bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing Disrupted Cellular Crosstalk Signaling Networks in Alzheimer’s Disease Using Single‐Nuclei Transcriptomics
Authors: Albanus Ricardo D'Oliveira , Brase Logan , You Shih‐Feng , Soriano‐Tarraga Carolina , Benitez Bruno A. , Cruchaga Carlos , Karch Celeste M. , Harari Oscar ,   The Dominantly Inherited Alzheimer Network
Published: December 2022

AbstractBackgroundGenetics and molecular studies have implicated multiple genes, pathways, and cell types in Alzheimer’s disease (AD) risk and progression. How these genes and pathways perturb and are modulated by brain cellular crosstalk networks have not been deeply characterized.MethodWe generated single‐nuclei transcriptomic profiles (snRNA‐seq) of parietal lobes from 67 donors from the Knight ADRC and DIAN brain banks, representing neuropathological‐free controls and AD cases from pre‐symptomatic and AD[1]. We estimated cellular crosstalk patterns among the brain cell types based on the expression of known ligand‐receptor pairs[2] and reconstructed the co‐expression network upstream and downstream of these ligand‐receptor pairs to determine how these signals are propagated across cells[3].ResultWe analyzed ∼294K high‐quality nuclei and identified six major cell populations[1]. We observed changes in cellular crosstalk patterns between controls and AD, with the largest involving microglial interactions (increased in AD, OR = 1.31, p = 8.94e‐11). Cellular interactions directly involving AD‐related genes[4] as either the receptor or the ligand were enriched for neuron‐microglia pairs (OR = 2.74, p = 4.41e‐15), and the majority (64.9%) codified for microglial cell membrane receptors, supporting the role for these cells in AD. We observed an increase in the frequency of a subset of interactions involving AD‐related genes in microglia when comparing pre‐symptomatic and AD individuals, suggesting correlation with pathological burden. These included TREM2‐semaphorin (neuron‐microglia, 4.38‐fold increase). We performed a comprehensive study of the microglial co‐expression networks up/downstream of these interactions and provided additional evidence of their association with Braak stage. The TREM2‐semaphorin neuron‐microglia interaction is predicted to directly propagate signals into a sub‐network associated with microglia activation, involving four genes from the HLA family previously implicated in AD. Furthermore, the neuronal co‐expression network had significant enrichment for AD‐related genes including CELF2 (OR = 2.10, p = 5.32e‐3), consistent with AD‐related genes in neurons propagating signals into microglia. We replicated these results in public snRNA‐seq studies and are currently validating these findings experimentally.ConclusionThis study reveals the role of cellular crosstalk in AD biology and identifies disruptions in neuron‐microglia interactions as an important component of AD pathology. In addition, we show that cellular crosstalk networks can directly modulate genes previously associated with AD (Figure 1).References:[1]https://doi.org/10.1101/2021.11.30.21267072; [2]PMID:32103204; [3]PMID:33853780;[4]PMID:30820047
Segregation of brain systems is associated with cognitive and eye movement performance in the general population
Authors: Coors Annabell , Zeng Weiyi , Breteler Monique M.B. , Ettinger Ulrich 
Published: December 2022

AbstractBackgroundThe human brain is a large‐scale network, which contains multiple segregated and functionally specialized systems. The organization of brain systems has been reported to change in a dedifferentiated way with increasing age. We investigated how age and sex are associated with brain system segregation during resting‐state in a large population‐based sample. Further, we analysed whether interindividual differences in the amount of brain system segregation are associated with cognitive and eye movement performance.MethodThe analyses were based on 3,256 participants (30‐95 years) of the Rhineland Study, a community‐based cohort study in Bonn, Germany. Functional connectivity (FC) was extracted from 200 ROIs within 7 systems (control, default, visual, somatomotor, dorsal attention, ventral attention and limbic) using resting‐state functional MRI acquired from 3T Siemens MAGNETOM Prisma MRI scanners. Segregation index was calculated using a previously established measurement taking the difference between mean within‐system FC and mean between‐system FC as a portion of mean within‐system FC. We assessed cognitive performance with tests for memory, processing speed, executive function and crystallized intelligence and an eye movement test battery. We used multivariable regression models to assess the relation between brain segregation index and cognitive and eye movement performance with adjustment for possible confounders.ResultThe global system segregation index decreased by 0.17 standard deviations (sd) per 10 years increase in age (95% confidence interval (CI): ‐0.19 – ‐0.14). Men had on average a 0.08 sd higher global system segregation index than women (95% CI: 0.02 – 0.15). Higher global system segregation was associated with higher performance in global cognition, processing speed, executive function, working memory and episodic verbal memory, and with lower crystallized intelligence. Additionally, higher global system segregation was associated with faster initiation of prosaccades and antisaccades.ConclusionHigher system segregation is beneficial for cognitive and eye movement tasks that place demands on processing speed, executive function and working memory, but crystallized intelligence is better when segregation is lower.
Promoting Inclusion of Sexual and Gender Minority Individuals in Aging and Alzheimer’s Disease and Related Dementias Research
Authors: Flatt Jason D. , Stites Shana D. , Kittle Krystal R. , Cicero Ethan C. , Anderson Joel G , Wharton Whitney 
Published: December 2022

