bluuebunny/crossref_metadata_2025_split huggingface dataset:
Choroid plexus protein turnover in human choroid plexus organoids recapitulates turnover in humans measured using stable isotope labeling kinetics (SILK)
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Moncur Eleanor , Tariq Kanza , Thorne Lewis , Watkins Laurence , Toma Ahmed , Fox Nick C , Bateman Randall J. , Mills Kevin , Pellegrini Laura , Paterson Ross W. 
Published: December 2023

AbstractBackgroundThe choroid plexus secretes protein‐rich cerebrospinal fluid (CSF). CSF turnover is a key mechanism for protein clearance. Neurodegenerative diseases such as AD are characterised by accumulation of excess proteins that form pathological inclusions. CSF flow dysregulation could therefore be involved in the pathophysiology of neurodegenerative diseases (ND) such as Alzheimer’s Disease. A method for measuring CSF turnover in vivo may be achieved by quantitating CSF derived protein kinetics, providing a biomarker tool with to interrogate the relationship between CSF flow disequilibrium and neurodegeneration.MethodUsing untargeted proteomics we identify the most abundant proteins in a) stem‐cell derived choroid plexus organoids and b) human CSF. We then develop targeted mass spectrometry methods to quantitate protein specific peptides in both matrices. Using a stable isotope (13C6 leucine) we label a) choroid plexus organoids and b) humans with suspected NPH undergoing a 72 hour lumbar drainage protocol. We collect serial samples of the CSF‐like organoid fluid and CSF. We then measure the ratio of labelled to unlabelled peptides to quantitate the rates of protein labelling (fractional synthesis rate) and label loss (fractional clearance rate), defining the protein turnover rate.ResultHighly‐expressed proteins in human CSF from nine individuals were also present in CSF‐like fluid from CP organoids. Of these common proteins, we were able to quantitate the turnover rates of transthyretin, apolipoprotein E, cystatin C and pigment epithelium‐derived factor, and the synthesis rates of serotransferrin and albumin. We will correlate these findings with clinical measures of CSF production.ConclusionChoroid plexus protein synthesis and clearance can be measured using SILK; choroid plexus organoid fluid protein turnover recapitulates that seen in human CSF.
Plasma IL‐6 levels are Negatively Associated with MRI‐Based Water Exchange Rate Across the Blood‐Brain Barrier
Authors: Pappas Colleen , Zachariou Valentinos , Bauer Christopher E. , Sudduth Tiffany L , Wilcock Donna M. , Shao Xingfeng , Wang Danny J.J. , Gold Brian T. 
Published: December 2023

AbstractBackgroundChanges in blood‐brain barrier (BBB) integrity are associated with cognitive decline in aging. Inflammatory processes are thought to contribute to BBB dysfunction but this link has been difficult to measure in humans using non‐invasive, in‐vivo methods. Recently, a novel magnetic resonance imaging (MRI) technique, diffusion‐prepared arterial spin labeling (DP‐ASL), has been shown to provide a means to test the water exchange rate across the BBB (kw) as well as arterial transit time (ATT) and cerebral blood flow (CBF). Here, we tested the association between these DP‐ASL measures and a specific plasma marker of inflammation, IL‐6, in older adults without dementia.MethodWe tested the association between kw, ATT, and CBF and a marker of peripheral inflammation in a sample of 58 older adults without dementia. Regions of interest (ROIs) included the putamen, caudate, and pallidum. Plasma IL‐6 levels were assessed using Simoa assays. IL‐6 was natural log transformed and data collected ≤ 1 year from the MRI visit were used for subsequent analyses. Multiple linear regression models, controlling for age, sex, and ROI size, tested the impact of plasma IL‐6 on kw, ATT, and CBF metrics. Both linear and quadratic effects of IL‐6 on the outcomes of interest were examined.ResultThere was a negative linear association between IL‐6 and kw in the putamen. As plasma IL‐6 levels increased, kw values decreased. In contrast, no relationships were observed between plasma IL‐6 and ATT or CBF in any of the ROIs tested.ConclusionOur results suggest that the water exchange rate across the BBB in the putamen was most uniquely associated with the peripheral proinflammatory cytokine, IL‐6. These findings could be indicative of the involvement of peripheral inflammation in reducing glymphatic clearance which would manifest as reduced water exchange rate across the BBB. The lack of association with ATT and CBF suggest that peripheral cytokines could act on a mechanism more closely related to water channel function rather than overall brain perfusion.
