bluuebunny/crossref_metadata_2025 huggingface dataset:
NFL and pTau species from plasma neuronal and astrocyte exosomes correlate with neuropathological development and neurodegeneration in Down Syndrome
Authors: Sukreet Sonal , Kim Elise K , Nauss Sophie N , O'Bryant Sid E. , Rafii Michael S , Rissman Robert A
Published: December 2023

Background

Individuals with Down Syndrome (DS) develop Alzheimer’s disease (AD). Plasma Neurofilament (NFL), phospho tau181, and 231 (pTau181 and 231) are currently considered promising blood‐based biomarkers of brain tau pathology in AD. However, it is still unknown whether the use of exosomal NFL and different pTau epitopes offers overlapping or complementary information about tau pathology information in this population. Using biobanked DSBI plasma samples, we aimed to understand the relationship between blood‐based exosome derived NFL, pTau181 and 231 with age, brain amyloid and tau pathology, APOE status, as well as cognitive and functional performance in non‐demented DS individuals. We hypothesized that the relationship between NFL, pTau‐181, and 231 derived from plasma neuronal and astrocyte exosomes (NDEs/ADEs) with that of other fluid and imaging biomarkers might help to accurately assess brain AD pathology in DS adults.

Method

Exosomes were isolated from the plasma of adult DS individuals who were enrolled in DSBI. Exosomes were precipitated and isolated using an ExoQuick kit. Isolated exosomes were enriched for NDEs and ADEs using antibodies against neuronal (L1CAM) and astrocyte (GLAST), respectively, followed by magnetic immunocapture and fluorescence‐activated cell sorting. NDEs and ADEs were assessed for their size and marker proteins by Nanosight, electron microscopy, and ELISA. NFL was quantified by SIMOA assays, while pTau epitopes 181 and 231 were quantified by MSD assays in NDEs and ADEs. We compared the diagnostic accuracy of exosomal p‐tau epitopes with NFL levels. We analyzed imaging data and cognitive measures in relation to NFL, pTau181, and pTau231 of NDEs and ADEs in adults with DS.

Result

Blood‐based NDEs and ADEs showed expected exosomal size, shape, and distribution. ELISA showed the presence of exosome marker proteins on NDEs and ADEs. The p‐tau epitopes showed correlations with each other. We showed significant correlations of exosomal NFL and pTau epitopes with age, brain amyloid, tau pathology, APOE status, and cognitive and functional performance.

Conclusion

The correlations reported here lay a foundation to study the use of plasma‐derived exosomal NFL and pTau181, and pTau231 as a “combination biomarker” in clinical trials and to better understand the neurodegenerative trajectories in DSAD.
Are changes in muscular strength following head‐down bed rest independently associated with improved cognitive function in older adults? A secondary analysis of a randomized controlled trial
Authors: Zou Jammy , Falck Ryan S , Balbim Guilherme Moraes , Davis Jennifer C , Madden Kenneth , Handy Todd C , Liu‐Ambrose Teresa
Published: December 2023

Background

Physical inactivity is common among older adults and is a risk factor for cognitive decline. Even a brief period of physical inactivity, such as bed rest due to hospitalization, in older adults has significant negative impacts. Exercise is strategy to counter the negative effects of physical inactivity. Exercise‐induced improvements in cardiorespiratory fitness is associated with improved cognitive function. Less is known regarding the contribution of exercise‐induced changes in muscle strength to changes in cognitive function. Thus, we aimed to examine the independent contribution of: 1) change in cardiorespiratory fitness; and 2) change in peak muscle torque of the lower extremity to changes in cognitive function in a randomized controlled trial (RCT) of head‐down bed rest (HDBR) vs. HDBR with exercise in healthy older adults.

Method

An analysis of a non‐blinded, parallel‐group, RCT of 22 healthy older adults (11 males and 11 females) aged 55‐65 years. Participants were randomized to: 1) 14 days of 6° HDBR (CON); or 2) HDBR with daily resistance and aerobic exercise training (EX). Outcome measures were taken at baseline and HDBR completion. The Flanker Inhibitory Control and Attention Task measured executive function. Physical fitness measures included: 1) maximal aerobic capacity (VO2max) using a bicycle ergometry test; and 2) knee extension isokinetic muscular strength (KE) using a Biodex dynamometer. We performed two separate multiple linear regressions to determine whether following 14 days of HDBR: 1) VO2max was associated with Flanker score, after accounting for ΔKE; and 2) KE was associated with Flanker score, after accounting for ΔVO2max. Each model was also adjusted for baseline Flanker score and the baseline physical fitness measure of interest.

Result

At baseline, average Flanker t‐score was 48.33, mean VO2max was 32.527 ml/kg/min, and knee extension strength was 64.472 Nm. VO2max at follow‐up was not significantly associated with Flanker performance (b = 0.232 ± 0.716; p = 0.635; R2
adj. = 0.285). However, greater KE strength was significantly associated with better Flanker performance (b = 2.023 ± 0.389; p = 0.043; R2
adj. = 0.633) at HDBR completion.

Conclusion

The maintenance of muscle strength even during brief periods of physical inactivity appears to be critical for cognitive health in older adults.
Real‐time Memory‐related Neurofeedback Training Improves Intrinsic Brain Oscillations in Older Adults
Authors: Liu Ziming , Jiang Yang , Cerel‐Suhl Sylvia , Suhl Jeremiah , Zhao Xiaopeng
Published: December 2023

Background

Mild cognitive impairment (MCI), manifesting as working memory deficits for example, is the most common and earliest symptom of Alzheimer’s disease and related dementias (AD/ADRD). To combat the brain aging processes, early intervention is needed. Electroencephalogram (EEG)‐based neurofeedback (NF) has been found to be beneficial in treating a variety of brain disorders. Increased intrinsic delta power and decreased alpha is associated with brain aging and AD pathologies. We have developed an ERP‐based NF protocol to reward memory‐related potentials. In this study, we aim to evaluate the effect of NF training protocol.

