bluuebunny/crossref_metadata_2025 huggingface dataset:
Technical performance and biotemporal stability evaluation of Olink proximity extension assay for blood‐based biomarker discovery
Authors: Mattingly Zoe A. , Celia Amanda M. , Kuo Yi‐kai , Trombetta Bianca A. , Ramirez Christopher , LaCasse Kathryn , Kivisäkk Pia , Carlyle Becky C. , Arnold Steven E.
Published: December 2021

Background

Novel biomarkers are necessary for improving differential diagnosis of Alzheimer’s Disease (AD), disease monitoring, and treatment personalization. Core cerebrospinal fluid (CSF) AD biomarkers: amyloid‐ß (Aß), total‐tau (T‐tau), and phosphorylated‐tau (P‐tau181) are strong markers of the presence of amyloid pathology, but are not suitable for measuring disease progression or drug response in a clinical trial . In this context, blood‐based biomarkers are increasingly desirable, as plasma is less invasive than CSF, enabling short‐term repeated sampling.

Method

Technical performance of Olink Proteomic’s multiplex proximity extension assay was evaluated using plasma samples from the MADRC longitudinal cohort. Over 400 analytes were measured on five off‐the‐shelf panels. Inter‐plate and intra‐plate coefficient of variations (CVs) were calculated from 3 samples run in duplicate on each plate. ANOVA was used to assess proportion of technical versus biological sources of variance. Multi‐protein investigations require consideration of multiple testing. Power calculations were performed using baseline samples from n=34 Controls and n=20 Dementia‐AD subjects to demonstrate optimal sample size for Olink studies.

Result

The majority of analyte mean CVs fell within the acceptable range for inter and intra‐plate measurements (<15%). Higher CVs were generally related to lower analyte abundance. Most analytes were relatively stable (Biotemporal CV < 15%) in control individuals year to year. ANOVA determined that the greatest source of variation in plasma was due to biological inter‐individual variability, as opposed to technical variation for all but 73 proteins. With regards to experimental power in a 450 protein experiment, a high effect size protein such as NfL required fewer than 50 samples per group to achieve confidence in observed significant differences. In contrast, the moderate effect size MCP‐1 required just under 500 samples per group when 450 proteins are measured. This decreased to n=400 if only 100 proteins are measured, and n=170 if MCP‐1 is measured alone.

Conclusion

Olink technology is technically robust and reliable, with biological factors being the primary source of variation for most proteins in plasma. Particularly for medium effect size proteins, sample size is an important consideration when planning experiments using this technology.
Levels of the synaptic proteins PSD‐95, SNAP‐25, and neurogranin are selectively increased in the cerebrospinal fluid of patients with Alzheimer’s disease
Authors: Kivisäkk Pia , Carlyle Becky C. , Ramirez Christopher E. , Trombetta Bianca A. , Mendes Muriel , Brock Mary , Rubel Carrie E. , Czerkowicz Julie , Graham Danielle , Arnold Steven E.
Published: December 2021

Background

Synaptic dysfunction and loss occur early in Alzheimer’s Disease (AD) dementia and are closely linked to cognitive decline. Levels of both pre‐ and post‐synaptic proteins are reduced in AD brains while recent studies have shown increased levels of synaptic proteins in the cerebrospinal fluid (CSF) already in the early stages of AD, presumably due to release from degenerating synapses. We measured CSF levels of the novel post‐synaptic marker PSD‐95 together with levels of SNAP‐25 (pre‐synaptic) and neurogranin (post‐synaptic), two emerging synaptic biomarkers, in subjects with AD, other neurodegenerative diseases (OND), and controls.

Method

CSF samples from 158 patients undergoing diagnostic lumbar punctures were selected from banked samples. Clinical diagnoses were established by chart review and AD status was verified by CSF ATN biomarkers. 30 subjects had mild cognitive impairment or dementia due to AD, 69 had OND, and 59 were neurological controls (NC). In addition, 30 CSF samples were obtained from healthy subjects (HC) participating in a research study. Levels of PSD‐95 and SNAP‐25 were measured by Quanterix SIMOA assays and neurogranin by an automated Euroimmun ELISA assay.

Result

All subjects had detectable CSF levels of PSD‐95, SNAP‐25, and neurogranin. Levels of all three synaptic markers were higher in AD subjects compared to subjects with OND (p=0.04, p<0.001, and p<0.001, respectively) and both control groups, while levels of SNAP‐25 and neurogranin were lower in OND subjects compared to NC (p=0.005, and p=0.025, respectively). There were tight correlations between levels of PSD‐95, SNAP‐25, and neurogranin with the strongest correlation between SNAP‐25 and neurogranin (r=0.87; r2=0.76; p<0.0001).

Conclusion

Our data suggest that PSD‐95 and other emerging synaptic markers are selectively increased in the CSF of subjects with AD and that levels of both pre‐ and post‐synaptic markers are tightly correlated. Specific biomarkers for AD‐associated synaptic pathology may hold promise to discriminate AD from other neurodegenerative disorders, to correlate with cognitive decline, and to monitor responses to disease‐modifying drugs reducing synaptic degeneration.
Differential impact of educational attainment on later life cognition by race/ethnicity in the Project Talent Aging Study
Authors: Thomas Marilyn D , Calmasini Camilla , Seblova Dominika , Manly Jennifer J , Lapham Susan , Peters Kelly , Prescott Carol Arlene , Mangurian Christina , Glymour M Maria
Published: December 2021

Background

Increased education reduces risk of late life cognitive impairment. However, racial/ethnic inequities in cognitive outcomes persist at all levels of education. These findings suggest the need to evaluate whether race/ethnicity modifies the association between education and cognition overall and within specific cognitive domains.