AbstractBackgroundIt is estimated that more than three million older adults aged 60+ in the U.S. identify as a sexual and gender minority (SGM) or lesbian, gay, bisexual and/or transgender or gender non‐binary, queer, intersex, asexual, and people with a gender identity, gender expression, or reproductive development that varies from traditional, societal, cultural, or physiological norms. SGM adults experience health disparities and many of these health disparities are risk factors for cognitive decline and Alzheimer’s disease and related dementias (ADRD). These risk factors include higher rates of subjective cognitive decline, cardiovascular disease, hypertension, diabetes, and depression compared to non‐SGM adults.MethodWe will describe community‐based participatory research approaches for engaging and recruiting SGM older adults into aging and ADRD research. We will describe best practices for collecting gender identity, sex assigned at birth, and sexual orientation. We highlight ways of reshaping healthcare practices and the broader system changes that are needed to ensure SGM people living with ADRD and their families (chosen and/or biological), receive culturally appropriate, person‐centered, and equitable care.ResultHistorical and ongoing social, structural, and institutional factors (stigma; oppression, discrimination; social exclusion; maltreatment by the healthcare system, healthcare professionals, and researchers) have created barriers for inclusion of SGM communities in health research and this may also extend to aging and ADRD research. We discuss how The RISE (Research Inclusion Supports Equity) Study is establishing a mutual commitment with SGM communities by building trust and on existing strengths, resources, and relationships within SGM communities are all necessary to promote SGM engagement and inclusion in research.ConclusionSGM persons living with ADRD and their care partners, as well as SGM ADRD caregivers in general are underrepresented in aging and ADRD research. These communities also experience structural, social, and financial barriers in accessing aging and healthcare services. Thus, there is a critical need for training and future research. We recommend that researchers and clinicians help advance equitable practices for SGM inclusion in research as it is necessary to improve the health and care of SGM communities affected by ADRD globally.
Quantitative amyloid‐PET measures in a memory clinic population
Authors: Collij Lyduine E. , Verweij Bart M. , Altomare Daniele , Caprioglio Camilla , de Gier Yvonne , García David Vállez , Alves Isadora Lopes , Hegde Manoj , Wolz Robin , Grootoonk Sylke , Gismondi Rossella , Stephens Andrew W , van Berckel Bart NM , Gispert Juan Domingo , Garibotto Valentina , Barkhof Frederik , Frisoni Giovanni B , Farrar Gill , Buckley Christopher ,   the AMYPAD consortium
Published: December 2022

