bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association of Blood‐based biomarkers and Cognitive Change as Measured by Ecologically Sensitive Digital Biomarkers
Authors: Lipton Richard B. , Garza Angel Garcia De La , Wang Cuiling , Derby Carol A. , Katz Mindy J. , Oravecz Zita , Hakun Jonathan G. , Sliwinski Martin J. , Ezzati Ali
Published: December 2023

Background

The Einstein Aging Study uses smartphones in an intensive burst design to digitally assess cognition up to 6 times daily for 2 weeks once a year. These burst assessments facilitate the estimation of novel cognitive markers including learning effects and asymptotic performance within bursts and over annual assessments. Here, we examine the influence of two blood‐based biomarkers, pTau‐181 and Neurofilament Light protein (NfL), on cognitive performance measured by digital cognitive markers at baseline and across 6 annual burst assessments.

Method

Participants were 293 older adults (Age = 77.4±4.9) free of dementia at baseline. Negative exponential models were used to examine two primary features of response time from the Symbol Search Test of processing speed: (1) learning rate across days within a burst and its change in rate of learning over annual follow‐up; and (2) asymptotic performance (i.e., fastest response time) at baseline and asymptotic change (the rate in which asymptotic performance changes across years). Asymptotic performance is thought to reflect best possible performance and to be relatively free of practice effects. The associations of pTau‐181 and NfL with these features at baseline and change over annual follow‐up were evaluated, adjusting for baseline age, sex, years of education and race/ethnicity.

Result

Primary model results are summarized in Table 1. The expected trajectory of symbol search response time across 16 study days within each of the six annual waves, for baseline levels of pTau‐181 and NfL is shown in Figures 1 and 2. Higher levels of both Tau‐181 and of NfL were associated with slower rates of learning in the baseline burst. Higher levels of these BBB at baseline were also associated with slower learning rates from burst to burst (over years) and with greater slowing in asymptotic performance over annual follow‐ups.

Conclusion

Higher levels of BBB of Tau and of neurodegeneration are associated with slower learning and with slower response times. These novel parameters derived from ambulatory cognitive testing show expected relationships with biomarkers supporting their validity. Future applications of ambulatory cognition could include the identification of subtle cognitive impairment and in measuring within person change in cognition in clinical trials or clinical practice.
Amyloid‐PET, tau‐PET, and their association in sporadic early‐onset Alzheimer’s Disease: Cross‐sectional and longitudinal data from the LEADS study
Authors: La Joie Renaud , Mundada Nidhi , Iaccarino Leonardo , soleimani‐Meigooni David N. , Zeltzer Ehud , Windon Charles , Tanner Jeremy A. , Heath Courtney Lawh , Shankar Ranjani , Amuiri Alinda , Cho Hanna , Ackley Sarah F , Blazhenets Ganna , Aisen Paul S. S , Eloyan Ani , Koeppe Robert A. , Carrillo Maria C. , Dickerson Brad C. , Apostolova Liana G. , Rabinovici Gil D.
Published: December 2023

Background

We aimed to describe amyloid‐ and tau‐PET in patients with sporadic Early Onset AD (sEOAD) from the Longitudinal Early‐onset Alzheimer’s Disease Study. We focused on amyloid‐tau relationships and on the association between i) age, sex, and ii) cross‐sectional and longitudinal PET measures.

Methods

In December 2022, we selected patients who fulfilled the following criteria: 1) clinical diagnosis of MCI or mild dementia, 2) available amyloid‐PET (18F‐florbetaben), tau‐PET (18F‐fortaucipir), and structural MRI, 3) positive amyloid‐PET based on a process including visual read and quantification. Image acquisition, quality control, and processing followed ADNI procedures. Florbetaben‐PET Centiloids and mean cortical Flortaucipir‐SUVR were extracted in native space using FreeSurfer. Cross‐sectional analyses were performed using general linear models; longitudinal analyses (up to 4 scans/patient) were performed using linear mixed effect models with random intercepts.

Results

Out of the 372 cognitively impaired patients included in LEADS, 280 (75.3%) were amyloid‐positive patients with sEOAD (Table 1 for demographics and clinical characteristics). Cross‐sectionally, Centiloids and cortical Flortaucipir‐SUVR were correlated (r = 0.29, p<.001; Fig 1a). Patient’s age was associated with cortical tau‐PET (older patients showing lower Flortaucipir‐SUVR, r = ‐0.47, p<0.001, Fig 1b) but not amyloid‐PET (r = ‐0.02, p = 0.68). Females showed greater amyloid (d = 0.43, p<0.001, Fig 1c) and tau‐PET burden (d = 0.35, p = 0.004), in the absence of sex differences in MMSE or CDR‐SB (d’s<0.16, p’s>0.37). Sex differences in tau‐PET remained significant (p = 0.04) when controlling for age and Centiloids. Both Centiloids and Flortaucipir‐SUVR increased longitudinally (p<0.001, Figure 3a‐b). The rate of Centiloid change was not modulated by age (time*age, p = 0.79) or sex (time*sex, p = 0.91). Changes in tau‐PET were independent of sex (time*sex, p = 0.15), but younger patients tended to show greater FTP‐SUVR progression (time*age, p = 0.07). In a subsample of 123 patients with at least 2 timepoints for both amyloid and tau‐PET (Fig 3c), rates of amyloid and tau changes were correlated (r = 0.22, p = 0.013).

