bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of life‐course traumatic brain injury with the risk of dementia: a nationwide twin study
Authors: Zhang Lulu , Yang Wenzhe , Li Xuerui , Dove Abigail , Qi Xiuying , Xu Weili 
Published: December 2021

AbstractBackgroundTraumatic brain injury (TBI) has been related to dementia, but the impact of life‐course TBI on dementia remains unclear. We aimed to examine the association between lifespan TBI and dementia, and to explore whether genetic and early‐life environmental factors contribute to this association.MethodWithin the Swedish Twin Registry,35,312 dementia‐free twins (mean age 62.78 years) were followed for up to 18 years.Life‐course TBI was assessed based on information from the SwedishNational Patient Registry (NPR) and participants were divided into five groups according to age at TBI occurrence (≤39, 40‐49, 50‐59, 60‐69, and ≥70 years). Dementia and cardiovascular disease (CVD, including heart disease and stroke) diagnoses were ascertained based on medical records in the NPR and the SwedishCause of Death Register. Data were analyzed using generalized estimating equation (GEE) and conditional logistic regression.ResultIn multi‐adjustedGEE model, the odds ratios (ORs, 95% confidence intervals [CIs]) of dementia were 1.29 (1.05–1.60) for TBI at any age, 1.01 (0.54–1.89)for TBI at ≤39 years, 1.11 (0.65–1.88) for TBI at 40‐49 years, 1.66 (1.13–2.45) for TBI at 50‐59 years, 1.84 (1.24–2.74) for TBI at 60‐69 years, and 0.86 (0.55–1.34) for TBI at ≥70 years, respectively. In the conditional logistic regression, the OR (95% CI) of dementia for TBI at any age was 1.59 (1.04–2.45). The difference in ORs from the two models was not statistically significant (P =0.40). In joint exposure analysis, the multi‐adjusted OR (95% CI) of dementia was 1.46 (1.04–2.04) for participants with TBI but no CVD and 2.64 (1.63–4.29) for those with both TBI and CVD (reference: absence of both TBI and CVD). There was significant additive (attributable proportion0.48, 95% CI 0.17–0.78) and multiplicative interactions (OR1.98, 95% CI 1.09–3.60) betweenTBI at 50‐69 years and CVD on dementia.ConclusionTBI, especially occurring at age 50‐69 years, is associated with increased risk of dementia, and the risk becomes greater in people with CVD.Genetic and early‐life environmental factors may not account for the TBI‐dementia association.
Food Dietary Choices Predict Brain Volume and Neurovascular Lesion Load 10 Years Later
Authors: Klinedinst Brandon S , Kharate Mihir , Willette Auriel A 
Published: December 2021

AbstractBackgroundThe population age structure in the U.S. is advancing, as to is the prevalence of Alzheimer’s disease and related dementias despite life expectancy stagnating in recent years. Decline in neural parameters like brain volume and lesion density are expected with advanced age, but rate and severity of loss and function vary widely. Here, we examined how 149 variables representing the total diet could predict or explain variation in total brain volume and lesion density.MethodsAmong 10,938 adults aged 45 to 80 from the UK Biobank, food choices for 149 items were measured using the 24‐hour Dietary Recall questionnaire and collected up to 5 times over the course of a year. Our outcomes of interest were total brain volume and white matter hyperintensity load, which were derived from a structural Magnetic Resonance Imaging scan conducted 10 years after baseline. Structural equation models of correlated outcomes, using a Backwards selection method (p<.05), were used to identify the most significant food choice predictors.ResultsOver a period of 10 years, more total brain volume was related to consuming more calories in general, water, various coffee preparations, and teas, hard cheeses, whole grain products, pomme fruits like apples and pears, and to some degree various desserts. Conversely, less total brain volume was seen with consuming more red and rose wine, certain vegetables and mushrooms, potatoes, crackers, and beef. For white matter hyperintensities, less lesion load was seen with consuming more mangoes, apiaceae vegetables like carrots and celery, allium vegetables like onions and leeks, spinach, sweet potatoes, and cow’s milk of any fat percentage. Conversely, greater lesion load was seen with consuming refined chocolates, processed meats and shellfish, fried potatoes, beets, eggs, mushrooms, and vitamin B6 or calcium supplements.ConclusionMaintaining brain health was generally related to consuming more water, fruits and vegetables, complex vs. simple carbohydrates, certain sweets, and dairy products while avoiding processed meats, eggs, and mushrooms. Future work will elucidate how whole food choices are related to functional brain imaging outcomes.
Effect of COVID‐19 on BPSD severity and caregiver distress: Trend data from national dementia‐specific behavior support programs in Australia
Authors: Whiting Daniel , Atee Mustafa , Morris Thomas , Cunningham Colm 
Published: December 2021