AbstractBackgroundIn clinical practice, visual assessment of amyloid‐PET images results in a binary classification (negative or positive) of amyloid status. While this approach has shown high clinical utility, the expected approval of disease‐modifying treatments warrants the need for objective amyloid burden quantification, to further support a high‐confidence diagnosis of Alzheimer’s disease (AD) and treatment decisions. We investigated two widely available quantification methods, i.e. Centiloid (CL) and z‐scores to optimize clinical use of amyloid‐PET.MethodsPatients with subjective cognitive decline plus (SCD+; N=220), mild cognitive impairment (MCI; N=293) or dementia (N=216) enrolled in the AMYPAD‐DPMS that have undergone amyloid‐PET imaging and passed quality control were included in the study. Acquired static (i.e. 90‐110 min. post‐injection) [18F]flutemetamol (N=380) or [18F]florbetaben (N=349) PET images were processed using GE Healthcare’s AMYPYPE PET‐only pipeline, providing global CL, z‐scores, and z‐scores for 7 cortical ROIs. Local readers provided visual read (VR) status and regional assessments.ResultsDemographics are shown in Table 1. In total, 364 (49.9%) patients were assessed as amyloid VR‐positive and showed significantly higher CL (U=3954, p<0.001) and global z‐score (U=4197, p<0.001) values across clinical stages compared to VR‐negative patients (Figure 1A). The proportion of VR‐positive patients increased with clinical stage (SCD+: 30.0%, MCI: 48.8%, dementia: 71.8%) and global amyloid burden (CL: H=24.97, p<0.001; z‐score: H=24.43, p<0.001) was also associated with disease severity (Figure 1B). VR‐positive patients with a primary etiological diagnosis of AD showed higher overall higher amyloid burden (CL: H=6.93, p=0.008; z‐score: H=5.54, p=0.019) and specifically in the pre‐frontal cortex (H=8.18, p=0.004) compared to patients with a non‐AD primary etiological diagnosis, though percentage of frontal VR‐positivity was highly similar between groups (AD: 97.2% vs. non‐AD: 96.6%). Global CL and z‐scores were highly correlated (ρ=.987, p<0.001), by a factor of 10 (Figure 1C).ConclusionOur results demonstrate high agreement between CL and z‐scoring quantitative measures in a clinical population. While initial results do not indicate differences in patterns of regional positivity between AD and non‐AD subjects, differences in global amyloid burden seem to be driven by known AD‐related early accumulating regions. Additional analyses comparing other etiological groups will be presented at the conference.
Motivating Alzheimer’s Disease and Related Dementia Risk Reduction Behaviors in Older Adults: Motivational Cessation Message Development Findings
Authors: Johnson Adrienne L. , Gleason Carey E. , Cook Jessica , Mahoney Jane , Piper Megan E. 
Published: December 2022

AbstractBackgroundSmoking, a modifiable risk factor for dementia, accounts for at least 14% of current Alzheimer’s disease cases. Older smokers are more likely to remain abstinent than younger adults when they use evidence‐based smoking treatment (EBST), thereby reducing their dementia risk. Unfortunately, older smokers are half as likely to try to quit than younger adults. Therefore, motivating older adults to quit using EBST is a vital public health priority.Method24 current smokers [M = 14.3 (SD = 9.5) cigarettes/day] with no dementia/MCI history, ages 50‐75 years, 83% White, 12.5% African American, 4% Mixed race, and 79% cisgender female completed a 2‐hour semi‐structured interview and survey via telephone that was analyzed using rapid content analysis.ResultThe most commonly reported health‐related concern was dementia/cognitive loss/loss of functioning, followed by cancer, heart attack/CVD, COPD/emphysema, pain/arthritis, falling, and death. Most participants believed they were at risk of their feared health‐consequence, and that quitting would help. Although all participants had seen previous advertisements for smoking cessation, the majority did not feel motivated to quit by these advertisements. Half of participants were unaware of any link between smoking and dementia, and only a quarter of participants remembered specifics about this link. The vast majority found a message about smoking raising dementia risk and quitting as a means to decrease that risk as motivating for cessation, with over half of participants stating this type of message would be more motivating than previous cessation advertisements. There were varied preferences for exact message content, but two broad categories arose: hope/change of quitting‐based messages and fear/risk of smoking‐based messages. Most participants were aware of smoking cessation pharmacotherapies from personal/relatives past use, but previous negative side effects, cessation failure, and cost were barriers to future use. Nevertheless, the majority of participants stated willingness to use some cessation pharmacotherapy. Many had not considered cessation counseling and were unaware how to access it; half were willing to use cessation counseling.ConclusionHopeful/change‐ and fear‐based messages around smoking and dementia risk could motivate cessation for older smokers. Although dementia is an important health consequence of smoking, older smokers are unaware of this modifiable risk factor.
Hypertensive disorders of pregnancy and markers of vascular brain pathology after 15 years: a prospective cohort study
Authors: Hussainali Rowina Farzia , Adank Maria C , Lamballais Sander , Vernooij Meike W. , Ikram M. Arfan , Steegers Eric A.P. , Miller Eliza C. , Schalekamp‐Timmermans Sarah 
Published: December 2022

