bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shared Decision‐Making in Dementia: A Scoping Review
Authors: Mattos Meghan K , Gibson Jessie , Jepson Laura , Ahn Soojung , Williams Ishan Canty 
Published: December 2022

AbstractBackgroundEvidence supports that older adults with cognitive impairment can reliably communicate their values and choices, even as cognition declines. Shared decision‐making (SDM), including the patient, family members, and healthcare providers, is critical to patient‐centered care. The aim of this scoping review was to synthesize what is known about SDM in dementia.MethodA scoping review was completed in PubMed, Ovid, and CINAHL. Keywords included content areas of dementia and shared decision‐making. Inclusion criteria were as follows: description of shared or cooperative decision making, cognitively impaired patient population, adult patient, and original research. Review articles were excluded, and those for which the formal healthcare provider was the only team member involved in the decision‐making (e.g., physician) and/or the patient sample was not cognitively impaired. Systematically extracted data were organized in tables, compared, and synthesized to identify what is known about SDM in dementia.ResultThe search yielded 263 non‐duplicate articles that were screened by title and abstract. Ninety‐three articles remained, and the full text was reviewed; 32 articles were eligible for this review. Studies were from across Europe (n = 23), North America (n = 7), and Australia (n = 2). The majority of the articles used a qualitative study design (qualitative only, n = 13; mixed‐method, n = 9), and 10 used a quantitative study design (intervention, n = 1; quasi‐experimental, n = 1; descriptive, n = 8). Categories of similar SDM topics emerged, including health promotion, end‐of‐life, advanced care planning, and housing decisions. The majority of articles focused on SDM regarding health promotion for the patient (n = 16). Topics related to health promotion included SDM in general patient care, activities of daily living, clinical appointments, fall prevention, diagnostic testing, and medications. Dementia diagnoses varied within studies and across the literature, ranging from mild cognitive impairment to late‐stage Alzheimer’s disease to dementia with Lewy bodies.ConclusionFindings illustrate that SDM requires deliberate effort and is preferred among family members, healthcare providers, and patients with dementia. Future research should include more robust efficacy testing of decision‐making tools, incorporation of evidence‐based SDM approaches based on cognitive status/diagnosis, and consideration of geographical/cultural differences in healthcare delivery systems.
A clinically relevant mouse model of the Trem2*R47H Alzheimer’s disease risk variant
Authors: Sasner Michael , Oblak Adrian L , Garceau Dylan , Kotredes Kevin P , Preuss Christoph , Uyar Asli , Pandey Ravi S , Lin Peter Bor‐Chian , Tsai Andy Po‐Yi , Carter Gregory W , Howell Gareth R , Lamb Bruce T ,   MODEL‐AD
Published: December 2022

AbstractBackgroundThe TREM2 (triggering receptor expressed on myeloid cells 2) locus harbors numerous relatively rare variants associated with Alzheimer’s disease risk. The TREM2*R47H allele is one of the strongest genetic risk factors for developing late‐onset Alzheimer’s disease; patients exhibit both earlier onset of symptoms and rapid cognitive decline. TREM2 is expressed by microglia in the brain and plays a key role in modulating microglial activity. TREM2 expression is increased in AD and is associated with recruitment of microglia to amyloid plaques. An experimental model is therefore critical to study mechanisms of late‐onset AD, and the MODEL‐AD set out to create a clinically relevant mouse model.MethodWe used CRISPR to engineer the R47H variant into the mouse Trem2 locus; this model is available as JAX #27918. This model, as well as two other CRISPR‐generated Trem2*R47H models, display a splicing event seen in mice, but not humans, that leads to a novel splice form with a deletion of 119bp at the 5’ end of exon 2 (Xiang et al, Molecular Neurodegeneration, 2018). This leads to a decrease in ∼50% of both transcript and protein levels in brain homogenate in the mouse, indicating that the model expresses mutant Trem2 protein, but is also a hypomorph. To generate a more clinically relevant model, we have modified the existing Trem2*R47H mouse allele by using CRISPR to humanize the exon 2 splice site. Expression in these models was compared to normal Trem2 levels using both RNA‐seq and Western blot.ResultThe new model, which we are calling Trem2*R47HHSS for humanized splice site (JAX #33781), showed normal levels of expression. Relative to B6J controls, this new model expresses normal levels of each of the four transcripts. No truncated transcript was detected. Protein levels were restored to wild‐type levels in the model with the humanized splice site.ConclusionWe expect that this model Trem2*R47H model will facilitate research into the mechanisms and pathways related to TREM2 genetic risk in late‐onset AD. For more information see www.model-ad.org.