Serine‐129 phosphorylation of α‐synuclein is a trigger for physiologic protein‐protein interactions and synaptic function
Authors: Parra‐Rivas Leonardo A , Madhivanan Kayalvizhi , Wang Lina , Boyer Nicholas P , Prakashchand Dube D , Aulston Brent D , Branes‐Guerrero Kristen , Rangamani Padmini , Roy Subhojit 
Published: December 2023

AbstractBackgroundα‐Synuclein (α‐syn) phosphorylation at the Serine‐129 (Ser129P) residue is a recognized pathologic hallmark of PD. Though only ∼4% of α‐syn is phosphorylated at this site under normal conditions, the tight endogenous regulation of α‐syn Ser129P suggests a physiologic role.MethodWe have use immunocytochemistry in cultured hippocampal neurons and immunohistochemistry in mouse brains to localize α‐syn Ser‐129P, optical pHluorin assays to report SV‐recycling and trafficking, multielectrode arrays (MEA) to examine neurotransmitter release, immunoprecitations and GST Pulldown assays to evaluate protein‐protein interactions, and AlphaFold2‐driven modeling to visualize how Ser129P induces conformational changes.ResultWe found that unlike native (total) α‐syn that is widely expressed throughout the brain, the overall pattern of α‐syn Ser129P is restricted, suggesting intrinsic regulation and putative physiologic roles. Surprisingly, preventing phosphorylation at the Ser‐129 site blocked the ability of α‐syn to attenuate activity‐dependent synaptic vesicle (SV) recycling – widely thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments α‐syn Ser‐129P, and this phosphorylation is required for α‐syn binding to VAMP2 and synapsin – two functional binding‐partners that are necessary for α‐syn function. AlphaFold2‐driven modeling suggests a scenario where Ser129P induces conformational changes in the C‐terminus that stabilizes this region and facilitates protein‐protein interactions.ConclusionOur data from cellular, in vivo, cell‐free systems, and molecular simulations strongly suggest that the pathology‐ associated Ser129 modification has a physiologic role at the synapse, which has broad implications for α‐syn pathophysiology and drug development.
Plasma biomarkers, memory impairment, and imaging measures of Alzheimer’s disease in American Indians
Authors: Suchy‐Dicey Astrid M , Rhoads Kristoffer , Longstreth W.T. , Umans Jason G , Blennow Kaj , Buchwald Dedra , Grabowski Thomas J , Reiman Eric M. , Zetterberg Henrik 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is best defined in vivo using quantifiable, objective markers reflecting amyloid deposition (A), pathologic tau (T), and neurodegeneration (N). However, gold standards for ATN (imaging or cerebrospinal proteins) are expensive, invasive, and/or impractical in low resource settings. Circulating proteins offer a practical alternative. Candidate plasma markers include amyloid‐β (Aβ40&42), phosphorylated tau‐181 (ptau), glial fibrillary protein (GFAP), and neurofilament light chain (NfL). However, no such markers have been evaluated in American Indians.MethodThe Strong Heart Study recruited 401 American Indians over 3 states in 2017‐2019 for MRI, cognitive testing, and clinical examination. MRI included T1 sequences, which were processed using FreeSurfer to quantify structural volumes. Neuropsychological testing incuded California Verbal Learning Test, which was operationalized into categories of memory impairment using indices of learning and recall. Plasma samples were sent to University of Gothenburg for Simoa Quanterix assay. Statistics included descriptive summary; multivariate regression; and receiver operating characteristic analysis.ResultThe study population was mean age 78 (SD 4.7, range 70‐95); majority female (71%); and 21% APOE ε4 allele carriers. An estimated 31% had any memory impairment (13.8% retrieval, 6.5% storage, 10.7% encoding). Median plasma marker values were: ptau 5.0pg/mL (range: 1.5‐442), Aβ40 128pg/mL (116‐175), Aβ42 8.2pg/mL (6.7‐9.7), GFAP 150pg/mL (0‐651), and NfL 31.6pg/mL (9.7‐343); median Aβ42:40 ratio 0.06. Comparing APOEε4 carriers to non‐carriers (Table1), ptau was +12%, Aβ40 ‐0.8%, Aβ42 ‐8.4%, Aβ4240 ‐16.7% (P = 0.006), GFAP +16.1%, NfL +3.2%, but only Aβ4240 was significant. Linear regressions with brain volumes identified significant associations for Aβ42, Aβ40, GFAP, and NfL (but not ptau) with ventricle, cortical, and overall volume; NfL was also associated with entorhinal and hippocampal volume. GFAP and ptau were significantly higher in those with memory encoding deficit; NfL higher with encoding or retrieval deficit (Table2). Although not significant, Aβ40 was lower with storage deficit, and Aβ42 with encoding or storage deficit. AUC range for plasma markers to discriminate memory impaired from intact: 0.4‐0.6.ConclusionThese data are a first look at ATN plasma markers in a population‐based cohort of American Indians, an underrepresented group in AD research. Future research should address generalizability and measurement validity.
Associations of Neighborhood Gentrification Status and Cognitive Decline in the Health and Retirement Study
Authors: Sims Kendra D , Willis Mary D , Bibbins‐Domingo Kirsten , Eng Chloe W. , Glymour M. Maria 
Published: December 2023

AbstractBackgroundGentrification, characterized by in‐migration of high socioeconomic (SES) residents into formerly disinvested neighborhoods, may impair late‐life cognitive function of existing residents. We hypothesized that disinvestment of neighborhood economic resources and reinvestment via gentrification both increase risk of cognitive decline among marginalized older adults.MethodWe analyzed 17,613 Health and Retirement Study participants (aged 51‐101), 67% Non‐Hispanic White) with data on our outcomes of interest: biennial scores on immediate and delayed word recall batteries (2010‐2016). With 2000 Census data, we operationalized census tract disinvestment based on disproportionately high proportions of minority residents, low SES, and renters for the corresponding county. We defined gentrification among disinvested tracts as greater than county‐median increases in White and college‐educated residents, household income, and housing costs between the 2000 Census and 2008‐2012 American Community Survey. We fit linear mixed models to evaluate associations of gentrification with cognitive level and change. We also evaluated racial‐ethnic differences in cognitive function by residence in tracts that were 1) not disinvested in 2000, 2) remained disinvested, or 3) gentrified by 2012. All models were adjusted by individual‐level age, gender, race‐ethnicity, educational attainment, marital status, home ownership, health insurance coverage, and memory score practice effects.Result56% of participants lived tracts that were disinvested in 2000; by 2012, 34% of disinvested tracts gentrified. Baseline memory performance was worse in invested (e.g., mean immediate = 4.9) than in initially disinvested tracts that either gentrified (mean = 5.3) or remained disinvested (mean = 5.4) (p<0.02 for test of mean differences). Neighborhood disinvestment from 2000‐2012 compared to investment in 2000 was associated with better 6‐year immediate recall trajectories among White participants (β; 95% CI: 0.18; 0.01, 0.39) but not among their Hispanic/Latino counterparts (‐0.14; ‐0.29, ‐0.01; p‐value for interaction compared to White participants = 0.04). We observed similar patterns for delayed recall (p‐value for interaction comparing Hispanic/Latino to White participants = 0.05). Neighborhood disinvestment or gentrification was not associated with recall trajectories among Black participants.ConclusionDifferential findings by race in this nationally representative sample indicate that disinvestment and gentrification do not equally impact older adult cognitive health.
