RESUMO
Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12â years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.
Assuntos
Doença de Alzheimer , Cognição , Fator A de Crescimento do Endotélio Vascular , Proteínas tau , Humanos , Doença de Alzheimer/sangue , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Masculino , Feminino , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Proteínas tau/metabolismo , Proteínas tau/sangue , Estudos Longitudinais , Idoso de 80 Anos ou mais , Cognição/fisiologia , Tomografia por Emissão de Pósitrons , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/sangue , Biomarcadores/sangueRESUMO
BACKGROUND: Recruiting to multi-site trials is challenging, particularly when striving to ensure the randomized sample is demographically representative of the larger disease-suffering population. While previous studies have reported disparities by race and ethnicity in enrollment and randomization, they have not typically investigated whether disparities exist in the recruitment process prior to consent. To identify participants most likely to be eligible for a trial, study sites frequently include a prescreening process, generally conducted by telephone, to conserve resources. Collection and analysis of such prescreening data across sites could provide valuable information to improve understanding of recruitment intervention effectiveness, including whether traditionally underrepresented participants are lost prior to screening. METHODS: We developed an infrastructure within the National Institute on Aging (NIA) Alzheimer's Clinical Trials Consortium (ACTC) to centrally collect a subset of prescreening variables. Prior to study-wide implementation in the AHEAD 3-45 study (NCT NCT04468659), an ongoing ACTC trial recruiting older cognitively unimpaired participants, we completed a vanguard phase with seven study sites. Variables collected included age, self-reported sex, self-reported race, self-reported ethnicity, self-reported education, self-reported occupation, zip code, recruitment source, prescreening eligibility status, reason for prescreen ineligibility, and the AHEAD 3-45 participant ID for those who continued to an in-person screening visit after study enrollment. RESULTS: Each of the sites was able to submit prescreening data. Vanguard sites provided prescreening data on a total of 1029 participants. The total number of prescreened participants varied widely among sites (range 3-611), with the differences driven mainly by the time to receive site approval for the main study. Key learnings instructed design/informatic/procedural changes prior to study-wide launch. CONCLUSION: Centralized capture of prescreening data in multi-site clinical trials is feasible. Identifying and quantifying the impact of central and site recruitment activities, prior to participants signing consent, has the potential to identify and address selection bias, instruct resource use, contribute to effective trial design, and accelerate trial enrollment timelines.
Assuntos
Projetos de Pesquisa , Humanos , Coleta de Dados , EscolaridadeRESUMO
OBJECTIVE: Elevated vascular risk and beta-amyloid (Aß) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aß interaction on cognitive decline. METHODS: We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aß burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aß on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aß effect on cognitive decline. RESULTS: We observed a significant interaction between elevated baseline FHS-CVD and Aß on greater ITC tau accumulation (p = 0.004), even in individuals with Aß burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aß on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aß on cognitive decline. INTERPRETATION: Vascular risks interact with subthreshold levels of Aß to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aß-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.
Assuntos
Doença de Alzheimer , Doenças Cardiovasculares , Disfunção Cognitiva , Humanos , Idoso , Pessoa de Meia-Idade , Proteínas tau , Disfunção Cognitiva/diagnóstico por imagem , Peptídeos beta-Amiloides , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Tomografia por Emissão de Pósitrons , BiomarcadoresRESUMO
Introduction: Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks. Methods: rs-fcMRI, amyloid beta (Aß) positron emission tomography (PET), PA (steps/day × 1 week), and longitudinal cognitive (Preclinical Alzheimer's Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used. We used linear and linear mixed-effects regression models to examine the associations between baseline PA and baseline network connectivity and between PA, network connectivity, and longitudinal cognitive performance. Results: Higher PA was associated selectively with greater connectivity in three networks previously associated with cognitive decline (default, salience, left control). This association with network connectivity accounted for a modest portion of PA's effects on Aß-related cognitive decline. Discussion: Although other mechanisms are likely present, PA may promote resilience with respect to Aß-related cognitive decline, partly by increasing connectivity in a subset of cognitive networks.
