RESUMO
Background and objective: Neuroinflammation is one of the pathological pathways of Alzheimer's disease (AD), mediating the progression of neurodegeneration. Polymorphisms of proinflammatory cytokines have been linked to increased AD risk. Identification of certain combinations of polymorphisms could help predict disease in its preclinical stage. The aim of the study was to evaluate differences in the prevalence of TNFα -850T (rs1799724), IL1A -889T (rs1800587), and IL6 -174C (rs1800795, Intron type) polymorphisms between AD patients and healthy controls (HC) and determine the impact of these SNPs in combination with the APOEε4 allele on AD risk. Materials and Methods: The study population is comprised of 107 patients with sporadic AD (AD group) and age- and gender-matched 110 persons without impaired cognitive functions (control group). TNFα -850C > T polymorphism was revealed by a PCR and restriction fragment length polymorphism (RFLP) method. Real time PCR was used for IL1A and IL6 SNP genotyping. APOEε genotyping was done via hybridization method. Results: The frequencies of TNFα -850T, IL1A -889T, IL6 -174C allele and genotype did not differ between the AD and HC groups (p > 0.05). IL6 -174C was not in HWE, and it was not analysed further. APOEε4 allele (p = 0.001) and 3/4 and 4/4 genotypes (p = 0.005) were more prevalent in AD patients. APOEε4 carriage increased the risk of AD (OR 2.65, p = 0.001), while TNFα -850T and IL1A -889T polymorphisms were not found as significant independent risk factors for AD. The presence of at least one IL1A -889T allele in combination with APOEε4+ was associated with a lower risk of AD (OR 2.24, p = 0.047) than the carriage of APOEε4+ alone (OR 2.70, p = 0.015). Conclusions: No significant differences of TNFα -850, IL1A -889, and IL6 -174 polymorphisms frequencies were found between AD and control groups. In APOEε4 carriers IL1A -889T polymorphism was found to reduce the AD risk determined by APOEε4 alone.
Assuntos
Doença de Alzheimer/sangue , Apolipoproteína E4/análise , Citocinas/análise , Polimorfismo Genético/genética , Fator de Necrose Tumoral alfa/análise , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Apolipoproteína E4/sangue , Citocinas/sangue , Feminino , Técnicas de Genotipagem/métodos , Humanos , Lituânia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Although ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with dementia and Alzheimer's disease (AD), no information is yet available for its contribution to AD pathologies. We investigated the relationship between the ABI and in vivo ß-amyloid (Aß) deposition and AD-specific neurodegeneration in cognitively normal (CN) elderly individuals. METHODS: A total of 256 CN elderly subjects who participated in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study, were included. All subjects underwent comprehensive clinical and neuropsychological assessments, ABI measurement, apolipoprotein E (APOE) genotyping, [11C]Pittsburgh Compound B (PiB)-positron emission tomography (PET), [18F]-fludeoxyglucose PET, and magnetic resonance imaging. RESULTS: A significant positive association was found between the ABI and global cerebral Aß retention measured by PiB-PET, even after controlling for age, sex, and APOE ε4. When three stratified ABI subgroups (ABI < 1.00, 1.00-1.29, and ≥ 1.30) were compared, the highest ABI subgroup (ie, ABI ≥ 1.30) showed significantly higher Aß deposition than that of the other subgroups. This relationship between Aß deposition and the ABI was significant only in APOE ε4 carriers, but not in noncarriers. No significant association was observed between the ABI and neurodegeneration in the AD-signature regions. CONCLUSION: Our findings suggest that a high ABI, possibly related to arterial stiffness, is associated with elevated brain Aß burden in cognitively healthy elderly individuals, particularly in APOE ε4 carriers.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/análise , Encéfalo , Cognição/fisiologia , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Índice Tornozelo-Braço , Apolipoproteína E4/análise , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Coortes , Feminino , Glucose/metabolismo , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons/métodos , República da Coreia/epidemiologia , Rigidez VascularRESUMO
BACKGROUND/OBJECTIVE: In population studies, most individuals with mild cognitive impairment (MCI) do not progress to dementia in the near term, but rather remain stable MCI or revert to normal cognition. Here, we characterized MCI subgroups with different outcomes over 5 years. SETTING/PARTICIPANTS: A population-based cohort (N=1603). MEASUREMENTS: Clinical Dementia Rating (CDR); self-reported medical conditions, subjective cognitive concerns, self-rated health, depressive symptoms, blood pressure, medications, blood pressure, APOE genotype, cognitive domain composite scores. DESIGN: We compared 3 MCI subgroups who progressed to dementia (n=86), stabilized at MCI (n=384), or reverted to normal (n=252), to those who remained consistently normal (n=881), defining MCI as CDR = 0.5 and dementia as CDR≥1. Using multinomial logistic regression