bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological and pathological 3R and 4R tau expression in marmoset brain
Authors: Huhe Hasi , Choi Sang‐Ho , Kofler Julia , Mou Yongshan , Ha Seung‐Kwon , Silva Afonso C , Rizzo Stacey J Sukoff
Published: December 2023

Background

Common marmosets (Callithrix jacchus) have recently emerged as an important model for studying aging and neurodegenerative disorders, including Alzheimer’s disease (AD). Amyloid‐β deposits in the cerebral cortex of marmosets present naturally with aging, which has now been widely reported. However, the role of tau in the marmoset brain has been understudied. The purpose of the present studies was to comprehensively examine 3R and 4R tau isoform expression in the marmoset brain.

Methods

The mRNA expression in the marmoset brain was confirmed by RT‐PCR. The total mRNA was isolated from frozen tissue of various age groups and reverse transcribed to cDNA, which was used for RT‐PCR. The sequence of each fragment was confirmed by the Sanger sequencing method. The tau protein expression in Sarkosyl soluble and insoluble fractions was examined by western blot using tau‐specific antibodies, and expression levels of 3R/4R were quantified by Dot blot. Synaptic tau expression was analyzed from crude synaptosome extractions of the frontal cortex. Pathological tau aggregates in cryo‐slices of a 10‐year‐old marmoset brain were visualized by immunohistochemistry.

Results

3R and 4R tau were expressed in the marmoset brain, with 3R tau predominately expressed in neonatal brains and 4R tau in adult/aged brains. 3R and 4R tau were also localized in synaptic regions of the frontal cortex. The Sarkosyl soluble tau was phosphorylated on T181, T217, and T231 sites with evidence of oligomers. Insoluble tau was phosphorylated on S396/S404 and S202/S205 sites and contained high molecular weight aggregates comprising 3R and 4R tau. Moreover, a 10‐year‐old marmoset brain case study demonstrated a paired helical filament structure in the hippocampus and intracellular 3R and 4R tau accumulation.

Conclusions

Our results reveal physiological and pathological 3R/4R tau distributions in the frontal and temporal cortex of the marmoset brain, confirming the presence of 3R tau and AD‐like pathological tau in aging marmosets. These data support the utility of common marmosets as appropriate models for studying AD and neurodegenerative disorders.
The AD Knowledge Portal: an open‐access platform for sharing data, tools, and results of aging and dementia research
Authors: Linden Abby Vander , Leanza Zoë , Britton Jessica S , Kallaher Amelia , Heath Laura M , Beck Jaclyn , Peña Anthony , Poehlman William L. , Yaxley Richard , Hendrickson Jared V , Wiley Jesse C , Leal Karina , Greenwood Anna K
Published: December 2023

Background

The AD Knowledge Portal (https://adknowledgeportal.org) is a community‐driven resource developed to support transparent evaluation and broad use of resources generated within the translational research portfolio of the National Institute on Aging (NIA). This open access platform aims to accelerate Alzheimer’s disease (AD) research and maximize therapeutic discovery through sharing and re‐use of data in adherence with FAIR (Findable, Accessible, Interoperable, and Reproducible) principles. The AD Portal allows the AD research community to find curated and contextualized data, evaluate hypotheses via independent experiments, and prioritize new mechanisms for therapeutic development.

Method

The AD Portal empowers researchers to share multi‐omics human and non‐human data with appropriate attribution for re‐use, and in compliance with necessary data governance and ethical guardrails. This is accomplished through the use of the secure Synapse data sharing platform–an NIH‐supported generalist repository–and a user‐friendly data portal website.

Result

The AD Portal currently hosts resources from nine research consortia and more than 50 grants related to dementia and aging. Data from over 15,000 individuals and 30,000 specimens–encompassing central and peripheral samples from brain banks, longitudinal cohorts, and model systems–are available. While the organizing focus is aging and dementia, the provided data are generated through a broad array of modalities, including genomics, transcriptomics, epigenetics, imaging, immunoassays, mass spectrometry‐based proteomics and metabolomics, behavioral assays, and more. In addition to raw and processed data, portal users can explore open‐access experimental mouse models, computational tools, publications, and summarized evidence for putative AD targets via integrated results explorers.

Conclusion

The AD Knowledge Portal offers the research community an accessible source of data, tools, and results for the study of AD and related dementias.
LC‐MS/MS‐based proteome profiling of CSF‐derived extracellular vesicles in Alzheimer’s disease
Authors: Tamayo Natalia Valle , Hirschberg Yael , Belbin Olivia , Cervantes‐González Alba , Sánchez‐Aced Érika , Gil Laia Lidón , Dolcet Sònia Sirisi , Lleó Alberto , Mertens Inge , Iulita Maria Florencia , Dols‐Icardo Oriol , Fortea Juan
Published: December 2023

Background

Extracellular vesicles (EVs) participate in the spread of pathological proteins between cells, contributing to the progression of neurodegenerative disorders, including Alzheimer’s disease (AD). As cerebrospinal fluid (CSF) reflects the biochemical environment of the brain, EVs from CSF constitutes a promising source to investigate novel biomarkers and therapeutic targets. We aimed to explore the unbiased proteome profile of CSF‐derived EVs from individuals with AD by label‐free quantitative liquid chromatography mass spectrometry (LC‐MS/MS).