Conclusion

In patients with sEOAD, amyloid‐ and tau‐PET are modestly correlated at baseline and continue to increase together over time. In EOAD, younger age is associated with higher tau‐PET burden, independent of amyloid. Females show greater amyloid and tau burden than males despite similar clinical severity measures.
Exploring the Utility of Biofluid‐Based Biomarkers in Early‐Onset Alzheimer’s Disease
Authors: Dage Jeff L.
Published: December 2023

Background

One goal of the longitudinal early onset Alzheimer’s disease study (LEADS) is to define fluid biomarker characteristics of early‐onset Alzheimer’s disease (EOAD). In this mid‐study cross sectional analysis, participants have undergone clinical and cognitive assessments, magnetic resonance imaging (MRI), positron emission tomography (PET), lumbar puncture, and blood draws. There is limited data available concerning comprehensive analysis of fluid biomarkers in an EOAD population and this study represents first results from the mid‐study analysis of a large multi‐site cohort.

Method

LEADS is an observational study with N = 371 subjects included in the mid‐study analysis (N = 165 with CSF and N = 324 with plasma biomarker data). CSF levels of Aβ1‐40, Aβ1‐42, tTau, pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay. Plasma levels of Aβ1‐40, Aβ1‐42, NfL, pTau231, and glial fibrillary acid protein (GFAP) were measured by immunoassay. Differences by diagnostic group and Spearman’s correlations with cognitive measures (MOCA, CDR‐SB, ADAS‐Cog) were evaluated for each fluid biomarker. Diagnostic accuracies were determined using area under the curve of receiver operating characteristics curve analysis which included APOE4 carrier status, age and sex in logistic regression models.

Result

Levels of CSF Aβ42/40, pTau181, tTau, SNAP25, and Ng in the EOAD group were significantly different from both cognitively normal and early‐onset non‐AD dementia groups; CSF NfL, YKL‐40 and VILIP‐1 did not vary by diagnosis. The combination of APOE ε4 carrier status, age, sex and CSF Aβ42/40 and pTau181 (Figure 1A) or plasma Aβ42/40 and pTau231 (Figure 1B) separated the EOAD group from CN and EOnonAD with Area Under the ROC curves of 0.99 and 0.89 respectively. The diagnostic accuracies of plasma Aβ42/40 or pTau231 were 0.80 and 0.86 respectively. In the pooled analysis, all CSF biomarkers except SNAP25 were correlated with cognition (Figure 2A). Within the EOAD group only CSF Aβ42/40, NfL, Ng, and SNAP25 were correlated with at least one cognitive measure (Figure 2B).

Conclusion

This study provides the first comprehensive analysis of fluid biomarkers in sporadic EOAD and will inform clinical trial designs that incorporate fluid biomarkers in patient selection, or as biomarker endpoints.
Cholinesterase inhibitors, cognitive decline, major cardiovascular events, and mortality in dementia with Lewy bodies
Authors: Xu Hong , Ferreira Daniel , Londos Elisabet , Eriksdotter Maria
Published: December 2023

Background

Cholinesterase inhibitors (ChEIs) are approved pharmacological treatment in Alzheimer’s dementia (AD) and dementia with Lewy bodies (DLB). Recent studies showed that ChEI‐use is associated with decreased risk of cardiovascular events and death in AD. This study explores the long‐term effects of ChEIs on cognition, the risk for hospitalization of major cardiovascular events and death in patients with DLB.

Method

We included DLB patients with mild‐moderate dementia(defined as Mini Mental State Examination(MMSE)≥10 points) from the Swedish Dementia Registry(SveDem). Patients starting on ChEI within 90 days of diagnosis were compared to patients with DLB not receiving ChEI. Major cardiovascular events(MACE) were defined as the composite of hospitalization of myocardial infarction or congestive heart failure or stroke. In an inverse probability of treatment weighting cohort, the association between ChEI‐use and cognitive trajectories were examined with mixed models and the risks of MACE or death with Cox models with balancing 45 confounders.

Result

893 ChEI‐use and 305 non‐users were included. The most frequently used ChEIs was rivastigmine(69%), followed by donepezil(21%) and galantamine(10%). There was no difference in MMSE scores between the two ChEI groups at baseline after weighting. During a median follow up time of 3.2 years (interquartile range1.7‐4.3), ChEI‐users showed slower cognitive decline (‐1.4 MMSE points/year, 95%confidence interval CI ‐1.8, ‐1.0) compared to non‐users (‐2.8 MMSE points/year, ‐3.9, ‐1.9). Of the ChEIs, galantamine was associated with the slowest cognitive decline (‐0.9 MMSE points/year, ‐1.8, ‐0.1). During follow up, 120(10%) events of MACE occurred, along with 666(56%) deaths. Compared to non‐users, ChEI‐use was not associated with risk for hospitalization for MACE (adjusted hazard ratio(aHR)0.89; 95% CI 0.43‐1.82) or risk of death (aHR 1.09; 0.87‐1.37).

