bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of microglial activation with Alzheimer’s pathologies, presynaptic loss, hippocampal atrophy, and cognitive decline
Authors: Lan Guoyu , Sun Pan , Cai Yue , Li Anqi , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundLoss of function of triggering receptor expressed on myeloid cells 2 (TREM2) and progranulin (PGRN), predominantly expressed by microglia in the brain, contribute to the development of Alzheimer’s disease (AD). Although animal studies suggest that the expressions of TREM2 and PGRN increase in activated microglia, their associations with AD‐related pathologies and subsequent outcomes are not well characterized. This study aimed to explore how cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) and PGRN relate to β‐amyloid (Aβ), tau, synaptic loss, neurodegeneration, and cognitive decline.MethodWe identified 610 ADNI participants with Aβ PET and CSF biomarkers measurements at baseline and 250 individuals with longitudinal CSF biomarkers measurements. All participants had concurrent longitudinal structure MRI and Preclinical Alzheimer’s Cognitive Composite (PACC) assessments. Using generalized linear models, we investigated the associations of CSF microglial biomarkers with Aβ PET, CSF p‐Tau181, CSF presynaptic biomarker growth‐associated protein‐43 (GAP‐43), hippocampal atrophy, and cognitive decline.ResultCSF p‐Tau181 levels rather than Aβ PET were positively associated with CSF microglial biomarkers, whereas higher Aβ PET SUVRs were related to attenuated effects of CSF p‐Tau181 on changes in CSF sTREM2 and CSF PGRN (Figure. 1). Mediation analyses further showed that Aβ PET and CSF p‐Tau181 had opposing effects on CSF microglial biomarkers (Figure. 2). In addition, CSF sTREM2 rather than CSF PGRN were positively associated with CSF GAP‐43 cross‐sectionally and longitudinally, independent of Aβ PET and CSF p‐Tau181 (Figure. 3). Furthermore, augmented microglial activation was associated with slower rates of hippocampal atrophy (sTREM2: standard β (βstd) = 0.11, p = 0.007; PGRN: βstd = 0.11, p = 0.003), but only CSF sTREM2 was related to reduced rates of cognitive decline (βstd = 0.11, p = 0.003).ConclusionThis study provides novel insights into the opposing microglial immune response to Aβ and tau pathologies, where elevated CSF p‐Tau181 rather than Aβ plaque is associated with microglial activation. TREM2‐dependent signaling may contribute to the microglia‐related presynaptic loss beyond Aβ and tau pathologies, and microglial activation is protective against hippocampal atrophy and cognitive decline. These findings are critical for understanding the roles of neuroinflammation in AD or other neurodegenerative diseases.
Immune modulatory therapeutics in AD ‐ can we find the Goldilocks zone?
Authors: Golde Todd E 
Published: December 2023

AbstractBackgroundImmunoproteostasis is a term describing the relationship between the immune system, proteinopathies present in many neurodegenerative disorders, and brain cell dysfunction. The relevance of immunoproteostasis to Alzheimer’s disease (AD) is supported by genetic, pathological, and modeling studies. Long‐standing dogma argues that immune suppression might be beneficial disease modification in AD, has now been challenged by more recent empirical data. More generally, manipulation of the immune activation states regardless of “direction”, has potential for harm as well as benefit; thus, caution is warranted before testing novel immune therapies in humans.MethodsI will present summary data from our own laboratory and collaborators and the broader published data to highlight the challenges of finding the Goldilocks zone for immune therapies in AD. I will also present new analysis arising from multi‐omic data generated in the accelerating medicine partnership consortium relating to immune activation states in mouse models of AD relevant pathologies and in humans as they develop AD.ResultsEmpirical preclinical data demonstrate that the balance of positive (e.g., amyloid reduction, synaptic integrity) and negative effects (e.g., excessive synaptic pruning, overt toxicities) of any immune manipulation may limit therapeutic benefit. Too often though preclinical studies are limited to a single time point and look at a very limited set of outcomes. Transcriptomic and proteomic studies demonstrate that innate immune responses during the development of pathology in mouse models may be quite disparate than what may occur in humans.ConclusionsAs a field we must grapple with whether we can identify immune manipulations that fall within a “Goldilocks zone”‐ where disease modification with minimal or no damage is achieved. We need both more stringent, less myopic, preclinical paradigms to evaluate potential immune therapies, and we also need better theragnostic tools to evaluate target engagement and disease modification by immune modulatory strategies in humans. Given the gaps in our knowledge regarding immune manipulations and broader impacts of these on brain function as well as the potential for any immune manipulation to have impacts that fall out of the Goldilocks zone and do more harm than good, a cautious more rigorous, data driven approach is warranted.
Conducting clinical research and embedding person‐centred care into the hospital setting during a global pandemic: Challenges and solutions
Authors: Burley Claire V , Williams Anna M , Chenoweth Lynnette 
Published: December 2023

