bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin‐like growth factor 1 (IGF1) gene therapy modulates behavior, neurogenesis, and synaptic proteins in a rat model of sporadic Alzheimer's disease
Authors: Villar Maria Florencia Zappa , Hanotte Juliette López , Pardo Joaquín , Reggiani Paula Cecilia 
Published: December 2020

AbstractBackgroundSporadic Alzheimer’s disease (SAD) is the most prevalent neurodegenerative disorder worldwide and it is characterized by progressive memory loss and cognitive impairment. Brain activation of insulin signaling preserves memory in animal models and appears beneficial for patients. In contrast, the role of insulin‐like growth factor 1 (IGF1) remains controversial. Our aim was to determine the possible protective actions of IGF1 in a rat SAD model induced by intracerebroventricular injection of streptozotocin (icv‐STZ). To this end, we drove the expression of IGF1 using a recombinant adenoviral vector, RAd‐IGF1.MethodWe evaluated 3 animal groups: Sham, STZ and STZ+IGF1. STZ and STZ+IGF1 groups were injected with 3 mg/kg icv‐STZ and, 7 days later, the STZ+IGF1 group received the icv‐RAd‐IGF1. During the last two weeks until the end of the study (day 24 post icv‐STZ), we performed several behavioral tests. Additionally, we analyzed neuroblast cells, synaptic proteins and IGF1‐signaling pathway proteins in the hippocampus.ResultIGF1 improved marble‐burying behavior, hippocampus‐dependent spatial memory, object recognition memory and decreased depression‐like behavior, all features affected by STZ. Also, brain IGF1 overexpression restored neurogenesis, enhanced SYT2, PSD95 and GAD65/67 levels, and modulated the IGF1 receptor signaling pathway in STZ animals.ConclusionResults indicate a protective role of IGF1 in our SAD model, as it was effective against behavior deficits and ameliorated hippocampal protein alterations induced by STZ. We conclude that IGF1 therapy has an interesting potential for SAD treatment.
Identification of multi‐issue protein quantitative trait loci (pQTLs) for Alzheimer disease
Authors: Yang Chengran , Farias Fabiana H.G. , Mihindukulasuriya Kathie A. , Davenport Richard , Wang Fengxian , Budde John P. , Rhinn Herve , Cruchaga Carlos , Harari Oscar 
Published: December 2020

AbstractBackgroundAlzheimer disease (AD) is a neurodegenerative disease, affecting around 5.8 million people in the United States as of 2019. It has been widely studied, but there is still no effective treatment. Using large‐scale Genome‐wide association studies and whole genome/exome sequencing, researchers have identified common and rare variants associated disease risk that can be used to build prediction models. However, there are limited studies that use high‐throughput genomic approaches to identify novel biomarkers beyond genetic variations.MethodWe profiled 1,305 proteins using SOMAscan platform for 971 CSF, 636 plasma, and 458 parietal lobe from participants of the Knight‐ADRC. We aim to identify the genetic architecture that govern protein levels and how do these proteins modulate AD risk, age at onset, rate of progression, and additional neurodegenerative traits. To do so, we first identified protein quantitative trait loci (pQTLs) from CSF, plasma, and brain tissues. Next, we inferred causality between proteins with significant pQTLs and AD and neurodegenerative traits employing Mendelian Randomization (MR) approaches.ResultWe identified pQTLs in each tissue. We found 26, 17, and 206 novel pQTLs, in brain, plasma and CSF respectively. We also successfully replicated several reported pQTLs from CSF (e.g. rs2673908 associated with the protein Siglec‐9) and plasma (e.g. rs12740374 associated with the protein Granulins). To infer the causality between proteins and AD or other neurological diseases, we performed MR analysis by using pQTLs as instrumental variables. Overall, we processed MR framework using proteins with significant pQTLs within each tissue on seven neurological‐related traits. Known protein‐disease relationships were replicated. For example, plasma Siglec‐3 (CD33) increases the AD risk, consistent with a larger plasma‐proteome MR analyses by Zheng and colleagues in 2019. We also uncovered the novel proteins in pathways associated with AD risk and additional endophenotypes. In total, we found between 6 to 25 potential new biomarkers for AD progression, depending on the tissue we evaluated. Similarly, we identified 2 to 21 proteins associated with for AD age at onset.ConclusionTaken together, these findings prioritized the proteins for the functional validation study. Thus, the findings helped identify potential biomarkers for AD or other neurological traits.
Raising awareness of Alzheimer’s clinical trials: Development of messages tailored to African American caregivers and individuals at risk
Authors: McGowan Melissa , Massett Holly A , Han Sae H , Watson Jennifer , Emmerson Karen , Burns Adam , Robinson Candice Watkins , Hummel Allyson , Silverberg Nina , Elliott Cerise L , Donley Grayson , Bernard Marie A 
Published: December 2020