models adjusted for demographics, we examined the associations of each group with selected baseline characteristics. RESULTS: With the normal group for reference, worse subjective cognitive concerns, functional impairments, self-rated health, and depressive symptoms were associated with being in any MCI group. Taking more prescription medications was associated with being in the stable MCI and reverter groups; diabetes and low diastolic blood pressure were associated with stable MCI. The APOE4 genotype was associated with stable and progressive MCI; stroke was associated with progressive MCI. All MCI subgroups were likely to have lower mean composite scores in all cognitive domains and more operationally defined impairments in attention, language, and executive function; reverters were more likely to lack memory and visuospatial impairments. CONCLUSIONS: MCI subgroups with different 5-year outcomes had some distinct characteristics suggesting different underlying causes. The progressors, unlike the reverters, had a profile broadly typical of Alzheimer's disease; the stable MCIs had other, including vascular, morbidity. These data shed light on the heterogeneity of MCI in the population. J Am Geriatr Soc 67:232-238, 2019.
Assuntos
Cognição , Disfunção Cognitiva/psicologia , Demência/epidemiologia , Progressão da Doença , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/análise , Pressão Sanguínea , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Demência/psicologia , Feminino , Humanos , Modelos Logísticos , Masculino , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/psicologiaRESUMO
Two thirds of all persons with late-onset Alzheimer's disease (AD) are women. Identification of sex-based molecular mechanisms underpinning the female-based prevalence of AD would advance development of therapeutic targets during the prodromal AD phase when prevention or delay in progression is most likely to be effective. This 3-year brain imaging study examines the impact of the menopausal transition on Alzheimer's disease (AD) biomarker changes [brain ß-amyloid load via 11C-PiB PET, and neurodegeneration via 18F-FDG PET and structural MRI] and cognitive performance in midlife. Fifty-nine 40-60 year-old cognitively normal participants with clinical, neuropsychological, and brain imaging exams at least 2 years apart were examined. These included 41 women [15 premenopausal controls (PRE), 14 perimenopausal (PERI), and 12 postmenopausal women (MENO)] and 18 men. We used targeted minimum loss-based estimation to evaluate AD biomarker and cognitive changes. Older age was associated with baseline Aß and neurodegeneration markers, but not with rates of change in these biomarkers. APOE4 status influenced change in Aß load, but not neurodegenerative changes. Longitudinally, MENO and PERI groups showed declines in estrogen-dependent memory tests as compared to men (p < .04). Adjusting for age, APOE4 status, and vascular risk confounds, the MENO and PERI groups exhibited higher rates of CMRglc decline as compared to males (p ≤ .015). The MENO group exhibited the highest rate of hippocampal volume loss (p's ≤ .001), and higher rates of Aß deposition than males (p < .01). CMRglc decline exceeded Aß and atrophy changes in all female groups vs. men. These findings indicate emergence and progression of a female-specific hypometabolic AD-endophenotype during the menopausal transition. These findings suggest that the optimal window of opportunity for therapeutic intervention to prevent or delay progression of AD endophenotype in women is early in the endocrine aging process.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/etiologia , Menopausa/psicologia , Idoso , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/análise , Apolipoproteína E4/análise , Biomarcadores , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Memória , Menopausa/fisiologia , Pessoa de Meia-Idade , Neuroimagem/métodos , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
New dual electrochemical and fluorescence sensitive curcumin-graphene quantum dots sensing platform coated on the transparent Indium-Tin-Oxide electrode was developed to sense APOe4 DNA, responsible of Alzheimer's disease. Curcumin molecule with its dual fluorescence and electrochemical properties was electropolymerized on GQDs-ITO surface. EDC/NHS chemistry was used to covalently immobilize an amino-substituted DNA probe via a malonic acid spacer. Quenching of curcumin signals following hybridized DNA complex was employed to quantify APOe4 DNA. Amperometric studies revealed an ultrasensitive behavior toward the formation of DNA complex with a sensitivity of 4.74â¯nA.mL.pg -1 and a limit of detection as low as 0.48â¯pgâ¯mL -1. The platform exhibits very good performances such as repeatability, reproducibility, selectivity and long storage stability. Fluorescence results were established for the support and the complementarity of electrochemical results. Founded results confirmed the ultrasensitivity of platform with comparable performances. Recorded results in human blood plasma demonstrated the high efficacy of curcumin system sensing even in the clinical matrix.
