bluuebunny/crossref_metadata_2025_split huggingface dataset:
A longitudinal multimodal biomarker study of memory clinic MCI patients with MBI – are there links to Alzheimer disease?
Authors: Ismail Zahinoor , Leon Rebeca , Yu Chen Hung‐ , Robert Philippe , Smith Eric E. 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) and mild behavioral impairment (MBI) are at‐risk states for incident dementia. MBI represents behavioral risk, and MCI represents cognitive risk. In memory clinic MCI patients, we interrogated the relationship between MBI status (+/‐), cerebral atrophy, cerebrospinal fluid (CSF) biomarkers, and incident all‐cause dementia and incident Alzheimer disease (AD) dementia.MethodMBI was operationalized as persistent neuropsychiatric symptoms (NPS) in MEMENTO study participants. MRI regions were selected a priori for Braak stages I‐V. CSF markers included amyloid‐β (Aβ), hyperphosphorylated‐tau (p‐tau), and tau. Linear regression models were fitted with regional thickness/volume or CSF markers as dependent variables, and MBI status as independent variable, adjusted for age, sex, and education. Logistic regression was conducted to investigate if MBI status was associated with amyloid‐β positivity (defined as <813 pg/mL), with MBI status as predictor, adjusting for age, sex, education and MMSE. Kaplan‐Meier curves were generated for dementia‐free survival out to 6 years. Cox proportional hazard regressions, adjusted for age, sex, education, MMSE score, and MCI subtype were utilized to investigate the rates of incident all‐cause dementia, as well as incident AD dementia, in MBI+ vs MBI‐ patients with MCI.ResultOf the 820 participants (mean age(±SD) 72.54(8.21), 57.80% female), 29.5% had MBI. Compared to MBI‐, MBI+ status was associated with lower entorhinal thickness (b = –0.066, p = 0.04) and smaller hippocampal volume (b = –0.069, p< 0.01). In the CSF subsample (n = 154, mean age = 69.6, 48.1% female), MBI predicted amyloid‐β positivity (odds ratio = 2.19, p = 0.05), and was associated with 7.4% lower Aβ42 level (p = 0.01), 17.8% higher CSF p‐tau/Aβ42 (p<0.01) and 18.9% higher t‐tau/Aβ42 ratio (p = 0.02). Longitudinally, MBI+ had lower dementia‐free survival (log rank test; p<0.0001), with adjusted hazard ratios (HRs) of 2.76 (95%CI 1.99‐3.8; p<0.001) for all‐cause dementia and 2.73 (95%CI 1.83‐4.07; p<0.001) for AD dementia.ConclusionMBI served as a clinical marker to identify a subgroup of MCI patients with Alzheimer disease‐related morphological changes in the entorhinal cortex and hippocampus, and CSF biomarkers consistent with AD. MCI with MBI had a greater incidence rate of AD dementia than MCI without MBI. MBI case status may be used to improve detection of prodromal AD in MCI.
Treatment with AV‐001, an Angiopoietin‐1 mimetic peptide, improves dementia outcomes in rats
Authors: Venkat Poornima , Gao Huanjia , Findeis Elizabeth L , Zacharek Alex , Powell Brianna , Landschoot‐Ward Julie , Lu Mei , Chopp Michael 
Published: December 2023

AbstractBackgroundVascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. We investigated the neurocognitive outcomes of multiple‐microinfarct (MMI) dementia in aged female rats. We previously found that treatment with AV‐001, a Tie2 receptor agonist, significantly improves memory and preference for social novelty in middle‐aged male rats subjected to MMI. In this study, we tested the therapeutic effects of AV‐001 in aged female rats subjected to MMI.MethodFemale, Wistar, rats were aged to 18m and randomly assigned to Sham, MMI, and MMI+1µg/Kg AV‐001 treatment groups (n = 8‐9/group). MMI was induced by injecting either 1000 (low dose, LD‐MMI) or 6000 (high dose, HD‐MMI), 70‐100µm sized cholesterol crystals into the internal carotid artery. AV‐001 treatment (1µg/Kg, i.p.) was initiated at 1d after MMI and administered once daily. A battery of neuro‐cognitive tests was performed at 21‐28d MMI.ResultLD‐MMI induces significant (p<0.05) neurological deficits evaluated using the modified neurological severity score (mNSS) test, starting at 1d after LD‐MMI and persisting at least up to 28d after LD‐MMI. Treatment of LD‐MMI with AV‐001 significantly improves neurological function at 21d and 28d after LD‐MMI compared to LD‐MMI control rats. Aged female rats subjected to LD‐MMI exhibit long term memory impairment in an olfactory learning based novel odor recognition test and a significantly lower preference for social novelty in the three‐chamber social test, although there were no changes in overall preference for sociability compared to Sham rats. Treatment of LD‐MMI with AV‐001 significantly improves long‐term memory and preference for social novelty compared to LD‐MMI control rats. HD‐MMI in aged female rats induces significant anxiety‐ and depression‐like behavior with increased freezing time in the open field test and decreased time spent in the open arms of the elevated plus maze compared to Sham rats. Treatment of HD‐MMI with AV‐001 significantly reduces anxiety like behavior indicated by increased time spent in the open arms of the elevated plus maze compared to HD‐MMI control rats.ConclusionAV‐001 is a novel therapeutic agent that may improve neurological deficits, memory impairment, and anxiety like behavior in aged female rats subjected to a MMI model of vascular dementia.
EEG network functional connectivity during sleep and in presence of network hyperexcitability in Alzheimer’s disease
Authors: Moguilner Sebastian G , Bender Alex C , Pellerin Kyle R , Sarkis Rani A , Lam Alice D 
Published: December 2023

AbstractBackgroundFunctional connectivity (FC) studies in Alzheimer’s disease (AD) have focused primarily on the awake resting state. Yet, sleep disturbances in AD are common and occur early in the disease. Network hyperexcitability in AD also arises during sleep, resulting in epileptiform activity and seizures, and impacting memory consolidation. Hence, understanding the FC changes that occur during sleep in AD could provide important biological insights. To date, no studies have examined FC changes occurring during sleep in AD and their relationship with network hyperexcitability.MethodUsing ambulatory scalp EEG recordings, we assessed sleep FC in cognitively normal healthy controls (HC, n = 35), individuals with early clinical stages of AD with no history or risk factors for epilepsy (ADNoEp, n = 44), and individuals with early clinical stages of AD and epilepsy related to AD (ADEp, n = 14). We measured FC using corrected amplitude envelope correlation and assessed FC on different scales, including channel‐pair associations, regional associations, seed‐based connectivity, and graph theory metrics. Machine learning classifiers were developed to determine whether sleep FC measures provide accurate discrimination between HC, ADNoEp, and ADEp.ResultThere were no significant differences in age, sex, or education between HC, ADNoEp, and ADEp. Compared to HC, the ADNoEp group had 1) reduced FC during REM sleep in the alpha band in posterior regions; and 2) increased FC during NREM2 sleep in the gamma‐band in frontal regions. Compared to ADNoEp, the ADEp group had reduced FC in NREM2 sleep in the delta‐band in temporal and posterior regions. Graph theory metrics corroborated these sleep stage‐ and frequency‐specific findings between groups. Machine learning classifiers using graph theory metrics as input features distinguished ADNoEp from HC, and ADNoEp from ADEp, with high performance (AUC>0.85).ConclusionAD is associated with sleep stage‐, frequency band‐, and region‐specific changes in FC. Network hyperexcitability in ADEp is also associated with changes in sleep FC, which are distinct from those seen in ADNoEp. Our findings expand understanding of brain network changes in AD to the sleep state and demonstrate sleep‐stage specific alterations in FC that may have important implications for understanding AD neurophysiology and for disease monitoring and therapeutic development.
Circulatory GSK‐3beta a new target against Alzheimer’s disease
Authors: Dey Sharmistha , Kumari Shiwani , Singh Abhinay Kumar , Yadav Yudhishthir 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is the progressive brain disorder which degenerate brain cells connection and causes memory loss. Though, AD is irreversible, it is not impossible to arrest or slow down the progression of the disease. However, this would only be possible if the disease is diagnosed at an early stage and early diagnosis requires clear understanding of pathogenesis at molecular level. Overactivity of GSK‐3β and p53 accounts for tau hyperphosphorylation, and amyloid‐β plaqueMethodWe explored GSK‐3β and p53 as blood‐based biomarkers for early detection of AD. Methods: The levels of GSK‐3β, p53, and their phosphorylated states were measured using surface plasmon resonance and verified using Western blot in serum from AD, mild cognitive impairment (MCI), and geriatric‐control (GC) subjects. The neurotoxic SH‐SY5Y cell line was treated with antioxidant Emblica Officinalis (EO) for rescue effect.ResultGSK‐3β, p53, and their phosphorylated state were significantly over expressed (p>0.001) in AD, MCI compared to GC and can differentiate AD, MCI from GC. The expression level of GSK‐3β and p53 proteins were found to be downregulated in a dose‐dependent manner after the treatment with EO in amyloid‐β induced neurotoxic cells.ConclusionThese proteins can serve as potential blood markers for the diagnosis of AD and EO can suppress their level. This work has translational value and clinical utility in the future.
Validity of cognitive function assessed by a subjective cognitive decline questionnaire as compared with objective cognitive tests in community‐dwelling older adults in China
Authors: Gao Mengyan , Huang Yuhui , Chen Xiao , Shen Jie , Pang Ting , Xu Xin , Zheng Yan , Wang Xiaofeng , Yuan Changzheng 
Published: December 2023

AbstractBackgroundSubjective cognitive decline (SCD) has been recognized as an early symptom of age‐related cognitive decline, but research on the validity of SCD questionnaire in the elderly population is limited. Thus, we aimed to evaluate the validity of a 7‐item SCD questionnaire in Chinese older adults.MethodThe study included 1585 participants (53.6% women; mean [SD] age: 78.7 [4.4] years) who completed the SCD questionnaire, Hasegawa Dementia Scale (HDS), and Mini‐Mental State Examination (MMSE) from the Rugao Longevity and Ageing Study (RuLAS) in 2019. MCI was defined according to established education‐specific cut‐off values of HDS and MMSE scores. We used sensitivity, specificity, Youden’s Index, and the receiver operating characteristic (ROC) curves to evaluate the discriminant ability of the SCD questionnaire. Spearman correlation coefficients were also used to measure the strength of correlation between SCD scores and objective cognitive function scores.ResultThe SCD score (range: 0‐7) with the cut‐off value of 4 displayed moderate‐to‐good sensitivity (Sen = 0.52) and specificity (Spec = 0.69), with Youden’s index of 0.21 and the area under the curve (AUC) of 0.62, in distinguishing cognitive impairment defined by objective cognitive tests. In addition, SCD scores have low‐to‐moderate correlations with overall scores of two cognitive tests (rHDS = ‐0.23; rMMSE = ‐0.28). Correlations between domain‐specific SCD and corresponding objective cognitive function scores ranged from ‐0.05 to ‐0.31.ConclusionOur study supported a reasonable discriminant ability of a 7‐item SCD questionnaire among Chinese older adults.
Amyloid Against Amyloid: Dimeric Amyloid Fragment Ameliorates Cognitive Impairments by Direct Clearance of Oligomers and Plaques
Authors: Lee Hee Yang , Baek Seungyeop , Cha Minhae , Yang Seung‐Hoon , Kim YoungSoo 
Published: December 2023

AbstractBackgroundAmyloid‐β (Aβ) in the form of neurotoxic aggregates is regarded as the main pathological initiator and key therapeutic target of Alzheimer’s disease. However, anti‐Aβ drug development has been impeded by the lack of a target needed for structure‐based drug design and low permeability of the blood–brain barrier (BBB). An attractive therapeutic strategy is the development of amyloid‐based anti‐Aβ peptidomimetics that exploit the self‐assembling nature of Aβ and penetrate the BBB.MethodHerein, we designed a dimeric peptide drug candidate based on the N‐terminal fragment of Aβ, DAB. In vitro assays were performed to verify the dissociating ability of DAB against Aβ(1‐42) aggregation. The therapeutic efficacy of DAB against Aβ was evaluated in the 5XFAD, a transgenic AD mouse model with aggressive amyloid accumulation. Following that, peptide mapping assays and molecular docking studies were utilized to elucidate DAB‐Aβ interaction, and we assessed the dissociative activity of DAB with sequence modifications to further understand active regions of DAB.ResultThrough in vitro assay we found that DAB solubilizes both neurotoxic Aβ(1‐42) oligomers and fibrils to monomeric states. Administration of DAB reduced amyloid burden in 5XFAD mice, and down‐regulated neuroinflammation and prevented memory impairment in the Y‐maze test. In peptide mapping assays, DAB was shown to bind and dissociate Aβ aggregates in a manner distinct to the Aβ(1‐17) fragment.ConclusionOverall, we designed a dimeric Aβ(1‐17)‐based peptide drug and demonstrated that DAB can solubilize aggregates of Aβ and has therapeutic potential as a structural basis for anti‐amyloid peptide drugs.
Alzheimer’s Disease‐impacted Expression of tRNA‐derived Fragments in Body Fluid: Implication for New Disease Biomarkers
Authors: Wu Wenzhe , Shen Audrey , Lee Inhan , Pappolla Miguel A , Fang Xiang , Bao Xiaoyong 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD), the most common type of dementia, affects over six million Americans aged 65 years and older. Although numerous research efforts were made on AD, the knowledge of the mechanisms and therapeutic strategies is still very limited. At present, identifying the prodromal stages of AD remains a significant challenge. tRNA‐derived RNA fragments (tRFs), a family of recently discovered small non‐coding RNAs (sncRNAs), express high in both human and primate hippocampus. Our recent discovery also revealed that some hippocampus tRF expression is much higher in AD patients compared with age‐matched health individuals.MethodHerein, we further characterized the expression of tRFs in CSF and serum from healthy, mild cognitive impairment (MCI), and AD patients, using a combination of T4 polynucleotide kinase (T4 PNK)‐RNA‐seq and qRT‐PCR specific to tRF validation.ResultOur results indicated tRF5‐ProAGG altered by AD in both CSF and serum samples, and serum AD‐impacted tRF5‐ProAGG showed a correlation to the disease severity. Notably, serum tRF5‐ProAGG showed a change tendency when MCI progresses to AD, suggesting that it is a promising biomarker for AD. We also predicted putative targets of tRF5‐ProAGG using our in‐house computational program and confirmed that some targets, such as SV2B, CDH8, and NEFL, were decreased in AD’s hippocampus. Interestingly, SV2B and tRF5‐ProAGG showed a negative correlation.ConclusiontRF5‐ProAGG shows the potential as an AD biomarker and plays a vital role in disease progression.
Persistent Systemic Inflammation Mediates the non‐Hispanic Black vs non‐Hispanic White Disparity in Cognitive Function: A Longitudinal Analysis
Authors: Higgins Cesar , Ware Erin B , Hicken Margaret , Zawistowski Matthew , Kobayashi Lindsay C , Adkins‐Jackson Paris AJ , Muhkerjee Bhramar , Bakulski Kelly M 
Published: December 2023

AbstractBackgroundRacialization is the process of grouping individuals into “races” based on phenotypic characteristics, assigning value to these groups, and disproportionately treating them. Racial health disparities may capture the differential impact of racialization, and subsequently, discrimination on these groups. In a longitudinal study of C‐reactive protein (CRP), a marker of systemic inflammation, we explored trajectories of inflammation between non‐Hispanic Black vs non‐Hispanic White participants and tested if persistent inflammation mediated the racial disparity in cognitive function.MethodsIn the US Health and Retirement Study (n = 4,719 adults aged >50), we used three repeated CRP and global cognitive measures at baseline (2006 or 2008), at year 4 (2010 or 2012), and year 8 (2014 or 2016). In multivariable generalized estimating equation models, we compared changes in cognitive function between non‐Hispanic Black vs non‐Hispanic White participants as a function of sustained elevated levels of CRP (all time points >3 vs. ≤3mg/L). We decomposed the racial disparity in cognitive function onto 1) the mediated effect due to elevated CRP, and 2) the portion attributable to the interaction between race and CRP.ResultsThe average age at baseline was 68.8 years. Non‐Hispanic Black participants (n = 599) had 24% higher CRP at year 4 and 18% higher at year 8, relative to non‐Hispanic White participants (n = 4,120). Non‐Hispanic Black participants with elevated CRP had 2.9 (95% CI: ‐3.2, ‐2.7) lower points on the global cognitive assessment than non‐Hispanic White participants. In a randomized analogue model, we found that 4% (95% CI: 1%, 6%) of the racial disparity in cognitive function was mediated by sustained elevated CRP, and 14% (95%CI: 5%, 23%) attributable to the interaction between race and sustained elevated CRP.ConclusionsSystemic inflammation mediates racialized disparities in cognitive function. The effect of persistent elevated levels of systemic inflammation on cognition differs when individuals are racialized as non‐Hispanic Black had they been racialized and treated as non‐Hispanic White.
Leveraging MODEL‐AD mouse strains to understand the role of toxicant exposures on LOAD risk
Authors: Howell Gareth R , Kotredes Kevin P , Minaeva Olga , Moncaster Juliet A , Haber Annat , Pandey Ravi S , Rizzo Stacey J Sukoff , Territo Paul R , Lamb Bruce T , Sasner Michael , Oblak Adrian L , Carter Gregory W , Goldstein Lee E ,   MODEL‐AD consortium
Published: December 2023

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is caused by interactions between genes and environment. However, current mouse models do not fully recapitulate LOAD phenotypes, limiting translatability to clinical needs. To address this, MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease) Consortium was established to create and phenotype new mouse models. The IU/JAX/PITT MODEL‐AD Center focuses on developing models with combinations of genetic risk factors, as well as humanizing APP (hAb) and MAPT. One use of these models is to determine the contribution of environmental factors to LOAD risk. Studies show associations between LOAD risk and exposure to ubiquitous environmental neurotoxicants, including arsenic (As), lead (Pb), and cadmium (Cd). All three are ranked in the “Top 10 Toxicants” of public health concern (As #1, Pb #2, Cd #7; ATSDR Toxic Substance Priority List). However, mechanisms driving increased risk are unknown.MethodNovel mouse models were created by genetic engineering or editing in C57BL/6J. Four to 24 months old mice and controls were phenotyped using a human‐relevant battery that includes cognitive performance, imaging, biometrics, transcriptomics, proteomics, metabolomics, neuropathology, and fluid biomarkers. Toxicants (As, Pb, Cd) were delivered using human‐relevant doses in drinking water. Exogenous toxicants (Pb, Cd, As) and endogenous biometals (Zn, Cu, Fe) in brain and blood samples were analyzed by elemental mass spectrometry mapping.ResultMore than 40 mouse models have been created carrying combinations of genetic risk factors in genes including APOE, Trem2, Abca7 and Mthfr. One strain, LOAD2 (triple homozygous for APOE4, Trem2*R47H, and hAb) shows molecular and transcriptomic changes associated with human LOAD. Short‐term exposure to As, Cd, or Pb also modified expression of LOAD‐relevant genes in LOAD2 mice and controls, including App and Vgf, in a toxicant‐specific manner. Elevated toxicant levels were detected in both brain and blood samples from exposed mice.ConclusionThese data indicate that exposure to common environmental toxicants may increase LOAD risk by modifying expression of specific genes and molecular pathways previously implicated in human LOAD. Studies are underway using additional MODEL‐AD models to determine the long‐term effects of neurotoxicant exposures.
Aging × Genetics × Environment: Characterization of Precision Disease Models for Preclinical Testing for Late‐onset Alzheimer’s disease
Authors: Rizzo Stacey J Sukoff , Haynes Katy A , Santos Diogo Francisco S. , Doolen Suzanne , Williams Sean‐Paul , Little Gabriela , Reddy Aman , Heaton Nicholas , Hart Jason T , Sasner Michael , Kotredes Kevin P , Garceau Dylan , Ingraham Cynthia , Pandey Ravi S , Preuss Christoph , Uyar Asli , Seyfried Nicholas T , Territo Paul R , Howell Gareth R , Carter Gregory W , Oblak Adrian L , Lamb Bruce T ,   IU/JAX/PITT MODEL‐AD Center
Published: December 2023

AbstractBackgroundThe ability to effectively translate therapeutic efficacy from the bench to clinical success for Alzheimer’s disease (AD) has been hampered in part due to limited recapitulation of the complexity of the disease in animal models. While analogous AD risk mutations have been engineered into animal models and have dominated the research field, these have primarily been familial, early onset risk alleles which do not capture the risk for AD for the majority of patients that present with sporadic late onset AD (LOAD).MethodThe IU/JAX/PITT MODEL‐AD consortium is focused on developing mouse models with genetic risk variants associated with LOAD, in combination with environmental risk factors and aging to enable improved translation. The present studies aimed to characterize mice expressing humanized Aβ in combination with multiple genetic risk factors (APOE4 and the R47H risk variant in the Trem2 gene; LOAD2) and aged in the presence of a high‐fat, high‐sugar diet (HFD).ResultLOAD2 mice exposed to HFD from adolescence (LOAD2+HFD) demonstrated aging changes relative to LOAD2 mice in the absence of HFD, including presentation of insoluble Aβ42 in brain and plasma, and increased inflammatory cytokines. 12‐month aged LOAD2+HFD mice also demonstrated increased NfL in CSF, as well as vascular and perfusion changes as measured by PET/MRI. By 18 months, LOAD2+HFD mice demonstrated reductions in hippocampal neurons as well as cognitive impairment relative to LOAD2 mice in the absence of HFD on a translational touchscreen task. Intriguingly, gene expression profiles and proteomic signatures of aged LOAD2+HFD mice aligned with ‘omics signatures of AD patients in the absence of core neuritic plaques, which were not detected up to 24 months of age.ConclusionMice with genetic risk for LOAD coupled with environmental risk factors demonstrate aging‐dependent changes in line with a spectrum and trajectory of features of clinical LOAD. From a precision medicine approach, our MODEL‐AD Preclinical Testing Core and our TREAT‐AD colleagues are prioritizing LOAD2+HFD mice as an important model system for evaluating the therapeutic potential of non‐amyloid targeting therapeutics as well as for prophylactic interventions initiated prior to significant amyloid accumulation.