Method

Three older males (ages, 63, 78, and 79) participated in a newly developed NF training protocol including baseline and memory‐related NF training (twice a week). Each participant was recorded using 90‐second of eyes closed (EC) before multiple NF sessions during each visit. Their brain signals were collected with a 14‐channel wireless electroencephalogram (EEG) headset and processed in real‐time. The NF training contained 2 sham sessions followed by 2 intervention sessions. Compared to the intervention, visual feedback in the sham was provided in random order rather than triggered by participants’ ERP fluctuations. The EEG signal collected with EC before the experiment (Baseline, T0), 3 days after the sham (Sham, T1), and 3 days after the intervention (post‐intervention, T2) were preprocessed as 4s epoch windows and computed as the delta, theta, alpha, beta, and gamma band power. The average EEG band powers from T0, T1, and T2 and memory performances from the three participants were calculated.

Result

The working memory performance (accuracy and reaction times during retrievals of memory target and rejection of nontarget) did not show significant change among the three participants. In contrast, the EC intrinsic delta and alpha power changed towards brainwaves seen in younger brains after several sessions of NF training. Additionally, sham also improves in the alpha band (associated with attention and vigilance).

Conclusion

The pilot results demonstrated the effectiveness of a newly developed NF training using working memory related potentials in two out of three older adults. The results indicate the promise of cognitive enhancement using event‐related potentials‐based NF training in real time.
Genomic analysis of fibroblasts from marmosets carrying early‐onset Alzheimer’s disease mutations in PSEN1
Authors: Carter Gregory W , Haber Annat , Duong Duc M. , Seyfried Nicholas T , Murai Takeshi , Schultz Laura , Huhe Hasi , Choi Sang‐Ho , Kofler Julia , Schaeffer David J , Hachem Stephanie , Mou Yongshan , Ha Seung‐Kwon , Park Jung Eun , Homanics Gregg E , Strick Peter L , Rizzo Stacey J Sukoff , Silva Afonso C
Published: December 2023

Background

Alzheimer’s disease (AD) is the most prevalent form of dementia and remains generally untreatable. The slow, age‐related development of AD and inaccessibility of early‐stage brain tissue has limited our understanding of its origins and progression. Large‐scale genetic studies and molecular analysis of postmortem brain samples have nominated dozens of candidate genes and proteins for therapeutic targeting or diagnostic biomarkers, generating a need for in vivo systems to study the underlying biological dysfunction and perform preclinical testing. Here, we report on genetic, genomics, and proteomic analysis of fibroblast lines derived from a colony of marmosets genetically engineered with rare familial variants in the PSEN1 gene.

Method

We performed whole‐genome sequencing on 14 individuals, including six mutant carriers. We validated the presence of the PSEN1 mutations and assessed variation at multiple other Alzheimer’s disease loci. Fibroblast cultures were obtained from 12 animals and assayed using a Nanostring AD gene expression panel and label‐free proteomics. This allowed us to quantify 800 transcripts and 2165 proteins per sample.

Result

We detected differential gene expression for genes enriched in neuron development and amyloid‐beta regulation, providing strong evidence for the functional relevance of the engineered variants. We quantitatively compared changes in marmoset PSEN1 fibroblasts to similar molecular measures in postmortem brain tissue and induced pluripotent stem cells (iPSCs) from human AD studies. Both gene and protein expression changes in the undifferentiated fibroblasts correlated with changes in iPSCs from human AD carriers reprogrammed into neuronal lineages. We also observed both transcriptomic and proteomic changes in marmoset PSEN1 cells that match those in postmortem AD brains.

Conclusion

These findings demonstrate that disease‐relevant pathways and processes are altered in fibroblasts from mutant marmosets, provide a roadmap for more advanced molecular studies of AD in aging marmosets and marmoset‐derived cell models, and outline a strategy to align marmoset models with human disease to facilitate robust translation.
Plasma phosphorylated tau 217 levels are highly stable under common pre‐analytical sample handling procedures
Authors: Gouda Mariam , Antwi‐Berko Daniel , van Leeuwenstijn Mardou S. S. A. , Hussainali Zulaiga , Bongers Bram , Vanbrabant Jeroen , in ’t Veld Sjors G.J.G. , Edelmayer Rebecca M. , Stoops Erik , Jeromin Andreas , Teunissen Charlotte E. , Verberk Inge M.W.
Published: December 2023

Background

The Standardization of Alzheimer’s Blood Biomarkers working group issued a standardized operating procedure (SOP) to mitigate effects of common pre‐analytical sample handling procedures on the Alzheimer’s blood‐based biomarkers. This SOP was based mainly on results obtained with blood‐based amyloid‐beta40 and amyloid‐beta42 assays. Now that various blood‐based phosphorylated (p)Tau assays enter the fore, we need to re‐assess the validity of the proposed blood handling SOP. We aimed to understand the effect of common pre‐analytical sample handling procedures on blood pTau217 levels.

Method

Blood was obtained from 62 volunteers at the polyclinic phlebotomy department (n = 31) and the Alzheimer Center Amsterdam (n = 31) of Amsterdam University Medical Centers. Blood samples from volunteers were handled according to one of the following experiments: variation in primary collection tube (K2EDTA versus serum, sodium‐citrate, lithium‐heparin), delayed centrifugation of K2EDTA tubes while kept at room temperature (RT; 20‐25°C) or in the fridge (2‐8°C; 30min versus 4h, 7h, 24h, 72h), hemolysis of K2EDTA plasma (no hemolysis versus low (100mg/dL hemoglobin) and high (500 mg/dL hemoglobin)) and repeated freeze‐thawing (FT) of K2EDTA plasma (no additional FT versus +1, +2, +4FT). Sample sets were measured with the pTau217 AlzPath prototype assay on the Simoa HD‐X. Recovery% was calculated as the concentration measured in the experimental condition divided over the concentration measured in the relevant reference condition. Median recovery change >10% was considered relevant.

