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1.
J Alzheimers Dis ; 79(3): 1041-1054, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427733

RESUMO

BACKGROUND: Understanding metabolic mechanisms associated with cognitive changes preceding an Alzheimer's disease (AD) diagnosis could advance our understanding of AD progression and inform preventive methods. OBJECTIVE: We investigated the metabolomics of the early changes in executive function and delayed recall, the earliest aspects of cognitive function to change in the course of AD development, in order to better understand mechanisms that could contribute to early stages and progression of this disease. METHODS: This investigation used longitudinal plasma samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort of participants who were dementia free at enrollment and enriched with a parental history of AD. Metabolomic profiles were quantified for 2,324 fasting plasma samples among 1,200 participants, each with up to three study visits, which occurred every two years. Metabolites were individually tested for association with executive function and delayed recall trajectories across age. RESULTS: Of 1,097 metabolites tested, levels of seven were associated with executive function trajectories, including an amino acid cysteine S-sulfate and three fatty acids, including erucate (22 : 1n9), while none were associated with delayed recall trajectories. Replication was attempted for four of these metabolites that were present in the Vietnam Era Twin Study of Aging (VETSA). Although none reached statistical significance, three of these associations showed consistent effectdirections. CONCLUSION: Our results suggest potential metabolomic mechanisms that could contribute to the earliest signs of cognitive decline. In particular, fatty acids may be associated with cognition in a manner that is more complex than previously suspected.

2.
Nat Genet ; 53(1): 65-75, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398198

RESUMO

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Assuntos
Grupos de Populações Continentais/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Invasividade Neoplásica , Razão de Chances , Neoplasias da Próstata/diagnóstico , Fatores de Risco
3.
Commun Biol ; 4(1): 63, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33437055

RESUMO

The study of metabolomics and disease has enabled the discovery of new risk factors, diagnostic markers, and drug targets. For neurological and psychiatric phenotypes, the cerebrospinal fluid (CSF) is of particular importance. However, the CSF metabolome is difficult to study on a large scale due to the relative complexity of the procedure needed to collect the fluid. Here, we present a metabolome-wide association study (MWAS), which uses genetic and metabolomic data to impute metabolites into large samples with genome-wide association summary statistics. We conduct a metabolome-wide, genome-wide association analysis with 338 CSF metabolites, identifying 16 genotype-metabolite associations (metabolite quantitative trait loci, or mQTLs). We then build prediction models for all available CSF metabolites and test for associations with 27 neurological and psychiatric phenotypes, identifying 19 significant CSF metabolite-phenotype associations. Our results demonstrate the feasibility of MWAS to study omic data in scarce sample types.

6.
J Natl Cancer Inst ; 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32853339

RESUMO

BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease. METHODS: Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

7.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

8.
Cancer Epidemiol Biomarkers Prev ; 29(7): 1381-1388, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32385116

RESUMO

BACKGROUND: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups. METHODS: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA ≥2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups. RESULTS: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel. CONCLUSIONS: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel. IMPACT: Our multiethnic investigation suggests potential for the 4K panel to improve current prostate cancer screening practices.

9.
Genet Epidemiol ; 43(6): 657-674, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31104335

RESUMO

Although Alzheimer's disease (AD) is highly heritable, genetic variants are known to be associated with AD only explain a small proportion of its heritability. Genetic factors may only convey disease risk in individuals with certain environmental exposures, suggesting that a multiomics approach could reveal underlying mechanisms contributing to complex traits, such as AD. We developed an integrated network to investigate relationships between metabolomics, genomics, and AD risk factors using Wisconsin Registry for Alzheimer's Prevention participants. Analyses included 1,111 non-Hispanic Caucasian participants with whole blood expression for 11,376 genes (imputed from dense genome-wide genotyping), 1,097 fasting plasma metabolites, and 17 AD risk factors. A subset of 155 individuals also had 364 fastings cerebral spinal fluid (CSF) metabolites. After adjusting each of these 12,854 variables for potential confounders, we developed an undirected graphical network, representing all significant pairwise correlations upon adjusting for multiple testing. There were many instances of genes being indirectly linked to AD risk factors through metabolites, suggesting that genes may influence AD risk through particular metabolites. Follow-up analyses suggested that glycine mediates the relationship between carbamoyl-phosphate synthase 1 and measures of cardiovascular and diabetes risk, including body mass index, waist-hip ratio, inflammation, and insulin resistance. Further, 38 CSF metabolites explained more than 60% of the variance of CSF levels of tau, a detrimental protein that accumulates in the brain of AD patients and is necessary for its diagnosis. These results further our understanding of underlying mechanisms contributing to AD risk while demonstrating the utility of generating and integrating multiple omics data types.