Assuntos
Doença de Alzheimer/diagnóstico , Apolipoproteína E4/análise , Curcumina/química , Técnicas Eletroquímicas , Fluorescência , Grafite/química , Pontos Quânticos/química , Humanos , Tamanho da Partícula , Espectrometria de FluorescênciaRESUMO
Many healthy volunteers choose to take part in Alzheimer's disease (AD) prevention studies because they want to know whether they will develop dementia-and what they can do to reduce their risk-and are therefore interested in learning the results of AD biomarker tests. Proponents of AD biomarker disclosure often refer to the personal utility of AD biomarkers, claiming that research participants will be able to use AD biomarker information for personal purposes, such as planning ahead or making important life decisions. In this paper, the claim that AD biomarkers have personal utility for asymptomatic individuals is critically assessed. It demonstrates that in the absence of clinical validity, AD biomarkers cannot have personal utility and do not serve research participants' autonomy. Over the next few years, many research groups will be confronted with participants' preferences to learn the results of AD biomarker tests. When researchers choose to make results available upon explicit request, they should ensure adequate information provision and education, notably on the uncertain clinical significance of AD biomarker information. Routine disclosure of AD biomarkers to cognitively unimpaired individuals in research settings cannot be justified with an appeal to the personal utility of AD biomarker information.
Assuntos
Doença de Alzheimer/diagnóstico , Pesquisa Biomédica/ética , Voluntários Saudáveis , Medicina Preventiva/ética , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/psicologia , Apolipoproteína E4/análise , Biomarcadores/análise , Revelação , HumanosRESUMO
The ε4 allele of the APOE gene is associated with poorer cognition in later life. This study aimed to advance understanding of how environments potentially moderate this genetic risk by focusing on childhood socioeconomic status (SES). Previous research across diverse national contexts has found that older adults from higher-SES families in childhood demonstrate better cognitive functioning than their lower-SES counterparts. Nevertheless, few studies have examined whether higher childhood SES might also promote later life cognition by mitigating the effects of ε4 carrier status. To address this gap, we used data from 3017 participants in the Wisconsin Longitudinal Study, which has followed a random sample of people who graduated from Wisconsin high schools in 1957. Childhood SES included parents' educational attainment, father's occupational status, and household income in adolescence. We constructed measures of memory and of language/executive functioning using scores from neurocognitive tests administered when participants were approximately ages 65 and 72. APOE ε4 status was measured through saliva samples. Results from cross-controlled multilevel models indicated that APOE ε4 status-and not childhood SES-independently predicted memory, whereas childhood SES-and not APOE ε4 status-independently predicted language/executive functioning. Moreover, a statistical interaction between APOE ε4 status and childhood SES for memory indicated that at baseline, higher childhood SES protected against the risk of APOE ε4 status, whereas lower childhood SES exacerbated the risk of APOE ε4 status. However, by follow-up, these moderating effects dissipated, and APOE ε4 status alone was associated with memory. We interpret these results in light of theorizing on differential susceptibility for poorer cognition across the life course.