Method

Data are from 2,078 participants of Project Talent Aging Study, a nationally representative study of high school students sampled in 1960 and followed up for cognitive assessments at the average age of 75 years. Three cognitive domains were selected, z‐scored, and evaluated separately and as a composite measure: verbal fluency, memory/recall, and attention. We used multivariable linear regression to estimate main associations between years of education and cognitive outcomes, and then evaluated statistical interaction with race/ethnicity. All models were adjusted for age, childhood socioeconomic status, childhood self‐reported health status, number of school absences, and adolescent cognitive ability.

Result

The sample included White (81.4%), Black (9.2%), and Other race/ethnicities (9.4%). Each additional year of education was associated with higher scores on the cognitive composite measure (β=0.053; 95% confidence interval [CI]=0.031, 0.076). In the cognitive composite model with interactions, the estimate for White respondents was β=0.048 (95% CI=0.024, 0.071) and the interaction with education for Black respondents was β=0.019 (CI=‐0.062, 0.099). Within cognitive domains, each additional year of education was associated with better verbal fluency (β=0.058; 95% CI=0.035, 0.081) and attention (β=0.040; 95% CI=0.017, 0.063), but not recall (β=0.014; 95% CI=‐0.011, 0.038). Among cognitive domain‐specific models with interactions, the attention domain estimate was significantly different for Black compared to White respondents: the estimate for White adults was β=0.030 (CI=0.005, 0.055) and the interaction with education for Black adults was β=0.106 (CI=0.022, 0.189).

Conclusion

Greater educational attainment predicted better overall cognition, verbal fluency, and attention for US adults. Associations for verbal fluency and memory were similar for racial groups; however, education offered an additional benefit for Black adults in the attention domain compared to White adults later in life. Future research should explore whether educational opportunities and quality may have differential cognitive implications across racial/ethnic groups.
Relationship of insulin resistance and glucose to tau PET positivity
Authors: Ennis Gilda E , Betthauser Tobey J , Koscik Rebecca L , Engelman Corinne D , Anderson Rozalyn , Christian Bradley T , Asthana Sanjay , Johnson Sterling C , Bendlin Barbara B
Published: December 2021

Background

Insulin resistance (IR) and hyperglycemia have been linked to increased dementia risk. In some animal studies IR and hyperglycemia have been associated with tau hyperphosphorylation. In a sample of predominantly healthy middle‐aged and older adults, we examined whether higher IR and fasting glucose were related to increased odds of tau PET positivity assessed using [F‐18]MK‐6240 positron emission tomography (PET). We also explored whether relationships to tau PET positivity were moderated by global amyloid pathology measured using [C‐11]PiB PET.

Method

Participants were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) and the Wisconsin Alzheimer’s Disease Research Center (ADRC) Clinical Core (Table 1). In the IR study, n=231 WRAP participants had homeostatic model assessment of insulin resistance (HOMA2‐IR) and PET. Twenty‐eight (12.1%) were tau PET positive (entorhinal MK‐6240 SUVR > 1.27; Betthauser et al., 2020) and 59 (25.5%) were amyloid PET positive (global PiB DVR > 1.19; Racine et al., 2016). In the Glucose study, n=332 participants (n=239 WRAP; n=93 Wisconsin‐ADRC) had fasting glucose and PET. Forty‐nine (14.8%) exhibited tau PET positivity and 81 (24.4%) were amyloid PET positive. Binary logistic regression tested whether HOMA2‐IR and glucose were related to odds of tau PET positivity. Global PiB DVR was explored as a moderator of HOMA2‐IR and glucose in separate logistic regressions.

Result

HOMA2‐IR and glucose were not significantly related to odds of tau PET positivity (ps > .37), controlling for age, sex and global PiB DVR (Figure 1). Higher global PiB DVR (standardized using cut‐point to center) was significantly related to greater odds of tau PET positivity [IR study: Exp(2.8), p < .001, 95%CI: 1.9‐4.1; Glucose study: Exp(3.1), p <.001, 95%CI: 2.3‐4.4]. Global PiB DVR was not a significant moderator of insulin or glucose (ps > .81; Figure 2).

Conclusion

HOMA2‐IR and glucose may not be related to tau pathology in cognitively unimpaired adults. The low proportion of participants who were tau PET positive likely limited the detection of significant interaction effects. Additional research is needed in samples with a greater proportion of diabetic and cognitively impaired participants to determine potential pathways linking IR and glucose to dementia.
Amphiphilic distyrylbenzene derivatives as potential therapeutic and imaging agents for the soluble amyloid‐β oligomers in Alzheimer’s disease
Authors: Mirica Liviu M
Published: December 2021

Background

New amphiphilic distyrylbenzene derivatives have been developed that target both the soluble Aβ oligomers and amyloid plaques in Alzheimer's disease (AD), as well as the extracellular p‐tau aggregates, Aβ‐mediated oxidative stress, and neuroinflammation.

Method

We have developed a novel amphiphilic distyrylbenzene derivative that exhibits high binding affinity for Aβ aggregates ‐ especially the Aβ oligomers, and a series of ex vivo and in vivo immunostaining and imaging studies were employed to probe the beneficial properties of this potential therapeutic agent.