Assuntos
Doença de Alzheimer/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Genômica/métodos , Metaboloma , Transcriptoma , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
10.
Neurology ; 92(16): e1878-e1889, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30867273

RESUMO

OBJECTIVE: To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated ß-amyloid (Aß) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. METHODS: Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aß burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aß was different among KL-VS heterozygotes compared to noncarriers. RESULTS: APOE4 carriers exhibited greater Aß burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aß load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aß burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. CONCLUSION: In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aß aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E4/genética , Adulto , Peptídeos beta-Amiloides/genética , Heterozigoto , Humanos , Longevidade , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Wisconsin
11.
Genet Med ; 21(9): 1969-1976, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30846882

RESUMO

PURPOSE: We aimed to estimate the carrier frequency of Zellweger spectrum disorder (ZSD), a rare autosomal recessive disease, and the associated disease incidence based on data from the Exome Aggregation Consortium (ExAC) of approximately 60,000 individuals. METHODS: We obtained variants from ExAC in 13 PEX genes associated with ZSD. Potentially pathogenic missense variants were identified with computational variant analysis tools according to three stringency levels. Using variants classified as potentially pathogenic, we estimated the carrier frequency and the associated incidence for the entire ExAC population and its subpopulations. We also evaluated variants based on pathogenicity criteria for sequence variant interpretation outlined by the American College of Medical Genetics and Genomics (ACMG) and calculated the carrier frequency and incidence based on those variants. RESULTS: The bioinformatically estimated incidence rate of ZSD in the ExAC population is 1 in 83,841 using our least stringent pathogenicity cutoff. Under clinical guidelines outlined by ACMG, the estimated incidence is 1 in 3,275,751 births. CONCLUSION: We outlined a process for estimating the ZSD disease carrier frequency and incidence in a large consortium using bioinformatics tools. Our results are close to current newborn screening estimates in New York of 1 in 90,000 births, estimated from 1.08 million screenings.


Assuntos
Exoma/genética , Triagem de Portadores Genéticos/métodos , Predisposição Genética para Doença , Síndrome de Zellweger/diagnóstico , Biologia Computacional , Bases de Dados Genéticas , Variação Genética , Humanos , Recém-Nascido , Mutação , Triagem Neonatal/métodos , Síndrome de Zellweger/epidemiologia , Síndrome de Zellweger/genética
12.
Aging (Albany NY) ; 11(4): 1262-1282, 2019 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-30799310

RESUMO

Understanding how metabolites are longitudinally influenced by age and sex could facilitate the identification of metabolomic profiles and trajectories that indicate disease risk. We investigated the metabolomics of age and sex using longitudinal plasma samples from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort of participants who were dementia free at enrollment. Metabolomic profiles were quantified for 2,344 fasting plasma samples among 1,212 participants, each with up to three study visits. Of 1,097 metabolites tested, 623 (56.8%) were associated with age and 695 (63.4%) with sex after correcting for multiple testing. Approximately twice as many metabolites were associated with age in stratified analyses of women versus men, and 68 metabolite trajectories significantly differed by sex, most notably including sphingolipids, which tended to increase in women and decrease in men with age. Using genome-wide genotyping, we also report the heritabilities of metabolites investigated, which ranged dramatically (0.2-99.2%); however, the median heritability of 36.2% suggests that many metabolites are highly influenced by a complex combination of genomic and environmental influences. These findings offer a more profound description of the aging process and may inform many new hypotheses regarding the role metabolites play in healthy and accelerated aging.