Assuntos
Transtornos Cognitivos/genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Classe Social , Idoso , Apolipoproteína E4/análise , Apolipoproteína E4/genética , Criança , Transtornos Cognitivos/fisiopatologia , Função Executiva/fisiologia , Feminino , Humanos , Idioma , Estudos Longitudinais , Masculino , Memória/fisiologia , Testes de Estado Mental e Demência , Saliva/química , WisconsinRESUMO
BACKGROUND/AIMS: To evaluate whether visual assessment of medial temporal lobe atrophy (vaMTA) can predict 2-year conversion from mild cognitive impairment (MCI) to dementia and progression of MCI and Alzheimer's disease dementia as measured by the Clinical Dementia Rating Scale Sum of Boxes score (CDR-SB). METHODS: vaMTA was performed in 94 patients with MCI according to the Winblad criteria and in 124 patients with AD according to ICD-10 and NINCDS-ADRDA criteria. Demographic data, the Consortium to Establish a Registry for Alzheimer's Disease 10-word delayed recall, APOE É4 status, Cornell Scale for Depression in Dementia, and comorbid hypertension were used as covariates. RESULTS: vaMTA was associated with MCI conversion in an unadjusted model but not in an adjusted model (p = 0.075), where delayed recall and APOE É4 status were significant predictors. With CDR-SB change as the outcome, an interaction between vaMTA and diagnosis was found, but in the adjusted model only delayed recall and age were significant predictors. For vaMTA below 2, the association between vaMTA and CDR-SB change differed between diagnostic groups. Similar results were found based on a trajectory analysis. CONCLUSION: In adjusted models, memory function, APOE É4 status and age were significant predictors of disease progression, not vaMTA. The association between vaMTA and CDR-SB change was different in patients with MCI and Alzheimer's disease dementia.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Lobo Temporal , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Apolipoproteína E4/análise , Atrofia , Biomarcadores , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Progressão da Doença , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Testes Neuropsicológicos , Valor Preditivo dos Testes , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologiaRESUMO
BACKGROUND: Olfactory impairment is common among older adults; however, data are largely limited to whites. METHODS: We conducted pooled analyses of two community-based studies: the Atherosclerosis Risk in Communities study (ARIC, 1,398 blacks and 4,665 whites), and the Health, Aging, and Body Composition study (Health ABC, 958 blacks and 1,536 whites) to determine the prevalence of anosmia and associated factors for black and white older adults in the United States. RESULTS: The overall prevalence of anosmia was 22.3% among blacks and 10.4% among whites. Blacks had a markedly higher odds of anosmia compared to whites in age and sex adjusted analyses (odds ratio [OR] 2.96, 95% confidence interval [CI] = 2.59-3.38). In both blacks and whites, higher anosmia prevalence was associated with older age and male sex. The highest prevalence was found in black men 85 years or older (58.3%), and the lowest in white women aged 65-69 years (2.4%). Higher education level, lower cognitive score, ApoE ε4, daytime sleepiness, poorer general health status, lower body mass index, and Parkinson disease were associated with higher prevalence of anosmia in one or both races. However, the racial difference in anosmia remained statistically significant after adjusting for these factors (fully adjusted OR = 1.76, 95%CI: 1.50-2.07). Results were comparable between the two cohorts. DISCUSSION: Anosmia is common in older adults, particularly among blacks. Further studies are needed to identify risk factors for anosmia and to investigate racial disparities in this sensory deficit.
Assuntos
Envelhecimento , Apolipoproteína E4/análise , Aterosclerose/epidemiologia , Cognição , Transtornos do Olfato , Idoso , Envelhecimento/fisiologia , Envelhecimento/psicologia , População Negra/estatística & dados numéricos , Escolaridade , Feminino , Avaliação Geriátrica/métodos , Disparidades nos Níveis de Saúde , Humanos , Masculino , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/etnologia , Transtornos do Olfato/psicologia , Prevalência , Fatores de Risco , Fatores Sexuais , Estados Unidos/epidemiologia , População Branca/estatística & dados numéricosRESUMO
BACKGROUND AND OBJECTIVE: The relationship between repeated concussions and neurodegenerative disease has received significant attention, particularly research in postmortem samples. Our objective was to characterise retired professional ice hockey players' cognitive and psychosocial functioning in relation to concussion exposure and apolipoprotein ε4 status. METHODS: Alumni athletes (N=33, aged 34-71â years) and an age-matched sample of comparison participants (N=18) were administered measures of cognitive function and questionnaires concerning psychosocial and psychiatric functioning. RESULTS: No significant group differences were found on neuropsychological measures of speeded attention, verbal memory or visuospatial functions, nor were significant differences observed on computerised measures of response speed, inhibitory control and visuospatial problem solving. Reliable group differences in cognitive performance were observed on tests of executive and intellectual function; performance on these measures was associated with concussion exposure. Group differences were observed for cognitive, affective and behavioural impairment on psychosocial questionnaires and psychiatric diagnoses. There was no evidence of differential effects associated with age in the alumni athletes. Possession of an apolipoprotein ε4 allele was associated with increased endorsement of psychiatric complaints, but not with objective cognitive performance. CONCLUSIONS: We found only subtle objective cognitive impairment in alumni athletes in the context of high subjective complaints and psychiatric impairment. Apolipoprotein ε4 status related to psychiatric, but not cognitive status. These findings provide benchmarks for the degree of cognitive and behavioural impairment in retired professional athletes and a point of comparison for future neuroimaging and longitudinal studies.