RESUMO
Older adults are encouraged to engage in multicomponent physical activity, which includes aerobic and muscle-strengthening activities. The current work is an extension of the Vitality, Independence, and Vigor in the Elderly 2 (VIVE2) study - a 6-month multicenter, randomized, placebo-controlled trial of physical activity and nutritional supplementation in community dwelling 70-year-old seniors. Here, we examined whether the magnitude of changes in muscle size and quality differed between major lower-extremity muscle groups and related these changes to functional outcomes. We also examined whether daily vitamin-D-enriched protein supplementation could augment the response to structured physical activity. Forty-nine men and women (77 ± 5 yrs) performed brisk walking, muscle-strengthening exercises for the lower limbs, and balance training 3 times weekly for 6 months. Participants were randomized to daily intake of a nutritional supplement (20 g whey protein + 800 IU vitamin D), or a placebo. Muscle cross-sectional area (CSA) and radiological attenuation (RA) were assessed in 8 different muscle groups using single-slice CT scans of the hip, thigh, and calf at baseline and after the intervention. Walking speed and performance in the Short Physical Performance Battery (SPPB) were also measured. For both CSA and RA, there were muscle group × time interactions (P < 0.01). Significant increases in CSA were observed in 2 of the 8 muscles studied, namely the knee extensors (1.9%) and the hip adductors (2.8%). For RA, increases were observed in 4 of 8 muscle groups, namely the hip flexors (1.1 HU), hip adductors (0.9 HU), knee extensors (1.2 HU), and ankle dorsiflexors (0.8 HU). No additive effect of nutritional supplementation was observed. While walking speed (13%) and SPPB performance (38%) improved markedly, multivariate analysis showed that these changes were not associated with the changes in muscle CSA and RA after the intervention. We conclude that this type of multicomponent physical activity program results in significant improvements in physical function despite relatively small changes in muscle size and quality of some, but not all, of the measured lower extremity muscles involved in locomotion.
Assuntos
Exercício Físico , Caminhada , Idoso , Suplementos Nutricionais , Exercício Físico/fisiologia , Feminino , Humanos , Extremidade Inferior , Masculino , Força Muscular/fisiologia , Músculo Esquelético/fisiologia , Caminhada/fisiologiaRESUMO
INTRODUCTION: Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aß), remains unclear. METHODS: We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aß. We next examined associations between cytokine levels and neuroimaging biomarkers of Aß/tau/neurodegeneration. RESULTS: Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aß (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aß (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aß. DISCUSSION: Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Peptídeos beta-Amiloides , Biomarcadores , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Humanos , Interleucina-12 , Tomografia por Emissão de Pósitrons , Proteínas tauRESUMO
In the present study, we tested the hypothesis that higher amyloid-beta (Aß) burden at baseline is associated with greater longitudinal decline in body mass index (BMI) in clinically normal adults. Participants from the Harvard Aging Brain Study (n = 312) and the Alzheimer's Disease Neuroimaging Initiative (n = 336) underwent Aß positron emission tomography at baseline. BMI was assessed longitudinally over a median of >4 years. Linear mixed models showed that higher baseline Aß burden was significantly associated with greater decline in BMI in both the Harvard Aging Brain Study (t = -1.93; p = 0.05) and Alzheimer's Disease Neuroimaging Initiative cohorts (t = -2.54; p = 0.01), after adjusting for covariates, including cognitive performance and depressive symptoms. In addition, the association of Aß burden with longitudinal decline in BMI persisted in both cohorts after excluding participants with diabetes/endocrine disturbances and participants classified as underweight or obese (BMI <18.5 or >30). These findings suggest that decline in BMI in clinically normal adults may be an early manifestation related to cerebral amyloidosis that precedes objective cognitive impairment. Therefore, unintentional BMI decline in otherwise healthy individuals might alert clinicians to increased risk of Alzheimer's disease.
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Índice de Massa Corporal , Encéfalo/metabolismo , Voluntários Saudáveis , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons , RiscoRESUMO
Importance: To reduce the rising incidence of clinical impairment due to Alzheimer disease, it is essential to define older adults at highest risk. Widowhood may be an unrecognized factor contributing to accelerated clinical progression along the Alzheimer disease pathway among cognitively unimpaired older adults. Objective: To determine whether widowhood status and level of brain ß-amyloid (ie, the Alzheimer disease pathologic protein) are additively or interactively associated with cognitive decline among cognitively unimpaired older adults. Design, Setting, and Participants: In this cohort study, 257 married, widowed, and unmarried (ie, never married, divorced, or separated) participants from the Harvard Aging Brain Study longitudinal cohort underwent baseline evaluation of neocortical ß-amyloid levels using Pittsburgh compound B positron emission tomography and 4 annual cognitive assessments. Data were collected from September 2010 to February 2017 and analyzed from July 2018 to July 2019. Main Outcomes and Measures: Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite. Results: Of the 257 participants, 153 (59.5%) were women, and the mean (SD) age was 73.5 (6.1) years; 145 participants (56.4%) were married (66 [45.5%] women), 77 (30.0%) were unmarried (56 [72.7%] women), and 35 (13.6%) were widowed (31 [88.6%] women). Compared with married participants, widowed participants demonstrated worsening cognitive performance after adjusting for age, sex, socioeconomic status, depression, and ß-amyloid levels (ß = -0.11; 95% CI, -0.19 to -0.04; P = .002) with no difference observed between married and unmarried participants. Furthermore, widowed participants with higher baseline ß-amyloid levels exhibited steeper cognitive decline (ß = -0.22; 95% CI, -0.42 to -0.03; P = .02), indicating both independent and interactive associations of ß-amyloid levels and widowhood with cognition. In a secondary model using dichotomous ß-amyloid-marital status groupings, the rate of cognitive decline among widowed participants with high ß-amyloid was nearly 3 times faster than among married participants with high ß-amyloid (widowed, high ß-amyloid: ß, -0.33; 95% CI, -0.46 to -0.19; P < .001; married, high ß-amyloid: ß, -0.12; 95% CI, -0.18 to -0.01; P < .001). Conclusions and Relevance: In a sample of cognitively unimpaired older adults, being widowed was associated with accelerated ß-amyloid-related cognitive decline during 3 years. Cognitively unimpaired, widowed older adults were particularly susceptible to Alzheimer disease clinical progression, emphasizing the need for increased research attention and evidenced-based interventions for this high-risk group.
Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico , Viuvez , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Estudos de Casos e Controles , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Fatores de RiscoRESUMO
IMPORTANCE: In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease. OBJECTIVE: To examine whether physical activity moderates the association of ß-amyloid (Aß) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study. Participants were required to have baseline Aß positron emission tomography data, baseline medical data to quantify vascular risk, and longitudinal neuropsychological and structural magnetic resonance imaging data. Data were collected from April 2010 to June 2018. Data were analyzed from August to December 2018. MAIN OUTCOMES AND MEASURES: Baseline physical activity was quantified with a pedometer (mean steps per day). Baseline Aß burden was measured with carbon 11-labeled Pittsburgh Compound B positron emission tomography. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC; median [interquartile range] follow-up, 6.0 [4.3-6.3] years). Neurodegeneration was assessed with longitudinal structural magnetic resonance imaging (2 to 5 scans per participant; median [interquartile range] follow-up, 4.5 [3.0-5.0] years), with a focus on total gray matter volume and regional cortical thickness. Physical activity and Aß burden were examined as interactive predictors of PACC decline and volume loss in separate linear mixed models, adjusting for age, sex, education, apolipoprotein E ε4 status, and, where appropriate, intracranial volume. Secondary models adjusted for vascular risk and its interaction with Aß burden. RESULTS: Of the 182 included participants, 103 (56.6%) were female, and the mean (SD) age was 73.4 (6.2) years. In models examining PACC decline and volume loss, there was a significant interaction of physical activity with Aß burden, such that greater physical activity was associated with slower Aß-related cognitive decline (ß, 0.03; 95% CI, 0.02-0.05; P < .001) and volume loss (ß, 482.07; 95% CI, 189.40-774.74; P = .002). Adjusting for vascular risk did not alter these associations. In these models, lower vascular risk was independently associated with slower Aß-related PACC decline (ß, -0.04; 95% CI, -0.06 to -0.02; P < .001) and volume loss (ß, -483.41; 95% CI, -855.63 to -111.20; P = .01). CONCLUSIONS AND RELEVANCE: Greater physical activity and lower vascular risk independently attenuated the negative association of Aß burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.
RESUMO
OBJECTIVE: Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-ß, the Alzheimer's disease (AD) pathologic marker. METHODS: Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-ß was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-ß on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-ß on change in social engagement. RESULTS: Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-ß-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (ßâ¯=â¯0.05, pâ¯=â¯0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (ßâ¯=â¯1.1, pâ¯=â¯0.02). This association was not modified by amyloid-ß, and there was no direct association of amyloid-ß with change in social engagement. CONCLUSIONS: Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.
