RESUMO
(1) Importance: Alzheimer's disease (AD) is complex and only partially understood. Analyzing the relationship between other more treatable or preventable diseases and AD may help in the prevention and the eventual development of treatments for AD. Risk estimation in a high-risk population, rather than a population already affected with AD, may reduce some bias in risk estimates. (2) Objective: To examine the rates of various comorbidities and cancers in individuals at high-risk for AD, but without a clinical diagnosis, relative to individuals from the same population with normal AD risk. (3) Design, Setting, and Participants: We conducted a study using data from the Utah Population Database (UPDB). The UPDB contains linked data from the Utah Cancer Registry, Utah death certificates, the Intermountain Health patient population, and the University of Utah Health patient population. Subjects were selected based on the availability of ancestral data, linked health information, and self-reported biometrics. (4) Results: In total, 75,877 participants who were estimated to be at high risk for AD based on family history, but who did not have an active AD diagnosis, were analyzed. A lower incidence of diabetes (RR = 0.95, 95% CI [0.92,0.97], p < 0.001), hypertension (RR = 0.97, 95% CI [0.95,0.99], p < 0.001), and heart disease (RR = 0.95, 95% CI [0.93,0.98], p < 0.001) was found. There was no difference in rates of cerebrovascular disease or other forms of dementia. Of the 15 types of cancer analyzed: breast (RR = 1.23, 95% CI [1.16, 1.30], p < 0.001); colorectal (RR = 1.30, 95% CI [1.21, 1.39], p < 0.001); kidney (RR = 1.49, 95% CI (1.29, 1.72), p < 0.001); lung (RR = 1.25, 95% CI [1.13, 1.37], p < 0.001); non-Hodgkin's Lymphoma (RR = 1.29, 95% CI [1.15, 1.44], p < 0.001); pancreas (RR = 1.34, 95% CI [1.16, 1.55], p < 0.001); stomach (RR = 1.59, 95% CI [1.36, 1.86], p < 0.001); and bladder (RR = 1.40, 95% CI [1.25, 1.56], p < 0.001), cancers were observed in significant excess among individuals at high-risk for AD after correction for multiple testing. (5) Conclusions and Relevance: Since age is the greatest risk factor for the development of AD, individuals who reach more advanced ages are at increased risk of developing AD. Consistent with this, people with fewer comorbidities earlier in life are more likely to reach an age where AD becomes a larger risk. Our findings show that individuals at high risk for AD have a decreased incidence of various other diseases. This is further supported by our finding that our high-risk group was also found to have an increased incidence of various cancers, which also increase in risk with age. There is the possibility that a more meaningful or etiological relationship exists among these various comorbidities. Further research into the etiological relationship between AD and these comorbidities may elucidate these possible interactions.
Assuntos
Doença de Alzheimer , Neoplasias , Humanos , Doença de Alzheimer/epidemiologia , Neoplasias/epidemiologia , Comorbidade , Incidência , Fatores de RiscoRESUMO
Asian Americans (AsA), Native Hawaiians, and Pacific Islanders (NHPI) comprise 7.7% of the U.S. population, and AsA have had the fastest growth rate since 2010. Yet the National Institutes of Health (NIH) has invested only 0.17% of its budget on AsA and NHPI research between 1992 and 2018. More than 40 ethnic subgroups are included within AsA and NHPI (with no majority subpopulation), which are highly diverse culturally, demographically, linguistically, and socioeconomically. However, data for these groups are often aggregated, masking critical health disparities and their drivers. To address these issues, in March 2021, the National Heart, Lung, and Blood Institute, in partnership with 8 other NIH institutes, convened a multidisciplinary workshop to review current research, knowledge gaps, opportunities, barriers, and approaches for prevention research for AsA and NHPI populations. The workshop covered 5 domains: 1) sociocultural, environmental, psychological health, and lifestyle dimensions; 2) metabolic disorders; 3) cardiovascular and lung diseases; 4) cancer; and 5) cognitive function and healthy aging. Two recurring themes emerged: Very limited data on the epidemiology, risk factors, and outcomes for most conditions are available, and most existing data are not disaggregated by subgroup, masking variation in risk factors, disease occurrence, and trajectories. Leveraging the vast phenotypic differences among AsA and NHPI groups was identified as a key opportunity to yield novel clues into etiologic and prognostic factors to inform prevention efforts and intervention strategies. Promising approaches for future research include developing collaborations with community partners, investing in infrastructure support for cohort studies, enhancing existing data sources to enable data disaggregation, and incorporating novel technology for objective measurement. Research on AsA and NHPI subgroups is urgently needed to eliminate disparities and promote health equity in these populations.