Assuntos
Traumatismos em Atletas/diagnóstico , Traumatismos em Atletas/psicologia , Concussão Encefálica/diagnóstico , Concussão Encefálica/psicologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Hóquei/lesões , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Aposentadoria , Transtornos do Comportamento Social/diagnóstico , Transtornos do Comportamento Social/psicologia , Adulto , Idoso , Apolipoproteína E4/análise , Traumatismos em Atletas/epidemiologia , Concussão Encefálica/epidemiologia , Transtornos Cognitivos/epidemiologia , Estudos Transversais , Humanos , Masculino , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Psicometria/estatística & dados numéricos , Valores de Referência , Transtornos do Comportamento Social/epidemiologia , Inquéritos e QuestionáriosRESUMO
The risk of Alzheimer's disease (AD) is highly dependent on apolipoprotein-E (apoE) genotype. The reasons for apoE isoform-selective risk are uncertain; however, both the amounts and structure of human apoE isoforms have been hypothesized to lead to amyloidosis increasing the risk for AD. To address the hypothesis that amounts of apoE isoforms are different in the human CNS, we developed a novel isoform-specific method to accurately quantify apoE isoforms in clinically relevant samples. The method utilizes an antibody-free enrichment step and isotope-labeled physiologically relevant lipoprotein particle standards produced by immortalized astrocytes. We applied this method to a cohort of well characterized clinical samples and observed the following findings. The apoE isoform amounts are not different in cerebrospinal fluid (CSF) from young normal controls, suggesting that the amount of apoE isoforms is not the reason for risk of amyloidosis prior to the onset of advanced age. We did, however, observe an age-related increase in both apoE isoforms. In contrast to normal aging, the presence of amyloid increased apoE3, whereas apoE4 was unchanged or decreased. Importantly, for heterozygotes, the apoE4/apoE3 isoform ratio was increased in the CNS, although the reverse was true in the periphery. Finally, CSF apoE levels, but not plasma apoE levels, correlated with CSF ß-amyloid levels. Collectively, these findings support the hypothesis that CNS and peripheral apoE are separate pools and differentially regulated. Furthermore, these results suggest that apoE mechanisms for the risk of amyloidosis and AD are related to an interaction between apoE, aging, and the amount of amyloid burden.
Assuntos
Amiloidose/sangue , Amiloidose/líquido cefalorraquidiano , Apolipoproteína E3/análise , Apolipoproteína E4/análise , Biomarcadores/análise , Encéfalo/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Sequência de Aminoácidos , Amiloidose/diagnóstico , Astrócitos/citologia , Astrócitos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Demência/sangue , Demência/líquido cefalorraquidiano , Demência/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Fish intake and the long-chain omega-3 polyunsaturated fatty acids (PUFAs) in fish have been suggested to lower the risk of cognitive decline. We assessed whether serum long-chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are associated with performance on neuropsychological tests in an older population and whether exposure to methylmercury, mainly from fish, or apolipoprotein-E4 (Apo-E4) phenotype can modify the associations. SUBJECTS/METHODS: A total of 768 participants from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were included. Cognitive function was measured using five neuropsychological tests: the Trail Making Test, the Verbal Fluency Test, the Selective Reminding Test, the Visual Reproduction Test and the Mini Mental State Exam. Multivariate-adjusted analysis of covariance and linear regression were used to analyze the cross-sectional associations. RESULTS: We found statistically significant associations between serum EPA+DPA+DHA and better performance in the Trail Making Test and the Verbal Fluency Test. The individual associations with EPA and DHA were similar with the findings with EPA+DPA+DHA, although the associations with DHA were stronger. No associations were observed with serum DPA. Pubic hair mercury content was associated only with a worse performance in the Trail Making Test, and mercury had only little impact on the associations between the serum PUFAs and cognitive performance. Apo-E4 phenotype did not modify the associations with PUFAs or mercury. CONCLUSIONS: Higher serum long-chain omega-3 PUFA concentrations were associated with better performance on neuropsychological tests of frontal lobe functioning in older men and women. Mercury exposure or Apo-E4 phenotype had little impact on cognitive performance.