Conclusion

In patients with DLB, ChEI‐use was associated with slower cognitive decline over 3.2 years on average, where galantamine presented the strongest effect. This may be explained by its modulatory effect on nicotinic receptors as well as its inhibitory effect on acetylcholinesterase. Interestingly, in contrast to our previous findings in AD, ChEI‐treatment in DLB was not associated with reduced MACE or mortality risk, which might be related with the more prominent autonomic dysfunction in DLB than in AD.
Premenopausal bilateral oophorectomy (PBO) is associated with reduced late‐life white matter integrity on diffusion MRI
Authors: Mielke Michelle M. , Frank Ryan D. , Christenson Luke , Reid Robert I. , Fields Julie A. , Vemuri Prashanthi , Rocca Walter A. , Kantarci Kejal
Published: December 2023

Background

Several studies suggest that premenopausal bilateral oophorectomy (PBO) is associated with an increased risk of cognitive impairment and dementia; however, the underlying brain changes are not well understood. Animal studies suggest that long‐term ovarian hormone deprivation in rats is associated with reduced white matter integrity, but few studies have been conducted among women. We assessed the impact of age at PBO before age 50 years on white matter integrity in a community‐based cohort of older women.

Method

Participants included 1,011 women enrolled in the Mayo Clinic Study on Aging (MCSA; 22 with PBO<40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years and 907 referent women). MCSA is a population‐based study of aging in Olmsted County, MN. PBO was abstracted from the medical records. Regional DTI metrics of fractional anisotropy (FA) and mean diffusivity (MD) were investigated using the Johns Hopkins University Atlas. Linear regression was used to examine the association between PBO age group and z‐scores of either FA or MD after adjusting for age at imaging and APOE.

Result

There were no differences in age at study visit (median = 72 years), education, APOE E4 frequency, or vascular comorbidities between the 3 groups of women with a history of PBO or referent women. Women with PBO<40 years, compared to referent women, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Women with PBO<40 years also had lower inferior frontal white matter FA and higher posterior thalamic radiation MD. Women who underwent PBO between 40‐44 years or 45‐49 generally did not have significant changes in white matter integrity compared to referent women.

Conclusion

Women who underwent premenopausal bilateral oophorectomy prior to the age of 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for the education of women at a low risk for ovarian cancer who are considering PBO for benign conditions.
PHYSICAL ACTIVITY ASSOCIATED TO LOWER PREVALENCE OFDEMENTIA IN BRAZILIAN OLDER ADULTS
Authors: Barcelos‐Ferreira Ricardo , Lopes Marcos A , Bottino Cassio M C ,   Old Age Research Group (Proter)
Published: December 2023

Background

Evidences indicate that physically active older individuals maintain healthy functioning longer than do sedentary peers. Some lifestyle could impact the risk of dementia including Alzheimer’s. In spite of this, the effect of physical activity on the relationship between age and the risk of dementia is unknown. This is a two‐phase study that aims to investigate the association of physical exercise and age with the prevalence of dementia in community older adults, from Ribeirao Preto city, state of Sao Paulo, Brazil.

Method

Cross‐sectional study of a randomized community‐based sample of 928 elderly subjects aged 60 years or older was performed. Standardized instruments for screening dementia and a socio‐economic questionnaire were applied to the subjects at home in phase I. The dementia diagnose was made at hospital in phase II, according to DSM‐V criteria.

Result

Overal Dementia was 6.0%. Alzheimer’s disease was the most frequent dementia (2.8%), followed by Vascular dementia (1.3%), and Mixed dementia (1.1%). Initial multivariate analysis showed sociodemographic factors associated to dementia. After adjusting for all the variables, multivariate analysis showed an association with age group ≥80 (OR = 6.7; p<0.001); household chores (OR = 2.7; p = 0.004); no employment (OR = 4.3; p<0.001); and stroke (OR = 4.5; p = 0.001). There was no association with gender, socioeconomic class, educational level, and alcohol use. Secondary analysis showed an inverse relationship between physical activity and age (OR = 0.4; p<0.001). After deliberately exclude age, the final model showed a significant association between higher rates of dementia and lack of physical activity (OR = 2.0; p = 0.024).

Conclusion

According to previous studies, in our sample, lack of exercise was associated with two fold higher risk of dementia, only after exclude age of the analysis. This result could be due to decreasing level of physical activity found in the oldest subjects. We suggest that relatively simple lifestyle changes such as increasing the practice of exercise could enhance cognitive performance in elderly people. Future investigations are needed to clarify the real impact of physical activity on the relationship between dementia and age.
Exaggerated translational repression of FMRP in AD synapses
Authors: Uneri Ayse , McArdle Colin J , Niere Farr , Craft Suzanne , Raab‐Graham Kimberly F
Published: December 2023

Background

Alzheimer’s Disease (AD) is a progressive cognitive disorder where synapse loss has been well documented. Identifying and restoring molecular targets that are involved in synapse loss is crucial in restoring balanced synaptic function and communication. FMRP is an RNA‐binding protein that is essential protein for synapse formation and stability, and is understudied in AD. Understanding how FMRP may be dysregulated at the synaptic level in AD is integral in developing treatments for AD.

Method

RNA‐immunoprecipitation of DJ‐1 was performed to detect whether DJ‐1 associates with the mRNA coding for FMRP. Synaptoneurosomes and postsynaptic densities we isolated from AD rodent model APP/PS1deltaE9 and postmortem human AD patients, as well as from appropriate controls, and performed Western blotting to analyze FMRP protein expression. SUnSET‐PLA assay was utilized to determine de novo synthesis of FMRP in DJ‐1 overexpression.