Assuntos
Asiático , Havaiano Nativo ou Outro Ilhéu do Pacífico , Havaí , Promoção da Saúde , Humanos , National Institutes of Health (U.S.) , Estados Unidos/epidemiologiaRESUMO
The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC). Data from research participants with GWAS and autopsy measures from the National Alzheimer's Coordinating Center and the Religious Orders Study and the Rush Memory and Aging Project were meta-analyzed. Notably, no variants in the locus were significantly associated with ADNC. However, several WWOX/MAF variants had significant adjusted associations with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC), HS, and brain arteriolosclerosis. These associations remained largely unchanged after adjustment for ADNC (operationalized with standard semiquantitative staging), suggesting that these associations are independent of ADNC. Thus, WWOX genetic variants were associated pathologically with LATE-NC, not ADNC.
Assuntos
Doença de Alzheimer/genética , Demência/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Proteínas Proto-Oncogênicas c-maf/genética , Proteinopatias TDP-43/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , MasculinoRESUMO
Importance: Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. Objective: To identify genetic variants associated with AD risk using a nonstatistical approach. Design, Setting, and Participants: Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer's Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. Main Outcomes and Measures: Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer's Disease Neuroimaging Initiative. Results: Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). Conclusions and Relevance: Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets.
Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Mutação/genética , População Branca/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Notch3/genética , Receptores Imunológicos/genéticaRESUMO
BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline. METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs from the linkage peaks that reduced risk for AD in an independent dataset and in a gene-based test. Finally, we experimentally characterized replicated SNPs. RESULTS: Rs142787485 in RAB10 confers significant protection against AD (p value = 0.0184, odds ratio = 0.5853). Moreover, we replicated this association in an independent series of unrelated individuals (p value = 0.028, odds ratio = 0.69) and used a gene-based test to confirm a role for RAB10 variants in modifying AD risk (p value = 0.002). Experimentally, we demonstrated that knockdown of RAB10 resulted in a significant decrease in Aß42 (p value = 0.0003) and in the Aß42/Aß40 ratio (p value = 0.0001) in neuroblastoma cells. We also found that RAB10 expression is significantly elevated in human AD brains (p value = 0.04). CONCLUSIONS: Our results suggest that RAB10 could be a promising therapeutic target for AD prevention. In addition, our gene discovery approach can be expanded and adapted to other phenotypes, thus serving as a model for future efforts to identify rare variants for AD and other complex human diseases.
Assuntos
Doença de Alzheimer/genética , Proteínas rab de Ligação ao GTP/genética , Idoso de 80 Anos ou mais , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Alelos , Animais , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Desequilíbrio de Ligação/genética , Masculino , Camundongos , Fatores de Risco , Fatores de Transcrição/genéticaRESUMO
INTRODUCTION: We sought to determine whether a systems biology approach may identify novel late-onset Alzheimer's disease (LOAD) loci. METHODS: We performed gene-wide association analyses and integrated results with human protein-protein interaction data using network analyses. We performed functional validation on novel genes using a transgenic Caenorhabditis elegans Aß proteotoxicity model and evaluated novel genes using brain expression data from people with LOAD and other neurodegenerative conditions. RESULTS: We identified 13 novel candidate LOAD genes outside chromosome 19. Of those, RNA interference knockdowns of the C. elegans orthologs of UBC, NDUFS3, EGR1, and ATP5H were associated with Aß toxicity, and NDUFS3, SLC25A11, ATP5H, and APP were differentially expressed in the temporal cortex. DISCUSSION: Network analyses identified novel LOAD candidate genes. We demonstrated a functional role for four of these in a C. elegans model and found enrichment of differentially expressed genes in the temporal cortex.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Biologia de Sistemas , Lobo Temporal/metabolismo , Doença de Alzheimer/induzido quimicamente , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Animais Geneticamente Modificados , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Translocases Mitocondriais de ADP e ATP/genética , Translocases Mitocondriais de ADP e ATP/metabolismo , NADH Desidrogenase/genética , NADH Desidrogenase/metabolismo , Mapas de Interação de Proteínas , Interferência de RNA/fisiologiaRESUMO
OBJECTIVE: Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs). METHODS: Alzheimer's Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aß1-42 and total tau CSF analytes. RESULTS: The GRN risk SNP (rs5848) status correlated with variation in CSF proteins, with the risk allele (T) associated with increased levels of AXL Receptor Tyrosine Kinase (AXL), TNF-Related Apoptosis-Inducing Ligand Receptor 3 (TRAIL-R3), Vascular Cell Adhesion Molecule-1 (VCAM-1) and clusterin (CLU) (all p<0.05 after Bonferroni correction). The TRAIL-R3 correlation was significant in meta-analysis with an additional dataset (p=5.05×10-5). Further, the rs5848 SNP status was associated with increased CSF tau protein - a marker of neurodegeneration (p=0.015). These data are remarkable since this GRN SNP has been found to be a risk factor for multiple types of dementia-related brain pathologies.