Method

EVs were obtained from 500 µL of CSF from sex and age‐matched cognitively healthy donors (HC, n = 10, mean age = 73±1.4) and patients with AD dementia (AD, n = 10, mean age = 76.2±0.9) by a high‐throughput size exclusion chromatography method (SmartSEC). Resultant EV fractions were characterized by nanoparticle tracking analysis (NTA). EVs were lysed and proteins were trypsinized overnight via S‐Trap filters (Protifi). The peptides were separated on an Evosep nano LC system and analyzed by the TimsTOF Pro (Bruker) mass spectrometer. Peptides were identified using PEAKS Online software (1% FDR). DAVID Bioinformatics Resources 6.8 was used to determine the gene ontology (GO) enrichment. We normalized log2 peptide intensities (quantiles) and determined the differential protein expression across groups by a linear mixed effects (fixed effects = diagnosis, random effects = peptide sequence) model using the MsqRob package in R. P‐values were adjusted using Benjamini‐Hochberg.

Result

NTA showed homogeneous EV size profiles (mean size = 113.4±1.41nm). We identified 2096 proteins with at least 1 proteotypic peptide. GO enrichment analyses showed “extracellular exosome” as the most statistically significant enriched term (p = 1.8×10−212), confirming the enrichment of EVs. Statistical inference analysis revealed 18 differentially expressed proteins between both diagnostic groups (adj.p<0.05), all of them increased in the AD group. (Fig 1). Some of the greatest changes include CLUS (log2FC = 0.61, adj.p = 8.38×10−4, Fig.2), SPB1 (log2FC = 1.15, adj.p = 1.23×10−2, Fig.3), LRP1 (log2FC = 3.43, adj.p = 1.23×10−2), KLK7 (log2FC = 2.59, adj.p = 1.23×10−2), SAP3 (log2FC = 2.09, adj.p = 3.1×10−2) and SHPS1 (log2FC = 1.03, adj.p = 4.25×10−3), which are proteins that have been previously associated with inflammation.

Conclusion

Our results reveal novel protein changes in CSF‐derived EVs from individuals with AD, which could be explored further to their applicability in distinguishing the different clinical stages across the AD continuum.
Study of TMEM106B expression levels under neurodegenerative conditions
Authors: Picard Cynthia , Miron Justin , Poirier Judes
Published: December 2023

Background

TMEM106B is a transmembrane protein involved in dendrite morphogenesis and lysosome trafficking. TMEM106B was identified as a susceptibility gene for frontotemporal lobar degeneration with TDP‐43 inclusions (FTLD‐TDP). Brain tissue from patients with FTLD‐TDP showed increased mRNA levels of TMEM106B compared to normal controls (Van Deerlin et al, Nat Genet 2010). Our goal is to study TMEM106B expression levels in other neurodegenerative conditions such as progressive supranuclear palsy (PSP), Alzheimer’s disease (AD) and a well‐established mouse model of entorhinal cortex lesions (ECL).

Method

Unilateral electrolytic lesions to the entorhinal cortex were conducted on two‐to‐three months old male C57BL/6j mice by stereotaxic surgery. For sham‐operated animals, the electrode was lowered only 1 mm without current and sacrifices were performed on the same day. All other lesioned mice were sacrificed 2, 7, 14, 21 or 40 days post‐lesion (DPL). Total RNA was extracted from frozen ipsilateral and contralateral hippocampi and expression profiles were measured with the Affymetrix Mouse ClariomTM D Assay. The Mayo Clinic Brain Bank collected RNA samples from temporal cortex and measured gene expression levels using next‐generation RNA sequencing (RNAseq). Results are available for 274 subjects with the following conditions: PSP, N = 84; AD, N = 82; pathological aging (PA), N = 30; and cognitively unimpaired (CU), N = 78.

Result

In the ECL mouse model, ipsilateral Tmem106b expression levels were significantly reduced during the deafferentation phase (DPL2: p = 0.046) and reached maximum levels during the reinnervation phase (DPL14: p = 0.030 and DPL21: p = 0.019), compared to sham‐operated animals. In human temporal cortices, TMEM106B expression increased progressively from CU (10.76±0.62), to PSP (11.25±0.43), PA (12.13±1.27) and finally AD (13.10±0.44) (mean CPM ±SEM). TMEM106B mRNA levels were significantly higher in AD compared to CU (p = 0.002) and PSP (p = 0.003).

Conclusion

Elevated levels of TMEM106B in FTLD‐TDP, AD and during the reinnervation phase of the ECL mouse model suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling, independently from tau‐mediated pathology. This hypothesis is consistent with TMEM106B levels found in PSP, which is characterized by abundant neurofibrillary tangles that differ in both distribution and composition from those associated with AD.
Physiological and behavioral characteristics of SuperAgers from everyday activities: An NIH U19 SuperAging Research Initiative study protocol
Authors: Roberts Angela C , Van Ooteghem Karen , Lim Andrew , Swartz Richard H. , Beyer Kit B. , Geula Changiz , Mesulam Marsel , Rogalski Emily J , McIlroy William
Published: December 2023

Background

Studying factors contributing to exceptional memory performances beyond the 8th decade, can be a valuable model for understanding dementia risk, prevention, and underlying mechanisms. Age‐associated changes in biological and physiological complexity, or system responsivity, form the foundation of the loss of complexity hypothesis in aging (Lipsitz & Goldberger, JAMA, 1992). Project 1 under the multisite NIH U19 SuperAging Research Initiative uses state‐of‐the‐art wearable technology, and data from real‐world contexts, to test the supposition that SuperAgers have preserved physiologic and behavioral complexity relative to their Controls in the domains of physical activity, autonomic responsiveness, sleep, and social engagement.

Method

SuperAgers are enrolling from five U.S. and Canadian sites of the SuperAging Research Initiative. SuperAgers refer to individuals aged 80 and older who have memory capacity considered average for those 2‐3 decades younger. In a fully remote data collection protocol, participants wear a multi‐sensor array comprised of 1 skin‐mounted trunk sensor (with ECG) and 2 wearable limb sensors, continuously over a 14‐day period with scheduled rest breaks every 3‐4 days. Participants complete a baseline orientation visit, and three brief check‐in visits with the study team over video conference. Using custom algorithms, developed by our research team, we will examine time‐varying changes in indices of physiologic and behavioral complexity, across multiple body systems, using both volume‐based and established multi‐scale entropy approaches to quantify differences between SuperAgers and their typically aging Controls. We plan to analyze sensor derived complexity metrics in relation to self‐reports of life‐space mobility.

Result

We will overview our remote data collection protocol and semi‐automated analytics pipeline. Barriers and facilitators to remote data collection will be discussed Preliminary data (N = ∼ 40) will be presented, with select case study examples. We will provide preliminary sensor adherence and user‐feedback from the cohort, comprised of a diverse sample of SuperAgers and Controls.

Conclusion

This is the first study to test the loss of complexity hypothesis across multiple physiological and behavioral domains simultaneously and in exceptional cognitive aging. Using sensitive tools to capture dynamic and complex behaviors, we will characterize SuperAgers in a way not afforded by point‐in‐time assessments that dominate the current literature.
Proteomics signatures of cerebrovascular pathology in TGFß1 overexpressing mice
Authors: Haqqani Arsalan S. , Stanimirovic Danica B. , Hamel Edith , Badhwar AmanPreet
Published: December 2023

Background

Vascular cognitive impairment and dementia (VCID), the second most prevalent of the age‐related dementias, develops as a consequence of various types of cerebrovascular insults that damage brain function (Corriveau et al. 2016). Accumulating lines of evidence point to a link between VCID, both sporadic (Kim et al. 2006) and genetic (Hara et al. 2009, Zellner et al. 2018) forms, and the transforming growth factor beta (TGFB) family signaling. Transgenic mice overexpressing a constitutively active form of TGFβ1 in the brain (TGF mice) recap the cerebrovascular pathology seen in VCID (Wyss‐Coray et al. 2000, Tong et al. 2015), and develop VCID when submitted to a comorbid cardiovascular risk factor for dementia (Trigiani et al. 2020). Our aim was to characterize the cerebrovascular proteome of TGF mice using mass spectrometry‐based quantitative proteomics.

Method

Eighteen, 6‐month‐old‐TGF and ‐wildtype (WT) mice (N = 9/group) were transcardially perfused and pial arteries harvested under a dissecting microscope. Arterial proteins were extracted, trypsin‐digested, fractionated by strong cation exchange (SCX, gel‐free method) and analyzed by nanoLC‐MS/MS using nanoAcquity UPLC and ESI‐LTQ Orbitrap. For total and/or differentially‐expressed proteins (≥2‐fold change, p≤0.01) we i) performed characterization of proteins, and demonstrated presence of ii) protein RNA‐transcript in mouse and human brain vascular cells using transcriptomics datasets, and iii) identified proteins present in human‐extracellular‐vesicles (EVs) using Vesiclepedia.

Result

We identified 3602 proteins in brain vessels of WT and TGF mice, including canonical vascular proteins (e.g. Claudin‐5), and 103 direct (N = 103) and indirect (N = 1,942) interactors of TGFβ1 (Fig1). We also identified 83 proteins demonstrating significantly altered levels in TGF mice. Level dysregulation in these proteins point to perturbations in brain vessel vasomotricity, remodeling, and inflammation. We further demonstrated that several of the differentially‐expressed mouse proteins are i) expressed in the human brain vasculature, and ii) found as cargo proteins in EVs.

Conclusion

We characterized the deleterious impact of TGFβ1 overproduction on the cerebrovascular proteome. Given the growing popularity of extracellular vesicles in blood as a novel and minimally invasive biomarker discovery platform for the age‐related dementias, including VCID, several of the proteins identified by us can serve as protein biomarkers in human.
Evaluation of NLRP3 and NLRP1 inflammasome pathways in patients with Alzheimer’s disease: a clinicopathological study
Authors: Toscano Eliana Cristina de Brito , Justo Alberto Fernando Oliveira , Grossi Laura Barbosa , de Paula Michelle Claudia Alves , Farias Daniela Souza , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Grinberg Lea T. , Teixeira Antonio L , Suemoto Claudia Kimie
Published: December 2023

Background

A growing body of evidence has suggested a detrimental role of NLRP1 and NLRP3 inflammasome in experimental AD. However, the characterization of these pathways in AD human brains is still missing. We aimed to characterize the hippocampal expression of the NLRP1 and NLRP3 inflammasomes in individuals with AD neuropathological change (ADNC) compared to age‐ and sex‐matched controls. We also sought to investigate the association of the expression of these proteins with cognitive abilities and AD‐pathology.

Method

The expression of NLRP1, NLRP3, caspase‐1, ASC, and hyperphosphorylated tau (p‐tau) was evaluated in the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB) of individuals with pure AD and controls (n = 28 per group), using immunohistochemistry. The percentage of the immunostained area (IA) and the optical density (OD) of the staining were quantified through semiautomatic morphometry. Cognitive abilities were evaluated using the Clinical Dementia Rating – sum of boxes (CDR‐SB) and the AD‐pathology was based on Braak staging and the Consortium to Establish a Registry for AD (CERAD) criteria. We applied the Mann‐Whitney test to compare control with ADNC hippocampi, linear regression to examine the association of inflammasome proteins with cognition and AD‐pathology, and Spearman coefficient to examine the correlation of these proteins with p‐tau.

Result

Sociodemographic and clinical variables were similar between the groups (Table 1). NLRP1 and caspase‐1 expression was predominant in neurons, while ASC was detected in glial cells. NLRP3 was expressed in neurons and glia. NLRP1 and NLRP3 deposits were observed in neuritic plaques. Except for NLRP1, all the inflammasome proteins were overexpressed in CA and SUB of individuals with ADNC compared to controls (p<0.05) (Figure 1). CDR‐SB and CERAD criteria were associated with increased IA for NLRP3, caspase‐1, and ASC; the Braak stage was associated with higher expression of caspase‐1 and ASC (p<0.05, Table 2). Interestingly, NLRP3 (r = ‐0.52, p = 0.009) and ASC expression (r = ‐0.43, p = 0.004) correlated negatively with OD of p‐tau immunostaining in the CA of individuals with ADNC

Conclusion

NLRP3 inflammasome pathway is up‐regulated in the ADNC hippocampi and was associated with AD‐pathology. Our results suggest that NLRP3 inflammasome contributes to cognitive impairment in AD.
Apolipoprotein E Status Mediates Pericyte Recruitment Mechanisms in the Presence of Excess Cholesterol
Authors: Laing Krystal K. , McQuaid Conor , Lao Patrick J. , Chagnot Audrey , Stefancova Dorota , Garcia Daniela Jaime , Fialova Nela , Brickman Adam M. , Wardlaw Joanna M , Montagne Axel
Published: December 2023

Background

Apolipoprotein E (APOE) is a multifunctional lipid transporter, involved in lipoprotein metabolism and mediation of cholesterol homeostasis. The E4 variant of APOE is a primary genetic risk factor for Alzheimer’s disease and has been associated with vascular conditions such as hyperlipidemia, hypercholesterolemia, atherosclerosis and coronary artery disease (CAD). The mechanisms underlying APOE involvement in blood‐brain barrier breakdown (BBB‐B) are not well understood. In vivo, in vitro and clinical models of E4 have all demonstrated distinct profiling of molecular factors involved in ECM remodelling ‐ such as upregulation of PDGF‐BB in plasma and downregulation of VEGF in CSF. Associations between PDGF‐BB and white matter disease burden have also been reported. Investigating how APOE contributes to BBB‐B, through its function as a lipid transporter, could be imperative to understanding the pathophysiology behind vascular contributions to dementia.

Method

Using data from the Alzheimer’s Disease Neuroimaging Institute (ADNI), we analyzed plasma concentrations PDGF‐BB, VEGF and serum‐derived lipoprotein cholesterol (measured as LDL.C/HDL.C) for 521 patients with differing APOE status (E3/E3: n = 216, E3/E4: n = 195, E4/E4: n = 60). The LDL.C/HDL.C ratio has been used to assess the prevalence lipoprotein particles in cardiovascular diseases, such as CAD and is a studied marker of lipoprotein expression.

Result

Our findings revealed that APOE‐dependent upregulation of PDGF‐BB was predicted by blood derived measures of VEGF, LDL.C/HDL.C and an interaction effect of both. Interestingly, results of this model for the E3/E4 subgroup were non‐significant, instead we found that PDGF‐BB and VLDL.C/HDL.C predicted white matter hyperintensity burden on MRI. To further explore this relationship, biofluidic protein quantification and immunohistochemical staining of humanized APOE knock‐in mice (APOEε3/ε3, APOEε3/ε4
and APOEε4/ε4
) are being conducted to characterize differences of peripheral vascular protein expression and brain‐specific PDGFRβ upregulation. In vitro modelling of pericyte‐endothelial cells is also being conducted to further investigate interactions of APOE‐dependent glio‐vascular signaling.

Conclusion

This study provides additional support to previous reports that APOE4 contributes to impaired cerebrovascular function through mechanisms related to pericyte recruitment, vascular destabilization, and cognitive impairment. It may also provide additional insights for concepts which focus on APOE‐dependent cholesterol trafficking and lipid metabolism contribution to BBB destabilization.
Heterogenous factors modulate social cognition across diverse settings in brain health and disease
Authors: Fittipaldi Sol , Legaz Agustina , Maito Marcelo Adrian , Hernandez Hernan , Altschuler Florencia , Canziani Veronica , Moguilner Sebastian , Castillo Josefina , Lillo Patricia , Slachevsky Andrea , Henriquez Fernando , Fraile‐Vazquez Matias , Santamaria‐Garcia Hernando , Campo Cecilia Gonzalez , Bertoux Maxime , Ibanez Agustin
Published: December 2023

Background

Social cognition dysfunction in neurodegenerative diseases such as the behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s Disease (AD) is typically ascribed to the underlying pathophysiological processes spanning specific atrophy and connectivity alterations. However, social cognition performance might be modulated by a set of more heterogenous, non‐specific factors, including demographics (sex, age, education, socioeconomic status), general cognitive and executive abilities, and behavior inside the scanner (i.e., movements), but their relative contribution is poorly understood. Here, we develop a machine learning approach to characterize multimodal factors that explain the inter‐individual heterogeneity of social cognition in a diverse multicentric sample.

Method

A total of 998 individuals > 50 years from international research networks in high‐ and middle‐income countries participated in this study: 102 with bvFTD, 339 with AD, 96 with mild cognitive impairment (MCI), and 461 with preserved cognition (with and without cognitive complaints). Social cognition was assessed with the Mini Social Cognition and Emotional Assessment (MiniSEA) battery, which includes tests of facial emotion recognition and theory of mind. After data harmonization, we implemented support vector regressions combined with bootstrapping to predict social cognition outcomes from multimodal features, including diagnosis, demographics, cognitive and executive functions, grey matter volume, fMRI resting‐state network connectivity, and movement artifacts, and assessed their relative contribution to performance (Figure 1). Models were assessed with the coefficient of determination R², Fisher’s F test, Cohen’s F², 95% confidence intervals, and p‐values.

Result

General cognitive and executive functions and years of education consistently emerged among the top predictive features of social cognition performance and explained more variance than diagnosis. Other features making significant contributions were: sex, the gray matter volume of relevant regions, and in‐scanner movements. Age and resting‐state network connectivity did not make any significant contribution to performance heterogeneity (Figure 2).

Conclusion

Social cognition performance was more strongly predicted by a set of heterogenous individual differences than by neurodegenerative diagnoses and associated brain signatures. Diagnoses might relate to complex profiles. Results highlight a critical modulator role of heterogeneity on social cognition, with implications for the neuropsychological assessment in brain health and disease across diverse, multi‐setting populations.
Medial Temporal Lobe White Matter Integrity is Related to Memory and Amyloid‐Beta Pathology in Aging
Authors: Parker Dana M , Adams Jenna N. , Taylor Lisa M. , Keator David B. , Sathishkumar Mithra , Harris Alyssa L. , McMillan Liv , Yassa Michael A.
Published: December 2023

Background

Damage to white matter (WM) within the medial temporal lobe (MTL) may underlie memory decline in aging and Alzheimer’s disease (AD). We measured MTL WM tract integrity through diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging (NODDI). We tested WM integrity associations with memory performance and amyloid‐β pathology in cognitively normal older adults.

Method

105 cognitively normal older adults (70.8 years old, 65% female) with diffusion MRI were processed with MRtrix3. Standard diffusion metrics of fractional anisotropy (FA) and mean diffusivity (MD) were calculated. NODDI MDT was used to generate the neurite density index (NDI), representing number of voxels with unhindered diffusion, and the orientation dispersion index (ODI), representing the variability of neurite orientation. We calculated these measures for MTL tracts from the JHU WM Atlas: cingulum‐hippocampus, fornix column/body, and fornix/stria terminalis. Participants received 18F‐florbetapir (FBP) to measure Aβ pathology (n = 94), and global FBP SUVR was calculated. Memory was measured with the Rey Auditory Verbal Learning Test delayed recall score (RAVLT, n = 81). Analyses covaried for age and/or education.

Result

Better memory was associated with lower ODI in the fornix column/body (r = ‐0.27, p = 0.018), with trends for higher FA (r = 0.021, p = 0.06) and lower NDI (r = ‐0.19, p = 0.09). Better memory was also associated with higher MD in the cingulum‐hippocampus (right: r = 0.23, p = 0.04; left: r = 0.25, p = 0.03), with trends for lower ODI (right: r = ‐.20, p = 0.08; left: r = ‐0.20, p = 0.09). Higher FBP SUVR was associated with increased FA in the fornix column/body (r = 0.31, p = 0.003) and a trend in the left cingulum hippocampus (r = 0.20, p = 0.054). Memory or FBP SUVR was not significantly related to integrity of the fornix/stria terminalis.

Conclusion

Integrity of fornix column/body and cingulum‐hippocampus were related to both memory performance and Aβ pathology. Our results suggest that using a combination of NODDI as well as diffusion tensor metrics provided a more robust understanding of memory impacts in aging.
Multiple Chronic Conditions and Midlife Cognitive Function in Black and White Adults: The Bogalusa Heart Study
Authors: Moukaled Shirine , De Anda‐Duran Ileana , Potts Kaitlin S , Fernandez‐Alonso Camilo , Libon David J , Bazzano Lydia
Published: December 2023

Background

In late‐life, multiple chronic conditions (MCCs) has been associated with cognitive decline and Alzheimer’s Disease and related dementias. However, this relationship has not been investigated in a middle‐aged population, a time when MCCs first begin to develop, or in rural and low socioeconomic settings, where individuals are at a higher risk of MCCs. We examined the relationship between MCCs and midlife cognitive function among Black and White men and women from a rural, community‐based cohort in Bogalusa, Louisiana.

Methods

This cross‐sectional study includes 1,223 Black (33%) and White (67%) individuals (mean age 48.10 ± 5.26; 59% female) from the Bogalusa Heart Study with a complete neuropsychological (NP) assessment, and no history of stroke. Six chronic conditions were selected from the CMS (Centers for Medicare & Medicaid Services) Data Warehouse, and defined using self‐reported data, medication use, and physiological/laboratory measures (Table 1). MCCs was defined as the coexistence of ≥2 conditions. NP performance was measured by global cognitive z‐scores (GCS) and by domain specific z‐scores for attention and processing, episodic memory, and executive function. All z‐scores were standardized for age, sex, and race. Regression models assessed the association between MCCs and cognitive outcomes, adjusting for alcohol consumption, smoking status, and education.

Results

A total of 66% participants had MCCs; 44.4% (n = 543) had 2 CCs, 17.8% (n = 218) had 3 CCs, and 3.8% (n = 46) had 4+ CCs. Compared to no chronic conditions, having 2,3, and ≥4 CCs was significantly associated with poorer executive function z‐scores after adjusting for covariates (all p’s < 0.05). Having three MCCs had the worst impact on executive function z‐scores (‐0.88(.20), p <0.001) (Table 2). The most prevalent conditions in this group were hypertension, dyslipidemia, and diabetes which co‐occurred in 87.7% (n = 165) of participants with three CCs.

Conclusion

This study suggests that the presence of MCCs is associated with lower executive function performance as early as midlife. Hypertension and dyslipidemia commonly occur together and are particularly prevalent in midlife. These findings highlight the importance of addressing chronic conditions earlier in life, a less studied and critical time window for potential prevention of adverse cognitive outcomes in late life.
Characterizing plasma biomarkers of Alzheimer’s Disease in aging marmosets and genetically engineered PSEN1 mutation carriers.
Authors: Rizzo Stacey J Sukoff , Schultz Laura , Mongeau Lauren , Huhe Hasi , Schaeffer David J , Schaeffer Lauren K Hayryren , Carter Gregory W , Park Jung Eun , Homanics Gregg E , Strick Peter L , Silva Afonso C
Published: December 2023

Background

Alzheimer’s Disease (AD) is a progressive disease that presents as a continuum evolution from preclinical AD to mild cognitive impairment and, ultimately, dementia. The phenotypic characterization of AD was unified under a biological construct research framework supported by the National Institutes on Aging and Alzheimer’s Association (NIA‐AA). This framework, referred to as ATN, is based on the presence of biomarkers for amyloid (Aβ, A), pathologic tau (T), and neurodegeneration (N). The present studies aimed to establish normative values of these biomarkers in our colony of outbred marmosets from infancy through aged individuals and compare them to the values from our population of marmosets genetically engineered with early onset familial mutations in the PSEN1 gene.

Method

Plasma (EDTA) and fibroblast media from skin biopsies were evaluated using MesoScale Discovery (MSD) Aβ peptide panel 4G8 ELISA and Human Neurofilament L (NfL) per the manufacturer’s protocols for each kit.

Result

There was a significant increase in the plasma Aβ42:40 ratio in PSEN1 mutation carriers relative to age‐ and sex‐matched wild‐type (WT) controls, which was also observed in culture media generated from fibroblasts of the same individuals. Longitudinal analysis of plasma Aβ revealed consistent levels in WT controls across multiple samplings with persistent increases in PSEN1 carriers. An increase in Nfl was observed in aging WT marmosets relative to young subjects.

Conclusion

We have optimized the detection of plasma biomarkers for amyloid and NfL in marmosets and established normative values within our colony. Importantly, these results demonstrate the sensitivity and validity of these reagents for tracking plasma Aβ longitudinally across the marmoset lifespan. Other clinically utilized commercially available reagents are in the process of being optimized and validated to enable an analogous marmoset ATN. Pilot studies are ongoing evaluating the potential of pTau plasma biomarkers as part of the longitudinal assessments. The application of the NIA‐AA Research Framework to marmosets will attain a more accurate characterization and understanding of the etiological sequence of events that lead to AD development, in line with the currently used framework in AD patients.
Neurofilament Light and mean Free Water as prognostic enrichment biomarkers for cognitive worsening and small vessel disease progression
Authors: Maillard Pauline , Beiser Alexa S. , Habes Mohamad , Tracy Russell P. , Kautz Tiffany F , Saklad Amy R. , Kivisäkk Pia , Lu Hanzhang , Arfanakis Konstantinos , Gold Brian T. , Kramer Joel H. , Wang Danny J.J. , Rosenberg Gary A. , Singh Herpreet , Schwab Kristin , Helmer Karl G. , Greenberg Steven M. , Arvind Caprihan , Seshadri Sudha , Decarli Charles , Satizabal Claudia L.
Published: December 2023

Background

Plasma neurofilament light (NfL) and free water (FW), a DTI‐derived measure, are considered, individually, sensitive markers of axonal damage that relate to cognition. A significant remaining challenge for clinical trials resides in identifying biomarkers able to detect, simultaneously, early SVD abnormalities and baseline cognitive impairment, particularly in non‐demented participants, who are also at risk of cognitive worsening and SVD progression during the trial.

Method

This study includes 200 non‐demented individuals from the MarkVCID‐UH3 cohort who had baseline NfL and baseline and follow‐up (1.3±0.5 years) cognitive assessment and MRI (Table 1). We used a composite measure of global cognitive function (GCF) using scores from the NACC‐UDS. WMH volumes were log‐transformed and corrected for intracranial volume. Annual change (Δ) in GCF and WMH was computed using baseline and follow‐up measures. A threshold, determined from 3 independent cohorts, was applied to FW measures to group individuals (low: <0.22 and high > = 0.22). Low and high NfL levels were defined using age‐based NfL z‐scores (low←0.5SD and high> = ‐0.5SD). We finally grouped individuals with both high NfL and FW levels (MULTIBIO+) vs. individuals with at least one biomarker with low level (MULTIBIO‐). We used linear regressions with either baseline GCF, baseline WMH, ΔGCF or ΔWMH as the dependent variable and, separately, baseline FW, NfL and MULTIBIO as the independent variable. Analyses were adjusted for relevant confounding variables.