Result

DJ‐1, which is an RNA‐binding protein that is overexpressed in AD synapses, associates with Fmr1, the mRNA coding for the protein FMRP. FMRP expression is decreased in AD synapses, as well as postsynaptic densities. When DJ‐1 is overexpressed in WT cultures, there is less newly synthesized FMRP.

Conclusion

Here, we show that DJ‐1 associates with Fmr1, which codes for another RNA‐binding protein, FMRP. DJ‐1 and FMRP are aberrantly expressed in AD synapses. DJ‐1 is overexpressed in AD synapses while FMRP is reduced. Furthermore, when DJ‐1 is overexpressed in WT cultures, FMRP synthesis is reduced, suggesting that DJ‐1 is a translational repressor of FMRP. Therefore, the reduction of FMRP in AD synapses are due to overexpression of DJ‐1, and the rescue of FMRP expression could potentially rescue synaptic loss in AD.
Training nursing home social workers in the Pre‐loss Group Support intervention
Authors: Supiano Katherine P , Andersen Troy C. , Bradbury Laura E , Gonzalez Kimberly Ponce
Published: December 2023

Background

Pre‐loss Group Support (PLGS) is a 10‐session multi‐modal, psychotherapy group intervention administered by nursing home social workers (NH‐SWs) for dementia family care partners (CPs) whose PLWD resides in a nursing home.1 While the overarching purpose of this project is to determine if telehealth‐delivered PLGS reduces risk of poor bereavement outcome in family CPs of PLWD when delivered by NH‐SWs, in this presentation we describe developing and applying the PLGS clinical training for NH‐SWs in this phase of our NIH‐Stage 52 implementation and dissemination study.

Method

Using professional actors, we created a simulated PLGS 10‐session group as a series of training videos. Training utilized our Stage‐3 PLGS Facilitator manual.3 We developed a training curriculum incorporating these video vignettes, didactic content, interactive case examples and pragmatic application concepts of PLGS for telehealth delivery to CPs by NH‐SWs. The full training is deliverable in one full day or two half day sessions and is provided on an interactive distance platform. Training was delivered to two cohorts of NH‐SWs in a stepped‐wedge design.

Result

We are evaluating this implementation study using the RE‐AIM measures.4 In this training phase, we have successfully achieved Reach—defined as buy‐in and training of NH SWs, Adoption—defined as uptake by NHs and SWs, and the first phase of Implementation—Defined as training completion. Trained NH‐SWs were assessed for satisfaction with the training. On a 7‐item satisfaction scale with a range of 3‐21, satisfaction rate was 95% (highly valuable), with 100% indicating they would recommend training to SWs in other facilities. In this session, we will share PLGS training content and procedures.

Conclusion

Nursing home SWs are the last clinicians with opportunity to support CPs as they approach the death of their PLWD in the facility. NH‐SWs have clinical expertise to learn and implement PLGS, allowing us to simultaneously evaluate telehealth SW training acceptability, telehealth delivered PLGS outcomes. Carefully tailoring PLGS training content and delivery for NH‐SWs to equip them for telehealth implementation, engagement to recruit and retain enthusiastic SWs, and available consultation have contributed to the success of this phase in the project.
Development of Moving Pictures GENIE‐an online gateway to dementia resources to support Culturally and Linguistically Diverse (CALD) communities
Authors: Antoniades Josefine , Brijnath Bianca , Radford Kylie , Lavrencic Louise , Dasgupta Jayashree , Parra‐Rodriguez Mario A , Franzen Sanne , Lock Kayla , Lay Veronica , Medel Carolina Navarro
Published: December 2023

Background

Over the past decades the use of technology in healthcare has increased exponentially, and the recent pandemic further accelerated the dependence on technology, both to access health and care services but also digital resources and information for health care consumers. Carers of people living with dementia from culturally and linguistically diverse (CALD) backgrounds have been disproportionately impacted as in‐language resources are scarce and locating them can be difficult. Thus, there is need to centralize digital resources to improve access for carers of persons living with dementia who speak languages other than English. Responding to this, our project co‐produced the GENIE (Global dEmeNtIa rEsources): a comprehensive, global online gateway to culturally and linguistically appropriate digital dementia resources.

Method

Methods comprised an environmental scan (academic literature and systematic online search) and online consultations with key stakeholders to identify resources. Resources were included if developed by healthcare organizations, dementia or aged care peak bodies, dementia advocacy groups, government departments, or academic organizations. The GENIE site was coproduced with CALD carers and providers in Australia. Data analytics are being collected via the website.

Result

The environmental scan highlighted the dearth of resources developed for CALD communities, and gaps in availability of digital dementia resources across many languages. Further, dementia resources identified via the literature search were often not available for public access, required payment, or were no longer available. More than 400 resources in 68 languages were identified and included in the gateway, and the site was made publicly available in November 2022. Data analytics show that the uptake of the resource has been good with > 700 new users and >3500 page views in the first two months.