Assuntos
Envelhecimento/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Demência/genética , Hipocampo/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Clusterina/líquido cefalorraquidiano , Bases de Dados Factuais , Demência/líquido cefalorraquidiano , Feminino , Proteínas Ligadas por GPI/líquido cefalorraquidiano , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Progranulinas , Membro 10c de Receptores do Fator de Necrose Tumoral/líquido cefalorraquidiano , Análise de Regressão , Fatores de Risco , Esclerose , Molécula 1 de Adesão de Célula Vascular/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a ß3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aß peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aß peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aß peptide production.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA Interferente Pequeno/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Biomarcadores/líquido cefalorraquidiano , Membrana Celular/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Neurônios/metabolismo , Neurônios/patologia , Interferência de RNA , RatosRESUMO
BACKGROUND: Prolactin is a polypeptide hormone secreted by the anterior pituitary gland that plays an essential role in lactation, tissue growth, and suppressing apoptosis to increase cell survival. Prolactin serves as a key player in many life-critical processes, including immune system and reproduction. Prolactin is also found in multiple fluids throughout the body, including plasma and cerebrospinal fluid (CSF). METHODS: In this study, we measured prolactin levels in both plasma and CSF, and performed a genome-wide association study. We then performed meta-analyses using METAL with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets. RESULTS: We identified 12 SNPs associated with increased prolactin levels in both biological fluids. CONCLUSIONS: Our efforts will help researchers understand how prolactin is regulated in both CSF and plasma, which could be beneficial in research for the immune system and reproduction.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Prolactina/sangue , Prolactina/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Proteínas Quinases Dependentes de Cálcio-Calmodulina/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Modelos Lineares , Desequilíbrio de Ligação , Metanálise como Assunto , Pessoa de Meia-Idade , Sulfotransferases/genéticaRESUMO
BACKGROUND: Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain. METHODS: We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3. RESULTS: Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression. CONCLUSIONS: Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).
Assuntos
Fosfatase Ácida/líquido cefalorraquidiano , Fosfatase Ácida/genética , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Encéfalo/enzimologia , Encéfalo/metabolismo , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/genética , Regulação Enzimológica da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Fatores de RiscoRESUMO
BACKGROUND: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. METHODS: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aß42 was used as a continuous trait in these analyses. RESULTS: The ptau181-Aß42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aß42) compared with elderly control subjects with no pathology (low ptau181, high Aß42). The FABP-Aß42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aß42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. CONCLUSIONS: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Proteína 3 Ligante de Ácido Graxo , Proteínas de Ligação a Ácido Graxo/líquido cefalorraquidiano , Feminino , Humanos , Imunoensaio/métodos , Oxirredutases Intramoleculares/líquido cefalorraquidiano , Estimativa de Kaplan-Meier , Fatores Inibidores da Migração de Macrófagos/líquido cefalorraquidiano , Masculino , Análise Multivariada , Fosforilação , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/líquido cefalorraquidianoRESUMO
We observed the changes in the angular measurements commonly used in the evaluation of the first metatarsal and first metatarsophalangeal joint in cadaveric specimens before and after frontal plane rotation of the first metatarsal. Measurements of the first and second intermetatarsal angle (IMA), hallux abductus angle, proximal articular set angle, and tibial sesamoid position (TSP) were taken after varying degrees of varus and valgus rotation of the first metatarsal. Standard dorsoplantar radiographs were taken at 0°, 10°, 20°, and 30° of valgus rotation of the first metatarsal and repeated at 10°, 20°, and 30° varus rotation of the first metatarsal. The data were analyzed using a mixed linear model to compare the change in each angle measurement over the range of valgus and varus rotation. The change in the TSP was significant in both valgus and varus rotations (p = .0004 and p = .028, respectively), an increase in valgus rotation causing an increase in the TSP and an increase in varus rotation causing a decrease in TSP. The change in the IMA was significant compared with valgus rotation (p = .028), showing that as the valgus rotation increased, the IMA also increased. However, compared with the varus rotation, the correlation was not significant (p = .18). The proximal articular set angle and hallux abductus angle measurements, compared with metatarsal rotation, showed positive trends but were not statistically significant. From our results and a review of the published data, we have hypothesized that frontal plane rotation of the first metatarsal is an integral component of hallux abducto valgus pathologic features, specifically in relation to the TSP and IMA.
Assuntos
Hallux/diagnóstico por imagem , Ossos do Metatarso/diagnóstico por imagem , Articulação Metatarsofalângica/diagnóstico por imagem , Idoso de 80 Anos ou mais , Cadáver , Feminino , Humanos , Radiografia , RotaçãoRESUMO
The first intermetatarsal angle (IMA) is known to decrease after first metatarsophalangeal joint arthrodesis, although the exact mechanism by which this decrease occurs is not known. We measured the first IMA and obliquity of the medial cuneiform on anteroposterior weightbearing preoperative and postoperative radiographs in 86 feet and analyzed the statistical correlation between the IMA and the medial cuneiform angle. A change in the first IMA after first metatarsophalangeal joint fusion showed a strong positive correlation with a change in cuneiform obliquity (p < .0001). This finding was consistent in the direction and magnitude in each of 3 clinical subgroups: normal, p = .087; moderate deformity, p = .011; and severe deformity, p = .10. A comparison of the preoperative IMA and cuneiform obliquity revealed a trend toward a positive relationship but did not reach statistical significance (p = .08). The preoperative association between the IMA and medial cuneiform obliquity was not significant in any clinical subgroup, and the postoperative association between the IMA and cuneiform obliquity was not significant (p = .65). Clinical subgroup analysis showed no significant association between the IMA and the normal (p = .73) and moderately (p = .69) deformed feet, although the postoperative association between the IMA and cuneiform obliquity in the severely deformed group was significantly (p = .034) positive. A linear relationship between the reduction of the first IMA and medial cuneiform obliquity after metatarsophalangeal joint fusion was observed. Our findings suggest that frontal plane rotation influences cuneiform obliquity.
Assuntos
Artrodese , Hallux Valgus/cirurgia , Ossos do Metatarso/diagnóstico por imagem , Articulação Metatarsofalângica/cirurgia , Ossos do Tarso/diagnóstico por imagem , Hallux Valgus/diagnóstico por imagem , Hallux Valgus/fisiopatologia , Humanos , Articulação Metatarsofalângica/diagnóstico por imagem , RadiografiaRESUMO
Recent genome-wide association studies of Alzheimer's disease (AD) have identified variants in BIN1, CLU, CR1 and PICALM that show replicable association with risk for disease. We have thoroughly sampled common variation in these genes, genotyping 355 variants in over 600 individuals for whom measurements of two AD biomarkers, cerebrospinal fluid (CSF) 42 amino acid amyloid beta fragments (Aß(42)) and tau phosphorylated at threonine 181 (ptau(181)), have been obtained. Association analyses were performed to determine whether variants in BIN1, CLU, CR1 or PICALM are associated with changes in the CSF levels of these biomarkers. Despite adequate power to detect effects as small as a 1.05 fold difference, we have failed to detect evidence for association between SNPs in these genes and CSF Aß(42) or ptau(181) levels in our sample. Our results suggest that these variants do not affect risk via a mechanism that results in a strong additive effect on CSF levels of Aß(42) or ptau(181).