Assuntos
Envelhecimento/sangue , Envelhecimento/fisiologia , Metabolômica , Idoso , Envelhecimento/genética , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais
13.
Alzheimers Res Ther ; 10(1): 124, 2018 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-30579367

RESUMO

BACKGROUND: Trimethylamine N-oxide (TMAO), a small molecule produced by the metaorganismal metabolism of dietary choline, has been implicated in human disease pathogenesis, including known risk factors for Alzheimer's disease (AD), such as metabolic, cardiovascular, and cerebrovascular disease. METHODS: In this study, we tested whether TMAO is linked to AD by examining TMAO levels in cerebrospinal fluid (CSF) collected from a large sample (n = 410) of individuals with Alzheimer's clinical syndrome (n = 40), individuals with mild cognitive impairment (MCI) (n = 35), and cognitively-unimpaired individuals (n = 335). Linear regression analyses were used to determine differences in CSF TMAO between groups (controlling for age, sex, and APOE ε4 genotype), as well as to determine relationships between CSF TMAO and CSF biomarkers of AD (phosphorylated tau and beta-amyloid) and neuronal degeneration (total tau, neurogranin, and neurofilament light chain protein). RESULTS: CSF TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals, and elevated CSF TMAO is associated with biomarkers of AD pathology (phosphorylated tau and phosphorylated tau/Aß42) and neuronal degeneration (total tau and neurofilament light chain protein). CONCLUSIONS: These findings provide additional insight into gut microbial involvement in AD and add to the growing understanding of the gut-brain axis.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/microbiologia , Microbioma Gastrointestinal , Metilaminas/líquido cefalorraquidiano , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
14.
BMC Genet ; 19(Suppl 1): 65, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30255764

RESUMO

BACKGROUND: Random forest (RF) is a machine-learning method that generally works well with high-dimensional problems and allows for nonlinear relationships between predictors; however, the presence of correlated predictors has been shown to impact its ability to identify strong predictors. The Random Forest-Recursive Feature Elimination algorithm (RF-RFE) mitigates this problem in smaller data sets, but this approach has not been tested in high-dimensional omics data sets. RESULTS: We integrated 202,919 genotypes and 153,422 methylation sites in 680 individuals, and compared the abilities of RF and RF-RFE to detect simulated causal associations, which included simulated genotype-methylation interactions, between these variables and triglyceride levels. Results show that RF was able to identify strong causal variables with a few highly correlated variables, but it did not detect other causal variables. CONCLUSIONS: Although RF-RFE decreased the importance of correlated variables, in the presence of many correlated variables, it also decreased the importance of causal variables, making both hard to detect. These findings suggest that RF-RFE may not scale to high-dimensional data.


Assuntos
Aprendizado de Máquina , Ilhas de CpG , Metilação de DNA , Epigenômica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/genética , Hipoglicemiantes/uso terapêutico , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue
15.
Neurobiol Aging ; 66: 177.e1-177.e5, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29395285

RESUMO

Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of initially asymptomatic adults, aged 36-73 years at baseline, enriched for a parental history of AD. A comprehensive cognitive test battery was performed at up to 5 visits. A factor analysis resulted in 6 cognitive factors that were standardized into z scores (∼N [0, 1]); the mean of these z scores was also calculated. In linear mixed models adjusted for age, gender, practice effects, and self-reported race/ethnicity, PLD3 V232M carriers had significantly lower mean z scores (p = 0.02) and lower z scores for story recall (p = 0.04), visual learning and memory (p = 0.049), and speed and flexibility (p = 0.02) than noncarriers. TREM2 R47H carriers had marginally lower z scores for speed and flexibility (p = 0.06). In conclusion, a functional variant in PLD3 was associated with significantly lower cognitive function in individuals carrying the variant than in noncarriers.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Cognição , Estudos de Associação Genética , Variação Genética/genética , Glicoproteínas de Membrana/genética , Fosfolipase D/genética , Receptores Imunológicos/genética , Sistema de Registros , Adulto , Idoso , Doença de Alzheimer/prevenção & controle , Feminino , Heterozigoto , Humanos , Aprendizagem , Estudos Longitudinais , Masculino , Memória , Pessoa de Meia-Idade , Testes Neuropsicológicos , Wisconsin
16.
Neurology ; 88(22): 2098-2106, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28468845

RESUMO

OBJECTIVE: To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether ß-amyloid (Aß) burden plays a moderating role in this relationship. METHODS: One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aß burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. RESULTS: Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aß burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aß burden showed even steeper cognitive decline (p = 0.033). CONCLUSIONS: In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aß burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtornos Cognitivos/genética , Predisposição Genética para Doença , Polimorfismo Genético , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/prevenção & controle , Progressão da Doença , Função Executiva , Feminino , Seguimentos , Heterozigoto , Humanos , Masculino , Memória Episódica , Pessoa de Meia-Idade , Sistema de Registros , Wisconsin
17.
Neurology ; 88(17): 1650-1658, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28341646