Conclusion

The Moving Pictures Genie project has produced one of the most comprehensive gateways to digital dementia resources to support carers and families who speak languages other than English currently available. In addition to the production of the resource, the project provides insights into the gaps in existing resources across languages and geographical regions. These findings will be useful to guide the direction of resource development to avoid duplication and enhance equity and benefit to CALD communities.
The Olfactory Stress Test does not replicate in a larger sample
Authors: Schofield Peter W. , Attia John , Ebrahimi Houman
Published: December 2023

Background

We previously published data showing that olfactory test performance changes on the University of Pennsylvania Smell Identification Test (UPSIT) following an intranasal ‘challenge’ with the anticholinergic atropine (an ‘Olfactory Stress Test’, (OST)) were significantly correlated with measures of cognition, hippocampal volume and APOE genotype in a small (n = 56) convenience sample of elders. The results suggested that this procedure might unmask incipient Alzheimer’s disease.

Here, we present data from two new studies, including an attempted replication of the above findings.

Method

In study one, the full 40 item UPSIT was administered to the left nostril to 56 individuals. Data from this study were used to determine the relationship between scores on the first 20 items (booklets 1+2) with those on the second 20 items (booklets 3+4) of the UPSIT.

The second study comprised 296 elders (aged 65 or older) who underwent olfactory testing, including the OST, assessment of cognition with the Audio Recorded Cognitive Screen, APOE genotyping, and hippocampal volume (in a subsample). In this study the first 20 items of UPSIT were always administered before and the second 20 items always after intranasal atropine and regression analyses were conducted to investigate for any association of the adjusted (see below) UPSIT change score following atropine with memory or hippocampal volume.

Result

In study 1, the mean score on the first 20 items of the UPSIT was 1.53 (SD 2.07) greater than the second 20 items (t = 5.55, p<.001). An appropriate adjustment factor derived from these data were used to scale the study 2 raw post atropine scores (from UPSIT booklets 3+4) into equivalent scores on booklets 1+2. These post‐atropine adjusted scores were then used in the calculation of the change in (adjusted) UPSIT following atropine.

In a series of stepwise linear regression analyses, after controlling for age, gender and education, the adjusted UPSIT change score did not predict any additional variance in memory scores or hippocampal volume.

Conclusion

In this larger study, we failed to replicate our earlier findings. The ’Olfactory Stress Test’ is unlikely to aid in the early detection of AD.
Visuospatial Dysfunction in Alzheimer’s Disease Maps to a Network Centered on the Inferior Parietal Lobule
Authors: Baratono Sheena R
Published: December 2023

Background

Visuospatial dysfunction is the predominant symptom in ∼5% of patients with Alzheimer’s disease (AD) and common in amnestic patients. If we can predict which patients are more likely to have trouble with visuospatial functioning, we can intervene earlier to prevent falls and car accidents and improve quality of life.

Method

There were 184 subjects with AD in the Alzheimer’s Disease Neuroimaging Initiative database with MRI scans and clock‐draw and clock‐copy scores ranging from 1‐5. Atrophy was defined as thinner than expected compared to age and sex matched controls. Subject network maps were generated averaging connectivity to each atrophied vertex using the normative connectome. Maps were compared to their behavioral scores generating behavior specific network maps. Atrophy networks were directly compared to a similar network generated from clock‐draw and stroke subjects.

Result

Atrophy did not correlate with clock‐draw and ‐copy scores but atrophy networks identified distinct distributed brain networks. Clock‐copy scores directly correlate with atrophy connected to the bilateral angular and visuomotor gyri, which were also hubs of the network derived from stroke and clock‐draw scores.

Conclusion

These results suggest that visuospatial dysfunction in AD does not occur due to atrophy in a single brain region but a distributed brain network. The concordance between atrophy in AD and stroke suggest that atrophy network mapping is a valid measure of connectivity underlying visuospatial dysfunction in AD.
Dysregulated processes and genes associated with Progressive Supranuclear Palsy: A transcriptomics analysis
Authors: Padilla‐Mendoza Juan‐Ramon , Rivera‐Osorio Jared , Flores‐Valdez Mauricio , Pradel‐Bernal Tamara Patricia , Silva‐Lucero Maria‐del‐Carmen , Gomez‐Virgilio Laura , Acosta‐Rodriguez Jose‐Luis , Cardenas‐Aguayo Maria‐del‐Carmen
Published: December 2023

Background

Progressive supranuclear palsy (PSP) is a rare sporadic neurodegenerative disease, the second most frequent form of atypical parkinsonism, and a 4R primary tauopathy. Clinically characterized by slowing of vertical saccades, vertical supranuclear gaze palsy, postural instability, axial rigidity, dysphagia, dysarthria, presence of early falls within the first year of onset of symptoms, as well as cognitive and behavioral alterations. As a primary tauopathy, abnormal tau aggregation is the most significant contributing factor for neurodegeneration.

Method

Microarray data from the medial temporal lobe (MTL) was obtained from ArrayExpress (E‐MEXP‐2280). Twelve samples were downloaded; seven were from PSP‐verified participants and 5 were from control subjects. The data were preprocessed using the R packages affy and preprocessCore. Data were then normalized using quantile normalization and log2‐transformation. We used processed data to perform principal component analysis (PCA) by using the function of R’s stats package to calculate principal components. We then used the limma R‐package to perform differential expression analysis (DEA). A corrected p‐value < 0.05 (Benjamini‐Hochberg for multiple tests) was considered statistically significant. Genes between a logarithmic fold change > 0.5 to 1 and < ‐0.5 to ‐1 were considered Differential expression genes (DEGs).