Result

Upon treatment of 5×FAD mice with an amphiphilic distyrylbenzene derivative, fluorescence imaging of the brain sections shows that this compound can easily penetrate the blood‐brain‐barrier and selectively bind to the Aβ oligomers, as confirmed by the colocalization with an Aβ oligomer‐specific antibody. Furthermore, when comparing the MFC‐treated mice vs. the vehicle‐treated mice, the total amount of Aβ species and the associated p‐tau aggregates was significantly decreased by up to 70%, along with a significant reduction in the amount of activated microglia.

Conclusion

The amphiphilic distyrylbenzene compound reported herein can attenuate the formation of amyloid plaques and associated p‐tau aggregates, while also reducing the microglia‐mediated neuroinflammatory response, which is uncommon among the previously reported amyloid‐targeting chemical agents.
Metabolomics analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Karaman Ibrahim , Pinto Rui , Solomon Alina , Ngandu Tiia , Correia Goncalo , Dehghan Abbas , Tzoulaki Ioanna , Matthews Paul M. , Lewis Matthew , Kivipelto Miia , Elliott Paul
Published: December 2021

Background

The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a randomized controlled trial that showed significant benefits on cognition for a 2‐year multidomain lifestyle intervention vs regular health advice in 1260 at‐risk older individuals from the general population. The aim of this study was to investigate the metabolic effects of the intervention and their association with cognitive outcomes.

Method

We acquired metabolomics data of blood plasma on two time points (baseline and 2 years) in a set of 1089 participants (547 intervention and 542 control). A multi‐technology platform consisting of using ultra‐high performance liquid chromatography ‐ mass spectrometry (UHPLC‐MS) and 1H nuclear magnetic resonance spectroscopy (NMR) was used to generate extensive measurement coverage of the metabolome. The data was acquired using both reversed‐phase chromatography (RPC) tailored for the retention and separation of both complex and neutral lipids and hydrophilic interaction liquid chromatography (HILIC) for the retention and separation of small polar metabolites. The UHPLC‐MS untargeted data contains a total of 10,825 metabolomic features, 1244 of them currently annotated. The NMR data contains measurements of both small and macromolecules, including 112 lipoprotein fractions (derived using Bruker lipoprotein subclass analysis: BI‐LISA). Data analysis was conducted using linear mixed models.

Result

Several baseline metabolite levels had a statistically significant association with cognition. Results will also be presented from ongoing analyses to investigate intervention effects on change in metabolites.

Conclusion

Complex metabolomics analyses are new in the context of multidomain lifestyle dementia prevention trials. While causality is yet to be investigated further, some of the metabolite classes and pathways observed (e.g. sphingolipids) have been previously implicated in cognitive decline and neurological disorders, suggesting early interpretable leads in the rich dataset at hand.
Childhood and adulthood traumatic events differentially associate with cognitive aging among Black and White elders in the Health and Retirement Study
Authors: Zuelsdorff Megan , Sonnega Amanda , Byrd DeAnnah R , Norton Derek , Deng Xinyue , Turner Robert
Published: December 2021

Background

Modifiable sociocontextual factors powerfully shape ADRD risk, and demonstrably contribute to well‐established racial disparities in cognitive aging. Stressful experiences occurring across the lifespan associate with brain aging and poor cognitive outcomes. However, the importance of timing and even type of stressor remains understudied. We examined relationships between childhood and adulthood traumatic events and cognition among non‐Hispanic Black and White older adults in the Health and Retirement Study (HRS).

Method

The sample included non‐demented adults (N=5,725) aged 65+ with lifetime stress data and complete cognitive testing at the 2006/08, 2010/12, and/or 2014/16 waves. Trauma measures included childhood (0‐11), and adulthood (0‐7) traumatic event counts. Outcomes included global cognition, immediate recall, and delayed recall (Telephone Interview for Cognitive Status). Each exposure‐outcome pair was investigated in separate linear mixed effect models including baseline trauma count, a quadratic trauma term to test for non‐linear relationships, and subject‐specific random intercept. Omnibus Likelihood Ratio Tests (LRT) were conducted to determine if number of traumatic events associated overall with each cognitive outcome. The sample was stratified by race before analysis.

Result

Black participants (N=651) were younger and reported less formal education than White participants (N=5,074). Number of traumatic events in adulthood did not vary by race, but Black participants reported slightly fewer childhood traumas (Table 1) than Whites. Among Whites, childhood traumas associated with poorer global cognition scores but traumas in adulthood showed very modest positive associations across cognitive domains. Among Black participants, no association between childhood trauma and later‐life cognition was observed. A significant non‐linear term for traumatic events indicated cross‐domain cognitive detriment associated with high exposure to adulthood trauma (Table 2; Figure 1).

Conclusion

Average exposure to traumas (eg., physical abuse, life‐threatening illness) was low, and in both Black and White older adults, some limited exposure to traumatic events during adulthood predicted modest cognitive benefit. Black HRS participants reporting many traumatic events during adulthood, but not childhood, showed dysfunction in global cognition and recall. Findings highlight importance of adverse events across the full life course, potential threshold effects and co‐occuring chronic stress conditions, and a need to identify resources that buffer impacts of trauma on biology and personal environment.
White matter diffusion abnormalities observed in cognitively normal elderly before conversion to mild cognitive impairment
Authors: Zhang Linda , Medina Miguel , Strange Bryan A
Published: December 2021

Background

Differences in white matter (WM) microstructure, as measured with diffusion tensor imaging (DTI), have been observed between cognitively normal, mild cognitively impaired (MCI), and Alzheimer’s disease (AD) patient groups. With increased focus on early intervention for AD, detection of preclinical changes is paramount; however, due to difficulties in predicting future conversion, few studies have investigated WM deterioration prior to symptom onset. Using DTI data from the Vallecas project (an 8‐year longitudinal study of healthy elderly individuals), we determine if WM changes can be found in cognitively normal individuals before conversion to MCI.