AbstractBackgroundGlobally, Coronavirus disease 2019 (COVID‐19) caused a significant disruption to the physical and mental well‐being of all individuals, including those living with dementia. Social restrictions and lockdown measures due to COVID‐19 have worsened the feelings of loneliness and behaviours and psychological symptoms of dementia (BPSD). National BPSD support programs in Australia are offered by Dementia Support Australia (DSA) through the Dementia Behavior Management Advisory Service (DBMAS) and the Severe Behavior Response Teams (SBRT). This study aims to investigate the impact of COVID‐19 on BPSD severity and related caregiver distress among referrals to DSA programs.MethodsA retrospective comparative analysis was conducted on the intake data of referrals to DSA between two periods: Pre‐COVID‐19 Period (January 2018‐Decmeber 2019) and COVID‐19 Period (January 2020‐July 2021). Referrals were compared on demographic characteristics (e.g., age), and BPSD severity (i.e., neuropsychiatric symptoms such as agitation) and caregiver distress as measured by the Neuropsychiatric Inventory (NPI). NPI scores were compared on a month‐to‐month basis between the specified periods.ResultsAcross the two periods, there were a total of 23,180 referrals eligible for the analysis. While no differences were noted in age, sex, or dementia subtype, there were elevated levels of NPI severity and caregiver distress scores during COVID‐19 Period compared to the Pre‐COVID‐19 Period. The month‐to‐month trends of these differences (Figure 1, Figure 2) reflect the timing of outbreaks across Australia. Specifically, there were no significant differences at the start of 2020 prior to the declaration of the pandemic, with an initial rise in NPI severity and distress through April after initial measures were implemented nationally in March 2020. These levels of severity and distress continued to rise through the remainder of 2020, alongside outbreaks in specific regions within Australia, such as Victoria (June‐October), and New South Wales (December/January). NPI severity and caregiver distress then began to return to Pre‐COVID levels from February‐May before elevating again with the outbreak of the Delta variant in Australia.ConclusionsCOVID‐19 has a significant impact on the severity levels of BPSD and related caregiver distress.
Pain intensity characteristics of referrals to national dementia behavior support programs in Australia
Authors: Atee Mustafa , Lloyd Rebecca Victoria , Morris Thomas , Cunningham Colm 
Published: December 2021

AbstractBackgroundRecognizing pain in people with advanced dementia who cannot effectively communicate is difficult. As such, pain is underdetected and undermanaged in this group and can lead to behaviors and psychological symptoms of dementia, impaired quality of life, and significant caregiver distress. Further, little is known about the clinical experience of pain intensity in dementia. This study aims to describe the pain intensity characteristics of referrals to Dementia Support Australia, a national dementia‐specific behavior support program in Australia.MethodsPain in a sample of referrals (period: January‐November 2020) was evaluated during various activities (rest vs movement) using PainChek®, a medical device application (app)(Figure 1) linked to a web admin portal (WAP)(Figure 2) for non‐verbal adults including those living with dementia. PainChek® consists of six domains (Face, Voice, Movement, Behavior, Activity, and Body) that have collectively a total of 42 items. The PainChek® app uses artificial intelligence to detect pain‐indicative facial action units (e.g., brow lowering) in combination with a digital checklist of non‐facial indicators to produce a pain intensity score as follows: 0‐6 (no pain), 7‐11 (mild pain), 12‐15 (moderate pain), ≥16 (severe pain). The difference in pain scores according to the activity status (rest vs movement) was computed using Cohen’s d values (e.g., 0.01‐ <0.50: very small‐to‐small).ResultsA sample of 75 referrals (84.2 ± 8.7 y, 50.6% male) from residential aged care homes were included in this study. A total of 79 pain assessments (rest n = 31, post‐movement n = 44, not assigned n = 4) were completed for the sample. Most referrals had a diagnosis of Alzheimer’s disease (n = 40, 50.6%), vascular dementia (n = 7, 8.9%) and mixed dementia (n = 8, 10.3%). Over one‐third (n = 29, 36.7%) of the sample had mild pain whilst one‐third (n = 26, 33%) had moderate‐severe pain. Across the sample, four out of six domain scores (Face, Voice, Movement, Activity) were higher after movement compared to rest e.g., Voice (d = 0.34) and Behavior (d = 0.38).ConclusionHigher pain intensities are prevalent in referrals with dementia, particularly after movement‐based activities, warranting the need for analgesic treatments.
Changes of Neuronal Plasticity in Postoperative Cognitive Dysfunction (POCD)
Authors: Zhang Yan 
Published: December 2021

