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Sökning: WFRF:(Weiner Michael W.)

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1.
  • Adams, Hieab H. H., et al. (författare)
  • Novel genetic loci underlying human intracranial volume identified through genome-wide association
  • 2016
  • Ingår i: Nature Neuroscience. - 1097-6256 .- 1546-1726. ; 19:12, s. 1569-1582
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
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2.
  • Hibar, Derrek P., et al. (författare)
  • Common genetic variants influence human subcortical brain structures
  • 2015
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 520:7546, s. 224-U216
  • Tidskriftsartikel (refereegranskat)abstract
    • The highly complex structure of the human brain is strongly shaped by genetic influences(1). Subcortical brain regions form circuits with cortical areas to coordinate movement(2), learning, memory(3) and motivation(4), and altered circuits can lead to abnormal behaviour and disease(5). To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume(5) and intracranial volume(6). These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 X 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.
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3.
  • Hibar, Derrek P., et al. (författare)
  • Novel genetic loci associated with hippocampal volume
  • 2017
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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4.
  • Thompson, Paul M., et al. (författare)
  • The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
  • 2014
  • Ingår i: BRAIN IMAGING BEHAV. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
  • Tidskriftsartikel (refereegranskat)abstract
    • The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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5.
  • Satizabal, Claudia L., et al. (författare)
  • Genetic architecture of subcortical brain structures in 38,851 individuals
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
  • Tidskriftsartikel (refereegranskat)abstract
    • Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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6.
  • Deming, Yuetiva, et al. (författare)
  • Sex-specific genetic predictors of Alzheimer’s disease biomarkers
  • 2018
  • Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322. ; 136:6
  • 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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7.
  • Gonzales, Mitzi M., et al. (författare)
  • Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment
  • 2018
  • Ingår i: International Journal of Geriatric Psychiatry. - : John Wiley & Sons Inc.. - 0885-6230. ; 33:10, s. 1305-1311
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To investigate the association between chronic subsyndromal symptoms of depression (SSD), cerebrospinal fluid (CSF) biomarkers, and neuropsychological performance in individuals with mild cognitive impairment (MCI). Methods: Participants included 238 older adults diagnosed with MCI from the Alzheimer's Disease Neuroimaging Initiative repository with cognitive and CSF amyloid beta (Aβ1–42), total tau (t-tau), and phosphorylated tau (p-tau) data. The Neuropsychiatric Inventory identified individuals with chronic endorsement (SSD group N = 80) or no endorsement (non-SSD group N = 158) of depressive symptoms across timepoints. CSF biomarker and cognitive performance were evaluated with linear regression models adjusting for age, education, gender, APOE genotype, global cognitive status, and SSD group. Results: As compared to the non-SSD group, the SSD group displayed lower CSF Aβ1–42 levels (β = −24.293, S.E. = 6.345, P < 0.001). No group differences were observed for CSF t-tau (P = 0.497) or p-tau levels (P = 0.392). Lower CSF Aβ1–42 levels were associated with poorer performance on learning (β = 0.041, S.E. = 0.018, P = 0.021) and memory (β = −0.012, S.E. = 0.005, P = 0.031) measures, whereas higher CSF t-tau levels were associated with poorer performance on measures of global cognition (β = 0.022, S.E = 0.008, P = 0.007) and language (β = −0.010, S.E = 0.004, P = 0.019). SSD was independently associated with diminished global cognition, learning and memory, language, and executive function performance over and above the effects of CSF biomarkers (all P < 0.05). Conclusions: MCI participants with SSD displayed diminished CSF Aβ1–42 levels but did not differ from non-SSD controls in CSF tau levels. Additionally, CSF biomarkers and SSD independently accounted for variance in cognitive performance, suggesting that these factors may uniquely confer cognitive risk in MCI.
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8.
  • Insel, P. S., et al. (författare)
  • Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology
  • 2016
  • Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878. ; 86:20, s. 1887-1896
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate. Methods: In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ 42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression. Results: Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline. Conclusions: A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ 42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline. © 2016 American Academy of Neurology.
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9.
  • Insel, Philip S., et al. (författare)
  • Cognitive and functional changes associated with Aβ pathology and the progression to mild cognitive impairment
  • 2016
  • Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580. ; 48, s. 172-181
  • Tidskriftsartikel (refereegranskat)abstract
    • Cognitively-normal people with evidence of β-amyloid (Aβ) pathology and subtle cognitive dysfunction are believed to be at high risk for progression to mild cognitive impairment due to Alzheimer's disease (AD). Clinical trials in later stages of AD typically include a coprimary endpoint to demonstrate efficacy on both cognitive and functional assessments. Recent trials focus on cognitively-normal people, but functional decline has not been explored for trial designs in this group. The goal of this study was therefore to characterize cognitive and functional decline in (1) cognitively-normal people converting to mild cognitive impairment (MCI) and (2) cognitively-normal β-amyloid-positive (Aβ+) people. Specifically, we sought to identify and compare the cognitive and functional assessments and their weighted combinations that maximize the longitudinal decline specific to these 2 groups. We studied 68 people who converted from normal cognition to MCI and 70 nonconverters, as well as 137 Aβ+ and 210 β-amyloid-negative cognitively-normal people. We used bootstrap aggregation and cross-validated mixed-models to estimate the distribution of weights applied to cognitive and functional outcomes to form composites. We also evaluated best subset optimization. Using optimized composites, we estimated statistical power for a variety of clinical trial scenarios. Overall, 55.4% of cognitively-normal to MCI converters were Aβ+. Large gains in power estimates were obtained when requiring participants to have both subtle cognitive dysfunction and Aβ pathology compared with requiring Aβ pathology alone. Additional power resulted when including functional as well as cognitive outcomes as part of the composite. Composites formed by applying equal weights to all measures provided the highest estimates of cross-validated power, although similar to both continuous weight optimization and best subset optimization. Using a composite to detect a 30% slowing of decline, 80% power was obtained for predicted Aβ+ converters with 375 completers/arm for a 30-month trial using a combination of cognitive/ functional measures. In the Aβ+ group, power to approach levels suitable for a phase III clinical trial would require considerably larger sample sizes. Composites incorporating both cognitive and functional measures may substantially increase the power of a trial in a preclinical (Aβ+) AD population with subtle evidence of cognitive dysfunction.
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10.
  • Karikari, Thomas, et al. (författare)
  • Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer's Disease Neuroimaging Initiative.
  • 2021
  • Ingår i: Molecular psychiatry. - 1476-5578. ; 26
  • Tidskriftsartikel (refereegranskat)abstract
    • Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4-89.2%), as well as to distinguish between Aβ- and Aβ+ individuals along the Alzheimer's continuum (AUC = 76.9%; 95% CI, 74.0-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.
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