AbstractBackgroundHigher rates of Alzheimer’s Disease (AD) and related dementias (ADRD) among African Americans compared to non‐Hispanic whites are well‐documented, as is the underrepresentation of African Americans in AD/ADRD clinical research. Key documented impediments to enrollment of African Americans are too few researchers offering studies and limited materials that provide culturally relevant information. This abstract presents findings from focus groups conducted by the National Institute on Aging (NIA) to identify salient, culturally appropriate message concepts that raise awareness, address barriers and motivate African Americans to consider participation in AD/ADRD studies.MethodNine focus groups (N=65) were conducted among three African American audiences who: 1) have a family history of AD/ADRD; 2) have no family history of AD/ADRD; and, 3) are caregivers of persons with AD/ADRD. Sessions explored participants’ knowledge, attitudes, and beliefs about AD/ADRD and AD/ADRD clinical research unaided and in the context of testing multiple message concepts designed to increase interest and encourage individuals to seek information regarding AD/ADRD clinical trials.ResultMessage concepts were categorized into three reaction types: positive, negative, and mixed. Concepts that positively increased interest in trials were those that portrayed hope for future generations, connected research with the potential to prevent/treat AD/ADRD, and directly addressed the higher AD/ADRD incidence rates among African Americans. Highlighting the need to find treatments that work for all races was a top motivator to consider a trial. Concepts that decreased interest in trials were those viewed as: being overly emotional; making generalizations about participants’ motivations; downplaying the history of medical abuse; and, using conditional language (“one day”, “may”, “hopefully”). All groups were more receptive to messages that established a realistic, personal connection. Concept visuals will be presented.ConclusionThis research conducted by the NIA improves our understanding of message concepts that are acceptable and motivating and which are unacceptable or inappropriate to African Americans around considering participating in AD/ADRD clinical research. The findings from this study will be used to develop, finalize and make available to the research community a suite of culturally appropriate, well‐tested materials to increase awareness of AD/ADRD and clinical research.
Comparison of cerebrospinal fluid phosphorylated tau 181 and 217 for cognitive progression
Authors: Mielke Michelle M. , Aakre Jeremiah A. , Algeciras‐Schimnic Alicia , Proctor Nicholas , Machulda Mary M. , Knopman David S. , Jack Clifford R. , Petersen Ronald C. , Dage Jeffrey L. 
Published: December 2020

AbstractBackgroundA previous study demonstrated that cerebrospinal fluid (CSF) phosphorylated tau 217 (pTau217), compared to phosphorylated tau 181 (pTau181), correlated more strongly with Tau PET and was better able to distinguish between AD and non‐AD neurodegenerative diseases. The aim of this study was to compare these two CSF tau markers for cognitive progression.MethodWe included 666 cognitively unimpaired (CU) and 89 mild cognitive impairment (MCI) Mayo Clinic Study on Aging community‐based participants (mean age of 71.6 years) with CSF amyloid and tau measurements. CSF amyloid‐beta 42 (Aβ42) was measured with automated electrochemiluminescence Elecsys immunoassays (Roche Diagnostics); a cut‐off of <1026 pg/ml was considered amyloid positive (A+). CSF pTau181 and pTau217 were measured with the Mesoscale discovery platform (MSD). Cutoffs of pTau181≥217 pg/ml and pTau217≥288 pg/ml were considered tau positive (T+). Cox proportional hazards models with time as the time scale were used to examine the relationship between the CSF markers and progression from CU to MCI and MCI to dementia. Covariates included age, sex, education, and APOE.ResultTau positivity (T+) based on pTau217 (HR = 2.45, 95% CI: 1.45, 4.11) was a greater risk factor for incident MCI compared to pTau181 (HR = 2.07, 95% CI: 1.19, 3.61). Among individuals who were A+T+, T+ based on pTau217 (HR = 3.01, 95% CI: 1.66‐5.45) was a greater risk factor of incident MCI than pTau181 (2.80, 95% CI: 1.48, 5.31). Among the 89 MCI participants, T+ based on pTau217 was a much greater risk factor for dementia (HR = 4.92, 95% CI: 1.37, 17.61) than pTau181 (HR = 1.55, 95% CI: 0.43‐5.55).ConclusionCSF pTau217 is a better marker of cognitive progression, especially from MCI to dementia, compared to CSF pTau181.
“I understand a fury in your words, but not the words”: The association of dementia caregiving styles and salivary cortisol
Authors: Leggett Amanda N , Hodgson Nancy A , Connell Cathleen M , Gitlin Laura N , Kales Helen C 
Published: December 2020

AbstractBackgroundDysregulated cortisol patterns are indicators of physiological stress and may show evidence that caregiving for a person living with dementia (PLwD) can get under the skin. While the stress process of caregiving has been well observed, less attention has focused on the cognitive‐behavioral care management styles of dementia caregivers and how they may impact care outcomes such as physiological stress. Prior work by this team has identified five distinct caregiving styles through qualitative analysis of an interview regarding caregivers’ cognitive‐behavioral care management approach: “Externalizers” (superficial understanding, self‐focused, expressions of anger or frustration), “Individualists” (provide care by going it alone, emotionally removed), “Learners” (recognize need to change approach but are stuck, emotionally turbulent), “Nurturers” (positive affect and empathy, reflect natural mastery), and “Adapters” (arsenal of acquired management strategies, adapt to challenges). We hypothesize that more maladaptive care styles (e.g. Externalizers, Learners) will show evidence of dysregulated cortisol patterns.MethodParticipants included 100 primary family caregivers for PLwD who were 74% female, 18% non‐White, and on average 64 years old. Saliva was collected via passive drool method over two days. Two markers of salivary cortisol, area under the curve (AUC), and cortisol awakening response (CAR) were examined as separate outcomes in linear regressions, with caregiving styles as the key predictors (Nurturers as the reference group), and demographic characteristics, caregiver burden, depression, and sleep disturbance as covariates.ResultAccounting for controls, having an Externalizer caregiving style was significantly associated with an elevated cortisol output (greater AUC), relative to having a Nurturer care style (β=0.33, p<.05). There was also a trend towards greater caregiver depression and larger AUCs (β=0.31, p=.059). Caregiving style was not significantly associated with the CAR.ConclusionHaving an Externalizing care style characterized by expressions of anger, frustration, and lack of understanding of dementia is associated with an elevated cortisol pattern. This dysregulated pattern may put Externalizers at increased risk for a number of physical and mental health conditions relative to other caregiving styles. Assessing caregiving style in addition to care stressors may help identify caregivers in need of targeted intervention and help prevent negative health outcomes.
The influence of neighborhood factors on biological measures of stress in home‐dwelling multi‐ethnic older adults with dementia
Authors: Hodgson Nancy A 
Published: December 2020

AbstractBackgroundRecently researchers have begun to examine the possible biological pathways through which neighborhood context may affect the health of vulnerable residents. Although stress is often hypothesized to contribute to the effects of neighborhoods on health, no studies have investigated associations of neighborhood characteristics and stress biomarkers in home dwelling persons living with dementia (PLwD). Identifying these biological pathways is fundamental to increasing our understanding of how neighborhoods can influence health and well being in vulnerable residents including those with dementia.MethodsGuided by the National Institute on Minority Health and Health Disparities Framework, this pilot study examined pathways linking both micro (individual level) and macro (neighborhood) level factors in home dwelling PLwD. The model was used to determine what community level factors (density, total crime index, median home value, and noise index) were associated with measures of salivary cortisol controlling for sociodemographics, dementia stage, and comorbid illnesses. The sample included 100 participants: 30 Whites, 39 African Americans, and 31 Latinos with an average age of 73.6. Saliva samples were collected using Salivette collection tubes over two days and stored at −20 °C until analysis.ResultsResidents of neighborhoods with lower housing value and higher noise and density were disproportionately composed of racial/ethnic minorities (with the patterning for Hispanics more pronounced than for blacks.) Significantly lower levels of cortisol at wakeup and a less steep decline was associated with adverse neighborhood environments (higher noise, crime, density, and lower housing value). The strongest relationship between neighborhood characteristics and cortisol levels was found for neighborhood crime. Individuals with dementia residing in higher crime neighborhoods had significant lower levels of cortisol at wakeup and with less pronounced initial declines than those residing in low crime neighborhoods.ConclusionGiven that lower cortisol at wakening and slower rate of decline in cortisol across the day are associated with adverse health outcomes, our analyses can inform the identification of risky communities that are most likely to benefit from health‐supportive community interventions to minimize the negative impacts of unsupportive community environment. These pilot results suggest that further investigation of the effects of neighborhood contexts on stress biomarkers and health outcomes in PLwD is warranted.
Proteomic, metabolomic, and transcriptomic examination of APOE transgenic mice
Authors: Mohler Eric G. , Ried Janina S. , Bahnassawy Lamiaa , Reinhardt Peter , Curado Marco Rocha , Bakker Margot H.M. , Nicolas Armel , Rao Francesco , Kohler Isabelle , Hankemeier Thomas , Ramaswamy Gayathri , Sáez María Eugenia 
Published: December 2020

AbstractBackgroundADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) is an Innovative Medicines Initiative (IMI) project that focuses on apolipoprotein E (APOE) as it relates to Alzheimer’s disease. As part of this effort, the utility of APOE transgenic mice as a model of human apoE function was investigated. Specifically, proteomic, metabolomic, and transcriptomic analyses were conducted in aged APOE transgenic mice: ε2/2, ε3/3, ε4/4, knock‐out (KO).MethodsTwo studies were conducted. An initial proteomic and metabolomic study was conducted in brain tissue from male and female 22‐month old APOE ε3/3 and ε4/4 mice. A second proteomic, metabolomic, and transcriptomic study was conducted in brain tissue from 16‐month old APOE ε2/2, ε3/3, ε4/4, or KO mice receiving a low‐fat/low‐sucrose or high‐fat/high‐sucrose diet.ResultsProtein changes (upregulated and downregulated) in 22‐month old APOE ε4 males and females relative to age/sex matched ε3 mice were related to apoE function (LDL), immune function (IgGs) and cellular structure/function. Metabolomic differences in APOE ε4 female and/or male mice relative to ε3 mice were observed for lysophospholipid metabolites, sphinganine; and cholic acid. Enrichment analysis of top genes from the different comparisons involving the ε4 allele (ε 4vs ε3, ε4vs ε2 and ε4 vs KO) showed effects in mitochondrial/respiratory chain and immune‐related pathways.ConclusionProteomic, metabolomic, and transcriptomic examination in APOE ε4 transgenic mice indicate genotype differences consistent with previously described effects of apoE on immune function and lipid signaling. Additional work in ADAPTED will characterize proteomic and metabolomic phenotypes in human‐derived inducible pluripotent stem cells and human patient samples. Comparison of the results across human cells, human samples, and the present findings will demonstrate the potential utility (or lack thereof) for APOE animal models. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This study was sponsored by AbbVie, Inc. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the abstract. Some authors are currently employed by AbbVie and may own AbbVie stock.
Teaching old drugs new tricks: Do cardiovascular medications effect cognitive decline?
Authors: Newby Danielle , Winchester Laura , Sproviero William , Fernandes Marco , Launer Lenore J. , Lovestone Simon , Nevado‐Holgado Alejo J 
Published: December 2020