AbstractConducting scientific research in the healthcare context is an ongoing challenge. Immediate clinical care and related tasks take priority out of necessity, often in difficult circumstances including unplanned staff absenteeism and turnover, and resource limitations. These challenges are further exacerbated in times of crisis, such as the current worldwide pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The pandemic disproportionately affects vulnerable populations, such as people living with dementia who rely on aged and healthcare services. Concurrently research studies aiming to improve health and aged care for these people are also being negatively impacted by the pandemic. There is a need for the development of guidelines that will support researchers to implement and maintain quality studies during pandemics, to prevent unnecessary delay in the dissemination of research findings, that have the potential to improve healthcare delivery quality and outcomes.This presentation first highlights the main challenges and solutions that have emerged in a study aiming to improve healthcare for people living with dementia in hospital settings, using evidence‐based person‐centred care. In addition to evaluating health outcomes for people living with dementia and cost‐effectiveness, we are using a knowledge translation framework (Goodenough et al., 2017; Damschroder et al., 2009) to evaluate the implementation of the intervention (process and outcomes) and determine nationwide scalability for hospital ward and care services. Evidence on how to adapt research processes to enable research programs to continue throughout the pandemic will be presented, followed by a set of guidelines to support researchers to engage successfully in clinical research during a pandemic. The guidelines aim to be generalisable to all clinical research projects that have been impacted by the current SARS‐CoV‐2 pandemic, as well as projects that may face future similar crises.ReferencesDamschroder LJ, Aron DC, Keith RE, et al. 2009. Fostering implementation of health research findings into practice: A consolidated framework for advancing implementation science. Implement Sci. 4(50):15 ‐20.Goodenough B, Young M. (2017). Innovation to Implementation for Dementia (i2i4dementia): A Practical Guide to Knowledge Translation in Health Care (with examples from aged care and dementia). Dementia Collaborative Research Centres, Australia. Access: DementiaKT.com.au
Modifiable Factors Associated with Mortality among the Oldest Old with Cognitive Impairment: A Longitudinal Study in China
Authors: Li Bingyu 
Published: December 2023

AbstractBackgroundThe oldest old (aged above 80 years) have the highest death rate, and CI (Cognitive Impairment) significantly increases risk of mortality. Studies investigating mortality associated with dementia mostly identified non‐modifiable factors, providing limited practical implications. This study aims to investigating factors associated with mortality among the oldest old with dementia, with particular focus on modifiable factors.MethodOur study included 6,997 older adults aged 80 years above who were diagnosed with CI. Data were from the Chinese Longitudinal Healthy Longevity Study (CLHLS). CI was measured by the Mini‐mental State Examination (MMSE). Cox proportional hazard regression combined with Least Absolute Shrinkage and Selection Operator (LASSO) was applied to select factors and evaluate their association with mortality of the oldest adults with CI.ResultOf the 6,997 participants, 6,451 died with median survival time of 2.2 years. 21 out of the 56 variables were selected from the LASSO‐penalized Cox regression model. Consistent with previous studies, the hazard of mortality increases by 19% with every incremental 10 years of age (95% CI: 12‐27%). The hazard of morality among women was 23% lower than that of men (95% CI: 18%‐29%). History of diabetes also increases the hazard of mortality. In terms of modifiable factors, daily outdoor activities, daily watching TV or listening to the radio, being married, good chewing ability are associated with lower mortality, while smoking and high systolic blood pressure increases the risk of mortality in a dose‐response manner.ConclusionSeveral modifiable factors are associated with mortality among the oldest adults with CI. Analysis suggests that healthy diet, cognitive stimulating leisure activities, marriage, and good chewing ability may contribute to lowering the risk of mortality among this population.
Association between regular laxative use and incident dementia in UK Biobank participants
Authors: Sha Feng 
Published: December 2023