Methods

From a baseline cohort of 824 cognitively normal 70‐85 year olds, 65 individuals converted to MCI over the study duration (mean age 77.0±4.29 years, 58% female). 65 non‐converters were matched by age, sex, and years of education to act as controls. DTI scans from one year before conversion were analysed using tract‐based spatial statistics implemented in FSL. Fractional anisotropy (FA), mean diffusivity (MD), and mode of anisotropy (MO) were compared between groups using non‐parametric permutation tests. A second comparison between future converters and all 759 non‐converters (mean age 74.0±3.92 years, 65% female) was also conducted, using age, sex, and years of education as covariates.

Results

In the unmatched comparisons, controls had higher FA in the left forceps minor (ForMin) and anterior corona radiata (CR) (p<0.05), and higher MO along the corpus callosum (CC) and ForMin (p<0.01). Future converters had higher FA in the left posterior CR and corticospinal tract (p<0.05), higher MD in the left anterior CR (p<0.05), and higher MO along the bilateral projection fibres (p<0.01). In the matched comparison, only MO differences were observed, with higher MO in controls along the body of the CC (p<0.05), and higher MO in future converters in the left projection fibres and the splenium of the CC (p<0.01). All significant results were FWE‐corrected.

Conclusions

Our results suggest that frontal commissural fibres begin to deteriorate in cognitively normal subjects destined to convert to MCI, whilst also demonstrating selective preservation of projection fibres. We also find that MO is a sensitive measure of white matter microstructural changes presaging cognitive decline, even in preclinical populations.
Comparison of remote and in‐person digital speech‐based measures of cognition
Authors: Stegmann Gabriela M , Hahn Shira , Liss Julie , Berisha Visar , Mueller Kimberly D
Published: December 2021

Background

Neuropsychological testing requires an in‐person visit with a trained administrator using standard/fixed materials. Speech‐based cognitive testing on mobile devices enables more frequent and timely test administration, but head‐to‐head comparisons of in‐person and remote versions of tests are rare. We compare responses to a well‐validated task conducted under supervised (in‐person) and unsupervised (remote) conditions.

Method

We used two data sets containing Cookie Theft picture descriptions (BDAE), one collected in‐person, under supervision (Wisconsin Registry for Alzheimer’s Prevention (WRAP); N = 912; age = 62.2 (SD = 6.7), 70% F) and one collected remotely, without supervision (participants online; N = 93, age = 36.5 (SD = 11.5), 65% F). WRAP participants were judged to be cognitively normal, and online participants self‐reported as healthy. Each participant provided one picture description, yielding 93 remote and 912 in‐person transcribed descriptions. Language metrics previously used in dementia research were extracted: word count (number of words spoken), MATTR (ratio of unique words to total number of words), pronoun‐to‐noun ratio, and semantic relevance. Comparing MATTR, pronoun‐to‐noun ratio, and semantic relevance values elicited in‐person and remotely is important because these characteristics have been found to be impacted by declines in cognition. Differences in word counts may reflect different levels of motivation in the two settings.

Result

Using Cohen’s d effect sizes, differences in mean word count between in‐person and remote participant transcripts was negligible (112 words in‐person and 118 words remote; d = .10, p = .21), the difference for semantic relevance was negligible (.19 in‐person and .18 remote, scale = 0 to 1; d = .14, p = .19), the difference for MATTR was small (.75 in‐person and .74 remote, scale = 0 to 1; d = .37, p<.05), and the difference for pronoun‐to‐noun ratio was moderate (.48 in‐person and .35 remote, scale = 0 to 1; d = .56, p <.05).

Conclusion

Results show that response length and semantic relevance of responses to the Cookie Theft picture description task are comparable under supervised, in‐person and unsupervised, remote conditions. Small to moderate differences in vocabulary (MATTR) and pronoun‐to‐noun ratio may be due to differences in age and merit further investigation.
Cognitive assessments in ADNI: Lessons learned from the ADNI psychometrics project
Authors: Crane Paul K. , Choi Seo‐Eun , Gibbons Laura E. , Mukherjee Shubhabrata , Zhu Ryoui , Scollard Phoebe , Lee Michael L. , Trittschuh Emily H. , Saykin Andrew J. , Mez Jesse , Mungas Dan M. , Wang Chun ,   ADNI Psychometrics Investigators
Published: December 2021

Background

The Alzheimer’s Disease Neuroimaging Initiative includes cognitive assessments at every study visit. We have had the opportunity to use modern psychometric approaches including confirmatory factor analysis (CFA) and item response theory (IRT) with these rich data. Here we discuss lessons learned from analyses of memory, executive functioning, language, and visuospatial functioning in ADNI.

Method

We analyzed data from all ADNI study waves. We considered granular data for each test. Our panel of experts considered each granular data element and assigned them to a single primary domain – memory, executive functioning, language, or visuospatial functioning – or to none of these. We then used CFA and IRT approaches to calibrate each domain separately. ADNI has extensive imaging and fluid biomarker data we used for validity assessments.

Result

The ADNI cognitive battery emphasizes memory assessment with multiple indicators. The assessment of language and executive functioning are less robust but are each measured with several indicators. The assessment of visuospatial functioning is much sparser. Assessment intensity is nicely reflected in measurement precision data, where standard errors of measurement are smallest for memory, intermediate for language and executive functioning, and largest for visuospatial functioning. Validity assessments were solid for all four domains. We have uploaded resulting composite scores (ADNI‐Mem, ADNI‐EF, ADNI‐Lan, and ADNI‐VS) to the Laboratory On Neuroimaging (LONI)‐hosted ADNI website.