Cerebrovascular accumulation of amyloid‐forming amylin secreted from the pancreas induces brain hypoxia
Authors: Verma Nirmal , Ly Han , Despa Florin 
Published: December 2022

AbstractBackgroundIslet amyloid polypeptide (amylin) is a β‐cell hormone co‐secreted with insulin. Histological analyses of human brains identified amylin deposits co‐localized with parenchymal and vascular β‐amyloid in humans with vascular cognitive impairment and Alzheimer’s dementia. Because circulating amyloid‐forming amylin triggers systemic hypoxia signaling, we sought to determine the relationship between circulating amylin levels and brain hypoxia markers in a transgenic rat model of amylin‐mediated neurological deficits.MethodTo assess amylin‐related brain hypoxia signaling, we performed a 16‐month longitudinal study in which rats that express amyloid‐forming human amylin in pancreatic β‐cells (HIP rats) were compared to wild type (WT) littermates that express non‐amyloidogenic rodent amylin (n=10 rats/group).ResultBlood amylin levels measured by ELISA were ∼2‐fold higher in 16‐month old HIP rats compared to WT littermates (P<0.01). The Thiovlavin T (Th T) fluorescence signal intensity in blood lysates from HIP rats increased compared to that in WT littermates indicating the presence of amyloid‐forming in the circulation in HIP rats (P<0.01). This was associated with higher amylin concentration in brain microvessel lysates (P<0.05) and amylin immunoreactivity signal intensity in brain sections. Plasma erythropoietin, a marker of systemic hypoxia was higher in HIP rats than in WT littermates (P<0.05), which correlated with brain accumulation of HIF‐2α (P<0.05) and HIF‐1α (P=0.07), and with altered mitochondrial DNA in brain tissue (P<0.05).ConclusionIncreased circulating levels of amyloid‐forming amylin promotes cerebrovascular amylin deposition leading to brain hypoxic‐ischemic injury. Future studies need to address functional effects of amylin‐induced brain hypoxia signaling in the brain.
Social isolation and cognitive function in middle aged and older adults in the Wisconsin Alzheimer’s Disease Research Center: Implications for the pandemic
Authors: Fischer Barbara L. , Van Hulle Carol A. , Umucu Emre , Wyman Mary F. , Chin Nathaniel A. , Johnson Sterling C. , Asthana Sanjay , Gleason Carey E. , Zuelsdorff Megan 
Published: December 2022

AbstractBackgroundSocial isolation and loneliness contribute to cognitive decline, and social isolation represents a key modifiable risk factor for dementia. Substantial interruptions in social engagement due to the COVID‐19 pandemic have heightened awareness of this issue, but common later‐life events may also reduce social connectedness. The neurocognitive impacts of such disruptions are unclear. Using the validated NIH Emotion Toolbox, we examined perceived social support and changes in perceived support as predictors of cognitive function in a sample of middle aged and older adults.Method672 participants from the Wisconsin Alzheimer’s Disease Research Center (ADRC) completed cognitive tests and Emotion Toolbox questionnaires at 2+ visits between 2017 and 2021 (mean interim = 1.7 years). Predictors comprised t‐scores on three perceived social support scales: Emotional Support, Instrumental Support, and Loneliness. Cross‐sectional analyses examined associations between social support and cognitive outcomes including memory (RAVLT Immediate and Delayed Recall) and processing speed/executive function (Trails A&B times). Using median t scores from the first and last available visit to categorize social support as high or low (for Loneliness, low loneliness was categorized as “high” social support), support over time was classified as stable‐high, stable‐low, or “change” (high‐low or low‐high). Mixed‐effects regression models examined the demographic‐adjusted predictor‐outcome relationships between social support and cognition across visits.ResultIn this ADRC sample (mean age 65.2, SD = 9.2; Table 1), all three social support scores associated cross‐sectionally (Table 2) with Trails A and B performance. Relative to stable‐high participants, those reporting either stable‐low or declines from high to low social support exhibited poorer performance on measures of processing speed/executive function. Conversely, participants in the low‐high group performed comparably on cognitive tests to those in the stable‐high group (Table 3; Figure 1).ConclusionSocial support associated with processing speed/executive function in this sample. Participants who reported a change in social support performed comparably to those with either stable high or stable low support, suggesting that processing speed/executive function associated with social support may be modifiable in the shorter term. These findings underscore the cognitive cost of social isolation and highlight the substantial benefits of maintaining ‐ and improving ‐ social connections among middle aged and older adults.