Result

Effects of the pre‐analytical sample handling variations on plasma pTau217 levels are presented in figure 1. Blood‐based pTau217 levels were highest in K2EDTA plasma (median (interquartile range (IQR)) %Recovery compared to K2EDTA, in serum: 34% (29‐42%), in sodium‐citrate: 21% (15‐27%), in lithium‐heparin: 7% (6‐8%)). Delayed centrifugation up to 72h either when tubes were kept at RT or when kept cold did not affect pTau217 levels, neither did hemolysis and repeated freeze‐thawing.

Conclusion

Using a primary collection tube other than K2EDTA results in substantially lower pTau217 levels. Otherwise, pTau217 level seems highly stable in plasma under diverse pre‐analytical sample handling conditions. According to the results, the consensus pre‐analytical blood handling SOP as published by the Standardization of Alzheimer’s Blood Biomarkers working group is still valid.
Inflammation blood profiles across neurodegenerative diseases
Authors: Malpetti Maura , Swann Peter , Chouliaras Leonidas , Ashton Nicholas J. , Tsvetanov Kamen A , Street Duncan , Whiteside David J , Cope Thomas E , Savulich George , Rittman Timothy , Surendranathan Ajenthan , Murley Alexander G , Stockton Katherine , Bevan‐Jones W Richard , Prats‐Sedano Maria A , Su Li , O'Brien John T , Rowe James B.
Published: December 2023

Background

Brain inflammation is an important pathogenic mechanism in many dementias, occurring early in the disease and being predictive of clinical decline. However, data on blood markers of inflammation across different dementia subtypes are limited. Here we assess inflammatory patterns of serum cytokines from patients with Alzheimer’s disease (AD), Lewy‐body dementia (DLB), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and motor neurone disease (MND).

Method

Blood samples were obtained from 422 participants (29 controls, 46 patients with AD, 35 with mild cognitive impairment (MCI), 38 with DLB, 52 with behavioural variant FTD, 51 with primary progressive aphasia, 58 with PSP, 53 with CBS, 60 with MND. Serum assays for 41 inflammatory markers used the MesoScale Discovery V‐Plex‐Human Cytokine 36 plex panel plus five additional cytokine assays. A Principal Component Analysis (PCA) across all participants was used to identify leading multivariate components, or profiles, of inflammation. Analysis of variance and Bayesian pairwise t‐tests were performed on the resulting components to compare each patient cohort to controls.

Result

Fifteen cytokines were undetectable in the majority (>50%) of participants and were thus excluded. The PCA of remaining 26 cytokines identified 3 components (explaining 18.3%, 8.5% and 6.4% variance, respectively). Component 1 was strongly represented by pro‐inflammatory cytokines (Figure 1, left). Kruskal–Wallis one‐way analyses of variance on the first component detected significant differences across the groups (χ2(8) = 24.3, p = 0.0021), and the Bayesian pairwise t‐tests identified significant differences between each patient cohort and controls, except for people with MCI (Figure 1, right). Component 2 did not differ between patients and controls. Component 3 split the cytokines into two subgroups, and was mainly loaded by patients with MCI, AD and MND (χ2(8) = 64.6, p<0.0001).

Conclusion

This data‐driven approach identified similar profiles of pro‐inflammatory responses across multiple neurodegenerative dementia types. Further analyses will clarify differences between diagnoses, relationships of the pro‐inflammatory patterns with clinical severity and brain changes captured by neuroimaging (PET and MRI).
Biomarkers disclose associations between Neuroinflammation and Synaptic Depletion in AD.
Authors: Rahmouni Nesrine , Woo Marcel , Tissot Cécile , Servaes Stijn , Therriault Joseph , Stevenson Jenna , Benedet Andrea Lessa , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Pascoal Tharick Ali , Zimmer Eduardo R , Rosa‐Neto Pedro
Published: December 2023

Background

While in healthy conditions, synaptic function is sustained by the interplay between neurons and glial cells. The presence of Alzheimer’s disease (AD) pathophysiology might impose synaptic alterations via neuroinflammatory responses from microglia and astrocytes. Imaging and fluid biomarkers allow for testing this conceptual framework in living individuals. Here, we aim at uncovering the associations between neuroinflammatory and synaptic markers in aging and AD.

Method

Participants were recruited from the Translational Biomarker for aging and dementia cohort (TRIAD). We analyzed cognitively unimpaired young (CUY, N = 20), cognitively unimpaired older adults (CU; N = 48) individuals, patients with mild cognitive impairment (MCI; N = 24), AD dementia patients (ADD; N = 16) participants. The endpoints were CSF 14‐3‐3 sigma‐delta (ζδ), CSF Growth Associated Protein 43 (GAP43) and neurogranin as markers of synaptic dysfunction. We modeled associations between these synaptic biomarkers with astrocyte and microglial related inflammatory markers as well as tau, amyloid and neurodegeneration biomarkers.