Conclusion

The composite scores we have developed will be useful for investigators integrating domain‐specific cognitive data in their analyses of ADNI data. The measurement precision findings have implications for future study design; for example, more robust measurement of visuospatial functioning may be a wise investment. Measurement precision findings also have implications for analytic strategies. Standard typical analyses ignore measurement precision and treat observed scores as if they were measured without error. We are developing hierarchical Bayesian modeling strategies that can incorporate both point estimates for domain scores along with standard errors of measurement. These models will account for measurement error, ensuring that inferences are valid across domains with very different measurement properties. We will make this code widely available as well.
A novel gut microbiome therapeutic derived from dietary polyphenols attenuates neuroinflammation in vivo in a model of C9orf72‐mediated frontotemporal dementia
Authors: Wu Henry , Smith Chad , Estill Molly , Sebastian Maria , Pasinetti Giulio Maria
Published: December 2021

Background

Frontotemporal dementia (FTD) is a neurodegenerative disorder with various genetic etiologies, the most prevalent of which include G4C2 expansions in the c9orf72 gene. Expansions produce dipeptide repeat proteins (DPR), forming aggregates with deleterious impacts on cellular processes and correlating with neuroinflammation. Glycine‐Arginine (GR) aggregates are the only significantly correlated DPR found in clinically relevant neuroanatomical regions of the brain. Our current study investigates the contribution of innate immunity to FTD pathogenesis and the attenuation of neuropathologies with the brain bioavailable microbiome‐derived metabolite, 3‐hydroxybenzoic acid (3‐HBA).

Method

Mice were transfected via intracerebroventricular injection with AAV9‐GFP(GR)100 or AAV9‐GFP and treated starting on Day 28 with either PBS vehicle or 50 mg kg‐1 of 3‐HBA. At 14 weeks mice were sacrificed and prefrontal cortex (PFC), somatosensory cortex (CTX), and hippocampal (HIPP) tissue was dissected and prepared for RNA sequencing. Differentially expressed genes (DEGs) were identified using DESeq2 and pathway alterations were detected using Ingenuity Pathway Analysis. ELISA for IL‐1β was conducted on PFC, CTX, and HIPP tissue. To determine the ability of 3‐HBA to reduce secretion of IL‐1β, primary microglia pretreated with 3‐HBA were stimulated with LPS+ATP and IL‐1β concentration was analyzed by ELISA.

Result

DEGs associated with FTD pathology, protein expression levels of the pro‐inflammatory cytokine IL‐1β, and subsequent amelioration via treatment with 3‐HBA were demonstrated to be a result of contributions from the innate immune system and inflammasome activation in microglia. Inflammatory pathways differentially enriched among treatment groups include TREM1 Signaling, the complement system, and NFκB signaling. GR‐100 Vehicle treated animals exhibited elevated IL‐β in cortical tissue. 3‐HBA was efficacious in vivo in rescuing IL‐1β levels in GR‐100 treated mice to levels of GFP animals. Primary microglia pretreated with 3‐HBA and stimulated with LPS+ATP significantly reduced IL‐1β release, signifying the efficacy of 3‐HBA in attenuating innate immune reactivity.

Conclusion

Pathways and genes associated with the innate immune system show enrichment in a model of FTD and are rescued by administration of 3‐HBA. Overexpression of IL‐1β in the cortex of GR‐100 Vehicle animals is attenuated by the administration of 3‐HBA. Our data implicates a gut‐brain axis mechanism of treatment for key FTD associated neuropathologies.
Functional connectivity is altered by APOE4 carrier status in cognitively healthy older adults
Authors: Green Zachary D. , Honea Robyn A , Vidoni Eric D , Burns Jeffrey M. , Morris Jill K
Published: December 2021

Background

Resting‐state connectivity allows for investigating brain network changes in pathologic states of aging, such as Alzheimer’s Disease (AD). Recently, brain network changes have been associated with AD‐related risk factors in asymptomatic individuals. We explored how brain network connectivity is affected by one such risk factor, apolipoprotein e4 (APOE4) carrier status.

Methods

In a sample of cognitively healthy older adults (n=102), we acquired demographic information, APOE4 carrier status, and resting‐state fMRI scans. Individuals were designated as “APOE4 carrier” by the presence of at least one APOE4 allele. No APOE2 carriers were included in the analyses. Using independent component analysis approaches for both individual de‐noising and group‐level analysis, we identified key brain networks traditionally associated with AD‐related decline. Utilizing nonparametric permutation inference, we tested for differences in connectivity to these networks based on APOE4 carrier status.

Results

We identified multiple networks with altered functional connectivity across groups, including networks associated with AD‐related decline. One key region, the anterior cingulate cortex, showed differences in connectivity with multiple resting state networks. Functional connectivity in these networks was decreased in APOE4 carriers compared to non‐carriers.

Conclusion

We highlight changes in functional connectivity dependent upon genetic risk. Our results add to a growing body of evidence that APOE4 carrier status, along with other risk factors for AD, alter large‐scale functional networks. Additional characterization of the interaction of APOE4 status and other AD‐related biomarkers on functional connectivity is warranted.
Biomarker‐based polygenic risk scores for profiling genetic susceptibility in Alzheimer's disease
Authors: Chasioti Danai , Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Gao Sujuan , Yan Jingwen , Saykin Andrew J.
Published: December 2021

Background

Precision medicine is designed to resolve heterogeneity in complex diseases such as Alzheimer’s (AD) to deliver timely and tailored treatment. Using ADNI data, we developed endophenotype‐specific polygenic risk scores (PRS) to assess the AD risk and to identify distinct genetic risk profiles among the converters.