Single amino acid change in the receptor binding domain of mouse APOE results in altered protein dynamics and worsened AD‐related cognitive impairment
Authors: Kaczorowski Catherine C. , Singh Surjeet , Kaur Harpreet , Hadad Niran , Telpoukhovskaia Maria , Zhang Jigang , Philip Vivek M. , O'Connell Kristen MS , Levine Zachary , Dunn Amy R 
Published: December 2022

AbstractBackground
APOE genotype is the strongest genetic modifier of late‐onset Alzheimer’s disease (AD) in humans. In genetically diverse mice, natural variation in the Apoe locus predicts AD‐related cognitive decline, with C57BL/6J (B6) mice harboring a protective variant compared to DBA/2J (D2) (Neuner 2019, Neuron). The mechanisms by which protective and detrimental Apoe/APOE variants affect cognitive decline in AD are not fully understood yet, but likely could provide an opportunity for personalized treatment and prevention strategies.MethodHere, we have used CRISPR/Cas9 gene editing to introduce the D2 Apoe variant into the B6 genome. We crossed these heterozygous APOEB6/E163D mice to B6 congenic heterozygous 5XFAD carriers in order to explore the effects of this single variant on AD‐related cognitive function, pathology, cell‐type specific gene dysregulation, and hippocampal and cortical network function. We also performed molecular dynamics modeling to ask how this variant affects APOE protein biophysics.Result5XFAD‐APOEB6/E163D mice showed exacerbated cognitive dysfunction compared to 5XFAD‐APOEB6/B6 mice, indicating that the single D2 variant in Apoe significantly contributes to AD‐related cognitive decline. We did not observe differences in amyloid pathology or phosphorylated tau across Apoe genotypes, suggesting that the effect on cognitive function is not mediated by pathological protein aggregation. However, snRNAseq revealed that excitatory neuron gene expression was substantially dysregulated in 5XFAD‐APOEB6/E163D mice compared to other cell types; we then performed in vivo electrophysiology to characterize how this translates to circuit‐level neuronal dysfunction. Finally, computational modeling of protein structure and function showed that the APOEE163D variant results in protein states most closely resembling human APOE4, particularly in the presence of lipids, suggesting that APOEE163D may show impaired lipid binding and transport function.ConclusionC57BL/6J mice harbor a protective Apoe variant which confers resiliency to AD‐related cognitive dysfunction. This protection, and–by the same measure–the detrimental effects of the DBA/2J variant of Apoe (APOEE163D), is likely ultimately mediated by altered neuronal gene expression and activity. We are currently exploring the intermediate mechanisms between APOEE163D and neuronal function; altered APOE protein states hint at impairments in lipid binding and transport, which may result in pathological lipid and protein accumulation affecting neuron function.
