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1.
JAMA Neurol ; 79(7): 652-663, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35639372

RESUMO

Importance: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. Objective: To determine whether rare missense variants on APOE are associated with AD risk. Design, Setting, and Participants: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. Main Outcomes and Measures: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. Results: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. Conclusions and Relevance: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.


Assuntos
Doença de Alzheimer , Idade de Início , Alelos , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E2/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Feminino , Genótipo , Humanos , Masculino
2.
Mol Ther Nucleic Acids ; 28: 450-461, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35505961

RESUMO

Presenilin 1 (PS1) is a central component of γ-secretase, an enzymatic complex involved in the generation of the amyloid-ß (Aß) peptide that deposits as plaques in the Alzheimer's disease (AD) brain. The M146L mutation in the PS1 gene (PSEN1) leads to an autosomal dominant form of early-onset AD by promoting a relative increase in the generation of the more aggregation-prone Aß42. This change is evident not only in the brain but also in peripheral cells of mutation carriers. In this study we used the CRISPR-Cas9 system from Streptococcus pyogenes to selectively disrupt the PSEN1 M146L allele in human fibroblasts. A disruption of more than 50% of mutant alleles was observed in all CRISPR-Cas9-treated samples, resulting in reduced extracellular Aß42/40 ratios. Fluorescence resonance energy transfer-based conformation and western blot analyses indicated that CRISPR-Cas9 treatment also affects the overall PS1 conformation and reduces PS1 levels. Moreover, our guide RNA did not lead to any detectable editing at the highest-ranking candidate off-target sites identified by ONE-seq and CIRCLE-seq. Overall, our data support the effectiveness of CRISPR-Cas9 in selectively targeting the PSEN1 M146L allele and counteracting the AD-associated phenotype. We believe that this system could be developed into a therapeutic strategy for patients with this and other dominant mutations leading to early-onset AD.

3.
Nat Genet ; 54(4): 412-436, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379992

RESUMO

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Disfunção Cognitiva/psicologia , Estudo de Associação Genômica Ampla , Humanos , Proteínas tau/genética
5.
BMC Genomics ; 23(1): 99, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35120450

RESUMO

BACKGROUND: Most dementia disorders have a clear genetic background and a number of disease genes have been identified. Mutations in the tau gene (MAPT) lead to frontotemporal dementia (FTD), whereas mutations in the genes for the amyloid-ß precursor protein (APP) and the presenilins (PSEN1, PSEN2) cause early-onset, dominantly inherited forms of Alzheimer's disease (AD). Even if mutations causing Mendelian forms of these diseases are uncommon, elucidation of the pathogenic effects of such mutations have proven important for understanding the pathogenic processes. Here, we performed a screen to identify novel pathogenic mutations in known disease genes among patients undergoing dementia investigation. RESULTS: Using targeted exome sequencing we have screened all coding exons in eleven known dementia genes (PSEN1, PSEN2, APP, MAPT, APOE, GRN, TARDBP, CHMP2B, TREM2, VCP and FUS) in 102 patients with AD, FTD, other dementia diagnoses or mild cognitive impairment. We found three AD patients with two previously identified pathogenic mutations in PSEN1 (Pro264Leu and Met146Val). In this screen, we also identified the recently reported APP mutation in two siblings with AD. This mutation, named the Uppsala mutation, consists of a six amino acid intra-amyloid ß deletion. In addition, we found several potentially pathogenic mutations in PSEN2, FUS, MAPT, GRN and APOE. Finally, APOE ε4 was prevalent in this patient group with an allele frequency of 54%. CONCLUSIONS: Among the 102 screened patients, we found two disease causing mutations in PSEN1 and one in APP, as well as several potentially pathogenic mutations in other genes related to neurodegenerative disorders. Apart from giving important information to the clinical investigation, the identification of disease mutations can contribute to an increased understanding of disease mechanisms.