Method

We used ADNI genetic, clinical and biomarker data for PRS development. We derived four ADRD endophenotype components including Amyloid (A), Tau (T), Neurodegeneration (N) and Vascular (V), by applying PCA on 11 phenotypic variables. Four individual biomarker PRSs (A, T, N, V) were obtained and combined into a single PRS (PRSATNV). Penalized regression (Lasso) applied for SNP selection and weight re‐estimation. Bootstrapping was used to minimize possible overfitting. On the ADNI test set, after removing participants with mild cognitive impairment (MCI), we estimated the odds and hazard of AD among the extreme PRSATNV quartiles (Q1,Q4). To identify biomarker‐specific genetic risk profiles among LMCI/AD participants, we performed K‐means clustering using the 4 biomarker PRSs (PRSA, PRST, PRSN, PRSV). Clustering was done based on APOE groups.

Result

The odds for AD individuals in the Q4 of PRSATNV was double those in Q1 (p=2.2e‐06, AUC=80%). On the same participants, we obtained a significant difference of 5 years in the AD onset between Q1 and Q4 (HR=2.2, p=6.9e‐03). Clustering restricted to LMCI/AD yielded 2 PRS clusters for ε3/ ε3 and ε3/ ε4 and 3 for ε4/ ε4 (Figure 1). In general, genetic risk profiles differed among the clusters for all APOE groups (PRSATNV in Table 1). The main difference was amyloid‐related for ε3/ ε3 carriers, neurodegeneration‐related for ε3/ ε4 and tau‐related for ε4/ ε4 (Table 1).

Conclusion

The combined biomarker PRS we developed successfully identified individuals in high risk for AD. Using clusters derived from endophenotype‐specific genetic information we were able to identify distinct biomarker‐related genetic profiles among converters. Endophenotype‐based PRS may be useful for risk stratification and development of genetically tailored therapeutics as different mechanisms may contribute to AD onset for a given individual. Validation in independent samples is a critical next step.
Effect of temporal meta‐ROI and Braak1&2 ROI on the dissociation between plasma pTau181 and PET statuses
Authors: Tissot Cécile , Kunach Peter , Therriault Joseph , Lussier Firoza Z , Benedet Andréa Lessa , Chamoun Mira , Pascoal Tharick A. , Servaes Stijn , Bezgin Gleb , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Jenna , Rahmouni Nesrine , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

Tau is usually assessed through cerebrospinal fluid or Positron Emission Tomography (PET). However, those methods are expensive and not readily available. Research is now focusing on cost‐effective blood‐based biomarkers to assess Alzheimer’s disease (AD) pathophysiologies. A novel immunoassay for plasma pTau181 has been created, and even though there are strong associations between plasma pTau181 and PET, no study has yet investigated which cortical area better reflects plasma tau.

Method

We assessed 269 individuals from the TRIAD cohort (164 CU, 60 MCI and 45 AD) that underwent plasma pTau181 assessment, [18F]MK6240 tau‐PET scan, [18F]AZD4694 amyloid‐PET scan to assess their amyloid‐b (Ab) status, an MRI and a neuropsychological evaluation. We conducted statistical analyses using R, first to calculate the threshold values for positivity in both tau assessing methods and to make comparisons between the groups. SUVR values for [18F]MK6240 were either based on Braak1 SUVR or temporal meta‐ROI SUVR.

Result

Using Receiver Operating Characteristic (ROC) curves, we established that the cut‐off for positivity for plasma pTau181 was 11.1060 pg/mL. When using Braak1 mask, the cut‐off for positivity was 1.040 SUVR (B1+/‐), while with temporal meta‐ROI it was 1.1827 (TMR+/‐). In both cases, we observed a majority of concordant individuals. However, we obtained 87 discordant individuals in the plasma/TMR, mostly plasma+/TMR‐, and 78 in the plasma/B1 analyses, mostly plasma‐/B1+ (Figure 1). Concomitant status of plasma/TMR was usually accompanied by a similar Ab status. However, in the Braak1 analyses, Ab status seemed to closely follow the PET status (Figure 2).

Conclusion

The cut‐off values for positivity using Braak1 mask is significantly smaller than when using temporal meta‐ROI. Using the temporal meta‐ROI mask, we had more discrepant individuals that were plasma+/TMR‐, with plasma‐/TMR+ individuals close to the threshold values. It was accurate at predicting negative biomarker statuses in CU participants, and positive in AD participants. Conversely, we had more plasma‐/B1+ individuals when using Braak1 mask, with values more spread around the plot. Due to low threshold values, portion of CU and MCI individuals were categorized as positive to both biomarkers. Finally, B1 status seemed to follow closely the Ab levels. Plasma pTau181 thus seems to reflect better temporal meta‐ROI tau.
Factors associated with early and late onset Alzheimer disease in Down syndrome
Authors: Lai Florence , Wang Cassandra , Mercaldo Nathaniel , Rosas H Diana
Published: December 2021

Background

Alzheimer disease (AD) onset in adults with Down syndrome (DS) typically occurs in the early 50s; however, the wide range from 40 to 70 years of age is poorly understood. Adults with DS commonly have co‐existing medical conditions which could influence age of onset and shed light on both risk and mitigation of AD in DS.