Result

According to ROC analyses contrasting CSF biomarkers, 14‐3‐3 ζδ was able to discriminate amyloid‐ β pathology in cognitively impaired individuals (AUC = 0.88) (Figure 1). The amyloid‐induced 14‐3‐3 ζδ increase was mediated by inflammatory astrogliosis measured by GFAP, whereas the tau induced 14‐3‐3 ζδ pathology was mediated by anti‐inflammatory cytokines (Figure 2). CSF levels of GAP43 and neurogranin were positively associated with TSPO measured with [11C]PBR28(Figure 3.1) and GFAP (Figure 3.2). [11C]PBR28 cluster‐based SUVRs was positively correlated to concentrations of (A) Neurogranin (p = 5.8e‐08) and (B) GAP‐43(p = 6.8e‐10).

Conclusion

The present observations support the framework in which glia‐related neuroinflammatory responses contribute to synaptic alterations in carriers of AD pathophysiology. We will discuss the implications and limitations of this framework.
18F GTP1 Tau PET image‐derived features improve the prediction of CDR‐SB progression in a multi‐modal model in prodromal to moderate AD
Authors: Toth Balazs , Bohorquez Sandra Sanabria , Monteiro Cecilia , Clayton David , Hibar Derrek P. , Anania Veronica , Abramzon Daniel , Sink Kaycee M. , Bittner Tobias , Teng Edmond
Published: December 2023

Background

Previous work from our group has shown that a model using a limited number of common clinical, demographic and MRI features can robustly predict CDR‐SB progression (Hibar et al. CTAD 2021) and that baseline Tau‐PET levels are associated with subsequent cognitive decline (Teng et al., 2021). However, the gain from combining these predictors has not previously been assessed. The aim of this work was to assess the additive prognostic value of including baseline [18F]GTP1 tau‐PET with the other common predictors.

Method

Baseline [18F]GTP1 images and MRI features were available from two crenezumab (NCT02670083 and NCT03114657; n = 51) and two semorinemab (NCT03289143; n = 360 and NCT038287747 placebo arm; n = 113) randomized clinical trials in prodromal to moderate AD populations. The benchmark linear model included age, sex, APOE4 status, education, diagnosis, baseline ADAS‐Cog 11, ADCS‐ADL, CDR‐SB and MMSE and hippocampus, ventricles and whole brain volume as predictors. In addition, the extended model included the whole cortical grey and temporal meta‐ROI [18F]GTP1 SUVR. A gradient boosted decision tree ensemble (XGBoost) model aimed to uncover potential nonlinearities and interaction among the features. Model performance was evaluated by r2 using bootstrapped confidence intervals and calibration.

Result

Our analyses included data from 524 participants (prodromal AD: 151, mild AD: 318, moderate AD: 55). The benchmark model yielded r2 = 0.175 [CI 0.122 – 0.241] with CDR‐SB in the overall sample. The [18F]GTP1 only model had r2 = 0.122 [0.071 – 0.185]. The extended linear model yielded r2 = 0.226 [0.163 – 0.299] and remained well calibrated. Point estimates of r2 were lower in the prodromal and mild versus the moderate subgroups. The performance of the XGBoost model on the holdout set (r2 = 0.230 [0.123 – 0.382]) was marginally better than the linear model, but results were variable among the diagnosis subgroups and further validation needs to be performed on a larger independent dataset.

Conclusion

The extended model including [18F]GTP1 SUVR features showed increased performance relative to the benchmark model. Therefore, [18F]GTP1 SUVR features may provide additional, meaningful information about patient prognosis and may be used as covariate adjustment factors to enhance treatment efficacy estimates in clinical trials. Analysis using [18F]GTP1 SUVR in other brain regions is being evaluated.
Late life learning, dementia, and overall health in underresourced settings: an investigation of the University for Seniors in Beirut, Lebanon
Authors: Elbejjani Martine , Hazzouri Adina Zeki Al , Kezios Katrina L , Sibai Abla
Published: December 2023

Background

Identifying modifiable factors that reduce Alzheimer’s disease and related dementias (ADRD) risk is a global public health priority. Several key social determinants of ADRD, such as years of education, are completed earlier in life, and thus are unamenable to change in older age. Evidence on the protective benefits of engaging in cognitively stimulating activities suggests that late life learning (“LLL”, non‐formal educational activities outside formal credentialed learning) may provide a unique window of opportunity, in older age, to mitigate ADRD risk by providing prospects for intellectual stimulation and social engagement. Yet, studies assessing assessed the benefits of LLL are scarce. Evaluations of cognitive and social benefits for LLL are particularly relevant for low‐resourced settings, where opportunities for engaged aging are limited.

Method

We designed a prospective cohort study (the LLL and Cognition 3LC study), capitalizing on an established and ongoing LLL program at the American University of Beirut, The
U
niversity
f
or
S
eniors (UfS). The UfS has been running for over 11 years, allowing to assess shorter‐ and longer‐term LLL influences on cognitive and overall health. Living in Lebanon, our population of older adults have endured multiple lifecourse and recent adverse psychosocial exposures. Our project will also examine the role of LLL in older age in mitigating the impacts of earlier psychosocial adversities on health.

Result

Our project is embedded within a capacity building program and close collaborations between researchers in the US and Lebanon, providing an infrastructure for research on dementia and psychosocial disparities in Lebanon and the region. We aim to recruit 500 previously enrolled UfS participants, 200 newly/prospectively enrolled UfS participants, and 700 age‐ and sex‐matched non‐UfS‐participating community residents (Figure 1). We plan to conduct cognitive assessments at baseline and a follow‐up visit using cognitive batteries designed aligned with the Harmonized Cognitive Assessment Protocol (HCAP). For a formal program evaluation of LLL on cognition and related outcomes, we will implement advanced analytical techniques (e.g., difference‐in‐difference estimation) (Figure 2).

