bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Association of Religious Attendance and Neuropsychiatric Symptoms, Cognition, and Sleep Disturbances in Dementia
Authors: Britt Katherine Carroll , Richards Kathy C , Kesler Shelli C , Acton Gayle C , Hamilton Jill B , Radhakrishnan Kavita C 
Published: December 2022

AbstractBackgroundNeuropsychiatric symptoms (NPS), cognitive decline, and sleep disturbances are commonly found in dementia and are indicators of dementia progression (Alzheimer’s Association, 2021; Santacruz Escudero, et al., 2019; Tsunoda, et al., 2020). Given the growing number of older adults with dementia and absence of a cure, it is increasingly important to identify protective factors that may slow progression of dementia, particularly since up to 40% of risk factors are modifiable (Livingston et al., 2020). A growing body of literature supports religion and spirituality as modifiable risk factors for mental and physical health, yet few studies have been conducted in older adults with dementia (Koenig et al., 2012; VanderWeele et al., 2017).MethodWe analyzed data from the Health and Retirement Study in 2000, 2006, and 2008 and sub‐study, Aging Demographics, and Memory Study in 2001‐2003, 2006‐2007, and 2008‐2009 to examine the association of religious attendance with neuropsychiatric symptoms, cognitive function, and sleep disturbances among older adults in the U.S. (N = 72) age 70 years and older with dementia. A cross‐sectional analysis using Spearman’s partial Rho correlation was utilized to determine associations beyond social interaction.ResultAged 73‐100 years, participants had a mean age of 84.23 (5.73) years, mean cognitive function (Clinical Dementia Rating)(Hughes et al., 1982; Morris, 1993) of 1.17(.53), were 35.5% male, and 64.5% female. Significant associations were found for reported religious attendance and caregiver‐reported NPS using the Neuropsychiatric Inventory (Cummings et al., 1994; Kaufer et al., 1998) (rs (97) = ‐ .124, 95% CI [‐.129, ‐.119], p<.0005), cognitive function as measured by CDR, rs (97) = ‐ .018, 95% CI [‐.023, ‐.013], p<.001), and caregiver reported sleep disturbance captured by 3 yes/no items (Jelicic et al., 2002; Moon et al., 2017), rs (97) = ‐ .275, 95% CI [‐.280, ‐.271], p<.0005). Increased religious attendance was associated with lower NPS, better cognitive function, and fewer sleep disturbances beyond adjusting for social interaction.ConclusionLongitudinal studies and clinical trials in large, diverse samples are warranted to further examine the relationship between religion and spirituality, and dementia progression.
Examining differences across cognitive trajectory profiles in late middle‐aged adults: Results from the Wisconsin Registry for Alzheimer’s Prevention
Authors: Du Lianlian , Hermann Bruce P , Jonaitis Erin M. , Burghy Cory , Cody Karly Alex , Betthauser Tobey J , Larget Bret , Chappell Richard J. , Janelidze Shorena , Hansson Oskar , Johnson Sterling C. , Koscik Rebecca Langhough 
Published: December 2022

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) and other dementias may accelerate in preclinical phases as brain pathology increases. Here we: 1) developed cognitive trajectory profiles using longitudinally‐based random slope and change point (CP) parameter estimates from a cognitive composite; and 2) examined how AD‐related biomarkers varied across these cognitive profiles.MethodWRAP participants with > = 3 Preclinical Alzheimer’s Cognitive Composite (PACC3) scores, dementia‐free at baseline, were included (n = 1068). Amyloid measures from positron emission tomography (PET) [C‐11]Pittsburgh Compound B (PiB; n = 361) scans included Global PiB DVR and proportion PiB+ (Global PiB DVR>1.16). Tau measures included PET MK‐6240 regional entorhinal cortex and hippocampal SUVR (n = 321). Neurodegeneration measures included MRI hippocampal volume and global brain atrophy (GBA; n = 581). Plasma measures included pTau217 (n = 166). Posterior median estimate person‐level CPs, slopes pre‐ and post‐CP, and intercepts at CP for PACC3 were extracted from Bayesian random CP mixed models (BRCPMM; age = time scale) and used to characterize cognitive trajectory profiles (K‐means clustering). We compared demographic, last visit cognitive statuses (cognitively unimpaired‐stable (CU‐S), CU‐declining (CU‐D), and MCI/Dementia), amyloid, tau, neurodegenerations and plasma measures across the cognitive trajectory profiles using analysis of variance, chi‐square and Fisher’s exact tests. Significant omnibus tests (p<.05) were followed with pairwise comparisons.ResultMean(sd) last cognitive assessment age was 66.6(6.6) years; PiB, MK, MRI scans and plasma occurred within mean(sd) 1.1(2.7), 1.6(1.4), .6(3) and .09(.7) years of cognitive assessment. Cluster analysis identified 3 groups of performance patterns representing highest to lowest risk of cognitive decline (high: n = 77(7.2%); intermediate: n = 446(41.8%); and low: n = 545(51.0%); Figure 1 & 2). The high risk group was older, had more females, APOE e4 carriers, and MCI/Dementia at last visit (Table 1). The high risk group also had worse PiB‐amyloid, MK‐tau, pTau217, and MRI‐neurogeneration levels than the lower risk groups (Table2; Figure 3).ConclusionIn this initially non‐demented sample, differences between cognitive clusters across multiple biomarkers and AD risk factors indicate that within‐person PACC3 performance patterns are sensitive to preclinical change. Identifying cognitive trajectory profiles may provide an opportunity for early intervention for high‐risk subjects at the right time for treatment and/or enrollment in a clinical trial.