Assuntos
Cognição/fisiologia , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Insaturados/sangue , Adulto , Idoso , Animais , Apolipoproteína E4/análise , Estudos Transversais , Feminino , Finlândia , Peixes , Avaliação Geriátrica/métodos , Cabelo/química , Humanos , Masculino , Mercúrio/análise , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/psicologia , Testes Neuropsicológicos , Fatores de Risco , Alimentos Marinhos/análiseRESUMO
Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and chromosomal sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the specific risk of the APOE-ε4 positive male which appears to emerge early in the aging process. Evidence for impact of the triad of AD risk factors is most evident in the temporal trajectory of AD progression and burden of pathology in relation to APOE genotype, age and sex. Collectively, the data indicate complex interactions between age, APOE genotype and gender that belies a one size fits all approach and argues for a precision medicine approach that integrates across the three main risk factors for Alzheimer's disease.
Assuntos
Envelhecimento , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Alelos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Apolipoproteína E4/análise , Apolipoproteína E4/metabolismo , Colesterol/metabolismo , Feminino , Genótipo , Homozigoto , Humanos , Masculino , Menopausa , Modelos Moleculares , Fatores de Risco , Fatores SexuaisRESUMO
STUDY OBJECTIVES: To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. METHODS: Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. RESULTS: Levels of orexin-A, amyloid beta 42 (Aß42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 ± 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Aß42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. CONCLUSIONS: Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov registration number NCT01962779.
Assuntos
Envelhecimento/líquido cefalorraquidiano , Envelhecimento/fisiologia , Cognição/fisiologia , Orexinas/metabolismo , Sono/fisiologia , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo , Idoso , Envelhecimento/metabolismo , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/análise , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Escolaridade , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Análise de Regressão , Síndromes da Apneia do Sono/diagnóstico , Síndromes da Apneia do Sono/fisiopatologia , Fatores de TempoRESUMO
IMPORTANCE: Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern. OBJECTIVE: To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years. EXPOSURES: Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death. MAIN OUTCOMES AND MEASURES: Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses. RESULTS: Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (ρ = 0.16; P = .02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (≥ 1 meal[s]/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (ß = -0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (ß = -0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (ß = -0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE ε4) carriers. Higher intake levels of α-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology. CONCLUSIONS AND RELEVANCE: In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology.
Assuntos
Doença de Alzheimer/patologia , Química Encefálica , Ácidos Graxos Ômega-3/administração & dosagem , Mercúrio/análise , Alimentos Marinhos/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/análise , Autopsia , Cerebelo/química , Cerebelo/patologia , Estudos Transversais , Registros de Dieta , Escolaridade , Feminino , Lobo Frontal/química , Lobo Frontal/patologia , Humanos , Masculino , Selênio/análise , Lobo Temporal/química , Lobo Temporal/patologiaRESUMO
Joint models initially dedicated to a single longitudinal marker and a single time-to-event need to be extended to account for the rich longitudinal data of cohort studies. Multiple causes of clinical progression are indeed usually observed, and multiple longitudinal markers are collected when the true latent trait of interest is hard to capture (e.g., quality of life, functional dependency, and cognitive level). These multivariate and longitudinal data also usually have nonstandard distributions (discrete, asymmetric, bounded, etc.). We propose a joint model based on a latent process and latent classes to analyze simultaneously such multiple longitudinal markers of different natures, and multiple causes of progression. A latent process model describes the latent trait of interest and links it to the observed longitudinal outcomes using flexible measurement models adapted to different types of data, and a latent class structure links the longitudinal and cause-specific survival models. The joint model is estimated in the maximum likelihood framework. A score test is developed to evaluate the assumption of conditional independence of the longitudinal markers and each cause of progression given the latent classes. In addition, individual dynamic cumulative incidences of each cause of progression based on the repeated marker data are derived. The methodology is validated in a simulation study and applied on real data about cognitive aging obtained from a large population-based study. The aim is to predict the risk of dementia by accounting for the competing death according to the profiles of semantic memory measured by two asymmetric psychometric tests.
