bluuebunny/crossref_metadata_2025_split huggingface dataset:
Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer’s Disease Neuropathology and Cognitive Decline
Authors: Phillips Jared , Seto Mabel , Winfree Rebecca L , Wang Yanling , Schneider Julie A , Bennett David A. A , Dumitrescu Logan C , Hohman Timothy J. 
Published: December 2023

AbstractBackgroundWe completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer’s disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane.MethodLeveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit.ResultHigher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/).ConclusionOur results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies.
Plasma based assessment of extracellular vesicles biomarkers in Alzheimer’s Disease
Authors: Dayarathna Thamara , Roseborough Austyn D , Gomes Janice , Khazaee Reza , Whitehead Shawn N , Leong Hon , Pasternak Stephen H 
Published: December 2023

AbstractBackgroundCurrently there are no widely accepted diagnostic tests for Alzheimer’s disease (AD). Although there is much excitement in the field of biomarker development, most proposed tests for AD are expensive, require highly specialized sample handling, invasive approaches or radiation exposure. The goal of this project was to develop non‐invasive AD biomarker assessment using nanoflow cytometry to examine proteins on circulating brain‐derived extracellular vesicles in plasma.MethodPlasma samples were collected from a population of individuals clinically diagnosed with MCI and mild, moderate or severe Alzheimer’s disease and cognitively intact control subjects. Plasma was incubated with fluorescently‐conjugated antibodies against candidate biomarkers including oligomeric amyloid, fibrillar amyloid, amyloidβ‐42, pTau‐T181, pTau‐T217, pTau‐S235, Ubiquitin, Neurofilament, α‐synuclein and synaptophysin. After incubation, labelled events were quantified using the Apogee Microplus nanoflow cytometer. Using Receiver‐Operator Curve (ROC) analysis, the ability of individual markers and various combinations to distinguish diagnostic groups was determined.ResultNanoflow cytometry quantification of pTau‐T181, pTau‐T217, pTau‐S235, pTau‐T231, Aβ‐42 (among others) successfully distinguished MCI and AD plasma from healthy controls. Using ROC analysis, our most sensitive antibodies (pTau‐ T231) separate controls from AD patients with an AUC of 0.96 (Sens: 0.95/Spec: 1.0). Other prominent antibodies include pTau 181 with an AUC of 0.93 (Sens: 0.92/Spec: 0.92). The most promising combination of antibodies combines beta‐amyloid42 and pTau‐181 to separate AD patients from controls with an AUC of 0.960 (Sens: 0.93, Spec: 0.92). Isolation of EVs from plasma and validation of marker labeling was performed with Western Blot, ELISA and transmission electron microscopy.ConclusionHere we demonstrate the use of nanoflow cytometry to directly quantitate proteins on circulating extracellular vesicles in plasma from MCI and AD patients. The assays are rapid, inexpensive, directly quantitative, and require mini sample volume and manipulation. Future studies are required involving a larger population of patients who have had ‘gold standard’ biomarkers (Amyloid and tau CSF measurements), longitudinal follow‐up and/or autopsy confirmed diagnosis of AD.