AbstractBackgroundPostoperative cognitive dysfunction (POCD) is defined as a prolonged cognitive function impairment that occurs within weeks to months of a surgical procedure. Clinically this is a well‐known risk of the surgical experience in the elderly, having been described as a consequence of anesthesia. The medial prefrontal cortex (mPFC) plays a critical role in remote, recent, and short‐term memories over a broad range of tasks. The effect of POCD on neuronal plasticity in mPFC remains controversial. The present study investigates the impact of laparotomy on cognition and synaptic functions.MethodMice were induced with 5% sevoflurane and maintained with 3 ‐ 4% sevoflurane continuously for 30 mins. Under sevoflurane anesthesia, a 2.5 cm longitudinal midline incision was made. Approximately 10 cm of intestine was exteriorized and vigorously rubbed for 2 min and stay outside the abdominal cavity for 1 min. Novel Object Recognition (NOR) test was performed 1hour and 24 hours for the short‐term and long‐term memory seven days after the surgery. Open field test (OFT) and The Elevated Plus Maze test, was performed to exclude motor dysfunction and anxiety. The miniature excitatory postsynaptic currents (mEPSC) and miniature inhibitory postsynaptic currents (mIPSC) were recorded on the 7 or 14 days after surgery.ResultIn the NOR test, mice with undergone laparotomy surgery had worse cognitive performance than the control group. There was no significance between the laparotomy group and the control group in the OFT test and Elevated Plus Maze test. There was no significance in the amplitude of the mEPSC between laparotomy and control group. However, the frequency increased significantly in the laparotomy group than the control group, which can last for 14 days. There was no significance of mIPSC in the amplitude and frequency between the laparotomy group and the control group.ConclusionThese findings demonstrated that laparotomy surgery under sevoflurane leads to learning and memory impairment in adolescent mice without altering motor dysfunction and anxiety. The increase in the presynapse release ability indicated the glutamatergic neuron abnormalities without altering the GABAergic neuron’s function. Our result suggested that postoperative cognitive dysfunctions may be related to surgical trauma and glutamate neurons abnormalities.
Microglia subtype transcriptomes differ between Alzheimer Disease and control human postmortem brain samples
Authors: Prater Katherine E , Green Kevin J , Chiou Kenneth L , Smith Carole L , Sun Wei , Shojaie Ali , Heath Laura M , Rose Shannon , Keene C. Dirk , Logsdon Benjamin A , Snyder‐Mackler Noah , Blue Elizabeth E , Young Jessica E. , Garden Gwenn A , Jayadev Suman 
Published: December 2021

AbstractBackgroundMicroglia‐mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer’s Disease (AD). Microglia subtypes are complex, with beneficial and harmful phenotypes. Understanding the gene expression networks which define the spectrum of microglia phenotypes is critical to identifying specific targets for neuroinflammation modulating therapies.MethodOur study utilized post‐mortem brain tissue from 22 total (7 male) participants; 12 (3 male) had significant AD neuropathic change. Nuclei isolated from prefrontal cortex were sorted for the myeloid marker PU.1 using fluorescence activated nucleus sorting (FANS). The FANS approach yields larger numbers of nuclei annotated as microglia with high quality sequence from each individual. We performed single‐nucleus RNA‐seq using the 10X Genomics Chromium platform.ResultsWe isolated more than 120,000 microglia nuclei, facilitating group comparisons based on disease state. Unbiased clustering revealed 10 microglia clusters and improved resolution of microglia heterogeneity compared to standard single‐cell approaches. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles including interferon‐stimulated, endo/lysosomal, neurodegenerative with a “disease‐associated microglia” (DAM) signature, as well as a metabolically active and autophagic cluster. Interestingly, the cluster proportionately enriched for AD individuals’ nuclei is not the DAM cluster but instead one of the clusters in which endo/lysosomal genes are highly upregulated. Furthermore, many of the genes in known AD risk loci are strongly differentially regulated in this AD associated cluster. We also identify a cluster of microglia that is proportionately enriched for control samples with upregulated cell cycle and proliferation genes. Trajectory analysis suggests that the paths AD and control nuclei take from unactivated “homeostatic” to various phenotypic states are also distinct.ConclusionUsing human AD tissue collected with uniform protocols we characterize the transcriptomic profiles of microglia subtypes in human brain. By enriching for myeloid cells prior to analysis we can resolve microglia subtypes revealing the diversity of microglia which are “inflammatory” as well as other microglia subtypes responding with induction of metabolic and lysosomal pathways. Our data identifies subtypes of microglia that are unique to AD and control individuals. These results support the possibility of pharmacological targeting of specific subtypes of microglia to alter AD progression.
The forceps minor white matter modulates cingulo‐opercular functional connectivity change in subjective cognitive decline
Authors: Ruiz‐Rizzo Adriana L , Viviano Raymond P , Daugherty Ana M. , Finke Kathrin , Müller Hermann J , Damoiseaux Jessica S. 
Published: December 2021