AbstractBackgroundCardiovascular disease affects multiple organs beyond those of the cardiovascular system including the brain. However, the mechanisms linking cardiovascular disease and cognitive decline are still poorly understood. Studies suggest specific cardiovascular medications targeting different mechanisms may slow cognitive decline and reduce dementia risk in later life. We investigated the association of specific blood pressure (BP) lowering medications and cognitive decline over time in a nation‐wide study of aging.MethodWe utilised the English Longitudinal Study of Ageing cohort accessed via the Dementia’s platform UK. At baseline this cohort contained over 10,000 dementia‐free adults older than 50 years old [mean age 65 years, 54% female, 39% hypertension] followed up to 15 years. We included individuals with either a diagnosis of hypertension, taking any BP lowering medications or having systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg [mean 144 SBP and 79 DBP mmHg]. Cognition was assessed at multiple time points using memory and executive function tests. We examined the following drug classes: angiotensin‐converting enzyme inhibitors and angiotensin II receptor blockers, beta‐blockers, calcium channel blockers, diuretics and any other blood lowering medications. We applied inverse probability weighting to linear mixed effect models to assess treatment effects and to control for factors that may influence the propensity to be treated with a BP‐lowering medication.ResultParticipants taking any BP‐lowering medication, regardless of drug class, had slower cognitive decline compared to non‐drug users. For example, drug users had an increase of 0.032 per year for memory tests (p value 0.0016). Comparing specific drug classes with no drug users or between the other drug classes, the overall trend indicates most drug classes slowed cognitive decline, however the results lacked statistical significance.ConclusionWe have established BP‐lowering medications effect cognitive decline. Further follow up is required to further understand the specific drug class effects using other real world datasets. This work provides an evidence base for further exploration into the management of cardiovascular health as a preventative strategy for maintaining brain health and slowing cognitive decline. In turn, this could inform health policy strategies for reducing dementia risk earlier in life.
Accounting for systematic spatiotemporal variation improves connectome‐based models of tau spreading in human Alzheimer’s disease
Authors: Vogel Jacob W. , Young Alexandra L. , Oxtoby Neil P. , Smith Ruben , Ossenkoppele Rik , Aksman Leon M , Strandberg Olof , La Joie Renaud , Grothe Michel J. , Rabinovici Gil D. , Alexander Daniel C. , Evans Alan C. , Hansson Oskar 
Published: December 2020

AbstractBackgroundStudies in cells, animals and humans have each provided evidence that, in an Alzheimer’s disease (AD) context, tau may be spreading through the brain transneuronally. This information may be useful for modeling the spread of tau in humans. However, such models are confounded by the substantial heterogeneity in spreading patterns observed in AD. In this talk, I will discuss i) application of an epidemic spreading model (ESM) to tau‐PET data to model the spread of tau through the human connectome; ii) application of a spatiotemporal subtyping algorithm to identify separable tau‐spreading patterns; 3) how accounting for these heterogeneous patterns can improve connectome‐based models.MethodThe ESM simulates diffusion of an agent through a system of connected brain regions measured with diffusion tractography. We compare simulations across 312 individuals to observed tau‐PET data. We next use the Subtype and Staging Inference (SuStaIn), an algorithm combining disease progression models with clustering, to identify spatiotemporal subtypes of tau spreading across 1143 individuals. We describe demographic, cognitive and genetic associations with each subtype, and evaluate their stability over time and across different radiotracers. Finally, we apply the ESM separately to each AD subtype to assess whether overall model accuracy is improved by accounting for individual subtype.ResultThe best‐fitting ESM used the entorhinal cortex as the model epicenter, and explained 70% of the variance in the overall tau‐PET pattern across subjects. SuStaIn identified four spatiotemporal subtypes with differing tau‐PET patterns and phenotypic profiles: Limbic‐predominant, limbic‐sparing, posterior, and lateral‐temporal. These same four subtypes were observed in a separate cohort using a different radiotracer (similarity 0.7‐0.9). 86% of subjects exhibited the same subtype at follow‐up. The ESM selected a different epicenter for each subtype, and accounting for subtype‐specific variation resulted in a 17% improvement in model performance.ConclusionConnectome‐based models explain the majority of spatial variation in tau‐PET patterns. However, a one‐size‐fits‐all approach fails to account for heterogeneity of tau‐spreading patterns. Four stable phenotypes were observed, which may be characterized by vulnerability of different cortico‐limbic networks. Accounting for this heterogeneity will be necessary for any predictive modeling of tau spreading moving forward.