AbstractBackgroundUse of OTC laxatives is common in the general population. The microbiome‐gut‐brain axis hypothesis suggests use of laxatives be associated with dementia. We aim to examine the association between regular use of laxatives and incidence of dementia.MethodThis prospective cohort study is based on 476,219 participants aged 40 to 69 years with no history of dementia. Regular use of laxatives is defined as self‐reported use in most days of the week for the last 4 weeks at baseline (2006‐2010). The outcomes are all‐cause dementia, Alzheimer’s disease and vascular dementia, identified from linked hospital admissions or death register (up to 2020).Result18,235 (3.6%) reported regular use of laxatives. Over a mean follow‐up of 9.8 years, 218 (1.3%) participants with regular use of laxatives and 1,969 (0.4%) with no regular use developed all‐cause dementia. Multivariable Cox regression models adjusting for sociodemographics, lifestyle factors, medical conditions and regular medication use showed that regular use of laxatives was associated with increased risk of all‐cause dementia (hazard ratio [HR] 1.51; 95% confidence interval 1.30‐1.75) and vascular dementia (HR 1.65; 1.21‐2.27), with no significant association observed for Alzheimer’s disease (HR 1.05; 0.79‐1.40). The risk of both all‐cause dementia and vascular dementia increased with the number of regularly used laxative types (P‐trend 0.001 and 0.04, respectively). Among the participants who clearly reported that they were using just one type of laxative (n = 5800), only those using osmotic laxatives showed a statistically significantly higher risk of all‐cause dementia (HR 1.64 [1.20‐2.24]) and vascular dementia (HR 1.97 [1.04‐3.75]). These results remained robust in various subgroup and sensitivity analyses.ConclusionRegular use of laxatives was associated with a higher risk of all‐cause dementia and vascular dementia, particularly in those who used multiple laxative types or osmotic laxative.
The effect of short Aβ(1‐38) peptides on cognitive decline and conversion to AD dementia: longitudinal data using the DELCODE cohort
Authors: Schneider Luisa Sophie , Freiesleben Silka Dawn , Wagner Michael , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Schmid Matthias , Peters Oliver 
Published: December 2023

AbstractBackgroundThe current research consensus is that long Aβ(1‐42) peptides are neurotoxic pathological hallmarks of AD. Interestingly, short Aβ peptides, such as Aβ(1‐38), appear to be less neurotoxic and may counteract AD neuropathology. However, research on Aβ(1‐38) is scarce and their effect on AD pathophysiology in humans in vivo remains unclear. Here, we investigate whether higher relative concentrations of Aβ(1‐38) levels in the cerebrospinal fluid (CSF), compared to Aβ(1‐42) alone, with phospho Tau (pTau) or with both, protect against cognitive decline and risk of conversion to AD dementia.MethodParticipants with subjective cognitive decline (n = 56), mild cognitive impairment (n = 60) and AD dementia (n = 61) from the DELCODE study with a likely pathological Aβ42/P‐tau ratio of > 9.68 at baseline were included. Cognitive performance was assessed annually for five years with the Mini‐Mental State Examination (MMSE) and the Preclinical Alzheimer Cognitive Composite (i.e., PACC5), which was derived from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Conversion to AD dementia was assessed with the Clinical Dementia Rating (CDR) and NINCDS‐ARDA criteria. CSF was collected at baseline. Data was analysed using statistical model fitting procedures for linear mixed models, i.e., Likelihood Ratio (LR) testing. Additionally, we controlled for baseline diagnostic status and the relative effect of Aβ(1‐42) and pTau.ResultHigher Aβ(1‐38) baseline levels were associated with better follow‐up performance on the PACC5 in all three groups across the AD continuum (p < .001). For the MMSE, only the MCI group showed significantly better follow‐up performance (p = .003), and a trend was found in the other groups (SCD: p = .090, AD p = .099). Furthermore, higher Aβ(1‐38) baseline levels decreased risk of conversion to AD dementia within three years by 88% (p = .003) in the SCD and MCI groups.ConclusionAcross the AD spectrum, higher Aβ(1‐38) levels protect against cognitive decline and reduce the risk of conversion to AD dementia. This could inform individual risk prediction in memory clinic patients.
Kidney function and risk of incident dementia in 202,702 UK Biobank participants
Authors: Yeh Tian‐Shin , Clifton Lei , Collister Jennifer , Liu Xiaonan , Hunter David J , Littlejohns Thomas J 
Published: December 2023