Conclusion

Our project aims to build a longitudinal cohort study, together with research and infrastructure capacities, to delineate LLL opportunities for dementia prevention in Lebanon and neighboring countries.
The Medical and Cognitive Research Unit in Austin Health, Australia
Authors: Woodward Michael
Published: December 2023

The Medical and Cognitive Research Unit (MRCU), Austin Health and University of Melbourne, is sited in Heidelberg, Australia at Austin Health, a large University Teaching Hospital. Part of the Aged and Continuing Care Department, it is headed by geriatrician Associate Professor Michael Woodward.

MCRU employs 25 staff‐ nurse coordinators, psychologists, medical doctors, scientists and administrative. Some 10 research affiliates each year complete projects in collaboration with the department, but the main focus is sponsored clinical trials. Research areas include Investigational Products for AD, with over 200 Phase 1‐4 trials completed over the last 30 years. Other research foci include wound healing, immunization and frailty.

AD research is accelerated when the skills to recruit into and conduct trials are developed and maintained in this centre of excellence. Close affiliation with clinical cognitive practice, including the Austin Health Memory Clinic and private practices of doctors working in MCRU attracts patients to such services, providing a pipeline of patients suitable for studies. These patients also contribute to large data bases, including the Alzheimer’s Disease Network (ADNet) and the Australian Imaging, Biomarkers and Lifestyle study (AIBL), and inturn these studies identify patients suitable for clinical trials in MCRU. The Head is one of 3 Medical Advisors to Dementia Australia, and as a member of the Dementia Australia Research Foundation funds dementia research throughout Australia. Numerous media exposures involve MCRU staff, raising national awareness of AD and related disorders‐ eg a recent National TV Documentary on mAbs for AD.

International AD research looks to large sites to conduct trials, and inturn these site develop research protocols and contribute to national and international meetings. MCRU has recently contributed to protocols involving several small molecules to treat AD.

International collaboration is a hallmark of a successful AD Research Centre‐ MCRU through AIBL and ADNet, and the affiliated Florey, have collaborated with ADNI and the World Wide FINGERS initiatives to better understand and prevent AD and related disorders.
Associations of Age and Sex with Levels of Tau PET in Screened Participants from Auτonomy, a Phase 2 Anti‐p‐tau Monoclonal Antibody Trial in Early Symptomatic Alzheimer’s Disease
Authors: Kolb Hartmuth C. , Fedgchin Maggie M , Quiceno Mary Ellen , Henley David , Saad Ziad S.
Published: December 2023

Background

The ongoing Auτonomy trial (NCT04619420) enrolls participants presenting with mild cognitive impairment (MCI) or mild AD dementia with a CDR Global Score of 0.5 and who are tau PET positive. The Janssen plasma p217+tau assay is used as a pre‐screen for eligibility to proceed to tau PET to reduce participant burden and improve screening efficiency. Using preliminary screening data available to date we report on associations of age and sex with tau PET, a biomarker for neurofibrillary tangle (NFT) burden, and with plasma p217+tau levels.

Method

18F‐MK6240 Tau PET SUVRs for 355 screened participants (180 female) were quantified in Braak Regions Of Interest (ROI)[1] 1 through 6 using cerebellar gray as reference region. Associations were analyzed using a linear model of regional SUVR as a function of age and sex. Additionally, models of association for plasma p217+tau in log(pg/ml) were considered.

Result

Age at baseline was not different (p>0.5) for female (70.84 y) versus male (70.49 y) participants. For Braak 3 ROI, tau PET SUVRs showed significant negative association for age (R2
partial = 16%, p<10−14), and increased levels in females (R2
partial = 2%, p<0.01). The results were qualitatively similar across Braak ROIs 1 through 4. For Braak ROIs 5, and 6, the effect of sex was no longer significant, although the trend remained in a consistent direction. For plasma p217+tau, we found significant negative association for age (R2
partial = 7%, p<10−6) and a trend for higher levels in female participants (R2
partial = 1%, p = 0.05).

Conclusion

In early Alzheimer’s disease participants who were screened with tau PET for the ongoing Auτonomy trial, higher SUVR was observed for younger versus older participants and in females versus males. The effect of age is likely due to the cohort’s cognitive uniformity whereby in younger participants, a higher tau burden as measured by PET is required for the same level of impairment as older participants[2]. The increased tau PET NFT levels observed in female participants is consistent with findings by Edwards et al. [3]. Associations of similar directions were also observed for plasma p217+tau.

[1] Schöll et al., Neuron 2016. [2] Jack et al., Brain 2018. [3] Edwards L et al., Neurobiology of Aging 2021
Light Exposure as a Nonpharmacological Intervention for Alzheimer’s Disease
Authors: Page Erik
Published: December 2023

Background

In recent years, significant advances have been made in our understanding of the non‐visible biological impact of light (Vetter et al, 2021). Many of these advances can be traced to the 2002 discovery of a previously unknown retinal photoreceptor known as the intrinsically photosensitive retinal ganglion cell, or ipRGC, which is now known to be connected directly to our master circadian clock in our superchiasmatic nucleus (SCN). Now a growing body of clinical and applied research has shown how light spectrum, intensity, and timing can be used to promote circadian entrainment, leading to significant improvements in human health outcomes, including for people with Alzheimer’s disease and related dementia (ADRD).

Method

Many of these clinical studies have used lighting interventions in elder care facilities to evaluate the impact of lighting as a nonpharmacological intervention to improve mood, anxiety, sleep quality, falls and other health metrics for ADRD populations. These studies typically gather light exposure and health metric information during control periods or with control populations using traditional lighting approaches and compare results to periods or populations under “circadian‐enhanced” lighting conditions, which generally means brighter and bluer lighting during the day and dimmer and redder light in the evening and night hours.

Result

The results from these studies have consistently demonstrated significant improvements in circadian entrainment, sleep quality, mood, anxiety, falls and other health metrics for ADRD populations under circadian‐enhanced lighting conditions.