Result

We obtained PSP brain transcriptomic data and searched for cellular and molecular dysregulated processes and genes possibly associated with the pathology. In PSP MTL patients, we detected DEGs and gene modules associated with synapse structure and activity, the endomembrane system, transcriptional regulation, mRNA processing, myelination, protein metabolic processes, and epigenetic processes such as miRNA metabolism, gene silencing, production of small RNA involved in RNA methylation. We detected seven possible transcription factors (TFs) that regulate the expression of DEGs in PSP, highlighting FOXO3, as the only one with a significantly deregulated expression in PSP patients.

Conclusion

These data suggest the participation of DEGs and TFs regulation in the development of PSP pathology and future investigations into the role that develops inside this pathology. We propose that 7 TFs, specially FOXO3, drive gene expression changes of dysregulated PSP genes. This study set the pathway to investigate the implication of these genes in PSP pathology and evaluate their possible use as new therapeutic targets.
Social engagement and cognitive decline: Exploring relationships between psychosocial functioning and cognitive performance in individuals with mild cognitive impairment
Authors: Rehan Sana , Phillips Natalie
Published: December 2023

Background

Psychosocial factors have been identified as potentially modifiable risk factors for dementia (Livingston et al, 2020).Multiple social factors (e.g., participation in social activities, social support, loneliness) and indicators of mental health (e.g., depression) are associated with cognitive performance cross‐sectionally and can predict cognitive decline and risk for Alzheimer’s disease (AD) over time. However, the association between various psychosocial factors and cognitive performance across specific neuropsychological domains remain understudied in individuals at‐risk for AD. This study examined whether current psychosocial function predicted cognitive performance in individuals with mild cognitive impairment (MCI), a critical risk‐state for AD.

Method

We used data from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study to examine psychosocial and cognitive functioning in 124 participants with MCI (MAge = 71.5 ± 6.4, MEducation = 15.5 ± 3.9). Psychosocial factors were measured using self‐reported questionnaires about mental health (e.g., depression, anxiety), perceived social function (e.g., social support, loneliness), and engagement with social networks (e.g., current participation, number of community activities). Cognitive function was assessed using a comprehensive battery of neuropsychological tests. We conducted a principal component analysis to derive composite scores for five cognitive domains (memory, executive function, verbal fluency, processing speed, and working memory). Multiple linear regression models were used to test the direct effects of various psychosocial variables on cognitive performance, controlling for age, sex, education, MoCA scores, and living circumstances.

Results

We found that better quality of life was associated with better scores on memory tests. We also found that current social participation was significantly associated with verbal fluency and processing speed. Specifically, those endorsing low current social participation had worse verbal fluency and processing speed scores than those endorsing normal or high current social participation.

Conclusion

These findings indicate that increased participation in one’s social networks, over other psychosocial factors, has a positive relationship with cognitive performance in multiple domains in individuals with MCI. Our findings provide groundwork for further psychosocial‐cognitive analyses in individuals with (or at risk for) AD to better understand the role of poor social engagement in cognitive decline.

References: Livingston et al. (2020). The Lancet, 396, 413‐446.
Supporting Alzheimer’s disease and related dementia research in low‐ and middle‐income countries
Authors: Martin Damali N , Ghaleh Maryam , Anderson Dallas
Published: December 2023

The greatest increases for AD/ADRD will occur in low‐ and middle‐income countries (LMICs), where approximately 71% of the global cases will reside. These projections might be confounded by temporal changes due to shorter survival after dementia, lack of education and awareness, lack of access to healthcare, inadequate diagnostic assessment, and variability in costs of care of the elderly with AD/ADRD, all of which could lead to under‐accounting of the AD/ADRD burden. Nevertheless, the projected increase underscores the importance of developing a strong, coordinated research agenda that will inform mitigation and prevention strategies for AD/ADRD in LMICs. National Institute on Aging (NIA) at the National Institutes of Health (NIH) is positioned to play a leading role in this endeavor, as the leading federal government institute for supporting research on aging and AD/ADRD. NIA’s interests, activities and scientific initiatives related to global health research has increased over the past year through collaborations with other NIH institutes and centers (including Fogarty International Center) and engagement with the global scientific community. Research supported under these initiatives could further inform future scientific priorities areas for AD/ADRD. Given the growth trajectory of its global health portfolio, NIA will continue to support coordinated approaches to identify research gaps and new opportunities to address the growing burden of AD/ADRD in LMICs, globally.
Poorer online cognitive performance is associated with genetic risk for Alzheimer’s disease and brain phenotypes in healthy mid‐life and older adults.
Authors: Lupton Michelle K , Gomez Lina , Mitchell Brittany L , Adsett Jessica , García‐Marín Luis M , Renteria Miguel E. , McAloney Kerrie , Ceslis Amelia , Thienel Renate , Robinson Gail , Breakspear Michael , Martin Nicholas G
Published: December 2023

Background

Self‐administered online cognitive testing offers a cost‐effective and flexible alternative to in‐person neuropsychological assessments. We used the Creyos platform (previously named Cambridge Brain Sciences) to assess cognitive function in a large sample (N = 1673) of middle aged and older adults participating in the PISA (Prospective Imaging Study of Aging) study. PISA aims to characterise the early symptoms and progression of Alzheimer’s disease at its prodromal phase.