Neighborhood greenspace as a social determinant of health and how associations with brain health outcomes may differ by race/ethnicity
Authors: Besser Lilah M. , Jimenez Marcia Pescador , Meyer Oanh L. , George Kristen M. , Adkins‐Jackson Paris AJ , Mitsova Diana , Galvin James E 
Published: December 2022

AbstractBackgroundResidential greenspaces such a parks and other areas of natural vegetation are social determinants of health that have been associated with brain health outcomes including Alzheimer’s disease and related disorders (ADRD). Greenspace access is associated with reduced risk of ADRD‐related comorbidities and increased participation in risk‐reducing behaviors such as physical activity. Therefore, exposure to greenspace may present an ideal opportunity to encourage risk‐reducing behaviors while intervening on the impact of comorbidities on brain health. Although structural determinants of health such as residential segregation and the built environment may influence these outcomes, racial/ethnic minoritized groups are less likely to live in neighborhoods where physical activity is feasible. Additionally, such groups have elevated risk for comorbidities that may increase risk for ADRD. Yet few known studies have investigated greenspace and brain health by racial/ethnic group.MethodWe will include papers previously identified in a published rapid scoping review on greenspace and brain health outcomes (Besser, 2020; n = 22), and will employ the same review methods from that paper to identify additional papers published since February 13, 2020. For each article, we will catalog the racial/ethnic composition of the sample, observed differences between racial/ethnic groups, methods employed, other related findings, as well as guiding theories, conceptual frameworks, and causal mechanisms.ResultWe will: 1) examine the extent to which the current literature investigates racial/ethnic differences in greenspace and brain health associations; 2) cover the potential mechanisms relating greenspace to brain health and how these mechanisms may differentially impact individuals based on race/ethnicity; and 3) discuss the methodological issues surrounding the study of racial/ethnic disparities in greenspace‐brain health associations. Lastly, we will describe greenspace characteristics for select existing datasets and cohorts by race/ethnicity to provide context for future investigations using these and similar resources.ConclusionThe goal of this review is to provide a foundation for understanding and a starting point for studies of racial/ethnic differences in greenspace‐brain health associations.
Is childhood or midlife socioeconomic status more predictive of brain health across race/ethnicity?
Authors: Turney Indira C , Avila Justina F , Lao Patrick J. , Igwe Kay C , Rivera Andres M. , Berroa Joncarlos , Brickman Adam M. , Manly Jennifer J 
Published: December 2022

AbstractBackgroundLower lifecourse socioeconomic status (SES) is associated with worse cognition and greater risk for Alzheimer’s disease (AD). Parental level of educational attainment is one indicator of childhood SES, which predicts myriad health outcomes throughout the lifespan. It is unclear whether midlife SES moderates the impact of childhood SES on midlife outcomes, like brain health. Subgroup differences are important for future risk reduction efforts; therefore, we tested whether midlife SES modifies the influence of childhood SES similarly in White, Black, and Latinx middle‐aged adults.MethodParticipants were 569 middle‐aged older adults drawn from the Offspring study of Racial/Ethnic Disparities in AD (adult children of WHICAP participants), who received MRI (mean age = 54.5 (SD = 10.6) years; 46 non‐Latinx White, 131 non‐Latinx Black, 392 Latinx; 66% women). We used general linear models to examine the relationship of childhood SES (e.g., parental education) with MRI markers of cerebrovascular disease (e.g., white matter hyperintensity volume; WMH) and whether MSES (e.g., educational attainment) moderated this relationship, controlling for sex/gender and age.ResultWhite participants were more likely to have higher childhood SES (F(2,568) = 199.3, p<.001) and MSES (F(2,568) = 36.1, p<.001), followed by Black, then Latinx participants. In the full sample, childhood SES was not associated with WMH volume. Race/ethnicity stratified models revealed that greater childhood SES was associated with lower WMH volume, but only in White participants (B = ‐0.60, CI = ‐0.109,‐0.010). Midlife SES was not associated with WMH volume in the full sample or within each race/ethnicity group. Among White participants, midlife SES did not modify the effect of childhood SES on WMH volume. Midlife SES was unrelated to WMH volume in Black and Latinx participants.ConclusionWe found that childhood SES predicts brain health in middle aged White people. We found racial and ethnic subgroup differences in the relationship of socioeconomic indicators to brain health. However, future studies aim to further understand mechanisms of brain health disparities by considering other SES indicators than parental and offspring education, larger subgroup sample sizes, absolute versus relative SES mobility, other lived experiences, and cognitive outcomes.