Assuntos
Apolipoproteína E4/análise , Pesquisa Biomédica/métodos , Demência/diagnóstico , Medição de Risco/métodos , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Pesquisa Biomédica/estatística & dados numéricos , Cognição/classificação , Simulação por Computador , Progressão da Doença , Feminino , França , Marcadores Genéticos , Humanos , Funções Verossimilhança , Estudos Longitudinais , Masculino , Modelos Estatísticos , Análise Multivariada , Valor Preditivo dos Testes , Estudos Prospectivos , Psicometria , Medição de Risco/estatística & dados numéricos , Fatores de TempoRESUMO
Human apolipoprotein E4 (APOE4) is a major risk factor for Alzheimer's disease (AD) and can greatly increase the morbidity. In this work, an ultrasensitive sandwich-type electrochemical immunosensor for the quantitative detection of APOE4 was designed based on fractal gold (FracAu) nanostructures and enzyme amplification. The FracAu nanostructures were directly electrodeposited by hydrogen tetrachloroaurate (HAuCl4) on polyelectrolytes modified indium tin oxide (ITO) electrode. The sensing performances of the modified interface were investigated by cyclic voltammetry (CV). After functionalization with HRP-labeled APOE4 antibody, the human APOE4 could be detected quantitatively by current response. The current response has a linear relationship with the logarithm of human APOE4 concentrations in a range from 1.0 to 10,000.0 ng/mL, with a detection limit of 0.3 ng/mL. The fabricated APOE4 electrochemical immunosensor exhibits strong specificity, high sensitivity, low detection limit and wide linear range. The detection of human APOE4 provides a strong support for the prevention of AD and early-stage warning for those susceptible populations.
Assuntos
Apolipoproteína E4/análise , Condutometria/instrumentação , Ouro/química , Peroxidase do Rábano Silvestre/química , Imunoensaio/instrumentação , Nanopartículas Metálicas/química , Apolipoproteína E4/química , Apolipoproteína E4/imunologia , Desenho de Equipamento , Análise de Falha de Equipamento , Fractais , Humanos , Nanopartículas Metálicas/ultraestrutura , Microquímica/instrumentação , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A key component of personalized medicine is companion diagnostics that measure biomarkers, for example, protein expression, gene amplification or specific mutations. Most of the recent attention concerning molecular cancer diagnostics has been focused on the biomarkers of response to therapy, such as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in metastatic colorectal cancer, epidermal growth factor receptor mutations in metastatic malignant melanoma. The presence or absence of these markers is directly linked to the response rates of particular targeted therapies with small-molecule kinase inhibitors or antibodies. Therefore, testing for these markers has become a critical step in the target therapy of the aforementioned tumors. The core capability of personalized medicine is the companion diagnostic devices' (CDx) ability to accurately and precisely stratify patients by their likelihood of benefit (or harm) from a particular therapy. There is no reference in the literature discussing the impact of device's measurement performance, for example, analytical accuracy and precision on treatment effects, variances, and sample sizes of clinical trial for the personalized medicine. In this paper, using both analytical and estimation method, we assessed the impact of CDx measurement performance as a function of positive and negative predictive values and imprecision (standard deviation) on treatment effects, variances of clinical outcome, and sample sizes for the clinical trials.
Assuntos
Ensaios Clínicos como Assunto/métodos , Marcadores Genéticos , Biologia Molecular/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Medicina de Precisão/métodos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Apolipoproteína E4/análise , Apolipoproteína E4/genética , Ensaios Clínicos como Assunto/estatística & dados numéricos , Diagnóstico Precoce , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Biologia Molecular/estatística & dados numéricos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Medicina de Precisão/estatística & dados numéricos , Reprodutibilidade dos Testes , Fatores de Risco , Prevenção SecundáriaRESUMO
BACKGROUND: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. METHODS: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. RESULTS: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. CONCLUSION: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment.