using raw spectra and intensity data. This study shows that the multi‐modal integration of genetics with CSF metabolomics helps in the functional interpretation of genetic variance, and could therefore serve as useful approach for other brain‐related disorders.
Clinical Variables Contributing to Identification of Mild Cognitive Impairment Individuals With Defined ATN Profile
Authors: Marcolini Sofia , Mondragon Jaime , Dominguez‐Vega Zeus T. , Maurits Natasha M. , De Deyn Peter Paul ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

Background

The framework globally used to classify Alzheimer’s Disease stages for research purposes includes three core biomarkers: A) Aβ burden; T) tau pathology; and N) neuronal injury. A lack of consensus exists in linking cognitive and behavioral tests used in everyday clinical practice to biological stages of dementia as defined by the ATN classification. The aim of the current study is to identify the clinical variables that best classify individuals into biologically defined cognitive profiles.

Method

A total of 751 subjects, from the Alzheimer’s Disease Neuroimaging Initiative cohort, were categorized into seven ATN groups: 112 cognitively unimpaired with ATN‐; 46 cognitively unimpaired with ATN or AT+; 65 cognitively unimpaired with T, N or TN+; 128 amnestic Mild Cognitive Impairment (aMCI) with ATN‐; 223 aMCI with ATN or AT+; 94 aMCI with T, N or TN+ and 83 dementia with ATN or AT+. The groups for which the features exhibited differences during data exploration were classified employing 28 cognitive, behavioral, and demographic features using a supervised machine learning algorithm, specifically, a random forest classifier in combination with a synthetic oversampling technique.

Result

We found that the selected features were not able to distinguish between all seven groups and in particular between the three cognitively unimpaired groups. Therefore, classification was only performed for the three ATN‐defined aMCI groups achieving 58% overall accuracy. The Logical Delayed Recall was the most relevant feature (explaining 17% of the variance), followed by the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale 13 (16%), Everyday Cognition Informant (8%), and Alzheimer’s Disease Assessment Scale 4 (8%). Marital status, Everyday Cognition Patient and sex were not relevant (0%).

Conclusion

Cognitive and behavioral tests were not able to accurately distinguish cognitively unimpaired individuals with different biological profiles. Although accuracy could be improved, our first results showed that a test of delayed memory, one of general cognition, and one on activities of daily living are relevant variables for distinguishing between patients with aMCI and different biological profiles. During diagnosis, treatment monitoring, or in research contexts, these variables might be informative in differentiating the three ATN‐defined aMCI profiles, especially when biomarkers are not available.
Associations between ruminative brooding and white matter change amongst healthy middle‐aged and older adults
Authors: Solé‐Padullés Cristina , Cattaneo Gabriele , Marchant Natalie L , Demnitz‐King Harriet , Cabello‐Toscano María , Mulet‐Pons Lídia , Solana Sánchez Javier , Tormos‐Muñoz Josep Mª , Bargalló Núria , Abellaneda‐Pérez Kilian , Pascual‐Leone Alvaro , Bartrés‐Faz David
Published: December 2023

Background

Repetitive Negative Thinking (RNT) includes negative thoughts about the future (worry) and past (ruminative brooding). RNT has been associated with Alzheimer’s disease (AD) pathology (Marchant et al. Alzheimers Dement. 2020;16(7)) and different patterns of functional connectivity of the triple network of attention, namely, the default mode, executive control and anterior salience networks (Solé‐Padullés et al. Front Aging Neurosci. 2022;14). However, the association between RNT and white matter microstructure is unclear (Demnitz‐King et al. Psychiatry Res Neuroimaging. 2021;316) and no existing studies have examined this association longitudinally among non‐clinical adults.

Method

Healthy adults (age range: 50‐70, 51.2% women) from the Barcelona Brain Health Initiative (Cattaneo et al. Front Aging Neurosci. 2018 11;10) completed the Perseverative Thinking Questionnaire (PTQ), Rumination Response Scale (RRS), and Penn‐State Worry Questionnaire (PSWQ) at baseline to measure RNT levels. Participants underwent a magnetic resonance imaging (MRI) with T1 and T2‐weighted acquisitions to assess volume of white matter hypointensities (WMH) at baseline (N = 588) and two years later (N = 425). Change in WMH was computed taking into account time interval between scans. Stepwise linear regression analyses were conducted to investigate associations between change in WMH and baseline age, sex, PTQ, PSWQ and RRS subscale scores (brooding, reflection and depression).