Assuntos
Doença de Alzheimer , Demência Frontotemporal , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Demência Frontotemporal/genética , Humanos , Glicoproteínas de Membrana , Mutação , Presenilina-1/genética , Presenilina-2/genética , Receptores Imunológicos
6.
Gait Posture ; 90: 489-495, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34628196

RESUMO

BACKGROUND: We study dual-task performance with marker-free video recordings of Timed Up-and-Go tests (TUG) and TUG combined with a cognitive/verbal task (TUG dual-task, TUGdt). RESEARCH QUESTION: Can gait parameters be accurately estimated from video-recorded TUG tests by a new semi-automatic method aided by a technique for human 2D pose estimation based on deep learning? METHODS: Thirty persons aged 60-85 years participated in the study, conducted in a laboratory environment. Data were collected by two synchronous video-cameras and a marker-based optoelectronic motion capture system as gold standard, to evaluate the gait parameters step length (SL), step width (SW), step duration (SD), single-stance duration (SSD) and double-stance duration (DSD). For reliability evaluations, data processing aided by a deep neural network model, involved three raters who conducted three repetitions of identifying anatomical keypoints in recordings of one randomly selected step from each of the participants. Validity was analysed using 95 % confidence intervals (CI) and p-values for method differences and Bland-Altman plots with limits of agreement. Inter- and intra-rater reliability were calculated as intraclass correlation coefficients (ICC) and standard errors of measurement. Smallest detectable change was calculated for inter-rater reliability. RESULTS: Mean ddifferences between video and the motion capture system data for SW, DSD, and SSD were significant (p < 0.001). However, mean differences for all parameters were small (-6.4%-13.0% of motion capture system) indicating good validity. Concerning reliability, almost all 95 % CI of the ICC estimates exceeded 0.90, indicating excellent reliability. Only inter-rater reliability for SW (95 % CI = 0.892;0.973) and one rater's intra-rater reliability for SSD (95 % CI = 0.793;0.951) were lower, but still showed good to excellent reliability. SIGNIFICANCE: The presented method for extraction of gait parameters from video appears suitable for valid and reliable quantification of gait. This opens up for analyses that may contribute to the knowledge of cognitive-motor interference in dual-task testing.


Assuntos
Marcha , Modalidades de Fisioterapia , Humanos , Reprodutibilidade dos Testes , Análise e Desempenho de Tarefas , Gravação em Vídeo
7.
Sci Transl Med ; 13(606)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380771

RESUMO

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid ß (Aß). Here, we describe the Uppsala APP mutation (Δ690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aß42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing ß-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aß, AßUpp1-42Δ19-24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Humanos
8.
Phys Ther ; 101(10)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34272869

RESUMO

OBJECTIVE: The purpose of the study was to establish reference values for the Uppsala-Dalarna Dementia and Gait (UDDGait) Timed "Up & Go" dual-task (TUGdt) test variables in cognitively healthy adults and to assess these variables' test-retest reliability. METHODS: For reference values, 166 participants were recruited with approximately equal numbers and proportions of women and men in the age groups 50 to 59, 60 to 69, 70 to 79, and 80+ years (mean age = 70 years, age range = 50-91 years, 51% women). For reliability testing, 43 individuals (mean age = 69 years, age range = 50-89 years, 51% women) were recruited. Two dt tests were carried out: TUGdt naming animals and TUGdt months backward, representing 8 test variables: time scores, costs (the relative difference between single-task and dt time scores), "number of animals," "number of months," "animals/10 seconds ," and "months/10 seconds ." Reference ranges for the variables were established by quantile regression in age- and sex-specific groups. For reliability, intraclass correlation coefficients (ICCs), standard error of measurement, minimal detectable change, and Bland-Altman plots were used. RESULTS: Reference values for the TUGdt test variables are presented for the 2.5th and 97.5th percentiles. The reliability of TUGdt time scores was excellent (ICCs between 0.85 and 0.86). "Number of animals" and "animals/10 seconds" as well as "months/10 seconds" showed fair to good levels of reliability (ICCs between 0.45 and 0.58), whereas the reliability for both cost measures and "number of months" was poor (ICCs between 0.34 and 0.39). CONCLUSION: Normative reference values, potentially useful for clinical and research purposes, were presented in 4 age- and sex-specific groups from 50 years and older. Reliability for the test variables varied between poor and excellent, the lower estimates partly explained by some variables being the ratio of 2 other variables. In UDDGait, TUGdt tests are intended for diagnostic and predictive purposes, for which these tests are promising and require further investigations. IMPACT: Normative reference values and test-retest reliability results for the UDDGait TUGdt test variables were presented. These results should be useful for both clinical and research purposes.


Assuntos
Cognição/fisiologia , Marcha , Voluntários Saudáveis , Psicometria/métodos , Valores de Referência , Caminhada/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modalidades de Fisioterapia , Equilíbrio Postural/fisiologia , Reprodutibilidade dos Testes , Fatores Sexuais , Análise e Desempenho de Tarefas
9.
Cell Mol Life Sci ; 78(8): 4019-4033, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33837451

RESUMO

Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer's disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a "genetic wasteland", and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.