AbstractBackgroundSubstantial evidence suggests an association between hypertensive disorders of pregnancy (HDP) and long term cerebrovascular health. We aimed to determine the associations between HDP and markers of vascular brain pathology fifteen years after pregnancyMethodThis was a nested cohort study embedded in a population‐based prospective cohort followed from early pregnancy. We included 538 women, 445 (82.7%) with normotensive index pregnancies and 93 (17.2%) with HDP in the index pregnancy. Fifteen years after pregnancy (median of 14.6 years 90% range 14.0; 15.7), women had a mean age of 46.5 years (SD = 4.2). These women underwent magnetic resonance imaging to assess brain tissue volumes as well as white matter hyperintensities (WMH), lacunar infarcts, and cerebral microbleeds as markers of vascular brain pathology.ResultWomen with prior HDP had 38% (95% CI: [8% ; 75%]) higher WMH volume compared to women with previous normotensive pregnancy. This association was driven by women with gestational hypertension, who had 48% (95% CI: [11% ; 95%]) higher WMH volume compared to women with previous normotensive pregnancy. No differences were found with infarcts or cerebral microbleeds. The development of chronic hypertension after pregnancy strengthened this result, especially in women with previous gestational hypertension.ConclusionA history of HDP was associated with more WMH burden fifteen years after pregnancy. This effect was driven by women with previous gestational hypertension. The development of chronic hypertension after pregnancy contributed to this effect. Women with a history of HDP should be evaluated and treated early for hypertension and other cardiovascular risk factors.
Segregation of brain systems is associated with cognitive and eye movement performance in the general population
Authors: Zeng Weiyi , Coors Annabell , Ettinger Ulrich , Breteler Monique M.B. 
Published: December 2022

AbstractBackgroundThe human brain is a large‐scale network, which contains multiple segregated and functionally specialized systems. The organization of brain systems has been reported to change in a dedifferentiated way with increasing age. We investigated how age and sex are associated with brain system segregation during resting‐state in a large population‐based sample. Further, we analysed whether interindividual differences in the amount of brain system segregation are associated with cognitive and eye movement performance.MethodThe analyses were based on 3,256 participants (30‐95 years) of the Rhineland Study, a community‐based cohort study in Bonn, Germany. Functional connectivity (FC) was extracted from 200 ROIs within 7 systems (control, default, visual, somatomotor, dorsal attention, ventral attention and limbic) using resting‐state functional MRI acquired from 3T Siemens MAGNETOM Prisma MRI scanners. Segregation index was calculated using a previously established measurement taking the difference between mean within‐system FC and mean between‐system FC as a portion of mean within‐system FC. We assessed cognitive performance with tests for memory, processing speed, executive function and crystallized intelligence and an eye movement test battery. We used multivariable regression models to assess the relation between brain segregation index and cognitive and eye movement performance with adjustment for possible confounders.ResultThe global system segregation index decreased by 0.17 standard deviations (sd) per 10 years increase in age (95% confidence interval (CI): ‐0.19 – ‐0.14). Men had on average a 0.08 sd higher global system segregation index than women (95% CI: 0.02 – 0.15). Higher global system segregation was associated with higher performance in global cognition, processing speed, executive function, working memory and episodic verbal memory, and with lower crystallized intelligence. Additionally, higher global system segregation was associated with faster initiation of prosaccades and antisaccades.ConclusionHigher system segregation is beneficial for cognitive and eye movement tasks that place demands on processing speed, executive function and working memory, but crystallized intelligence is better when segregation is lower.
Reduced Vascular Disease Mortality Associated with Improved 5‐Year Survival in an AD Cohort Followed for 25 years
Authors: Pavlik Valory N 
Published: December 2022

AbstractBackgroundIt is important to monitor all‐cause and cause‐specific mortality in AD cohorts to assess impacts of new therapies and advances in management of co‐morbidities.MethodWe compared all‐cause and cause‐specific morality in four cohorts of Alzheimer’s disease (AD) patients ≥ 65 years old followed in an academic memory center from 1995‐2019. Patients’ clinical and neuropsychological histories were obtained from an electronic data base. Vital status and cause of death through 2019 were ascertained using the National Death Index (NDI). Cohorts were defined based on enrollment date (1995‐1999, 2000‐2004, 2005‐2009, 2010‐2014). Hazard ratios (HRs) for five‐year all‐cause and cause‐specific mortality were compared across cohorts using Cox proportional hazards and competing risks regression, adjusting for age, sex, education, duration of symptoms at baseline, history of vascular disease, and baseline MMSE score.Result713 patients met selection criteria, and 686 deaths occurred within five years of baseline. Mean age at baseline was 78.7 ±6.5 and mean age at death was 82.2 ± 6.4 years. AD/Dementia accounted for proportionally more deaths over time: 39%, 46%, 55%, and 58% of deaths in Cohorts 1‐4 respectively. All‐cause mortality was significantly lower in Cohort 4 than in Cohorts 1‐3 (HR Cohort 2vs1 = .99±.10, p = .97; HR Cohort 3vs1 = .95±.09, p = .62; HR Cohort 4vs1 = .63±.07; p = . <001). There was a temporal trend toward reduced CVD mortality (HR Cohort 2vs1 = .69±.14; p = .06; HR Cohort 3vs1 = .67±.13; p = .04; HR Cohort 4vs1 = .40 ±.10; p = .001).ConclusionThe increasing proportion of AD deaths and increased survival in Cohort 4 is likely due to decreases in CVD mortality. The mortality experience of Cohort 4 can serve as a benchmark for future trends, particularly as new therapies are approved and impacts of the Sars‐CoV2 epidemic are observed.
TREM2 differentially modulates parenchymal and vascular pathology in a mouse model of cerebral amyloid angiopathy
Authors: Zhong Rui , Gram Andrea , Li Ling 
Published: December 2022

AbstractBackgroundCerebral amyloid angiopathy (CAA) features cerebral vascular deposition of pathological amyloid‐beta protein (Aβ) and plays an important role in the multimorbidity of aging brains including Alzheimer’s disease (AD), but it is less understood compared to parenchymal Aβ plaques. Triggering receptor expressed on myeloid cells 2 (TREM2), a key player in innate immune response, is exclusively expressed in microglia in the brain and mediates Aβ clearance and subsequently alleviates neuroinflammation. Loss‐of‐function mutations in TREM2 increase the risk of AD. Recent studies on TREM2 function using TREM2 knockout (KO) in transgenic (Tg) AD mice have shown that TREM2 modulates parenchymal Aβ deposition in the brain, although the direction of the effect depends on the specific Tg background and the stage of the disease development. However, the impact of TREM2 on CAA had not been investigated.MethodsTREM2 KO mice were crossed with SwDI mice (C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax), a model of CAA and AD, to generate SwDI/TREM2WT, SwDI/TREM2Het, and SwDI/TREM2KO mice. At the age of 16 months, the mice were euthanized for tissue collection. ELISA was utilized for the assessment of Aβ40 and Aβ42 levels in brain tissue homogenates, and histochemical and immunohistochemical or immunofluorescent assays were used to evaluate amyloid deposition, astrogliosis, and microgliosis. All results were analyzed using GraphPad Prism 9.ResultsTREM2 deficiency markedly increased overall Aβ load in SwDI/TREM2KO mice compared to SwDI/TREM2WT or SwDI/TREM2Het in the cortex, hippocampus, and thalamus. Intriguingly, TREM2 deletion led to a dramatic decrease in CAA in vasculature‐enriched regions, such as thalamus, along with reduced microglial association with CAA. Consistent with previous reports, Aβ plaque‐associated microglia were significantly reduced in SwDI/TREM2KO mice. Additional experiments are underway to explore the molecular mechanisms underlying the distinct impact of TREM2 deficiency on Aβ plaques and CAA.ConclusionDeletion of TREM2 increases the overall brain Aβ load whereas decreases CAA, suggesting the differential role of TREM2 in the regulation of parenchymal versus vascular deposition of Aβ in the brain.