Result

Baseline age (t = 3.71, p<0.0001) and brooding (t = 2.82, p = 0.005) were associated with increased WMH across scans (see partial regression plots, Fig 1A/B). No cross‐sectional associations were observed between volume of WMH and RNT‐related variables.

Conclusion

Brooding was associated with increase of WMH in healthy adults. Brooding, a maladaptive form of emotion regulation, enhances repetitive focus on one’s distress and is associated with altered connectivity of attentional networks and greater asymmetry of the Superior Longitudinal Fasciculus in depressed adults (Pisner et al. Neuroimage Clin. 2019;24). Our results are of importance considering that: WMH correlate with CSF‐amyloid in cognitively unimpaired older adults (Wei et al. Brain Behav. 2019;9(12)) and this is the first longitudinal study focusing on white matter change as related to psychological variables linked to cognitive decline and AD‐related pathology. The putative impact of psychological factors on brain integrity can be detected even at sub‐clinical levels and in earlier stages within the dementia continuum.
An exploratory pilot study on diffusion MRI measurement of cortical microstructural neurodegeneration for the assessment of dementia in a Japanese hospital setting
Authors: Ridgway Gerard R , Nakajima Takashi , Torso Mario , Valotti Michele , Hardingham Ian , Ehsan Omar , Chance Steven A
Published: December 2023

Background

The use of diffusion MRI (dMRI) to assess cortical microstructure has demonstrated promise for measuring neurodegeneration in Alzheimer’s disease (PMID:33174658, PMID:36281682) and frontotemporal dementia (PMID:32641807, PMID:34686217) using retrospective research datasets. The ultimate translation of research findings to clinical practice requires prospective studies in hospital settings. A pilot study at the National Hospital Organization, Niigata, was designed and successfully delivered.

Method

The study was registered on Oct 5th 2021 (jRCT1032210367). Scanning took place between Oct 13th 2021 and June 30th 2022, on a 1.5T Philips Ingenia. MRI data was transferred using a secure cloud gateway (Cimar). A total of 10 healthy controls (HC), 10 Alzheimer’s disease (AD) patients, and 5 frontotemporal dementia (FTD) patients were recruited.

Structural (3D T1‐weighted) and dMRI (2mm isotropic, 32 directions at b = 1000 s/mm2) scans were used to calculate cortical mean diffusivity and three neuropathologically‐inspired cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+). Metrics were also summarized over AD signature regions (Ridgway et al., CTAD 2022).

Result

Of the n = 25 cases, 18 had clear clinical diagnoses after neurological and radiological assessment, while 7 were more complex (including focal bleeding, focal ischemia, meningioma, supra‐sellar tumour). Characteristics are given in Table 1.

Figure 1 plots two whole‐brain measures: PerpPD+ and AngleR. A threshold of PerpPD+ > 1.325 has 100% sensitivity to the 8 clear AD cases, with 86% specificity for 7 controls vs AD. Results were less clear for FTD using whole‐brain measures alone.

The Cohen’s d effect size for clear AD versus clear HC was 2.82 using whole‐brain PerpPD+. Using signature regions (Figure 2b) improved separation to d = 3.08 for PerpPD+, compared to d = 1.87 for the cortical thickness signature (Figure 2a).