Assuntos
Doença de Alzheimer/genética , Cromossomos Humanos Y , Mosaicismo , Neoplasias da Próstata/genética , Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica , Humanos , Células Matadoras Naturais/metabolismo , Leucócitos/metabolismo , Masculino
10.
J Alzheimers Dis ; 81(2): 629-640, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814444

RESUMO

BACKGROUND: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. OBJECTIVE: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. METHODS: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. RESULTS: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). CONCLUSION: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Demência Frontotemporal/líquido cefalorraquidiano , Inflamação/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Estudos Transversais , Feminino , Demência Frontotemporal/diagnóstico , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
11.
Artigo em Inglês | MEDLINE | ID: mdl-33153203

RESUMO

The aim of this study was to investigate whether Timed Up-and-Go (TUG) dual-task (TUGdt) tests predict dementia incidence among patients with subjective or mild cognitive impairment (SCI; MCI). Other study objectives were to determine whether TUGdt improves dementia prediction compared to a) demographic characteristics and standard cognitive tests alone; and b) TUG and Verbal Fluency performed separately. Patients (n = 172, age range 39-91 years, 78 women) with SCI or MCI performed TUGdt tests, including 1) naming animals and 2) reciting months backwards, and clinical cognitive tests at baseline. Diagnoses were identified at follow-up after 2.5 years. Logistic regression was used to predict dementia incidence, receiver operating characteristic (ROC) curves and c-statistics for predictive capacity. Analyses were stratified by age and gender. At follow-up, 51 patients had developed dementia. The TUGdt result "animals/10 s" was associated with dementia incidence (standardized odds ratio (OR) = 4.06, 95% confidence interval (CI) 2.28-7.23, p < 0.001), more so among patients under the median age of 72 years (standardized OR = 19.4, 95% CI 3.53-106.17, p < 0.001). TUGdt "animals/10 s" improved dementia prediction compared to demographic characteristics and standard tests alone (c-statistics 0.88 to 0.94) and single-task tests (c-statistics 0.86 to 0.89), but only in the younger patient group. TUGdt has the potential to become a useful tool for dementia prediction.


Assuntos
Disfunção Cognitiva , Demência , Memória Episódica , Adulto , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Estudos de Coortes , Demência/diagnóstico , Demência/epidemiologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
12.
Nat Metab ; 2(10): 1135-1148, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33067605

RESUMO

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.


Assuntos
Sistema Cardiovascular/metabolismo , Mapeamento Cromossômico , Sistemas de Liberação de Medicamentos , Genômica , Transportador 1 de Cassete de Ligação de ATP/genética , Asma/genética , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Desequilíbrio de Ligação , Análise da Randomização Mendeliana , /genética , Proteoma , Locos de Características Quantitativas , Receptores CCR2/genética , Receptores CCR5/genética
13.
Atherosclerosis ; (307): 11-15, Aug., 2020. tab.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1122622

RESUMO

BACKGROUND AND AIMS: Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD. METHODS: Individuals with CKD stages 3-5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample. RESULTS: In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 ± 2.9 years (range 0.005-12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean ± SD change of 2.9 ± 1.2 years (range 0.1-4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07-1.75), p = 0.013). CONCLUSIONS: Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.


Assuntos
Biomarcadores , Doenças Cardiovasculares , Insuficiência Renal Crônica , Proteômica
14.
BMC Geriatr ; 20(1): 258, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727472