Herpes Simplex Virus‐1 Proteins Drive Alzheimer’s Disease Pathologies in Humans
Authors: Shemesh Or A. , Hyde Vanesa , Chattarjee Krishnashish , Zhou Chaoming , Fisher Greg , Pururav  , Lin Amanda , Caldwell Jill , D'Aiuto Leonardo 
Published: December 2023

AbstractBackgroundDNA and RNA of Herpes Simplex Virus 1 (HSV‐1) were found in the brains and serological samples of Alzheimer’s disease (AD) patients. Such molecular presence of HSV‐1 in AD patients is especially intriguing as HSV‐1 virions are rarely detected in AD brains.MethodsTo follow the molecular footsteps detected, we imaged viral proteins in postmortem human AD brains at superior resolution using expansion microscopy, a tissue manipulation method that physically expands the samples by a factor of 4.5x, allowing a 40 nm imaging resolution, and immunolabeled herpetic proteins, AD pathologies and cell markers.ResultsWe found an abundance of herpetic proteins, previously undetectable with standard methods, across large brain areas. Importantly, we found that HSV‐1 proteins strongly co‐localized with AD pathologies. Consequently, we hypothesized that expression of HSV‐1 proteins during latency may be linked to AD pathology. We are now in the process of characterizing the HSV‐1 proteome in AD brains by imaging key proteins in expanded AD brain slices and examining their colocalization with AD pathologies across brain areas and disease stages. As a complementary system to the fixed human brain slices, we introduced HSV‐1 in human derived brain organoids and imaged the relationships between viral proteins and the formation of AD pathologies via expansion microscopy. We found that HSV‐1 infection triggered these pathologies, pointing out that viruses may be triggers of immune responses driving AD.Conclusionsthis study sheds light on one common pathogen, HSV‐1, while serving as a framework to unveiling molecular causation between infectious agents and AD hallmarks.
Modifiers of Individual Differences and Within‐person Changes in the Aging White Matter
Authors: Burzynska Agnieszka Z 
Published: December 2023

AbstractMy talk will focus on: 1) longitudinal changes and plasticity, and 2) lifestyle and health modifiers of white matter (WM) health in aging.First, individual differences in changes in WM microstructure may be key for identifying preclinical stages of dementia, opening new opportunities for early interventions. I will present the outcomes from a meta‐analysis and systematic review (Colmenares et al., in preparation) based on 28 diffusion tensor imaging (DTI) studies in healthy adults from the past 10 years, addressing the following questions: Over what time periods can decline in WM microstructure be detected using MRI? Do within‐person changes accelerate with age and vary by brain region? What are the modifiers of within‐person changes in WM? Also, for decades, adult WM has been perceived as a “passive” (i.e., only relaying electrical signals) and “static” (i.e., not capable of or involved in neuroplasticity). Despite emerging evidence in rodents on short‐term structural WM changes, evidence for such experience‐induced plasticity in adult humans remains inconclusive. Thus, I summarize evidence from clinical studies to discuss whether the adult WM microstructure is malleable with experience, and what interventions may be the most promising in inducing a change. I will also present our findings on exercise‐induced WM plasticity in older age, using DTI and T1/T2 ratio imaging (Colmenares et al., 2021, Burzynska et al., 2017).Second, lack of physical activity (PA) and sedentary lifestyles are independently associated with increased risk of metabolic and cardiovascular diseases, mortality, and ADRD. Regular PA decreases inflammation and improves vascular function and perfusion. In contrast, insufficient PA and/or excessive sedentary behaviors is known to upregulate markers of metabolic stress and inflammation. I will briefly review our past work relating sensor‐measured PA with WM health, measured with DTI. Then, I will present our ongoing work using quantitative MRI, such as Myelin Water Imaging and Neurite Orientation Dispersion and Density Imaging. For example, I will present associations between systemic health (i.e., BMI, waist circumference, blood pressure, blood glucose and cholesterol), sensor‐measured physical activity (i.e., time spend sedentary and in light, moderate or vigorous physical activity), and myelin and axonal content in healthy adults.