Caregiving Burdens in Aphasic Dementia and the Relationship to Communication Challenges
Authors: Roberts Angela C , Santos Haylie N , Gill Nathan Pruneau , Zhang Hui , Rogalski Emily J. 
Published: December 2022

AbstractBackgroundPrimary progressive aphasia (PPA) is a clinical dementia syndrome. Impairments in language are the primary and persistent symptom, and severely limit participation in everyday activities and family conversations. PPA is also associated with high caregiving burden. Few studies have examined the relationship between conversation difficulties and caregiving burdens. We tested the hypothesis that the severity of care partner (CP) perceived conversation difficulties predicts caregiving burdens.MethodA mediation analysis focusing on the Baron‐Kenny approach was conducted using baseline data from 78 CPs (62% female) enrolled in the Communication BridgeTM‐2 randomized control trial of a speech‐language intervention for mild to moderate PPA. Measures included the Conversation Difficulties subscale of the Perception of Conversation Index‐Dementia Alzheimer’s Type (PCI‐DAT) and the subscales of Montgomery Burden Interview (MBI), namely objective burden subscale (perceived infringement on tangible aspects of life), subjective demand subscale (perception that the dependent person is overly demanding), and subjective stress subscale (perception of emotional impact). Higher ratings indicate higher burden and greater conversation difficulties.ResultCPs had a mean age of 64.5 years (SD = 10.76), education level of 16.2 years (SD = 2.77), and a relationship duration with the PPA participant of 38.6 years (SD = 15.29). Eighty‐six percent were spouses, 5% were adult children, and 9% were friends or siblings. CPs endorsed a broad range of burden severity with a mean objective burden score of 9.29/30 (Range = 6 to 26; SD = 4.01), subjective demand burden score of 5.81/15 (Range = 5 to 12; SD = 1.41), and subjective stress burden score of 8.43/20 (Range = 5 to 16; SD = 2.72) as well as a range of perceive conversation difficulties (M = 42.34/154, Range = 6 to 105, SD = 22.88). Higher conversation difficulties were associated with higher ratings of caregiving burden for objective burden (p < 0.001) and subjective stress burden (p = 0.010). Significant mediating variables included activities of daily living and CP depression scores.ConclusionThe current study shows an association between both subjective and objective caregiving burden and conversation difficulties. Given this relationship, it will be important to determine whether interventions that successfully address conversation difficulties may also decrease caregiving burden.