Metabolomics Technologies for Defining Diet Influences on Brain Metabolome and in Alzheimer’s Disease
Authors: Dorrestein Pieter 
Published: December 2022

AbstractBackgroundDiet and our gut microbiota influence brain function. This is also true in Alzheimer’s disease. Technologies are emerging to inventory the complexity of the gut microbiome produced chemicals and also the complexity of chemicals released in the body from types of food we ingest. Many of these chemicals can cross blood brain barrier and can impact brain function.MethodIn this presentation, we will describe new technologies that enable us to understand the true diversity and complexities of the small molecules that can be detected using an MS/MS‐based untargeted metabolomics platform. Strategies, such as MASST, FoodMASST, and reference data‐driven metabolomics that enable an empirical readout of diet effects on metabolic profiles of AD patients will be discussed (Figure 1a).ResultThese new computational strategies provide a direct roadmap to relate diet, and diet ingredients, to clinical phenotypes such as empirical readout of variability of diet composition (Figure 1b), and how machine learning strategies, such as regression analysis, are employed to understand how the diet readouts relate to microbiome composition, cognition, and memory function from analysis of Alzheimer’s cohorts (Figure 1c). We will describe the influences of diet on brain metabolome in AD patients and links to imaging changes.ConclusionWe have developed a new metabolomics approach that can provide an empirical, and even retrospective, diet readout form clinical samples of AD patients. We illustrate how diet components relate to clinical symptoms in AD.
Deficiency of NMDA receptor subunit GluN3A as a pathogenic factor for endogenous amyloid deposition and sporadic Alzheimer’s disease
Authors: Yu Shan P , Zhong Weiwei , Berglund Ken , Gu Xiaohuan , Jiang Michael Q , Wei Ling 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease, evolving amyloidosis and tau protein hyperphosphorylation, synapse dysfunction, neuron degeneration and cognitive deficits. Investigations based on the Aβ/tau hypothesis have been performed in transgenic animal models expression familial/mutated AD genes. However, treatments based on this hypothesis have not provided effective clinical therapies. Hyperactivity of the glutamatergic NMDA receptor (NMDAR) is a common pathophysiology of AD and has been viewed as a consequence of Aβ pathology. Among NMDAR subunits, GluN3A is a unique inhibitory subunit that suppresses NMDA currents and Ca2+ influx. Recent evidence from rodent and human studies shows that GluN3A is widely expressed and plays important functional roles in neonatal and adult brains. Ca2+ overload is a trigger of excitotoxicity, while GluN3A plays a regulatory role of Ca2+ homeostasis. The role of GluN3A regulation in AD is unknown.MethodGluN3A knockout mice, gene modifications, immunohistochemistry, Western blotting, MEA recordings, Ca2+ imaging, pathological examinations, functional and behavioral tests.ResultChronic neuronal hyperactivity and Ca2+ dysregulation caused by GluN3A deficiency lead to slowly advanced “neurodegenerative excitotoxicity”, dementia and AD pathology in an age‐dependent manner. Ca2+ imaging and MultiElectrode Array recordings in GluN3A KO brain slices revealed moderate but sustained elevation of cytosolic Ca2+ levels, neuronal hyperactivity, and impaired synaptic plasticity compared to age matched controls. Aging GluN3A KO mice showed increased Ca2+‐dependent signals, chronic inflammation, neuronal loss and disease symptoms including early onset of olfactory dysfunction followed by cognitive deficits. β‐Amyloid deposition and tau protein hyperphosphorylation were identified as a late pathology in the cortex and hippocampus. Expression of GluN3A in the GluN3A KO brain prevented AD progression. Early treatment at the pre‐clinical stage using the NMDAR antagonist memantine prevented symptoms in GluN3A KO mice. Western blot analysis of AD patient’s brains showed lower levels of GluN3A in the cortex compared to normal aging subjects.ConclusionOur results identified a novel amyloid‐independent mechanism that the deficiency of GluN3A alone causes a slight lifelong Ca2+ dyshomeostasis, leading to AD pathophysiology and amyloid pathology. The long‐term GluN3A modulation of NMDARs signifies new therapeutic targets and possible preventive interventions for a sporadic type of AD.