Method

A 12‐year retrospective chart review was conducted on 350 adults with DS, of whom 219 had AD, with mean onset age of 52.51 years and one standard deviation (SD) of 6.07. This AD cohort was divided into three age‐of‐onset groups: Typical Onset (TO) within 1 SD of the mean, Early Onset (EO) with >1 SD below the mean, and Late Onset (LO) with >1 SD above the mean. We analyzed factors hypothesized to influence dementia: sex, level of intellectual disability (LID), Apolipoprotein E (APOE) status, obstructive sleep apnea (OSA), and presence and onset age of hypothyroidism, seizures, and menopause. Analysis of variance or the chi‐square test of independence was used to assess differences amongst the three groups for continuous and categorical variables, respectively.

Results

As we hypothesized, medical co‐morbidities influence AD onset age in DS. Significant differences across the groups, particularly in the EO‐AD group included: greater percentage with OSA (p=0.015); younger age of hypothyroidism onset (p<0.001); greater percentage with seizures (p=0.018); and seizure onset age (p=0.001). We were unable to detect differences with respect to sex, menopause age, presence of APOE E4 or baseline LID.

Conclusions

Age of onset of medical co‐morbidities in DS, and not just their presence, is an important risk factor for dementia. Autoimmune/inflammatory processes in hypothyroidism could contribute to AD pathophysiology. Hypoxemia or hypercarbia from OSA may be risk factors for developing dementia. Proper screening and rigorous mitigation of hypothyroidism and OSA at their inception could possibly influence the course of AD in DS. Greater incidence of seizures may indicate that EO‐AD is more aggressive. The proximate timing of seizures and AD onset suggests that seizures may herald imminent dementia. Understanding the pathophysiology of these conditions could elucidate mechanisms in AD.
Outreach and recruitment of African Americans for Alzheimer’s disease studies during the COVID‐19 pandemic
Authors: Starks Takiyah D , Caban‐Holt Allison M , Williams Kelvin , Adams Larry D , Haines Johnathan L , Beecham Gary W , Reitz Christiane , Cuccaro Michael L , Vance Jeffery M , Pericak‐Vance Margaret A , Byrd Goldie S
Published: December 2021

Background

Recruiting African Americans in AD studies remains a challenge, particularly during a pandemic, where major health disparities in this population are illuminated. The recruitment literature suggests myriad factors that contribute to the underrepresentation of AAs, including, but not limited to “mistrust” in researchers and their institutions. Maintaining a continuous presence in the AA community builds trust even when traditional outreach methods are not allowed. We continued to provide outreach and recruitment opportunities through COVID education and food for families as we educated them about AD, and opportunities for study participation.

Method

While our traditional outreach methods for recruiting AAs were interrupted, we continued to conduct AD outreach using virtual platforms, mobile phone calls, family conference calls and food distributions. We hosted nine webinars on COVID‐19 to maintain a presence in local and national AA communities and to remain connected to existing AD participants. We reached over 160,000 persons through webinars and social media. We established new relationship new faith leaders in the AA community who co‐hosted COVID‐19 webinars and also expressed interest in forming partnerships on AD education. In addition, we hosted food drives in AA communities that not only addressed food insecurity and COVID prevention, but also AD education and AD research opportunities. At the food drives we distributed bags with masks, hand sanitizers, AD brochures, booklets and study participation information.

Result

Between October and December of 2020, 64 AAs who attended food drives expressed interest in AD studies that required blood draws and cognitive testing. Fifteen enrolled in our genetic study, 15 requested additional follow‐up and 13 expressed interest in participating in more than one study.

Conclusion

Prior research suggests that recruiting AAs into AD studies requires continuous engagement. We used multiple strategies to maintain contact with the AA community and existing research participants, and successfully increased enrollment in the last quarter of the year. Maintaining consistent and continuous engagement facilitates trustworthiness with AAs and yields positive recruitment outcomes, even in a pandemic where traditional recruitment methods are limited.
CSF sTREM2 predicts markers of blood brain barrier integrity and amyloid beta metabolism independent of APOE‐ε4 status
Authors: Weiner Rebecca L. , Dumitrescu Logan , Blennow Kaj , Zetterberg Henrik , Gifford Katherine A. , Pechman Kimberly R. , Jefferson Angela L. , Hohman Timothy J.
Published: December 2021

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor commonly studied for its roles in microglial regulation and amyloid beta deposition in Alzheimer’s disease (AD). Its soluble form, sTREM2, measurable in cerebrospinal fluid (CSF) is a novel biomarker of microglial activity. CSF sTREM2 has been associated with AD progression and biomarkers of neurodegeneration (for which tau is one), while associations with amyloid‐β biomarkers have been inconclusive. Furthermore, cerebrovascular injury commonly co‐occurs with AD, contributes to clinical progression, and drives microglial activation through independent signaling cascades. However, sTREM2 associations with cerebrovascular pathology have been largely unexplored.

Method

Leveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6.33 , male=67%, mild cognitive impairment=47%), associations between baseline CSF sTREM2 concentrations (measured using an in‐house immunoassay) and CSF AD biomarkers (Aβx‐42, Aβ1‐42, Aβx‐40, total tau, and phosphorylated tau) and cerebrovascular injury (CSF/plasma albumin ratio) were assessed using linear regression. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status.