Sex differences in functional network topological measures in the APP‐PS1 mouse model of amyloidosis
Authors: Simon Zachary D , Chakrabarty Paramita , Febo Marcelo 
Published: December 2023

AbstractBackgroundIncreased amyloid beta (Aβ) plaque deposition is linked to synaptic communication deficits in Alzheimer’s disease (AD). Functional deficits observed at the synaptic level are thought to alter neural communication across regions playing roles in cognition and affect. There is also growing evidence of a greater risk of AD in women, but the extent to which this involves differential responses to amyloidosis remains to be investigated. We tested the hypothesis that amyloid deposition alters functional network topology.MethodMale and female mice (9‐month‐old) harboring human mutation amyloid precursor protein (Swedish APP KM670/671NL) and presenilin‐1 (PS1) (the APP‐PS1 [line 85] mouse) (Tg) and wildtype littermate controls (nTg) were tested on 3 consecutive days on a fear conditioning paradigm. On day 1, mice received training for 15 minutes using a series of 4 trials in the presence of an unconditioned stimulus (US) foot shock (0.90mA, 1 second) following a 20‐second conditioned stimulus (CS) tone (60dB). On day 2, mice received CS but not US in a ‘recall’ session. On day 3 the recall session was repeated with contextual cues modified. Following conditioning, mice were scanned on an 11.1 Tesla scanner under combined dexmedetomidine/isoflurane sedation using single shot echo planar images with echo time of 15 ms and repetition time of 1.5 seconds (600 total repetitions; 0.3mm2 in plane resolution, 0.7 mm slice thickness n = 17 slices). Images were processed and analyzed using nodes created on the common coordinate framework mouse atlas (version 3) and graph theory algorithms in brain connectivity toolbox.ResultAll mice developed robust CS freezing behavior, expressed during both recall sessions. Freezing behavior did not differ between Tg vs. nTg male and female mice. However, we observed significant differences in several measures of functional connectivity in APP‐PS1 mice that were driven by effects of amyloid in female mice. Compared to sex‐matched controls, female Tg mice had lower clustering, assortativity and node strength. These differences were not observed in Tg vs nTg males.ConclusionThe results suggest that amyloid plaque burden reduces integration of neural activity (as measured by low clustering and assortativity) in female but not male APP‐PS1 mice.
Sleep breathing patterns and neurocognitive function in a diverse Hispanic/Latino cohort
Authors: González Kevin A , Tarraf Wassim , Kosik Eena , Guarian Kenton , Voytek Bradley , González Hector M , Ramos Alberto R 
Published: December 2023

AbstractBackgroundSleep disorders are common in patients with Alzheimer’s Disease (AD). Obstructive sleep apnea (OSA), characterized by intermittent cessation of breathing and hypoxemia, has been associated with increased risk of AD and worse cognitive function. However, the interacting effects of neurocognitive function with sleep breathing patterns, independent of the apnea‐hypopnea index, (a measure of OSA severity) have not been carefully studied. We use a novel approach to analyzing home sleep apnea data to examine breathing patterns and their relationships with neurocognitive function.MethodThe Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective multicenter study of diverse Latinos. Around 16,000 diverse Hispanic/Latinos were recruited from four major metropolitan cities. Participants used an ARES unirecorder device for a single night of unsupervised at home recording. We used python package “bycycle” to cannula data (sampled at 10Hz). Bycycle uses a time domain approach to parameterizing rhythmic time‐series data. We extracted breathing rate (breaths per minute), breathing variability (interquartile range of breathing rate) and time spent in inhalation phase (percent time). Participants ages ≥45 (unweighted n = 5,957) were tested in their preferred language using a brief battery including: B‐SEVLT (3‐trials sum) and Delayed Recall (memory), World Fluency (verbal fluency), and Digit Symbol Substitution (executive function). Covariates used in our models are described in Table 1. All presented estimates were weighted for appropriate generalization to the HCHS/SOL target population.ResultIn unadjusted models, all breathing measures were negatively associated with cognitive function, but only breathing rate remained significant after full covariate adjustment (Figure 1). We found significant interactions between breathing rate and sex, as well as age for verbal fluency models. Being female and older age were associated with steeper slopes of cognitive under‐performance for both breathing rate and breathing variability (Figure 2).ConclusionThese results suggest that breathing patterns outside apneas‐hypopneas may be as critical in understanding sleep related changes and cognitive function in an aging population. Given cessation of breathing during an apnea‐hypopnea event, breathing variability may add more precision to account for varying oxygen demands. Further studies should examine whether breathing instability is also associated with cognitive decline, impairment, and dementia.