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Sökning: WFRF:(Serrano Geidy E)

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1.
  • Guerreiro, R., et al. (författare)
  • Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
  • 2018
  • Ingår i: Lancet Neurology. - : Lancet Ltd. - 1474-4422. ; 17:1, s. 64-74
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
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2.
  • Palmqvist, S., et al. (författare)
  • Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders
  • 2020
  • Ingår i: Jama-Journal of the American Medical Association. - : American Medical Association. - 0098-7484. ; 324:8, s. 772-781
  • Tidskriftsartikel (refereegranskat)abstract
    • Key PointsQuestionWhat is the discriminative accuracy of plasma phospho-tau217 (P-tau217) for differentiating Alzheimer disease from other neurodegenerative disorders? FindingsIn this cross-sectional study that included 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated Alzheimer disease from other neurodegenerative diseases (area under the receiver operating characteristic curve of 0.89 in a neuropathologically defined cohort and 0.96 in a clinically defined cohort), with performance that was significantly better than established Alzheimer disease plasma- and MRI-based biomarkers but not significantly different from key CSF- or PET-based biomarkers. MeaningAlthough plasma P-tau217 was able to discriminate Alzheimer disease from other neurodegenerative diseases, further research is needed to validate the findings in unselected and diverse populations, optimize the assay, and determine its potential role in clinical care. ImportanceThere are limitations in current diagnostic testing approaches for Alzheimer disease (AD). ObjectiveTo examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD. Design, Setting, and ParticipantsThree cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n=301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n=178), AD dementia (n=121), and other neurodegenerative diseases (n=99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017). ExposuresPlasma P-tau217. Main Outcomes and MeasuresPrimary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET]). ResultsMean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P<.05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P<.001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P>.15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman rho =0.64; P<.001), but not without (Spearman =0.15; P=.33), beta -amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF A beta 42:A beta 40 ratio, and MRI measures (AUC range, 0.67-0.90; P<.05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P=.22). Conclusions and RelevanceAmong 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care. This cross-sectional study compares the accuracy of plasma tau phosphorylated at threonine 217 (P-tau217) levels vs other plasma-, MRI-, CSF-, and PET-based markers for distinguishing Alzheimer from other neurodegenerative diseases in 3 cohorts in Arizona, Sweden, and Columbia with or at risk for dementia.
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3.
  • Janelidze, Shorena, et al. (författare)
  • Increased CSF biomarkers of angiogenesis in Parkinson disease
  • 2015
  • Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878 .- 1526-632X. ; 85:21, s. 1834-1842
  • Tidskriftsartikel (refereegranskat)abstract
    • To study biomarkers of angiogenesis in Parkinson disease (PD), and how these are associated with clinical characteristics, blood-brain barrier (BBB) permeability, and cerebrovascular disease.
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4.
  • Janelidze, Shorena, et al. (författare)
  • Plasma P-tau181 in Alzheimer’s disease : relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia
  • 2020
  • Ingår i: Nature Medicine. - : Nature Publishing Group. - 1078-8956. ; 26:3, s. 379-386
  • Tidskriftsartikel (refereegranskat)abstract
    • Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer’s disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87–0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94–0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials.
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5.
  • Kun-Rodrigues, Celia, et al. (författare)
  • A comprehensive screening of copy number variability in dementia with Lewy bodies.
  • 2019
  • Ingår i: Neurobiology of aging. - : Elsevier. - 1558-1497. ; 75
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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6.
  • Kun-Rodrigues, Celia, et al. (författare)
  • Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies
  • 2017
  • Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 01974-580 .- 1558-1497. ; 49
  • Tidskriftsartikel (refereegranskat)abstract
    • . C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of . C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of . C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that . C9orf72 repeat expansions are not causally associated with DLB.
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7.
  • Mattsson-Carlgren, Niklas, et al. (författare)
  • Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau
  • 2021
  • Ingår i: EMBO Molecular Medicine. - : Federation of European Neuroscience Societies and Blackwell Publishing Ltd. - 1757-4676.
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.
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