Results

We found that, as compared with MULTIBIO‐, MULTIBIO+ group had significantly lower baseline GCF and higher baseline WMH (p = 0.033 and p<0.001), as well as accelerated ΔGCF and larger ΔWMH (pvalues<0.01, Table 2, Figure 1). Individually, although FW was associated with baseline WMH and accelerated ΔGCF, neither FW nor NfL levels simultaneously explained baseline cognition and SVD burden, or simultaneous ΔGCF and ΔWMH (Table 2).

Conclusion

These findings emphasize the potential of combining NfL and FW measures as a prognostic enrichment biomarker panel for identifying individuals with both early SVD abnormalities and cognitive impairment and who are also at risk of cognitive worsening and substantial SVD burden progression during clinical trials.

Data collection and sharing for this project was funded by NINDS/NIA as part of the MarkVCID Consortium (U24NS100591, UH2NS100599, UH2NS100605, UH2NS100588, UH2NS100608, UH2NS100606, UH2NS100598, UH2NS100614)
Discovering correlates of off‐target 18F‐MK6240 signal in community‐dwelling adults
Authors: Johnson Aubrey S. , Zou James , Smith Anna C. , Okafor Amarachukwu , Guzm Diana S. , Kreisl William Charles , Brickman Adam M. , Luchsinger José A. , Lao Patrick J.
Published: December 2023

Background

18F‐MK6240 binds hyperphosphorylated tau protein in neurofibrillary tangles, a hallmark of Alzheimer’s disease(AD); however, the tracer may also bind to other similarly structured molecules, known as off‐target binding. Off‐target binding is inconsistent across individuals and can lead to biased quantitative assessment, making it difficult to accurately identify neurofibrillary tangle pathology. We examined variable off‐target binding by performing a correlation analysis with demographic factors, vascular risk, lifestyle factors, and co‐morbidities.

Methods

Ninety‐five participants (65±3yrs; 67% women; 42/58% White/Black; 66% Hispanic; 12±4yrs education) in the Northern Manhattan Study of Metabolism and Mind(NOMEM) underwent 18F‐MK6240(90‐110min) and 18F‐Florbetaben(90‐110min) PET imaging and completed surveys, including age, sex, education, exercise levels, and medical history. Only visually‐determined amyloid‐negative participants were included to increase the likelihood that elevated tau PET signal was off‐target. Tau SUVR (cerebellar gray matter reference region) was calculated for composite Braak stages (I/II, III/IV, V/VI) and two known off‐target regions, the choroid plexus and the extra‐cerebral space around the brain. The extra‐cerebral mask was generated by dilating the gray/CSF boundary of the ANTs probability map and then subtracting the brain. Percent of variance explained (r2) from general linear models are reported between off‐target regions and factors of interest.

Results

Descriptively, 18F‐MK6240 off‐target binding in choroid plexus was positively correlated with SUVR in Braak stage regions I/II (r2 = 0.37;p<0.001) and III/IV (r2 = 0.44;p<0.001) to a larger extent than V/VI (r2 = 0.21;p<0.001), while off‐target binding in the extra‐cerebral space was positively correlated with Braak stages I/II (r2 = 0.07;p<0.001) to a lesser extent than III/IV (r2 = 0.13;p<0.001) and V/VI (r2 = 0.18;p<0.001), suggesting that proximity of key AD regions to off‐target regions increases the likelihood of confounded signal. Off‐target binding in the choroid plexus was elevated amongst self‐identified Hispanic participants (r2 = 0.19;p<0.001). Extra‐cerebral off‐target binding was negatively associated with participant weight (r2 = 0.12;p<0.001).

Conclusion

Extra‐cerebral off‐target binding of 18F‐MK6240 may confound signal in key AD regions in amyloid‐negative participants. Off‐target binding should be accounted for regionally and methods for capturing extra‐cerebral signal are critical. Understanding the role of factors related to tracer distribution, including weight, and sociodemographic factors will enhance the quantification of 18F‐MK6240 for the early detection of neurofibrillary tangle pathology.
Restriction of dietary protein slows the development and progression of Alzheimer’s disease in 3xTg mice
Authors: Babygirija Reji , Sonsalla Michelle M , Han Jessica , Calubag Mariah , Trautman Michaela , Green Cara , Matouska Ryan , Tobon Anna , Michael John , Yeh Yang , Lamming Dudley
Published: December 2023

Background

Caloric restriction (CR) promotes health and longevity in diverse species and has been successful in ameliorating Alzheimer’s disease (AD) pathology in mouse models and non‐human primates. However, CR may be difficult to adhere to, which makes the reduction of specific macronutrients without restricting calories an attractive alternative. Low protein intake is associated with healthy aging and reduced mortality in humans, and protein restriction (PR) extends the lifespan and healthspan of many mouse models. In this study, we examined the effects of PR on metabolic health and AD pathology in the 3xTg mouse model of AD.

Method

We placed male and female 3xTg mice as well as non‐transgenic (NTg) controls on either a Control diet (21% of calories from protein) or a PR diet (7% of calories from protein) starting at 6 months of age. We assessed the effect of PR on metabolic health, cognition, and AD neuropathology along with targeted metabolomics on plasma samples to identify the abundance of metabolites and dysregulated metabolic pathways.