AbstractBackgroundThe ‘cingulo‐opercular’ network (CON) functional connectivity (FC) decreases in aging and mild cognitive impairment. However, little is known about the cross‐sectional differences or longitudinal changes in CON FC in subjective cognitive decline (SCD). Frontal white‐matter tracts such as the forceps minor exhibit alterations in SCD and, thus, might play a relevant role for CON FC in SCD. Thus, we tested (i) whether baseline SCD predicts CON FC decrease over three years and (ii) whether white matter in the forceps minor modulates that effect.MethodSixty‐nine healthy older participants (13 males; 68.33 ± 7.95 years old) underwent resting‐state functional and diffusion‐weighted magnetic resonance imaging. Forty‐nine of those participants were further enrolled in 2 follow‐ups, about 18 months apart each. The degree of SCD was assessed at baseline with the memory functioning questionnaire (MFQ; greater score indicating more SCD). After imaging data preprocessing, we obtained the average CON FC (correlation between 5 regions) for each time point and the neurite density of the forceps minor (‘structural connectivity’, SC), which was then averaged across time points. A latent growth curve model was fit to the longitudinal FC data, setting the intercept at the last time point. The model tested whether baseline MFQ predicted FC after 3 years (latent intercept) and/or its rate of change (latent slope) and whether the interaction between SC and MFQ predicted the latent intercept of FC.ResultWe did not find evidence of baseline MFQ as a predictor of CON FC after 3 years (b = ‐0.19, 95% confidence interval, CI, [‐0.49, 0.11], p = 0.211) or its rate of change (b = ‐0.17, [‐0.37, 0.03], p = 0.093). However, we found that SC (averaged across all time points) modified the relation between MFQ and FC after 3 years (intercept, b = 0.20, [0.03, 0.37], p = 0.020; FIG).ConclusionGreater SCD predicts lower CON FC after 3 years in individuals with relatively low neurite density in the forceps minor. This evidence implies that CON FC alterations in SCD are dependent upon the forceps minor’s white matter and that these alterations might be associated with attentional or executive‐function changes in SCD.
Investigating the secretion of small heat shock proteins in reactive astrocytes in Alzheimer’s disease
Authors: Yang Fangjia , Sung Katherine , Sanchez Maria Jimenez 
Published: December 2021