Assuntos
Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico , Participação Social/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Progressão da Doença , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and ß-amyloid (Aß). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. Objective: To examine sex differences in the cross-sectional association between Aß and regional tau deposition as measured with positron emission tomography (PET). Design, Setting and Participants: This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aß PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET. Main Outcomes and Measures: A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aß as well as sex and APOE ε4 on these regions after controlling for age were also examined. Results: The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aß). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: ß [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aß burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: ß [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07). Conclusions and Relevance: Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Apolipoproteína E4/genética , Encéfalo/metabolismo , Carbolinas , Meios de Contraste , Estudos Transversais , Córtex Entorrinal/diagnóstico por imagem , Córtex Entorrinal/metabolismo , Etilenoglicóis , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Fatores Sexuais , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/metabolismo , TiazóisRESUMO
OBJECTIVES: Amyloid-beta (Aß) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. METHODS: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aß (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aß PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. RESULTS: Higher levels of Aß and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aß was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aß. A significant interaction between tau and Aß was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. INTERPRETATION: Our results are consistent with the supposition that both Aß and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1-3 ANN NEUROL 2019;85:181-193.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Memória Episódica , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons/métodosRESUMO
BACKGROUND: The Lifestyle Interventions and Independence for Elders (LIFE) clinical trial demonstrated that a structured program of physical activity (PA) reduced mobility-disability in older adults by up to 28%. It remains unknown whether the benefits of LIFE PA can be translated to older adults at risk for mobility-disability in real-world community-based settings. To address this knowledge gap, we conducted the ENhancing independence using Group-based community interventions for healthy AGing in Elders (ENGAGE) pilot study and examined the safety, feasibility, and preliminary effectiveness of translating LIFE PA to a community-based senior center. METHODS: Forty older adults with severe lower extremity functional limitations (age: 76.9 ± 7.3 years; body mass index: 32.7 ± 8 kg/m2; 85% female; short physical performance battery score: 6.3 ± 2.2) were randomized to 24 weeks of PA or a health education control intervention. RESULTS: Community-based PA was safe (serious adverse events: PA vs health education, 0:2; nonserious adverse events: PA vs health education, 3:1) and participants successfully adhered to the PA intervention (65.2%). Compared to health education, PA participants who attended ≥25% of scheduled visits had meaningful and sustained short physical performance battery improvements at follow-up (between group short physical performance battery score differences: ~0.7 units). CONCLUSIONS: ENGAGE has demonstrated the preliminary safety, feasibility, and effectiveness of LIFE PA in a real-world community-based setting. Larger-scale translational studies are needed to further disseminate the benefits of LIFE PA to vulnerable older adults in a variety of community-based settings.
Assuntos
Exercício Físico , Promoção da Saúde , Envelhecimento Saudável , Estilo de Vida , Acidentes por Quedas/prevenção & controle , Acidentes por Quedas/estatística & dados numéricos , Idoso , Boston/epidemiologia , Depressão/terapia , Função Executiva , Estudos de Viabilidade , Feminino , Humanos , Masculino , Limitação da Mobilidade , Desempenho Físico Funcional , Projetos Piloto , Qualidade de Vida , Método Simples-Cego , População UrbanaRESUMO
OBJECTIVE: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and ß-amyloid (Aß) burden have an interactive association with regional tau burden. METHODS: Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aß (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) PET imaging on the same participants. Aß PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aß as interactive predictors of tau deposition, adjusting for age, sex, APOE ε4 status, and the time interval between baseline and the tau PET scan. RESULTS: We observed a significant interaction between FHS-CVD and Aß burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aß burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16). INTERPRETATION: Elevated vascular risk may influence tau burden when coupled with high Aß burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Doenças Cardiovasculares/epidemiologia , Proteínas tau/metabolismo , Idoso , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Carbolinas , Meios de Contraste , Córtex Entorrinal , Feminino , Voluntários Saudáveis , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons , Risco , Medição de Risco , Lobo Temporal , TiazóisRESUMO
BACKGROUND: Health-related quality of life (HRQoL) and absence of depressive symptoms are of great importance for older people, which may be achieved through lifestyle interventions, e.g., exercise and nutrition interventions. The aim of this investigation was to analyze the effects of a physical activity program in combination with protein supplementation on HRQoL and depressive symptoms in community-dwelling, mobility-limited older adults. METHODS: In the Vitality, Independence, and Vigor 2 Study (VIVE2), community-dwelling men and women with an average age of 77.5 ± 5.4 years, some mobility limitations and low serum vitamin D levels (25(OH)Vit D 22.5-60 nmol/l) from two study sites (Stockholm, Sweden and Boston, USA) were randomized to receive a nutritional supplement or a placebo for 6 months. All took part in a physical activity program 2-3 times/ week. The primary outcome examined in VIVE2 was 400 M walk capacity. HRQoL was measured using the Medical Outcomes Study 36-item Short Form Health Survey (SF36), consisting of the Physical Component Summary (PCS) and Mental Component Summary (MCS), and depressive symptoms were measured using The Centre for Epidemiologic Studies Depression Scale (CES-D). In the sensitivity analyses, the sample was divided into sub-groups based on body measures and function (body mass index (BMI), appendicular lean mass index (ALMI), handgrip strength and gait speed). RESULTS: For the whole sample, there was a significant improvement in both MCS, mean (95% CI) 2.68 (0.5, 4.9) (p 0.02), and CES-D -2.7 (- 4.5, - 0.9) (p 0.003) during the intervention, but no difference was detected between those who received the nutritional supplement and those who received the placebo. The results revealed no significant change in PCS or variation in effects across the sub-categories. CONCLUSIONS: This study demonstrates that a six-month intervention using a physical activity program had positive effects on mental status. No additional effects from nutritional supplementation were detected. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, March 2 2012, NCT01542892 .