Associations of NREM Slow Wave Activity and Regional in‐vivo tau PET deposition in black and white community‐dwelling cognitively normal older‐adults with normal sleep
Authors: Bubu Omonigho Michael M , Umasabor‐Bubu Ogie Queen , Kovbasyuk Zanetta , Valkanova Elena M , Mbah Alfred , Cejudo Jaime Ramos , Turner Arlener , Hu Lu , Williams Natasha , Jean‐Louis Girardin A , de Leon Mony J. , Masurkar Arjun V. , Wisniewski Thomas , Varga Andrew , Osorio Ricardo S 
Published: December 2023

AbstractBackgroundIn this proof‐of‐concept study, we examined whether NREM slow wave activity (SWA) is associated with regional in‐vivo tau deposition; and whether race‐specific differences exist in this association, in clinically normal older adults with normal sleep, in the context of Aβ.MethodThis was a cross‐sectional analysis of baseline data from 21 community‐dwelling cognitively normal older‐adults with normal sleep. Participants were matched on age, sex, BMI, and APOE4 carrier status in a 1:3 ratio, blacks: whites. Normal sleep was defined as 6‐9 h of total sleep time and absence of AHI4%>15 and AHI4%>5 with sleepiness. SWA was defined as power between 0.5‐4.0 Hz during NREM with NREM cycles characterized as stages NREM 2‐3 of ≥15 min. terminated by rapid eye movement (REM) or wakefulness of ≥5 min. Tau burden was assessed using 18F‐PI2620. Linear mixed‐effects models with random intercept and slope were used to assess associations between NREM SWA, and regional in‐vivo tau PET deposition, respectively, controlling for Aβ, age, BMI, sex, APOE4‐status, education and other sleep variables.ResultOf the 21 participants, 7 (33.3%) were black, 12 (57.1%) were women and 5 (24%) were APOE4 carriers. The mean (SD) age, and education were 69.1 (5.5), and 17.2 (3.8) years respectively. NREM SWA was associated with tau deposition in the entorhinal cortex, inferior and middle temporal ROIs, including gray matter neocortical ROIs i.e., anterior ventral striatum, orbitofrontal, precuneus, superior frontal, lateral temporal and posterior cingulate gyrus cortices (p <.01 for all). Racial differences existed in the entorhinal cortex, and inferior and middle temporal ROIs, including the lateral temporal, parietal, precuneus and posterior cingulate gyrus cortices (p <.02 for all), with black participants having lower tau levels relative to white participants. Divergent NREM SWA and tau associations were observed in the entorhinal cortex, precuneus, and inferior and middle temporal ROIs with NREM SWA negatively correlated with tau‐PET levels in whites and positively correlated in blacks.ConclusionRacial differences in physiological sleep features, uniquely associated with tau levels in the brain, may reflect one mechanism of how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks.
Detection of mild cognitive impairment of Alzheimer’s disease and tauopathy differentiation by phospho‐tau396
Authors: Wang Shih‐Hsiu Jerry , Wu Ling , Ervin John F. , Gilyazova Nailya , Xu Bin 
Published: December 2023

AbstractBackgroundIn recent years, CSF and blood‐based biomarkers have been developed for premortem diagnosis of AD. However, no well‐established biomarkers are currently available for early detection of AD in patients with mild cognitive impairment (MCI), a transitional stage between normal cognition and dementia. As tau aggregates in AD brains are highly phosphorylated, we sought to develop novel biomarkers for early diagnosis of AD and differential diagnosis of tauopathies by detecting site‐specific phospho‐tau (p‐tau) epitopes.MethodA panel of site‐specific p‐tau antibodies were screened for their ability to detect high molecular weight “smear‐like” tau aggregates from brain extracts of AD, PSP, CBD, and Pick’s disease patients by Western blotting. Selection of tau phosphorylation sites is based on the high frequencies of these sites reported in AD patients from recent high‐resolution quantitative post‐translational modification mapping. Selected candidates were further tested for their ability to differentiate subjects with AD vs. other tauopathies and MCI vs. cognitively normal controls by ELISA assays and immunohistochemical staining of postmortem brain tissue followed by machine learning‐based image analysis.ResultAmong the antibodies screened, p‐tau396 was able to differentiate between AD vs. controls (AUC: 0.983, P<0.0001), AD vs, CBD (AUC: 0.986, p = 0.0001), and AD vs. PSP (AUC: 0.967, p<0.0001). More importantly, ptau396 was able to detect subjects with MCI vs. cognitively normal controls (AUC: 0.835, p = 0.0032). Immunohistochemical staining of postmortem brain tissue with p‐tau396 antibody also showed increased neurofibrillary tangle pathology in the hippocampus and temporal cortex of subjects with MCI. Machine learning‐based image analysis reliably detected more severe tau burden in subjects with MCI vs. cognitively normal controls, even among subjects with the same Braak stages.Conclusionp‐tau396 is a promising novel biomarker for early detection of AD and differential diagnosis of AD from other tauopathies. Ongoing work is aimed at developing ultrasensitive assays, such as SIMOA, to detect p‐tau396 from patient blood and CSF.
Neurophysiological activity linked to Alzheimer’s disease pathology relates to longitudinal cognition and progression to mild cognitive impairment.
Authors: Rudolf Jonathan E Gallego , Wiesman Alex I , Baillet Sylvain , Villeneuve Sylvia ,   the PREVENT‐AD research group
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) is defined by the pathological accumulation of amyloid‐beta (Aβ) and tau in the brain. Regional deposition of these proteins is associated with changes in frequency‐defined neurophysiological activity that can be detected using non‐invasive magnetoencephalography (MEG). Here we examined whether these neurophysiological alterations were associated with participants’ demographics and longitudinal changes in cognition. Additionally, we addressed the clinical utility of MEG to predict progression to mild cognitive impairment (MCI), as compared to other established AD imaging biomarkers.MethodsWe used Positron Emission Tomography (PET) to measure the deposition of whole‐brain Aβ ([18F]NAV4694) and tau ([18F] Flortaucipir), Magnetic Resonance Imaging (MRI) to measure hippocampal volume and resting‐state MEG to capture neurophysiological activity in a group of clinically unimpaired older adults with family history of AD (PREVENT‐AD cohort; n = 103). We implemented a multivariate partial least squares (PLS) analysis to test the association between imaging markers (i.e., neurophysiological activity and AD proteinopathy) and participants’ clinical profiles (i.e., demographic‐clinical variables and longitudinal cognition data). For the second analysis we used logistic regression models to assess the added value of neurophysiological activity to predict MCI progression compared to established MRI/PET imaging markers (n = 100; 14 MCI progressors).ResultsThe PLS analysis identified significant latent variables that linked proteinopathy‐related neurophysiological activity slowing to older age, lower education, positive APOE ε4 status and longitudinal deficits in cognition across multiple domains (Figure 1). The initial logistic regression model included demographic and clinical variables and had an AUC = 0.772, which increased to 0.794 after adding the MRI hippocampal volume. Incorporating MEG spectral power from temporal regions where tau accumulates resulted in a considerable increase in accuracy with an AUC = 0.873. The model including Aβ and tau PET on top of MRI and MEG markers reached an AUC = 0.905 (Figure 2).ConclusionOur results show that the neurophysiological changes linked to AD pathology are associated with longitudinal cognitive impairment across multiple domains. MEG spectral power from early tau accumulating regions improved the accuracy for predicting MCI progression, contributing information beyond traditional demographic/clinical variables and structural MRI and representing a more accessible and less invasive alternative compared to PET imaging.
A population‐based investigation of brain changes related to Alzheimer’s disease in middle‐aged adults in Brazil
Authors: Leite Renata Elaine Paraizo , Rodriguez Roberta Diehl , Socher Karen L R , Suemoto Claudia Kimie , Brucki Sonia Maria Dozzi , de Lucena Ferretti‐Rebustini Renata Eloah , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Grinberg Lea T. , Nitrini Ricardo 
Published: December 2023

AbstractBackgroundGiven the progressive nature of neurodegenerative pathologies, great effort has been made to create diagnostic tools for detecting neurodegenerative changes in their early stages. However, the lack of information about the frequency of neurodegenerative changes in mid‐age adults impacts biomarker interpretation and sensitivity improvement. In addition, recent clinicopathological studies have shown than even a low Alzheimer’s disease (AD) neuropathological burden can significantly impact neuropsychiatric function. Finally, clinicopathological studies point to a role of small cerebrovascular changes in the cognitive decline of individuals with zero or low neurodegenerative burden; however, it remains unclear if small vascular brain lesions can impact cognition in younger mid‐age individuals.MethodWe evaluated the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic and heterogeneous group under 65 years of age at the moment of death, most of them with low educational level (Table 1). A semi‐structured interview with an informant was performed to obtain socioeconomic and clinical data. Internationally accepted neuropathological criteria were used for pathologic diagnosis.ResultSome degree of neurofibrillary pathology was found in 53% (n = 145) of the individuals, while neuritic plaques were found in 10% (n = 26) of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was similar among individuals with and without cognitive impairment. However, a higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neuropsychiatric symptoms was noted in 59% (n = 160) of the cases. High frequency of cerebrovascular risk factors such as hypertension (63.9%), smoking (58.5%) and alcohol intake (27.5%) was also observed in the entire sample (n = 275) (Table 1).ConclusionOur data shows that AD neuropathological changes can begin in mid‐age and corroborates findings from other series with predominantly older Caucasians of high scholarity that have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction.
Glutamate Release and Uptake in CNS of Young and Aged Mice Compared to a Knock‐In Mouse Model of Alzheimer’s Disease
Authors: Sulkowski Brittany A. , Suhail Cocanut , Pomerleau Francois , Huettl Peter , Murphy Paul , Gerhardt Greg A 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) and aging of the CNS are complex, heterogenous processes involving both structural and functional changes to neuronal and glial elements. While neuronal cell loss is well known, issues surrounding how age impacts both AD development and dementia and the metabolic and pathological changes that concomitantly occur are unclear. Major gaps in knowledge in aging of the CNS and AD involve changes in the excitatory/inhibitory balance between glutamate and GABA release and regulation with prior research supporting either elevated or reduced levels of resting glutamate.MethodTonic and phasic glutamate release were measured in real time in vivo through the utilization of enzyme‐based microelectrode arrays (MEAs). Young adult male and female C57BL6 mice (5‐8 months old) were the wild‐type (WT) control group and were compared to male and female old APP/PS1 knock‐in mice (13‐24 months old) and age matched WT controls. Glutamate was recorded in the hippocampus, frontal cortex, and striatum. Following recordings of basal glutamate levels, DL‐threo‐beta‐hydroxyaspartate (TBOA), was locally injected (100 nl/ 50mg/ml) in the brain to study glutamate uptake.ResultThere was a trend for basal glutamate levels to be increased in the hippocampus of both aged APP/PS1 and aged WT mice when compared to young WT animals with highest levels in the aged WT group. In both the frontal cortex and striatum, there was a trend for decreased basal glutamate levels in aged APP/PS1 and WT mice when compared to young WT animals with lowest levels seen in the aged WT group for both brain regions.ConclusionThere were differences in glutamate extracellular regulation seen within the hippocampus, frontal cortex, and striatum of all animal groups and ages. In addition, we see evidence for age‐related increases in glutamate within the hippocampus of the aged animal groups. These data support that glutamate regulation is not homogenous in the CNS and that aging of the CNS may result in the greatest effect on glutamate regulation in the CNS, rather than genes that are implicated in the etiology of AD such as the APP and PS1 genes.Support provided by NIH grants RF1AG070952 and 1P01AG078116.
Strategies for recruiting African Americans into aging research: The Health and Aging Brain Health Disparities (HABS‐HD) Study.
Authors: Munoz Haydee Izurieta , Large Stephanie E , Bailey Patricia , O'Bryant Sid E. , Johnson Leigh 
Published: December 2023

AbstractBackgroundDespite the increase in Alzheimer’s disease (AD) research among ethnic and racial minority populations, they are underrepresented in research and successful recruitment of diverse cohorts remains challenging. Culturally specific recruitment strategies and community engagement are needed to increase diverse participant enrollment in aging research. In 2020, we designed and implemented a strategy to recruit 1,000 African Americans (AA), 50 years and older into the Health & Aging Brain Study‐ Health Disparities (HABS‐HD) project. In this study, we examined the effectiveness of recruitment strategies among this group.MethodHABS‐HD is an epidemiological study of cognitive aging among diverse communities. The team recruited an initial cohort of 1,000 non‐Hispanic whites and 1,000 Mexican Americans using a community‐based approach. This foundation was expanded to reach the AA community through the engagement of key stakeholders and the use of an integrated marketing and outreach strategy. Recruitment methods included an integrated approach combining traditional marketing (print, radio); social media (influencers and online ads), and in person community recruitment and education events at local churches, barbershops, health fairs, etc. The reach and enrollment data were collected and analyzed.ResultOut of 4066 participants that were interested in HABS‐HD, 1362 (33.5%) identified as AA. While recruiting the AA cohort outreach team participated in over 140 community events, ranging from state fairs, barbershops, and church events. Enrollment data indicated participants heard of us through word of mouth (35%); community events (21.6%); news (12.7%); refer a friend program (6.8%); print media (6.4%) radio (4%); and social media (3.6%). In terms of traditional marketing and overall general study awareness, the social media approach reached 179,200 individuals. Of this number12.1% of people interacted with the landing site and then a further 747 clicked to sign up. The reach of our radio advertising was 2,200,000 listeners.ConclusionRecruiting diverse communities into research involves targeting the recruitment techniques and materials to the target population. The creation of a culturally appropriate media campaign and utilizing community based methods such as outreach, engagement, and collaboration between the research team and key stakeholders in the community led to the successful recruitment of AA into our study.