AbstractBackgroundPoorer kidney function could represent a novel modifiable risk factor for dementia, however previous findings are inconclusive. In the current study, we utilized a large population‐based cohort with long follow‐up to investigate whether glomerular filtration rate (GFR), an indicator of kidney function, and albuminuria, an indicator of kidney damage, were associated with an increased risk of all‐cause dementia.MethodThe sample consisted of 202,702 UK Biobank participants aged ≥60 years and free from dementia and end‐stage kidney disease at baseline between 2006‐2010. Estimated GFR was derived from serum creatinine and cystatin C (eGFRcr‐cys) and categorized as ≥90 (normal/high function), 60‐89 (mildly decreased function) and <60 ml/min/1.73m2 (moderately/severely decreased function). Albuminuria was defined using the urinary albumin to creatinine ratio (ACR). ACR was categorized into <3 (normal/mildly increased), 3‐30 (moderately increased), and >300 (severely increased) mg/mmol. Incident dementia was determined through cohort‐wide linkage to hospital and death records. The associations were assessed using Cox proportional‐hazard models adjusted for age, sex, ethnicity, socioeconomic status, education, household income, country, smoking status, alcohol intake, body mass index, hypertension, diabetes, and APOE‐ε4 allele status.ResultOver 15 years of follow‐up, 6,042 participants developed incident dementia. The fully‐adjusted Hazard Ratios (HR) were 1.00 (95% Confidence Interval [CI] 0.94‐1.06) and 1.42 (95% CI 1.28‐1.58) for eGFRcr‐cys 60‐89 and <60 respectively, compared to ≥90 ml/min/1.73m2. Moderately/severely decreased eGFRcr‐cys remained associated with incident dementia after restricting to participants with more than 10 years of follow‐up (HR = 1.33, 95% CI 1.13‐1.56). The HRs for moderate and severely increased ACR were 1.16 (95% CI 1.07‐1.26) and 2.24 (95% CI 1.79‐2.80), respectively, compared to normal/mildly increased ACR (<3mg/mmol). Dose‐response associations were observed when combining eGFRcr‐cys and ACR, with those in the severest eGFRcr‐cys and ACR group having the greatest risk of dementia (HR = 4.70, 95% CI 2.34‐9.43).ConclusionKidney dysfunction and albuminuria were associated with a higher risk of incident all‐cause dementia. These findings provide additional evidence that kidney dysfunction could be a potential modifiable risk factor for dementia or target for identifying those at high risk of the condition.
Neurofunctional Correlates of Activities of Daily Living in Patients with Posterior Cortical Atrophy
Authors: Chu Min , Lv Xuedan , Yang Caishui , Wu Liyong 
Published: December 2023

AbstractBackgroundResearch on posterior cortical atrophy (PCA) has concentrated on cognitive decline, especially visual processing deficits. However, few studies have focused on the activities of daily living (ADL), and no study has investigated the neurometabolic basis of ADL impairments. We aimed to identify regions of hypometabolism associated with ADL in PCA patients.MethodTwenty‐nine PCA patients, 35 typical Alzheimer’s disease (tAD) patients, and 26 healthy volunteers were recruited. Each subject completed a scale for total ADL [TADL, including basic ADL (BADL) and instrumental ADL (IADL) subscales] and 18F fluorodeoxyglucose positron emission tomography. Voxel‐wise multivariable regression analysis was conducted at the level of the whole‐brain, PCA‐related hypometabolism patterns, and PCA‐specific hypometabolism patterns.ResultThe general cognitive status of PCA patients was similar to tAD patients; however, they performed worse in TADL, BADL, and IADL. In all analysis levels, TADL was associated with the bilateral parietal lobe, including the right superior parietal lobe, right inferior parietal cortex, right angular gyrus, and left superior parietal lobe. BADL was associated with the bilateral parietal lobe located in the right superior parietal lobe, right inferior parietal cortex, and left superior parietal lobe. IADL was associated with the bilateral superior parietal lobe. Bilateral superior parietal lobe hypometabolism was associated with TADL, BADL, and IADL.ConclusionHypo‐metabolism in the bilateral superior parietal lobes contributes to the decline of ADL in PCA, which is a promising target for future non‐invasive neuromodulation interventions.
Altered anterior insular metabolic connectivity in asymptomatic MAPT P301L carriers
Authors: Chu Min , Nie Binbin , Jiang Deming , Wu Liyong 
Published: December 2023