Conclusion

This talk will provide an overview of our current understanding of how light exposure impacts human physiology. We will discuss several completed and ongoing clinical studies conducted with ADRD populations, including several studies on which the speaker has been the Principal Investigator. We will cover what questions remain in this area and what studies can be developed in the future to address them. Finally, we will close with a discussion of tools, products, building designs and daily routines that can be applied today by clinicians and caregivers that are most likely to improve the health and wellbeing of ADRD patients based on what is known today about the impact of light exposure.
Life course financial mobility and later‐life memory function and decline by gender and race/ethnicity: an intersectional analysis of a multi‐ethnic cohort study
Authors: Kobayashi Lindsay C , Peterson Rachel , Avila Justina F , Amofa Priscilla A , Vila‐Castelar Clara , Meza Erika , Shaaban C. Elizabeth , Whitmer Rachel A. , Gilsanz Paola , Mayeda Elizabeth Rose
Published: December 2023

Background

Intersectionality is a theoretical framework capturing joint aspects of social identity (e.g., Black Women experience racism and sexism), which may allow richer understanding of ADRD disparities. We investigated whether life course financial mobility may be differentially associated with later‐life memory function and rate of change across intersectional identities defined by gender and race/ethnicity.

Method

Data were from KHANDLE and STAR, harmonized cohorts of integrated healthcare system members in Northern California (n = 2,347). Life course financial mobility was defined using measures of financial capital in childhood and adulthood as “consistently high”, “low childhood, high adulthood”, “high childhood, low adulthood”, and “consistently low”. We clustered individuals into 32 strata representing intersectional identities of gender and race/ethnicity across life course financial mobility trajectories. Verbal episodic memory was assessed over three waves using the Spanish and English Neuropsychological Assessment Scales (SENAS). We used mixed‐effects linear regression models with individuals nested within intersectional identity strata, adjusted for early‐life confounders. Models with and without fixed effects of gender, race/ethnicity, and financial mobility were estimated to evaluate if the random effects of the 32 intersectional identity strata contributed variance to the memory intercepts and slopes beyond these additive fixed effects.

Result

Participant mean baseline age was 73 years; 38% were men, 62% were women; 17% were Asian, 48% were Black, 15% were Latinx, and 21% were White. Consistently high financial capital was positively associated with baseline later‐life memory (0.124 SD units; 95% CI: 0.010, 0.238), as was financial mobility from low childhood to high adulthood (0.099 SD units; 95% CI: ‐0.032, 0.230), albeit non‐significantly. Neither was associated with memory decline. In a model without fixed effects of gender, race/ethnicity, and financial mobility, intersectional identities defined by these three factors contributed to 12% of variance in later‐life memory. After adding fixed effects to the model, the impact of intersectional identities on memory variance was reduced to 0.2% (Figure 1).

Conclusion

Consistently high financial capital and upward financial mobility from childhood to adulthood have positive associations with later‐life memory at baseline, but not rate of change. These association are similar across intersectional identities defined by gender and race/ethnicity.
Within‐network changes in strength of the default mode network relate to Alzheimer’s Disease biomarkers in APOE e4 carriers
Authors: Koenig Katherine A , Durgerian Sally , Lowe Mark J , DiFilippo Frank A , Bekris Lynn M. , Leverenz James B , Rao Stephen M.
Published: December 2023

Background

Resting state functional connectivity measured with MRI (rsfMRI) is disrupted in Alzheimer’s Disease (AD), although reports of rsfMRI changes in adults with the apolipoprotein E (APOE) ε4 genotype (e4+) have been inconsistent. Here, we compare default mode network (DMN) connectivity between e4+ and non‐carriers (e4‐) groups and assess the relationship to AD‐related biomarkers.

Method

Sixty‐five e4+ (mean age 70.2 ± 4.1; 33 males) and 60 e4‐ (mean age 71.9 ± 4.1; 28 males) subjects underwent a whole‐brain anatomical MPRAGE and a rsfMRI scan. To focus on the DMN, ROIs were placed in the bilateral posterior cingulate cortex (PCC). The most highly correlated voxels between the left and right PCC ROIs were used to calculate left and right PCC rsfMRI z‐maps. Group differences were assessed and mean connectivity in each significant region was correlated with Aβ PET centiloid values and cerebrospinal fluid (CSF) Aβ42/ Aβ40 ratio, phosphorylated‐tau (p‐tau 181), and total‐tau (t‐tau).

Result

Eight regions showed group differences (p < 0.05; Figure 1). In the e4+ group, right PCC connectivity to the bilateral anterior middle temporal gyri (Figure 1: ROIs 1 and 2) was negatively related to both centiloid score (p < 0.03) and to CSF p‐tau (p < 0.008; Figure 2). Left PCC connectivity to the right anterior middle temporal gyrus was negatively related to centiloid score (r = ‐0.26, p < 0.042) and CSF p‐tau (r = ‐0.31, p < 0.024). Biomarker values in the e4‐ group were not significantly related to connectivity.

Conclusion

Our findings are consistent with reports of weakened DMN connectivity in e4+ adults and suggest that differences in connectivity strength may be mediated by amyloid or tau deposition.

This work was supported by the National Institutes of Health (R01AG022304).
Alzheimer’s Disease (AD): Vitamin B12 deficiency is associated with lower Mini‐Mental State Exam (MMSE) scores
Authors: Komatsu Caroline , Komatsu Ricardo S.
Published: December 2023

Background

Alzheimer’s Disease (AD) is the leading cause of dementia in the elderly and several lines of evidence indicate that B12 hypovitaminosis is linked to AD. The biochemical pathways involved in AD that are affected by vitamin B12 are APP processing, Aβ fibrillization, Aβ‐induced oxidative damage as well as tau hyperphosphorylation and tau aggregation.