Method

We have utilised our Australia‐wide population based sample recruitment pool of research participants with genome wide genotyping. Participants completed a comprehensive online survey and online cognitive assessments, including Creyos, consisting of 12 self‐administered tasks covering memory, executive function, language, and visuo‐spatial domains. Using genetic profile scores in a sample size of 1,673 (70% female, aged 42‐75 years, mean 60.8). We tested the association between cognitive test results and genetic risk for Alzheimer’s disease and related phenotypes including structural neuroimaging measures.

Results

Our findings indicate a significant association of Alzheimer’s polygenic risk scores (PRS) with cognitive test results in healthy individuals within memory and executive function domains. The results of analyses with additional genetic profile scores including psychiatric traits and structural neuroimaging measures will also be presented.

Conclusion

Those who are at high genetic risk for Alzheimer’s disease have reduced cognitive function prior to dementia diagnosis from middle age. Our results highlight the utility of online cognitive testing as a cost‐effective alternative to in person testing for large scale studies and the potential for it’s used as a pre‐screening approach to identify those at high risk of Alzheimer’s disease.
Training and Accompaniment Model for Expanding ADRD Research in LMICs – The Atlantic Fellows for Equity in Brain Health Experience
Authors: Valcour Victor
Published: December 2023

Background

Often, global health programs are designed to train individuals from low‐ and middle‐income countries (LMICs) with training provided in more resourced regions. Subsequently, the trainees return to their home community with limited additional resources. When research is funded, capacity‐building is rarely prioritized and partnership for core administrative and study management needs is absent. A program of ‘accompaniment’ where programs partner with trainees after their training period is less frequent and could alter the landscape of research capacity building for dementia.

Methods

The Atlantic Fellows for Equity in Brain Health program provides both a one‐year in‐residence learning experience and seeks to accompany fellows as they return to their home community. Resources and activities in the post‐training period include funding for small pilot projects, networking and community building, training in grants management, support for logistic and administrative activities related to grants, partnering with grant and manuscript writing and assistance with data collection and management.

Results

Over seven years, Atlantic Fellows have received 137 Pilots Awards ($25k each) for activities in 41 countries. Many of these awards serve as launching pads for future funding. For example, the Multi‐Partner Consortium for Dementia Research in Latin America (ReDLat) grew out of a Pilot awarded to an Atlantic Fellow from Latin America uniting 14 research centers across six Latin American countries aiming to identify the unique genetic and social determinants of health that drive Alzheimer’s disease and related dementias. Work is underway and includes prominent capacity building activities with more than $12M in committed from global partners. More than 1454 individuals have been enrolled. Eleven Atlantic Fellows are directly involved in the project. Other examples include work in Brazil that has now been transformed into US National Institutes of Health funding. New work is currently launched in East Africa leading to competitive research applications under review.

Conclusions

An intentional model of accompaniment can achieve substantial impact on dementia research in LMICs.
A global approach to the epidemiology of cognitive ageing and dementia: Cohort Studies of Memory in International Consortium (COSMIC)
Authors: Sachdev Perminder S.
Published: December 2023

COSMIC (COhort Studies of Memory in International Consortium) is an international consortium of longitudinal studies of cognitive aging and dementia, currently comprising 57 cohorts from 39 countries across 6 continents, comprising 186,000 participants (49% White, 8% Black, 21% Asian, 20% Hispanic, 2% Other). COSMIC embraces the power of collaboration through horizontal partnerships, with pooled and coordinated analyses after rigorous harmonization to examine ethno‐geographic differences in risk/protective factors and biomarkers, harness data from under‐represented populations, and permit cross‐validation in a field notorious for non‐replicable results. Analyses thus far have demonstrated that the cross‐national variation in prevalence of MCI is lower than generally reported, with commonality of most risk factors. The effect sizes of risk factors do, however, vary in populations, with APOE*4 and diabetes being associated with greater rates of decline in Asian than White populations. High school education is a significant threshold for protection against cognitive decline in later life, especially in Black and Asian populations. Physical activity shows a dose‐dependent relationship with incident dementia, suggesting that older adults should do three to six hours of physical activity per week for maximum cognitive benefits. The range and depth of such findings continues to grow, as is the community of researchers in both high and low‐middle income countries. With its global reach, open sharing of data and diverse network of researchers, COSMIC is creating a truly global epidemiology of dementia that is needed to deal with the world‐wide inequity in research, and meet the ambitious goals of the 2017 World Health Assembly to address the global epidemic of dementia and the hopes of people at risk of dementia everywhere.
Enhancing diversity in global ADRD Research: African Dementia Consortium (AfDC) and the Alzheimer Disease Sequencing Project (ADSP)
Authors: Akinyemi Rufus
Published: December 2023