Clinical utility of plasma biomarkers to identify preclinical Alzheimer’s disease in the community
Authors: Lage‐Martinez Carmen , López‐García Sara , Martínez María García , Martínez‐Dubarbie Francisco , Pozueta Ana , Arroyo Juan Martin , Pardo Andrea Corrales , Irure‐Ventura Juan , Rodríguez Eloy Rodríguez , Sanchez‐Juan Pascual 
Published: December 2022

AbstractBackgroundSeveral plasma biomarkers have shown good correlation with brain amyloidosis measured by CSF biomarkers and PET, but their utility to identify subjects with Alzheimer’s disease(AD) brain pathology at the community level is not well known. Neuropsychological tests might be a more accessible alternative.MethodOur aims were to assess the utility of plasma p‐tau231, plasma GFAP, and plasma NFL to identify individuals with preclinical AD, and to compare it with the utility of current neuropsychological tests for early AD detection: Preclinical Alzheimer's Cognitive Composite 5(PACC5), Spanish version of Face‐Name Memory Exam(S‐FNAME), Logical Memory Test (LMT‐WMSIII), and Free and Cued Selective Reminding Test(FCSRT). Our study population was a community‐based cohort that enrolls individuals older than 55 living in Cantabria, a region in northern Spain. Exclusion criteria include a diagnosis of dementia or other cognitive disorders. AD+ status was defined by abnormal levels of both CSF amyloid‐β1‐42/1‐40 ratio and CSF p‐tau181. General linear models were used to compare biomarker and cognitive results between AD+ subjects and the rest of the population, with age and sex as covariates. ROC curves were built to compare the utility of each test to identify AD+ cases.ResultThe total sample included 156 individuals, 30 of them AD+. AD+ subjects showed significantly higher levels of GFAP (mean difference 78.04, p<0.00001) and p‐tau231 (mean difference 5.53, p 0.00040), but not NFL (mean difference 1.16, p 0.63), compared to non‐AD (table 1). After adjusting by age, sex, APOE4 carrier status, and AD status, age and sex were still independent predictors of GFAP levels, but not of p‐tau231 (table 2). FCSRT delayed recall and LMT‐WMSIII total score were significantly lower in AD+ than in non‐AD cases, but not S‐FNAME nor PACC5 (table 1). Both plasma GFAP and p‐tau231 showed an AUC of 0.75 to identify AD+ individuals (table 3, figure 1). Neuropsychological tests obtained non‐significantly smaller AUC than plasma biomarkers.ConclusionIn our community‐based population, plasma GFAP and p‐tau231 were useful to identify individuals with preclinical AD, but not plasma NFL. Although probably with a lower performance, early detection cognitive tests may also be helpful to identify AD cases in the community.
Alzheimer’s Disease modeling using hiPSC neurons and microglia
Authors: Gordon Kara L. , Rines Christine G. , Handley Cherie , Basa Ranor C. B. , Price Jeffrey H. , McDonough Patrick M. 
Published: December 2022

AbstractBackgroundNeuroinflammation is an important topic in neurodegenerative disease research. Scientists have established multiple protocols for differentiating microglia, neurons, and astrocytes from human iPSCs, which enable the study of neuroinflammation in vitro. Here we describe the use of Vala Sciences’ imaging platform, the IC200 Kinetic Image CytometerTM (KIC), to develop screening assays for Alzheimer’s Disease (AD) in cultures with hiPSC‐derived microglia and neurons.MethodWe cultured iCell Glutaneurons with microglia in 384‐well dishes. To detect microglia phagocytosis, we cultured microglia with pHrodo‐Red Zymosan beads or β‐amyloid fragments and then acquired timelapse videos over 5‐24 hours. To measure neuronal activity, we loaded cells with Rhod‐4 calcium dye and imaged at 4fps. We also fixed and immunolabeled cells for neurite and synapse analysis. All assays were scanned using the IC200 KIC. We developed algorithms for our CyteSeer image analysis software to automate neurite tracing, synapse detection, analysis of calcium activity, and microglia phagocytosis and morphology for single cells in a co‐culture system.ResultIn microglia, we demonstrated an increase in uptake of pHrodo‐Red labeled Zymosan beads with increasing concentration of Zymosan particles and in response to IL‐4. We also demonstrated differential engulfment of β‐amyloid 1‐40 and β‐amyloid 1‐42 by microglia. While investigating the effects of microglia on neuronal health, we observed increased neuronal survival, neurite outgrowth, and pre‐synapse count in glutamatergic neurons co‐cultured with microglia when compared to glutamatergic neurons cultured alone. In neuron‐microglia co‐cultures exposed to increasing doses of β‐amyloid 1‐42 fragments, we observed neuronal hyperactivity (increased calcium event frequency), which may reflect disease‐associated stress.ConclusionOur data demonstrate that healthy microglia regulate neuronal heath. Our system can serve as a model for testing inflammatory insults related to AD. To further our research with genetic variants with AD susceptibility, we have created an isogeneic panel of ApoE variants using CRISPR‐Cas9, and plan to characterize them in the culture systems developed above to validate a disease model from these lines.