RESUMO

OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant. The participants underwent lumbar puncture for CSF collection. ß-Amyloid 42 (Aß42), Aß40, total tau (t-tau), and phosphorylated tau (p-tau) were quantified by immunoassays, and Aß42/Aß40 and tau/Aß42 ratios were computed. CRF was estimated from a validated equation incorporating sex, age, body mass index, resting heart rate, and self-reported physical activity. Covariate-adjusted regression analyses were used to test for associations between the PRS and CSF biomarkers. In addition, by including a PRS×CRF term in the models, we examined whether these associations were modified by CRF. RESULTS: A higher PRS was associated with lower Aß42/Aß40 (p < 0.001), higher t-tau/Aß42 (p = 0.012), and higher p-tau/Aß42 (p = 0.040). Furthermore, we observed PRS × CRF interactions for Aß42/Aß40 (p = 0.003), t-tau/Aß42 (p = 0.003), and p-tau/Aß42 (p = 0.001). Specifically, the association between the PRS and these CSF biomarkers was diminished in those with higher CRF. CONCLUSIONS: In a late-middle-aged cohort, CRF attenuates the adverse influence of genetic vulnerability on CSF biomarkers. These findings support the notion that increased cardiorespiratory fitness may be beneficial to those at increased genetic risk for AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Aptidão Cardiorrespiratória/fisiologia , Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Clusterina/genética , Estudos de Coortes , Estudos Transversais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Sistema de Registros , Risco , Wisconsin , Proteínas tau/líquido cefalorraquidiano
18.
Alzheimers Dement (Amst) ; 7: 48-55, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28239641

RESUMO

INTRODUCTION: Capillary hypoperfusion is reported in asymptomatic adults at-risk for Alzheimer's disease (AD), but the extent that can be explained by reduced flow in intracranial arteries is unknown. METHODS: One hundred fifty-five asymptomatic adults enriched for AD risk (mean age 61 years) completed arterial spin labeling (pcASL) and 4D-flow MRI sequences. Voxel-wise regression models investigated the relationship between mean flow in bilateral cerebral arteries and capillary perfusion, and tested potential moderators of this relationship. RESULTS: Mean arterial blood flow through middle cerebral arteries (MCAs) and internal carotid arteries was positively associated with perfusion in large cortical clusters (P < .05, false discovery rate corrected). Trends were observed for the interactions MCA flow × age and MCA flow × cardiovascular risk on cerebral perfusion (P < .001, uncorrected). DISCUSSION: These findings provide evidence that capillary perfusion measured via pseudocontinuous arterial spin labeling is strongly dependent on inflow from larger cerebral arteries. Further studies are warranted to investigate possible alterations between macrovascular and microvascular flow in advanced age and elevated cardiovascular risk in asymptomatic adults at risk for AD.

19.
J Alzheimers Dis ; 55(2): 473-484, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27662287

RESUMO

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-ß (Aß) deposition and neurodegeneration: Aß clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aß deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aß deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Transtornos Cognitivos/etiologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina/metabolismo , Apolipoproteínas E/genética , Transtornos Cognitivos/diagnóstico por imagem , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Fatores de Risco , Tiazóis/metabolismo , Proteínas tau/líquido cefalorraquidiano
20.
Per Med ; 14(1): 17-25, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-29749824

RESUMO

This study assessed perspectives on whole-genome sequencing (WGS) for rare disease diagnosis and the process of receiving genetic results. Semistructured interviews were conducted with adult patients and parents of minor patients affected by idiopathic diseases (n = 10 cases). Three main themes were identified through qualitative data analysis and interpretation: perceived benefits of WGS; perceived drawbacks of WGS; and perceptions of the return of results from WGS. Findings suggest that patients and their families have important perspectives on the use of WGS in diagnostic odyssey cases. These perspectives could inform clinical sequencing research study designs as well as the appropriate deployment of patient and family support services in the context of clinical genome sequencing.


Assuntos
Testes Genéticos/ética , Medicina de Precisão/psicologia , Doenças Raras/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude Frente a Saúde , Criança , Exoma , Feminino , Testes Genéticos/métodos , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Doenças Raras/diagnóstico , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/ética
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