AbstractBackgroundMolecular chaperones have protective functions in neurodegeneration by preventing misfolding of aggregation‐prone proteins. These functions have been mostly studied in neurons. However, members of the family of chaperones known as small heat shock proteins (sHSPs), including HSPB1, CRYAB, and HSPB8, are specifically expressed in glial cells rather than in neurons, and their levels increase in astrocytes in human post‐mortem Alzheimer’s disease (AD) brain.While traditionally considered intracellular proteins, novel extracellular functions have been attributed to chaperones in cancer or the immune system. Interestingly, HSPB1 is also found in senile plaques suggesting these can also be extracellular in the brain. We hypothesize that sHSP can be extracellular and aim to investigate whether sHSPs are secreted from astrocytes in Alzheimer’s disease brain.MethodWe used human post‐mortem brain sections from Alzheimer’s disease patients to investigate changes in extracellular/intracellular localization of HSPB1. To further explore sHSPs secretion, we used primary mouse astrocytes. Reactive astrocytes were induced by TNFα and IL‐1α, mimicking the local environment in the diseased brain. We investigated changes in astrocyte cell lysates and the astrocyte conditioned media by Western blot. To investigate the secretion mechanisms, we also use size exclusion chromatography (SEC) and nanoparticle tracking analysis (NTA)ResultAlthough sHSPs are intracellular chaperones, Our analysis of AD patients post‐mortem brain sections suggested that extracellular HSPB1 might increase around astrocytes that are close to amyloid plaques. In primary mouse astrocytes, we also found an increase in sHSPs in the extracellular media when astrocytes become reactive upon treatment with TNFα and IL‐1α. We further investigated their mechanism of secretion by fractionating the astrocyte conditioned media using SEC. NTA and proteinase K protection assays show that the sHSPs were not present in extracellular vesicle fractions, but rather free in the media.ConclusionOur study suggests that HSPB1 is secreted from astrocytes near to plaques in AD brain, as well as from reactive astrocytes in culture, and this secretion is not dependent on extracellular vesicles. The mechanisms behind how sHSPs are secreted and their extracellular functions still need to be explored.
Modularity of rsfMRI networks across aging, sexes, and processing speed
Authors: Bustos Nicholas , Nowling Duncan , Warner Graham , Joseph Jane E 
Published: December 2021

AbstractBackgroundFunctional brain networks shift and adapt with task and environmental demands throughoutneural development and aging, which are both known to have gender specific profiles. The modularity ofthese networks has been shown to decrease with healthy aging but there is debate surrounding sexdifferences in aging and how dimorphisms relate to neurodegenerative pathologies such as Alzheimer’s(AD). This study used resting state functional magnetic resonance imaging(fMRI) to examine sexdifferences in network modularity in mild cognitive impairment (MCI) and healthy control (HC) groups toexplore its potential as a clinical biomarker of a prodromal AD.MethodParticipants included 90 MCI subjects age 55 to 77 (M = 68.19 years), and 127 HC subjects age45 to 84 (M = 66.53 years). Resting state fMRI scans were analyzed using standard preprocessing anddouble regression pipeline in FSL (version 6.0). BOLD time series were extracted from 280 brain regionsusing the Power atlas. Brain Connectivity Toolbox was used to compute the modularity graph theory metric.Generalized linear mixed modeling was used to examine the modularity metric Q as a function of sex andTrails‐A score in HC and MCI.ResultA significant interaction between sex and Trails‐A score was found (Wald c2=4.7, p=.031) withinthe HC group. Males showed a decrease in modularity with increased processing speed on Trails‐A in linewith previous findings, whereas females showed no association. No significant interactions were found forMCI groups.ConclusionThese results confirm previous work correlating modularity with task‐specific connectivityand performance. Future analyses should focus on divergences between sexes in brain network modularityto inform differential diagnoses of AD.
TDP‐43 aggregation and inhibition using antibodies targeting RRM2‐CTD domain
Authors: Arias Carlos Quintero , Esposto Josephine C , Martic Sanela 
Published: December 2021

AbstractBackgroundTDP‐43 is a highly conserved protein localized to the nucleus. Under pathological conditions, it forms fibrillar aggregates, characteristic of Amyotrophic Lateral Sclerosis (ALS) progression. The exact mechanism of TDP‐43 aggregation and formation into a pathological state has yet to be elucidated, but is an important therapeutic target to consider.MethodsIn vitro full‐length phosphorylated TDP‐43 (pS410)protein was agitated and aged, with and without the presence of TDP‐43 specific antibodies. Immunoblotting was used to confirm the binding of antibodies to TDP‐43. Aggregation was monitored using spectroscopic methods, Thioflavin T (ThT), and turbidity. Transmission electron microscopy (TEM) visualized the formation and structure of phospho‐TDP‐43 aggregates.ResultsThe agitation and extensive aging (days) were required to induce aggregation of insoluble phospho‐TDP‐43 aggregates and formation of ThT positive fibrils. When exposed to an antibody specific to the RRM2‐CTD domain on TDP‐43, aggregation was inhibited in a concentration‐dependent manner and fibril formation was reduced.ConclusionsInhibition of TDP‐43 aggregation and fibril formation using antibodies demonstrates the potential for epitope‐specific treatment of TDP‐43 proteinopathies.1) Esposto, J., & Martic‐Milne, S. (2021). Phosphorylated TAR DNA‐binding protein‐43: aggregation and antibody‐based inhibition. Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1867, https://doi.org/10.1016/j.bbadis.2021.166234.