Electrophysiological markers of early Alzheimer’s Disease proteinopathy in the human brain
Authors: Rudolf Jonathan E Gallego , Wiesman Alex I , Binette Alexa Pichet , Villeneuve Sylvia , Baillet Sylvain 
Published: December 2022

AbstractBackgroundAlzheimer's Disease (AD) is characterized by the pathological accumulation of amyloid‐beta (Aβ) and hyperphosphorylated tau proteins in the brain. Animal models have demonstrated that early Aβ accumulation induces neuronal hyperexcitability (Stargardt et al., 2015), whereas later additive effects of Aβ and tau lead to suppression of neuronal activity that parallels disease severity (Busche et al., 2020). Although neural hypo‐excitability has been reported in the later stages of AD, it remains unknow if such a shift from hyper‐ to hypo‐excitability exists at the macroscopic level in the human brain of asymptomatic individuals (Figure 1).MethodsWe used Positron Emission Tomography to measure the deposition of whole‐brain Aβ ([18F] NAV4694) and medial temporal tau ([18F] Flortaucipir) and resting‐state Magnetoencephalography (MEG) to capture the neurophysiological changes related to AD pathology in a group of clinically unimpaired older adults with family history of AD (PREVENT‐AD cohort; McSweeney et al., 2020). We used linear mixed effects models to test the association between MEG spectral power and Aβ across cortical regions, and the interactive effect of tau accumulation on this relationship. We then used linear regressions to test if the observed associations between MEG spectral power and AD pathology related to longitudinal cognitive performance, evaluated annually using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).ResultsAβ deposition was associated with neural hyper‐activity, as reflected by a positive association between Aβ SUVR values and MEG spectral power in higher frequencies (alpha [8 ‐ 12 Hz]) and a negative association in slow frequencies (delta [2 – 4 Hz]; Figure 2). The accumulation of medial temporal tau predicted a shift in these associations towards a hypo‐activation pattern (increased neural slowing), which was related to longitudinal decreases in attention scores (Figure 3).ConclusionOur results support the hypothesis that Aβ induces neural hyper‐activity in asymptomatic individuals, while the additive effects of Aβ and tau accumulation lead to a shift towards neural slowing that relates to cognitive deficits. These early detectable electrophysiological changes may represent novel non‐invasive biomarkers of the preclinical stages of AD and may potentially help predicting cognitive trajectories and disease progression in the AD continuum.
Comparison of lipidomic profiling and spatial distribution in brain of a genetic mouse model of Alzheimer’s disease using DESI Imaging Mass Spectrometry: regional lipid dyshomeostasis in AD.
Authors: Lazarian Artur , Costa Ana Paula , Fowler Brandon , Zandkarimi Fereshteh , McIntire Laura Beth 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is one of the biggest health challenges worldwide. It is culpable for millions of deaths annually, the annual associated costs reach many billions, and these trends are expected to increase dramatically over the next decades. Yet, the underlying cause of AD is not yet understood and therefore no effective treatment is available to date.Lipidomic data from autopsy brain, human plasma and animal models highlight severe lipid dyshomeostasis in AD. Specifically, previous studies have shown that the loss of polyunsaturated fatty acids among multiple phospholipid classes is common in AD affected human brain and mouse models. Thus, the disruption of lipid metabolism and the homeostasis are thought to play a crucial role in the development of AD pathology. It is likely then, that specific pathways in lipid metabolism underlie AD disease mechanisms leading to clinical impairment.Therefore, in order to understand the full etiology and progression of disease, it is critical to identify specific and regionally dysregulated lipid species in both healthy and AD affected brain tissues.MethodIn order to interrogate differences in the lipid species between brains from WT and a genetic mouse model of AD across aging, DESI Imaging Mass Spectrometry (IMS) was used to detect regional composition of brain tissue with the Synapt G2‐Si (Waters). We have successfully developed a workflow for quantitative and qualitative lipidomics profiling for mouse brains by using 10µm coronal‐cut brain slices at 60µm resolution.ResultIn this study, we compared the brains of WT and AD mice of different ages, namely 8, 12 and 22 years old. By applying DESI IMS, we have shown regional dysregulation of specific lipid species in different brain areas including specific early changes in the hypothalamus region of the mouse brain.ConclusionWe have shown that certain ions, such as m/z 327.233 which corresponds with the polyunsaturated fatty acid DHA, is highly abundant in the putative hypothalamus region of AD mouse brains of various ages compared to that of the wild type. This suggests early and persistent dysregulation of polyunsaturated lipid content associated with genetic drivers of AD in a mouse model.