The World Health Organization (WHO) Dementia Research Blueprint was recently launched with priorities including enhancing greater diversity and inclusivity in dementia research with adequate representation of different geographic, ethnic and regional populations. This aligns with one of the primary goals of the Alzheimer Disease Sequencing Project (ADSP) to develop and provide a rich and diverse dataset of clinical, genomic, and biomarker data that can be analyzed to accelerate our understanding of AD with implications for better prediction and discovering novel precision diagnostics and therapeutics. The increasing population of the elderly in Africa, huge genetic heterogeneity of indigenous African populations and recent findings of ancestry‐ specific protective variants in the region of the APOE ε4 gene in a modest African AD cohort provide a strong rationale to enhance indigenous African involvement in global AD genomic studies. The ADSP is collaborating with the African Dementia Consortium (AfDC) to increase the ADSP’s global resource by including underrepresented participants of African ancestry from both the United States and multiple countries in Africa. The study in Africa involves multiple sites in nine African countries operating under the AfDC. We are identifying and enrolling participants and obtaining DNA and plasma samples for whole genome sequencing and biomarker assays. In addition, socio‐demographic, clinical, and neurocognitive data will be obtained on all participants using protocol‐guided evaluation procedures that have been developed to accommodate different cultures and to support phenotype harmonization, and for joint studies of biological and social risks. This collaboration, and the integrated approach toward data harmonization and management is a prototype for global ascertainment of complex human diseases.
Age‐ and Sex‐ dependent changes in Translocator Protein 18 kDa (TSPO) expression, cellular sources, and association with amyloid‐β plaques in the 5XFAD murine model of Alzheimer’s Disease
Authors: Perez Daniel Andres Martinez , McGlothan Jennifer L. , Guilarte Tomás R
Published: December 2023

Background

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects cognition, memory, and social abilities with devastating effects on individuals and families. The hallmark AD pathology is the formation of amyloid‐β‐(Aβ)‐plaques and Tau neurofibrillary tangles leading to neurodegeneration. Neuroinflammation, and microglia activation, also play an important role in the initiation and progression of AD, a process that begins earlier than cognitive decline. TSPO is a well‐validated and widely used biomarker of neuroinflammation that is expressed in glial cells, and it is markedly increased in the brain of AD subjects and in AD animal models. Previous studies have not assessed a detailed trajectory of TSPO in the progression of AD. In the present study, we determined the age‐and sex‐dependent increase in brain TSPO levels, cellular sources, and association with Aβ‐plaques in parallel with behavior.

Method

Behavioral performance was measured using the Barnes Maze (cognition) in male and female wild‐type (WT) and 5XFAD mice at 3 months (3M), and 7 months (7M). To evaluate pathological endpoints, we measured Aβ‐load (number, size, and % area covered), TSPO quantitative autoradiography using the TSPO‐specific radioligand [3H]‐DPA‐713, and quadruple‐label immunofluorescent confocal imaging to determine the cellular sources of the TSPO response and its association with Aβ‐plaques.

Result

At 3M, we observed no significant differences in behavioral performance between WT and 5XFAD in either sex. At 7M, 5XFAD males showed no cognitive dysfunction, however, there was a significant cognitive impairment in 5XFAD females. We found an increase of Aβ‐plaques in an age‐and sex‐dependent manner. TSPO autoradiography showed a significant increase in TSPO levels in 5XFAD mice in both sexes and ages with a higher increase in females. Furthermore, we show that TSPO expression is colocalized with plaque‐associated microglia and not astrocytes.

Conclusion

These results indicate that brain TSPO is an early biomarker of neuroinflammation and TSPO levels increase at the same time that Aβ‐aggregation and much earlier than cognitive decline. Furthermore, the increase in TSPO levels was associated with microglia surrounding or embedded with Aβ‐plaques suggesting a role in plaque formation.
Developing Integer‐based Risk Scores for Predicting the Risk of Incident Cognitive Impairment in Cognitively Normal Older Adults
Authors: Petersen Kellen K. , Nallapu Bhargav Teja , Grober Ellen , Lipton Richard B. , Morris John C. , Hassenstab Jason J. , Gordon Brian A. , Davatzikos Christos , Ezzati Ali
Published: December 2023

Background

We aimed to developed integer‐based risk scores for predicting incident cognitive impairment up to 10 years in initially cognitively normal older adults.

Methods

Participants were 479 older adults (aged 60 to 90) from longitudinal studies of aging and Alzheimer’s disease from the Knight ADRC at Washington University in St. Louis. The primary outcome was incident cognitive impairment, defined as conversion from Clinical Dementia Rating (CDR®) 0 to >0. The sample was divided into training (60%) and test (40%) sets. Feature‐sets were formed from combinations of four categories of variables: demographics (D), genetics (G), cognitive measures (C), and biomarkers (B) (Details in Figure 1 legend). Utilizing a modified version of the AutoScore‐Survival algorithm, variables were ranked based on variable importance using reduction in predictive accuracy due to replacement with a random permutation value in combination with Random Survival Forests. Variables were iteratively included in constructing risk score models based on coefficients of Cox regression models.

Results

Five risk score models were developed using five feature‐sets. All models retained age, APOE4 status, free recall from the Free and Cued Selective Reminding Test, hippocampal atrophy, and Tau positivity when included as potential variables in the feature‐sets. The risk score derived from the DGCB model had a Harrell’s concordance index (C‐index) of 0.754 and integrated Area Under the ROC Curve (iAUC) of 0.792. The best performing model without biomarkers used the DGC feature‐set and had a C‐index of 0.694 and iAUC of 0.699 while the risk score using the DG feature‐set only had a C‐index of 0.632 and iAUC of 0.647. Participants who had risk scores in the top quartile of the DGCB model risk score had an increased rate of conversion to CDR > 0.

Conclusions

We developed five risk score models for predicting incident cognitive impairment. Risk scores consisted of different sets of measures which differed in ease‐of‐access and costs. Using such simple risk scores that do not include biomakers as clinical decision support tools is practical in the clinical setting. Including biomarkers in risk scores provides slight improvement to classification accuracy, emphasizing their importance in research settings.