AbstractBackgroundThe insula is the predominant brain region impaired in behavior variant frontotemporal dementia (bvFTD). However, structural and functional changes in the sub‐insula in the asymptomatic stage of bvFTD are unknown. The aim of this study is to describe structural and functional changes in insular subregions in asymptomatic carriers of the P301L mutation of the microtubule‐associated protein tau (MAPT) gene and patients with bvFTD.MethodSix asymptomatic MAPT P301L mutation carriers and 12 MAPT negative control subjects of the same pedigree were enrolled, along with 30 patients with a clinical diagnosis of bvFTD and 30 matched controls. All subjects underwent hybrid positron emission tomography/magnetic resonance imaging. Atlas‐based parcellation using a fine‐grained Brainnetome Atlas was conducted to assess gray matter (GM) volume, metabolism, and metabolic connectivity in the sub‐insula (region of interest).ResultThere was no significant GM atrophy or hypometabolism in insula subregions in asymptomatic MAPT P301L carriers, although decreased metabolic connectivity between vIa‐middle temporal gyrus, vIa‐temporal poles, dIa‐middle temporal gyrus and dIa‐temporal poles; and increased connectivity between vIa‐orbitofrontal, vIa‐dorsal lateral superior frontal gyrus, and dIa‐orbitofrontal and dIa‐dorsal lateral superior frontal gyrus were observed. Patients with bvFTD had significant atrophy and hypometabolism in all insula subregions and decreased metabolic connectivity in the whole brain, including vIa/dIa‐middle temporal and vIa/dIa‐temporal poles. The standardized uptake value ratios of vIa and dIa were negatively associated with behavioral disinhibition scale scores.ConclusionMetabolic connectivity is altered in vIa and dIa subregions of the sub‐insula in MAPT P301L mutation carriers before the occurrence of atrophy, hypometabolism, and clinical symptoms.
Increase in Matrix Metaloproteinase‐10 is associated with tau, neurodegeneration and reduced brain perfusion in the right temporal lobe
Authors: Michopoulou Sofia , Prosser Angus , Dickson John , Guy Matt J , Teeling Jessica , Kipps Christopher 
Published: December 2023

AbstractBackgroundBlood brain barrier dysfunction amplifies neuroinflammation, which may drive Alzheimer’s Dementia (AD) pathology. Regional cerebral blood flow (RCBF), measured by HMPAO SPECT, is an established biomarker for AD diagnosis. Matrix Metalloproteinase‐10 (MMP‐10), an enzyme involved in blood brain barrier function through regulating the breakdown of extracellular matrix, was recently proposed as a biomarker of progression to AD. In this study, we examine the relationship between RCBF and levels of MMP‐10 in the cerebrospinal fluid (CSF).Materials and MethodsDatasets of 91 participants from a heterogenous clinical cohort, investigated for dementia due to cognitive complaints were analysed. CSF levels of MMP‐10 were measured using the OLINK proximity extension array platform. HMPAO SPECT scans were analysed using Statistical Parametric Mapping (SPM). A univariate linear regression model was used in SPM to quantify the impact of MMP‐10 changes on brain perfusion.ResultsSPM results showed that higher levels of MMP‐10 in CSF are associated with significant reduction in RCBF (family‐wise error corrected p<0.05). The neuroimaging signature of changes in RCBF with increasing MMP‐10 is outlined in Figure 1. The main cluster of reduction in perfusion is on the right temporal lobe with an additional cluster on the right medial frontal lobe.ConclusionIncreased levels of MMP‐10 in CSF have been associated with blood brain barrier vulnerability and faster cognitive decline in AD. Here we identified a right sided neuroimaging signature in RCBF with increasing levels MMP‐10. This may indicate that by the time of symptoms onset the right side is the fastest progressing as it is catching up with the left side. Right sided changes have been previously associated with delusions, disinhibition and irritability in AD and linked with increased carer burden. The significant reduction in RCBF of the right temporal lobe identified in our study, further reinforces a role for MMP‐10 as a marker of progression to AD.Acknowledgement: Dr Sofia Michopoulou, is funded through an Integrated Clinical Academic Lectureship by Health Education England (HEE) / NIHR for this research project (NIHR301287). The views expressed in this publication are those of the authors.