Method

103 outpatients with the diagnosis of AD conforming to criteria proposed by NINCDS‐ADRDA (2011), followed‐up at a public university hospital, had their vitamin B12 levels assessed and MMSE scores evaluated.

Result

91 patients (88,35%) presented vitamin B12 normal range (200 – 800 pg/mL) and 12 patients (11,65%) presented vitamin B12 deficiency (≤ 200 pg/mL). From the normal range group, 13 patients (14,29%) presented severe cognitive impairment (MMSE < 10), 33 patients (36,26%) presented moderate cognitive impairment (MMSE = 10 – 20) and 45 patients (49,45%) presented mild cognitive impairment (MMSE > 20). From the deficiency group, 2 patients (16,8%) presented severe cognitive impairment, 5 patients (41,6%) presented moderate cognitive impairment and 5 patients (41,6%) presented mild cognitive impairment. Both groups, vitamin B12 normal range and deficiency, had on average the same educational level: 2,91 and 3,42 years, respectively.

Conclusion

In this sample of patients with AD, B12 hypovitaminosis is associated with lower MMSE scores when compared to vitamin B12 normal range.
Psychological pathways linking social networks to verbal fluency decline: Implications for Black‐White cognitive disparities
Authors: Lee Ji Hyun , Sol Ketlyne , Zaheed Afsara B , Morris Emily P. , Palms Jordan D , Scambray Kiana Alexis , Taylor Lauren , Zahodne Laura B.
Published: December 2023

Background

Growing literature has identified social networks (SN) as a naturally occurring, modifiable resource for cognitive health. Less is understood about psychological mechanisms through which SN factors influence cognition and whether SN factors play a role in racial cognitive disparities in the US. This study 1) investigated prospective associations between SN factors and changes in verbal fluency; and 2) examined the mediating roles of loneliness and depressive symptoms in the SN‐verbal fluency link among diverse older adults.

Method

Participants were 455 non‐Hispanic Black (NHB) and White (NHW) older adults (Mage = 63.6; 53% Black) from the Michigan Cognitive Aging Project (MCAP), a community‐based, racially balanced, longitudinal study of Black and White adults transitioning to late life in Southeast Michigan. At baseline, participants completed neuropsychological assessments in person and were followed up via telephone two years later. Marital status, living arrangement, network size, network composition, and relationship quality (support and strain) were queried at baseline. We used latent difference score modeling to analyze how SN factors are associated with changes in verbal fluency. Next, a sequential mediation model was used to test for mediating pathways via loneliness and depression.

Result

Being married, larger network size, higher support, and lower strain were each uniquely linked to shallower declines in verbal fluency via lower loneliness and depressive symptoms. Independent of these psychological mediators, having a higher proportion of friends in one’s network was directly linked to shallower declines in verbal fluency. Compared to White participants, Black participants reported a lower proportion of friends and were more likely to have never been married, but they also reported less loneliness.

Conclusion

Our findings suggest that loneliness and depression represent a psychological stress pathway linking some, but not all, SN features to cognitive decline. Further, Black‐White differences provide evidence of both risk and resilience. Racial disparities in verbal fluency decline were partially explained by a lower proportion of friends (risk) but were partially offset by lower loneliness (resilience) among Black adults. This study highlights the multi‐faceted nature of SN and differential pathways by which SN factors shape cognitive health across racial groups.
Association of Type‐2 diabetes mellitus with voxelwise tau uptake patterns
Authors: Tennant Victoria R , Wheeler Koral V , Lee Noelle , Hall Brandon J , Ances Beau , Toga Arthur W. , Christian Bradley T. , O'Bryant Sid E. , Mapstone Mark , Yaffe Kristine , Braskie Meredith N
Published: December 2023

Background

Dysfunctional insulin signaling and elevated hemoglobin‐A1c (HbA1c) ‐ both associated with type‐2 diabetes mellitus (T2DM) ‐ may result in increased tau hyperphosphorylation, thereby increasing the risk of Alzheimer’s Disease (AD)‐related neuropathology in T2DM patients. Individuals with both AD and T2DM show different profiles of tauopathy compared to individuals with just AD. Here, we evaluated voxelwise tau‐PET patterns with and without T2DM to clarify T2DM‐associated patterns of tau deposition in cognitively intact older adults.

Method

We examined 502 cognitively intact adults from the Health and Aging Brain Study: Health Disparities who had available 18F‐PI‐2620 tau‐PET, florbetaben‐PET (Aβ) (n = 462), MRI T1‐weighted scans (Siemens‐3T), and blood HbA1c levels (n = 492) (Table1). Voxelwise regression models were run in SPM12 using warped 18F‐PI‐2620 standardized uptake value ratio (SUVR) images as the outcome variable (gray matter of the posterior cerebellum reference region) and covarying for age, sex, and education. The first model assessed the effect of T2DM consensus diagnosis on tau uptake. The second model examined the relationship between HbA1c and tau uptake. Both voxelwise regression models were rerun adding global Aβ‐SUVR, obesity, and hypertension as covariates (Figure1).

Result

Voxelwise regressions were corrected at voxel p<0.001, cluster FWE p<0.05. T2DM diagnosis was associated with higher 18F‐PI‐2620 uptake in the medial and inferior occipital regions, posterior cingulate, and parahippocampus. Higher HbA1c levels were associated with more 18F‐PI‐2620 uptake in parietal and frontal regions. When covarying for global Aβ‐SUVR, obesity, and hypertension, T2DM diagnosis was associated with 18F‐PI‐2620 uptake in the posterior cingulate. In the HbA1c model, no clusters survived FWE correction after covarying for global Aβ‐SUVR, obesity, and hypertension (Figure1).