RESUMO

BACKGROUND: Discrimination between early-stage dementia and other cognitive impairment diagnoses is central to enable appropriate interventions. Previous studies indicate that dual-task testing may be useful in such differentiation. The objective of this study was to investigate whether dual-task test outcomes discriminate between groups of individuals with dementia disorder, mild cognitive impairment, subjective cognitive impairment, and healthy controls. METHODS: A total of 464 individuals (mean age 71 years, 47% women) were included in the study, of which 298 were patients undergoing memory assessment and 166 were cognitively healthy controls. Patients were grouped according to the diagnosis received: dementia disorder, mild cognitive impairment, or subjective cognitive impairment. Data collection included participants' demographic characteristics. The patients' cognitive test results and diagnoses were collected from their medical records. Healthy controls underwent the same cognitive tests as the patients. The mobility test Timed Up-and-Go (TUG single-task) and two dual-task tests including TUG (TUGdt) were carried out: TUGdt naming animals and TUGdt months backwards. The outcomes registered were: time scores for TUG single-task and both TUGdt tests, TUGdt costs (relative time difference between TUG single-task and TUGdt), number of different animals named, number of months recited in correct order, number of animals per 10 s, and number of months per 10 s. Logistic regression models examined associations between TUG outcomes pairwise between groups. RESULTS: The TUGdt outcomes "animals/10 s" and "months/10 s" discriminated significantly (p < 0.001) between individuals with an early-stage dementia diagnosis, mild cognitive impairment, subjective cognitive impairment, and healthy controls. The TUGdt outcome "animals/10 s" showed an odds ratio of 3.3 (95% confidence interval 2.0-5.4) for the groups dementia disorders vs. mild cognitive impairment. TUGdt cost outcomes, however, did not discriminate between any of the groups. CONCLUSIONS: The novel TUGdt outcomes "words per time unit", i.e. "animals/10 s" and "months/10 s", demonstrate high levels of discrimination between all investigated groups. Thus, the TUGdt tests in the current study could be useful as complementary tools in diagnostic assessments. Future studies will be focused on the predictive value of TUGdt outcomes concerning dementia risk for individuals with mild cognitive impairment or subjective cognitive impairment.


Assuntos
Disfunção Cognitiva , Demência , Idoso , Cognição , Disfunção Cognitiva/diagnóstico , Estudos de Coortes , Estudos Transversais , Demência/diagnóstico , Feminino , Humanos , Masculino
15.
Atherosclerosis ; 307: 11-15, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32702535

RESUMO

BACKGROUND AND AIMS: Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD. METHODS: Individuals with CKD stages 3-5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample. RESULTS: In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 ± 2.9 years (range 0.005-12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean ± SD change of 2.9 ± 1.2 years (range 0.1-4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07-1.75), p = 0.013). CONCLUSIONS: Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.


Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Metaloproteinase 12 da Matriz , Proteômica , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco
16.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-32150995

RESUMO

New methods to screen for and identify early-stage dementia disorders are highly sought after. The purpose of this pilot study is to develop a study protocol for a dual-task test aimed at aiding the early detection of dementia disorders. We used the Timed Up-and-Go (TUG) test, which is a mobility task involving starting in a sitting position, standing up, walking three meters to cross a line on the floor, turning around, walking back and sitting down again. We combined TUG with the verbal task of naming different animals. Pilot study participants were 43 individuals with and without established dementia diagnoses who attended a clinic for memory assessment. Video-recorded test performances were systematically analysed. Deviant test performances concerning the interplay between test administration and participants' responses to the assessment instructions were revealed and led to refinements being made to the final study protocol. Exploration of the dual-task test outcome measures in a sub-sample of 22 persons, ten with and twelve without dementia, indicated that step-length and number of named animals after the turning point of the dual-task test might constitute appropriate measures for examining this kind of sample. We concluded that the refined study protocol is feasible for testing individuals undergoing initial memory assessments and healthy controls. Follow-up studies with larger samples are being carried out and will bring new knowledge to this area of research. It may also provide an opportunity for further studies exploring possibilities for broad clinical implementation.


Assuntos
Cognição , Demência , Técnicas e Procedimentos Diagnósticos , Caminhada , Demência/diagnóstico , Técnicas e Procedimentos Diagnósticos/normas , Marcha , Humanos , Memória , Projetos Piloto , Gravação em Vídeo
18.
Nat Commun ; 11(1): 163, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919418

RESUMO

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.


Assuntos
Fibrilação Atrial/genética , Cardiomiopatias/genética , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Função Ventricular Esquerda/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatias/patologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Inibidor de Quinase Dependente de Ciclina p21/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Fatores de Risco
19.
Eur J Hum Genet ; 28(3): 349-357, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31654039

RESUMO

Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.


Assuntos
Envelhecimento/genética , Deleção Cromossômica , Cromossomos Humanos Y/genética , Mosaicismo , Polimorfismo Genético , Envelhecimento/sangue , Células Sanguíneas/metabolismo , Humanos , Masculino
20.
Int J Epidemiol ; 48(6): 2018-2025, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363756

RESUMO

BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium. METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries. RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH. CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.


Assuntos
Hipertensão/epidemiologia , Fumar/efeitos adversos , Hemorragia Subaracnóidea/epidemiologia , Adulto , Índice de Massa Corporal , Causas de Morte , Escolaridade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Análise de Regressão , Fatores Sexuais , Fumar/epidemiologia , Hemorragia Subaracnóidea/mortalidade , Suécia/epidemiologia
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