Result

We found that a long‐term PR diet had substantial metabolic benefits for both male and female 3xTg and NTg mice, promoting leanness and glycemic control. We also found that consumption of low protein diet significantly improved cognitive performance and reduced multiple aspects of AD neuropathology including tau phosphorylation, Aß plaques and gliosis. Phosphorylation of the mTORC1 substrate S6K1 was decreased and the major autophagy cargo receptor P62 was increased in PR‐fed 3xTg mice, which suggests that reduced mTORC1 signaling may mediate the beneficial effects of PR on AD pathology. Targeted metabolomics revealed that several metabolites involved in nucleic acid metabolism and amino acid metabolism were altered between control fed and PR fed mice in a sex specific manner.

Conclusion

Our findings suggest that lowering dietary protein may be a novel way to slow or even prevent AD. In addition, drugs that mimic the effects of PR may be an effective pharmaceutical approach to combat AD pathology.
Cognitively select older adults in the Dallas lifespan Brain Study exhibit higher positive personality traits and resilience to amyloid pathology
Authors: Monier Sarah A. , Smith Evan T. , Hennessee Joseph P. , Bacci Julia R. , Park Denise C.
Published: December 2023

Background

In the present study, we investigated differences in amyloid (Aβ) burden and personality traits in cognitively‐select older adults compared to average‐functioning older adults. Conscientiousness, in particular, has been linked to Alzheimer’s Disease (AD) pathology, and we hypothesized that adults who were high in cognition would exhibit enhanced conscientiousness. Of additional interest was whether high functioning older adults in the Dallas Lifespan Brain Study would evidence reduced AD pathology.

Method

We tested 285 cognitively‐normal participants (ages 55‐90) and collected conscientiousness scores using the Revised NEO Personality Inventory (NEO‐PI‐R). Participants also underwent PET imaging with radiotracer AV‐45, 18F‐Florbetapir, a radiotracer that is used to measure Aβ protein in the brain. Mean cortical SUVR was computed across 8 cortical regions of interest, normalized to cerebellar gray matter. In addition, participants completed a cognitive battery, underwent an MRI scan, and completed self‐reports for depression and fitness. We designated those participants scoring at or above the mean episodic memory of a middle‐aged (ages 35‐54) reference group, as “cognitively‐select” (N = 69), and those scoring below the mean, as “cognitively‐normal” (N = 216). Dependent variables of interest included global and regional amyloid (Aβ), cortical morphometry, depression, fitness, conscientiousness, and various cognitive measures.

Result

Cognitively select participants were younger (p = .043), more educated (p = .021), and had higher positive personality traits, including self‐discipline (p = .01), openness to ideas (p = .013), and competence (p = .015), compared to cognitively‐normal. Although the groups did not differ in global Aβ pathology load (p = .083), cognitively select exhibited less pathology in specific regions including lateral temporal areas (p = .049). Regression analysis controlling for sex, age, education, and MMSE, revealed a significant group by global Aβ interaction on fluid ability (p = .034), where greater Aβ load predicted lower scores in cognitively normal older adults only.

Conclusion

These findings provide evidence that cognitively privileged adults show resistance to decline across many domains and demonstrate resilience to amyloid pathology. Discussion will focus on longitudinal change in amyloid accumulation, cortical thinning, and cognitive decline, as well as the concept of reserve.
Cerebrovascular reactivity in amnestic and non‐amnestic mild cognitive impairment
Authors: Umfleet Laura Glass , Cohen Alexander D , Pommy Jessica , Allen Margaret , Obarski Shawn , Mason Lilly , Berres Halle , Franczak Malgorzata , Wang Yang
Published: December 2023

Background

Cerebrovascular disease (CVD) is implicated in the pathogenesis and clinical presentation of Alzheimer’s Disease. Cerebrovascular reactivity (CVR) is considered a more direct estimate of cerebrovascular integrity. CVR is a potential promising biomarker for examining pathological cognitive decline in older adults though, to date, findings have been inconclusive, possibly partly due to variability in methodological approaches. In this study, we add to the limited literature on CVR in mild cognitive impairment (MCI). We provide preliminary evidence for CVR differences in MCI phenotypes compared to older adult cognitively normal controls. We hypothesized that they amnestic phenotype (aMCI) will have lower CVR than non‐amnestic (naMCI) and both groups will show lower CVR compared to controls. We also performed exploratory correlational analyses between CVR and neuropsychological test scores.

Method

CVR was assessed in 22 controls, 11 aMCI, 9 naMCI cohorts using a breath‐holding task functional magnetic resonance imaging (fMRI). fMRI data were preprocessed and analyzed using AFNI. All participants underwent neuropsychological testing. T‐tests and ANOVA/ANCOVA analyses were conducted to compare controls to MCI groups on CVR metrics and cognitive tests of memory, language, processing speed, and executive functioning. Partial correlation analyses between CVR derived from regions‐of‐interest (Yeo 1‐7 ROIs) and different cognitive functions were conducted.

Results

CVR was found to be significantly lower in MCI compared to controls across all Yeo functional networks, ps < .001, which was mostly driven by the aMCI phenotype. naMCI showed intermediate patterns between aMCI and controls, though results were not significant, ps > .05. Regional CVR values along Yeo networks were positively correlated with cognitive measures of processing speed, executive functioning, and memory.

Conclusion

This is the first study to evaluate CVR differences in MCI phenotypes. Consistent with previous research, we found that CVR is lower in MCI compared to controls. While group differences between naMCI and controls (also between naMCI and aMCI) did not reach statistical significance, visual inspection of CVR mean values showed preliminary evidence that naMCI had lower mean values across all ROIs compared to controls and higher mean values compared to aMCI. Future research is needed to examine differences in CVR between MCI phenotypes.