Conclusion

Independent of common T2DM comorbidities and brain amyloid, T2DM subjects demonstrated a 18F‐PI‐2620 tau uptake pattern that was different from the characteristic age‐associated medial temporal lobe pattern. Our voxelwise approach allowed us to identify regions that may distinguish T2DM‐related pathology from AD‐related changes. The difference in significant clusters between models could be due to HbA1c levels being controlled by medication in some T2DM patients – an area for future study.
Gyrification abnormalities in young adult presymptomatic carriers of frontotemporal lobar degeneration mutations
Authors: Vargas Andrea Gorham , Lombardi Jolina , Zhang Liwen , Flagan Taru M. , Mandelli Maria Luisa , Brown Jesse A. , Rosen Howard J. , Kantarci Kejal , Ramos Eliana Marisa , Miller Bruce L. , Seeley William W. , Tempini Maria Luisa Gorno , Lee Suzee E.
Published: December 2023

Background

Presymptomatic C9orf72 expansion carriers show regions of low local gyrification index (lGI) as early as their thirties (Caverzasi et al. JNNP 2019) and regions of gyrification decline have been reported (van Veenhuijzen et al. Ann Neurol 2022). These findings raise the question as to whether abnormal gyrification represents a neurodevelopmental difference or early neurodegeneration in frontotemporal lobar degeneration (FTLD) mutation carriers. Yet, previous studies focusing on young adults is lacking and no study has explored gyrification in the two other common FTLD mutations, GRN and MAPT. Here, we analyzed lGI in young adult presymptomatic FTLD mutation carriers.

Method

LGI quantifies buried cortex within the sulcal folds compared to the visible cortex on the outer surface, with larger values indicating more folding (Schaer et al. IEEE trans med imaging 2008). Mean lGI values, as measured by a parcel‐wise analysis implemented in FreeSurfer v.6.0, were compared between 31 presymptomatic (preSx) carriers (12 C9orf72, 13 MAPT, 6 GRN, mean age: 25.2 ± 3.91 years) and 28 demographically‐matched healthy controls (HC: mean age: 25.6 ± 3.8 years). We used ANCOVA to compare all presymptomatic carriers combined (preSxAll) and HC to identify regions with significant lGI differences regressing age, sex, education, handedness, total intracranial volume and scanner type as nuisance covariates. Significant group differences were analyzed by Dunnett’s post‐hoc tests between each mutation subgroup and HC (p<0.05).

Result

Compared to HC, preSxAll had higher mean gyrification in the right caudal (F = 5.07, p = 0.03) and rostral anterior cingulate (F = 6.22, p = 0.17), and lower lGI in the left middle temporal gyrus (F = 4.22, p = 0.046). Within these regions, post‐hoc analyses showed that preSx GRN had greater gyrification in the right caudal anterior cingulate (t = 2.57, p = 0.039, 95% CI = [0.005, 0.248]) and preSx C9orf72 had lower lGI in the left middle temporal gyrus (t = ‐3.14, p = 0.009, 95% CI = [‐0.37, ‐0.04]) vs. HC.

Conclusion

Young adult FTLD mutation carriers displayed higher gyrification in the right anterior cingulate and lower gyrification in the left middle temporal gyrus compared to HC. Future studies in children will confirm the extent to which these gyrification abnormalities represent neurodevelopmental differences.
Glutathione level variations in brain and blood in healthy aging and Alzheimer’s disease continuum: A systematic review
Authors: Detcheverry Flavie , Mianoor Zainab , Senthil Sneha , Narayanan Sridar , Badhwar AmanPreet
Published: December 2023

Background

Oxidative stress (OS) plays an important role in healthy and pathological aging, particularly Alzheimer’s disease (AD). To protect against the harmful effects of OS, the body uses antioxidants, the most prevalent being glutathione (reduced form, GSH) (Dwivedi et al., 2020). The consistency of GSH perturbations with age and in the AD continuum has not been systematically assessed. We address this knowledge gap by conducting a systematic review of GSH variations in brain and blood in healthy aging and the AD continuum.

Method

PubMed searches were conducted up to January 2023. 15 keyword combinations were used to identify studies investigating GSH levels in (i) brain (in‐vivo using magnetic resonance spectroscopy (MRS) and in autopsy tissue using biochemical assays) and/or (ii) blood (plasma, serum) using biochemical assays (Fig1A,B). We considered individuals between 18‐39 years (yrs) as young‐adults, 40‐59 yrs as middle‐aged, and ≥60 yrs as old‐adults.

Result

42 studies met inclusion criteria (Fig1A,B; Fig2).

BRAIN
: Good to excellent reproducibility was reported by 12 MRS studies (3T, N = 6; 4T, N = 1; 7T, N = 5). For studies investigating age‐specific changes in cognitively unimpaired adults (CU, N = 6), GSH levels were significantly reduced in the majority (50%; temporal, occipital, limbic) of ROIs investigated in old‐ relative to young‐ or middle‐aged adults. Relative to CU, while brain GSH levels were reported to be lower by the majority (5/7) of AD dementia studies, MCI studies lacked consensus, with decreases (N = 3), increases (N = 2) and no significant change (N = 2) reported.

BLOOD
: Blood GSH levels were lower with increasing age in CU (5/7), and further decreased in patients (5/7).

In both brain and blood, the majority (4/7) of AD continuum studies assessing cognition reported poorer cognitive functions with lower GSH levels.

Conclusion

Our systematic review demonstrates that (a) in‐vivo MRS measurements of GSH are reliable; (b) GSH levels in CU generally decrease with increasing age; and (c) GSH levels are reduced in AD relative to age‐matched CU, and reduced GSH is associated with cognitive impairment. Interventions to increase GSH levels may therefore have beneficial effects in AD.