Bacillus Calmette‐Guérin (BCG) treatment of bladder cancer protects against Alzheimer’s Disease in older adults: The Massachusetts General Brigham cohort
Authors: Weinberg Marc S. , Magdamo Colin G. , Zafar Affan , Chung Sunny , Arnold Steven E. , Das Sudeshna 
Published: December 2022

AbstractBackgroundRetraining the immune system offers a potential means of preventing or treating Alzheimer’s disease (AD). Vaccines can confer non‐specific beneficial effects (NSBEs), impacting diseases far afield from the original target. The Bacillus Calmette‐Guérin (BCG) vaccine, used worldwide in the prevention of tuberculosis, causes NSBE on non‐TB respiratory infections, type 1 diabetes, and multiple sclerosis. BCG is the gold‐standard therapy for non–muscle‐invasive bladder cancer. Recently, several retrospective studies have associated intravesicular BCG treatment of bladder cancer with lowered risk of AD (Gofrit et al., 2019, Klinger et al., 2021, Kim et al., 2021). We sought to replicate the retrospective study in a large cohort of patients in the Massachusetts General Brigham (MGB) System.MethodWe retrieved 30y of electronic health records from MGB, consisting of 17,920 subjects with new bladder cancer diagnoses. We limited records to patients aged >50y, without a previous dementia diagnosis, and with at least one year MGB follow‐up after diagnosis. Using natural language processing (NLP), we identified and assigned pathological stages to each patient’s first transurethral resection of bladder tumor (TURBT) surgical pathology report. The study population consisted of non‐muscle‐invasive bladder cancer (NMIBC) patients (n = 6467). The intervention group was patients who had any exposure to intravesical BCG, determined by semiautomated methods using NLP and manual validation. The control group was NMIBC patients without exposure to intravesical BCG.ResultWe found a protective effect of BCG on the risk of dementia. Cox analysis of time to AD: HR 0.84, CI (0.7‐0.99), p = 0.049, age and sex‐adjusted. In a stratified analysis by age, the effect of BCG treatment on patients 70 or older was more pronounced (HR 0.77, CI 0.63‐0.95, p = 0.017), whereas there was no effect on patients younger than 70 (HR 0.98, CI 0.72 ‐ 1.36, p = 0.98).ConclusionFindings from our large retrospective study suggest an overall protective effect of BCG treatment on the subsequent incidence of Alzheimer’s Disease, with the effect largely drawing from patients 70yo or older. Further survival and competing risk analyses will be provided to contextualize the basis for these apparently beneficial effects of BCG.
Plasma pTau markers correlate with an imaging surrogate marker of hyperphosphorylation in mouse models of Alzheimers disease
Authors: Parekh Parag A , Badachhape Andrew , Menon Renuka , Bhavane Rohan , Srivastava Mayank , Bhandari Prajwal , Devkota Laxman , Sun Xianwei , Tanifum Eric , Ghaghada Ketan , Devaraj Sridevi , Annapragada Ananth 
Published: December 2022

AbstractBackgroundWe previously reported Cell surface vimentin (CSV) as a surrogate marker for cells in a hyperphosphorylative state, leading to pathological tau deposits in mouse models. Here were investigate the correlation between a Magnetic Resonance Imaging (MRI) marker of CSV and changes in the plasma pTau biomarkers at early stages of tau pathology. We studied total tau, ptau181 and ptau 231 in the plasma of mice at 2 and 5months of age prior to the formation of frank pathology, and with emerging pathology respectively, and compared them to the signal from the MRI marker of CSV.MethodTransgenic P301S and APP/PSEN1 mice and their wild‐type littermates were injected intravenously with liposomal nanoparticles bearing small molecule Withaferin (WNP) as a targeting ligand, and Gd/DOTA as an MRI readout, at 2‐ and 5‐ months of age. Animals (n=10 each) underwent magnetic resonance imaging (MRI) using T1 weighted sequences to visualize brain localization of CSV‐targeted liposomes. Blood was collected in EDTA tubes by puncture of facial vein post‐MRI scan. Plasma samples were centrifuged at 1000xg for 10mins at 4⁰C within 30mins of collection and stored at ‐80⁰C. Plasma concentrations of tau species were measured using the multiplex xMAP Luminex platform with kit‐based reagents, Milliplex for ptau181, total tau and Procartaplex for ptau231.ResultMRI signal enhancement was observed in 2‐month old transgenic mice but not in WT mice in both P301S and APP/PSEN1 AD models. Concurrently, we observed higher expression of ptau 181 in the TG mice over WT littermates. Similar results were also observed in the 5‐month old mice.ConclusionMRI with CSV targeted nanoparticles demonstrates brain signal that correlates with pTau181, consistent with the cell surface marker of hyperphosphorylation marking the same process that results in hyperphosphorylated tau species being formed in the transgenic mice. The results strengthen the mechanistic basis of a cell‐surface vimentin targeted agent being a suitable marker of very early‐stage development of tau pathology and furthermore demonstrates localization of the pathology. The use of readily available and relatively inexpensive MRI for this purpose has huge advantages over existing methods for the identification of early stage tau pathology.