Result

Higher baseline CSF sTREM2 concentrations predicted an increased CSF/plasma albumin ratio, indicative of compartmental blood brain barrier (BBB) permeability (p=1.36e‐07). Additionally, higher levels of sTREM2 predicted increased CSF protein levels of Aβx‐40 (p=1.53e‐09), and Aβx‐42 (p=7.73e‐03), but not Aβ1‐42 (p=0.26) levels, indicating a possible role for the TREM2 axis in regulating or responding to amyloid beta species composition. We also replicated previous associations between higher CSF sTREM2 and higher CSF tau (p=6.14e‐07) and p‐tau (p=1.82e‐08).

Conclusion

We report a novel association between sTREM2 and a marker of BBB integrity, highlighting opportunities for further investigation of the TREM2 axis with cerebrovascular injury. We also report a novel association between sTREM2 and amyloid‐β abundance that does not seem to reflect amyloid burden in the brain, and we replicate an sTREM2 association with markers of neurodegeneration. Future work will seek to better characterize the timing of sTREM2 changes relative to markers of BBB dysfunction and AD pathogenesis.
Instrumental variable meta‐analysis of the effect of systolic blood pressure reduction on cognitive change: Evidence from randomized trials of antihypertensive therapies
Authors: Ackley Sarah F , Zimmerman Scott C , Pamula Meenakshi , Peterson Rachel L , George Kristen M , Whitmer Rachel A , Corrada Maria M , Hughes Tim M , Glymour Maria M
Published: December 2021

Background

Previous meta‐analyses of trials of antihypertensive drugs have only evaluated the effect of randomization to treatment on cognition, without accounting for duration of treatment or degree to which treatment decreased blood pressure. We assumed that any cognitive benefit of antihypertensive treatment would be proportional to the magnitude of change in systolic blood pressure (SBP) achieved and the duration of follow‐up during which a lower SBP was sustained.

Method

We aggregated data from randomized trials of antihypertensive drugs which reported data on change in both SBP and the Mini Mental Status Exam (MMSE). We estimated the effect of decreasing SBP on annual cognitive change for each trial using an instrumental‐variable approach. This was determined for each trial separately using maximum‐likelihood estimation, assuming differences in cognitive change between treatment arms was proportional to the difference in SBP between the groups and the duration of follow‐up. For interpretability, we expressed effects as difference in MMSE per 10mmHg change in SBP per year. Results were combined using a fixed‐effects meta‐analysis.

Result

Out of 8 trials (N=70,734; follow‐up: 2.3 to 6 years), 7 suggested benefit of SBP reduction on cognitive change, with 2 of these 8 trials reaching statistical significance. No trials showed statistically significant cognitive harm. The pooled estimate suggested that a 10mmHg decrease in blood pressure slowed MMSE decline by 0.033 (95% CI: 0.023 to 0.044) points per year.

Conclusion

Randomized‐controlled trials of antihypertensives indicate that decreases in SBP slow cognitive decline. Even with a clinically substantial decrease in blood pressure, the average long‐term effect appears likely to be modest. Instrumental‐variable meta‐analysis can be used to provide an estimated annual benefit per change in SBP, allowing results from trials of heterogeneous treatments to be put on the same scale. Such estimates have more clinical relevance than standard intent‐to‐treat estimates.
Towards a better characterization of dementia in northeast Brazil: Numbers from a reference center in Recife
Authors: Mota Andreia Braga , Lins Maria Eduarda Pires , Lima Silva , de Oliveira Xavier Ramos Julia , Souza Ana Rita , Zacarias Bruno Felipe Vieira , Ramos Bruno , da Silva Rodrigo Cavalcanti Machado , Brandao Simone Cristina Soares , Barbosa Breno José Alencar Pires
Published: December 2021

Background

dementia numbers are increasing rapidly with a substantial contribution from low and middle‐income countries. There’s a limited number of reports in Brazil, mostly modest initiatives from south‐eastern, more developed areas, such as the Tremembe study which reported a 17,5% prevalence of dementia in 630 elderly subjects. With a population of approx. million individuals, the metropolitan region of Recife is among the largest cities of Northeast Brazil, a region of profound social disparities and high prevalence of low‐literacy.

Method

this is a single‐center, descriptive and health records‐based analysis of patients evaluated in the Dementia outpatient clinic of the Neurology and Neurosurgery Unit at the Federal University of Pernambuco in the timeframe between 2018 ‐ 2019.

Result

60 patients had their data available and were included for descriptive analysis. Mean age was 69 years old (+ 7.6 SD) with 62% of women and 6 years of formal education. 46% of all cases were referred for evaluation from neighboring cities and states. The mean Mini‐mental state examination in the first consultation was 15/30 and patients had a significant burden of functional impairment with a mean Pfeffer score of 21/30 (+ 9.8 SD). Hypertension (40%), Diabetes (71%) and Anxiety (85%) were frequent comorbidities. Regarding access to neuroimaging methods, 75% subjects had access to either CT (16/60) or MRI (39/60) and 12 individuals were further evaluated with molecular neuroimaging (SPECT and/or FDG‐PET). Formal neuropsychological evaluation, CSF biomarkers and advanced amyloid/tau imaging were not available. Alzheimer’s dementia was diagnosed in 45% individuals and another 45% had criteria for mixed vascular and degenerative conditions. 18% presented with other neurodegenerative syndromes such as FTD and Lewy bodies dementia. The mean follow up time in our service was of 19.8 months.

Conclusion

patients referred for evaluation were mostly in moderate to advanced stages of dementia, with a significant prevalence of mixed‐type and non‐Alzheimer’s pathologies. This data could suggest a referral bias and poor access to specialized clinics. Despite a modest sample size and heterogeneous data, the present study may contribute towards a better characterization of dementia numbers in Northeast Brazil.