| 1. |
- Dumitrescu, L., et al.
(författare)
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Sex differences in the genetic predictors of Alzheimer's pathology
- 2019
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 142, s. 2581-2589
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Tidskriftsartikel (refereegranskat)abstract
- Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 x 10(-8)) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 x 10(-8)) but not females (P = 0.85, sex-interaction P = 2.9 x 10(-4)). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
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| 2. |
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| 3. |
- Deming, Yuetiva, et al.
(författare)
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Sex-specific genetic predictors of Alzheimer’s disease biomarkers
- 2018
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 136:6, s. 857-872
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.
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| 4. |
- Jefferson, A. L., et al.
(författare)
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The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview
- 2016
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 52:2, s. 539-559
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. Objective: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. Methods: From September 2012 to November 2014, 335 participants age 60-92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73 +/- 8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72 +/- 7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. Results: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values <0.001), were more likely to be APOE epsilon 4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower A beta(42) (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. Conclusion: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline.
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| 5. |
- Gifford, W. A., et al.
(författare)
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Managerial leadership for research use in nursing and allied health care professions: a systematic review
- 2018
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Ingår i: Implementation Science. - : Springer Science and Business Media LLC. - 1748-5908. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Leadership by point-of-care and senior managers is increasingly recognized as critical to the acceptance and use of research evidence in practice. The purpose of this systematic review was to identify the leadership behaviours of managers that are associated with research use by clinical staff in nursing and allied health professionals. Methods: A mixed methods systematic review was performed. Eight electronic bibliographic databases were searched. Studies examining the association between leadership behaviours and nurses and allied health professionals' use of research were eligible for inclusion. Studies were excluded if leadership could not be clearly attributed to someone in a management position. Two reviewers independently screened abstracts, reviewed full-text articles, extracted data and performed quality assessments. Narrative synthesis was conducted. Results: The search yielded 7019 unique titles and abstracts after duplicates were removed. Three hundred five full-text articles were reviewed, and 31 studies reported in 34 articles were included. Methods used were qualitative (n = 19), cross-sectional survey (n = 9), and mixed methods (n = 3). All studies included nurses, and six also included allied health professionals. Twelve leadership behaviours were extracted from the data for point-of-care managers and ten for senior managers. Findings indicated that managers performed a diverse range of leadership behaviours that encompassed change-oriented, relation-oriented and task-oriented behaviours. The most commonly described behavior was support for the change, which involved demonstrating conceptual and operational commitment to research-based practices. Conclusions: This systematic review adds to the growing body of evidence that indicates that manager-staff dyads are influential in translating research evidence into action. Findings also reveal that leadership for research use involves change and task-oriented behaviours that influence the environmental milieu and the organisational infrastructure that supports clinical care. While findings explain how managers enact leadership for research use, we now require robust methodological studies to determine which behaviours are effective in enabling research use with nurses and allied health professionals for high-quality evidence-based care.
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| 6. |
- Hohman, Timothy J, et al.
(författare)
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Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau.
- 2018
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 75:8
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Tidskriftsartikel (refereegranskat)abstract
- The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy.This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017.Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles.Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β=0.41; 95% CI, 0.27-0.55; P<.001) and phosphorylated tau (β=0.24; 95% CI, 0.09-0.38; P=.001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β=0.41; 95% CI, 0.20-0.62; P<.001) but not among amyloid-negative individuals (β=0.06; 95% CI, -0.18 to 0.31; P=.62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden.We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.
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| 7. |
- Osborn, K. E., et al.
(författare)
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Cerebrospinal fluid beta-amyloid(42) and neurofilament light relate to white matter hyperintensities
- 2018
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 68, s. 18-25
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Tidskriftsartikel (refereegranskat)abstract
- White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of beta-amyloid(42) deposition (A beta(42)), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 +/- 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-epsilon 4 carrier status. A beta(42) (beta = -0.001, p = 0.007) and NFL (beta = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and A beta(42) accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury. (C) 2018 Elsevier Inc. All rights reserved.
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| 8. |
- Libby, J. B., et al.
(författare)
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Whole blood transcript and protein abundance of the vascular endothelial growth factor family relate to cognitive performance
- 2023
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 124, s. 11-17
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Tidskriftsartikel (refereegranskat)abstract
- The vascular endothelial growth factor (VEGF) family of genes has been implicated in the clinical devel-opment of Alzheimer's Disease (AD). A previous study identified associations between gene expression of VEGF family members in the prefrontal cortex and cognitive performance and AD pathology. This study explored if those associations were also observed in the blood. Consistent with previous observations in brain tissue, higher blood gene expression of placental growth factor (PGF) was associated with a faster rate of memory decline (p= 0.04). Higher protein abundance of FMS-related receptor tyrosine kinase 4 (FLT4) in blood was associated with biomarker levels indicative of lower amyloid and tau pathology, op-posite the direction observed in brain. Also, higher gene expression of VEGFB in blood was associated with better baseline memory (p= 0.008). Notably, we observed that higher gene expression of VEGFB in blood was associated with lower expression of VEGFB in the brain (r =-0.19, p= 0.02). Together, these re-sults suggest that the VEGFB, FLT4, and PGF alterations in the AD brain may be detectable in the blood compartment.Published by Elsevier Inc.This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )
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| 9. |
- Milfont, T. L., et al.
(författare)
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On the Relation Between Social Dominance Orientation and Environmentalism: A 25-Nation Study
- 2018
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Ingår i: Social Psychological and Personality Science. - : SAGE Publications. - 1948-5506 .- 1948-5514. ; 9:7, s. 802-814
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Tidskriftsartikel (refereegranskat)abstract
- Approval of hierarchy and inequality in society indexed by social dominance orientation (SDO) extends to support for human dominance over the natural world. We tested this negative association between SDO and environmentalism and the validity of the new Short Social Dominance Orientation Scale in two cross-cultural samples of students (N = 4,163, k = 25) and the general population (N = 1,237, k = 10). As expected, the higher people were on SDO, the less likely they were to engage in environmental citizenship actions, pro-environmental behaviors and to donate to an environmental organization. Multilevel moderation results showed that the SDO-environmentalism relation was stronger in societies with marked societal inequality, lack of societal development, and environmental standards. The results highlight the interplay between individual psychological orientations and social context, as well as the view of nature subscribed to by those high in SDO.
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| 10. |
- Moore, E. E., et al.
(författare)
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Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences
- 2020
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Introduction While Alzheimer's disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. Methods Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n= 18, 75 +/- 8 years), moderate (n= 89 72 +/- 7 years), and severe subtypes (n= 18, 78 +/- 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-epsilon 4 status, CSF biomarkers of amyloid beta (A beta), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. Results Stages differed at baseline onAPOE-epsilon 4 status (early < middle = late;p-values < 0.03) and CSF A beta (early > middle = late), phosphorylated and total tau (early = middle < late;p-values < 0.05), and neurogranin concentrations (early = middle < late;p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late;p-values < 0.03). Discussion Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets.
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