Conclusion

The pilot study demonstrated practical feasibility and good performance for distinguishing AD from HC using cortical diffusivity measures acquired at the 1.5T field‐strength common in hospitals in Japan. Future work will investigate FTD signature regions. A larger multicentre study assessing diagnostic accuracy using additional AD biomarkers is warranted.
Yerba mate (Ilex paraguariensis) consumption and risk of cognitive impairment: a prospective study project
Authors: Guillen Jonathan Cubas , Gatto Emilia , del Hierro Xavier Merchan , Rojas Galeno , Melcon Carlos Mario , Eizaguirre Barbara , Gonzales Claudio , Crotti Beatriz , Tribbia Liliana Teresita , Gilbert Afra , Taravini Irene
Published: December 2023

Background

Aging is the main risk factor for neurodegenerative diseases, such as Alzheimer’s disease (AD) dementia. Yerba mate (YM) tea or mate Ilex paraguariensis is an infusion widely consumed in Argentina and other South American countries such as Brazil, Paraguay, and Uruguay. Experimental studies suggest a YM antioxidant and protective effect against amyloid deposition in AD. Previously, our group and others identified an inverse association between YM consumption and Parkinson’s Disease. The aim of this project is to evaluate a potential association between YM consumption and the risk of cognitive impairment development.

Method

Two different stages were designed. Stage I is a descriptive study designed. Adult patients fulfilling mild cognitive impairment criteria (MCI) evaluated at the Sanatorio de la Trinidad Mitre between January 2021 and December 2022 will be included. Each participant or their caregiver will be invited to complete a survey about lifestyle and nutritional information, including YM consumption. Stage II is a case‐control study. Patients with MCI will be distributed by severity and subtypes of MCI. The control group will be constituted by individuals with normal cognitive evaluations matched by age, sex and educational level who agree to answer the afore mentioned survey. All data will be recorded in an anonymized electronic database and statistical analysis will be carried out. Project duration is estimated at 12 months for each stage.

Result

Results from stage I will describe epidemiological and clinical characteristics of patients with MCI and the frequency and duration of YM consumption in this group of patients, as well as any potential correlation between neuropsychological tests and YM consumption. Results from stage II are expected to identify an inverse association between the magnitude of YM consumption and MCI.

Conclusion

Observational evidence of the association between YM consumption and MCI might be the first step to develop experimental studies using Ilex paraguariensis in neurodegenerative cognitive disorders.
Modulating Effects of Vitamin K2 on Oxidative Stress Induced Organelle Damage in Alzheimer’s Disease
Authors: Shandilya Shruti , Ruokolainen Janne
Published: December 2023

Background

Current treatment strategies for AD are either involved in an improved amyloid‐beta precursor protein (APP) processing via inhibition and/or activation of enzymatic machinery. Whereas, others drug regimen includes the use of putative tau kinase inhibitors, microtubule stabilizers and tau immunotherapies. Moreover, therapies to combat oxidative stress are currently being devised because oxidative stress plays a major role innneurodegeneration. Interestingly, current studies are being focused on the screening of bioactive compounds for their effect on prevention of Aβ formation, oxidative stress reduction and targeting organelle dysfunction, which will potentiate the use of bioactive compounds to prevent AD in early stages. Vitamin K2 is one of the bioactive compounds which has gained importance for its role as an antioxidant.

Method

To understand the neuroprotective effect of vitamin K2 during metabolic complications, SH‐SY5Y cells were treated with streptozotocin for 24 h and menadione for 2 h in a dose dependent manner, followed by the post treatment of vitamin K2 for 5 h. Modulating effects of vitamin K2 on cell viability, Lactate Dehydrogenase release, reactive oxygen species (ROS), mitochondrial membrane potential, ER stress marker (CHOP), an indicator of unfolded protein response (UPR) p‐IRE1α, GSK 3α/β, total tau and Aβ 42 were studied.

Result

Vitamin K2 significantly reduced the neuronal cell death by inhibiting the cytotoxicity, ROS levels and helped in the retainment of mitochondrial membrane potential. Moreover, vitamin K2 significantly decreased the expression of CHOP protein along with the levels and the nuclear localization of p‐IRE1 α, thus showing its significant role in inhibiting chronic ER stress mediated UPR and eventually apoptosis. In addition, Vitamin K2 significantly downregulated the expression of GSK 3 α/β together with the levels of total tau protein, with petite effect on secreted Aβ 42 levels.

Conclusion

Vitamin K2 ameliorated mitochondrial damage, ER stress and tauopathy mediated neuronal cell death, highlighting its role as a novel antioxidative therapeutics targeting related cellular processes.