Assuntos
Afeto/fisiologia , Suplementos Nutricionais , Exercício Físico/fisiologia , Exercício Físico/psicologia , Qualidade de Vida/psicologia , Afeto/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Boston/epidemiologia , Depressão/epidemiologia , Depressão/psicologia , Depressão/terapia , Feminino , Força da Mão/fisiologia , Humanos , Vida Independente/psicologia , Masculino , Limitação da Mobilidade , Suécia/epidemiologia , Vitamina D/administração & dosagem , Caminhada/fisiologia , Caminhada/psicologiaRESUMO
INTRODUCTION: Our objective was to investigate the effect of sex on cognitive decline within the context of amyloid ß (Aß) burden and apolipoprotein E genotype. METHODS: We analyzed sex-specific effects on Aß-positron emission tomography, apolipoprotein, and rates of change on the Preclinical Alzheimer Cognitive Composite-5 across three cohorts, such as the Alzheimer's Disease Neuroimaging Initiative, Australian Imaging, Biomarker and Lifestyle, and Harvard Aging Brain Study (n = 755; clinical dementia rating = 0; age (standard deviation) = 73.6 (6.5); female = 55%). Mixed-effects models of cognitive change by sex, Aß-positron emission tomography, and apolipoprotein ε4 were examined with quadratic time effects over a median of 4 years of follow-up. RESULTS: Apolipoprotein ε4 prevalence and Aß burden did not differ by sex. Sex did not directly influence cognitive decline. Females with higher Aß exhibited faster decline than males. Post hoc contrasts suggested that females who were Aß and apolipoprotein ε4 positive declined faster than their male counterparts. DISCUSSION: Although Aß did not differ by sex, cognitive decline was greater in females with higher Aß. Our findings suggest that sex may play a modifying role on risk of Alzheimer's disease-related cognitive decline.
Assuntos
Doença de Alzheimer/epidemiologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Disfunção Cognitiva/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Sintomas Prodrômicos , Fatores de Risco , Fatores SexuaisRESUMO
Importance: Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and ß-amyloid (Aß) pathology commonly co-occur in older adults and are significant causes of cognitive impairment. Objective: To determine whether vascular risk and Aß burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aß burden, hippocampal volume, fludeoxyglucose F18-labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease. Design, Setting, and Participants: In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aß-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017. Main Outcomes and Measures: Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aß burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ε4 status. Results: Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (ß = -0.064; 95% CI, -0.094 to -0.033; P < .001) and higher Aß burden (ß = -0.058; 95% CI, -0.079 to -0.037; P < .001). The interaction of the FHS-CVD risk score and Aß burden with time was significant (ß = -0.040, 95% CI, -0.062 to -0.018; P < .001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (ß = -0.055; 95% CI, -0.086 to -0.024; P < .001), even after adjustment for Aß burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities. Conclusions and Relevance: In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aß burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.
Assuntos
Envelhecimento , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/epidemiologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Idoso , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Fatores de RiscoRESUMO
BACKGROUND: Nutritional supplementation and physical activity have been shown to positively influence muscle mass and strength in older adults. The efficacy of long-term nutritional supplementation in combination with physical activity in older adults remains unclear. METHODS: Mobility-limited (short physical performance battery [SPPB] ≤9) and vitamin D insufficient (serum 25(OH) D 9-24 ng/mL) older adults were recruited for this study. All subjects participated in a physical activity program. Subjects were randomized to consume a daily nutritional supplement (150 kcal, 20 g whey protein, 800 IU vitamin D, 119 mL beverage) or placebo (30 kcal, nonnutritive, 119 mL). In a prespecified secondary analysis, we examined total-body composition (dual energy X-ray absorptiometry), thigh composition (computed tomography), and muscle strength, power, and quality before and after the 6-month intervention. RESULTS: One hundred and forty-nine subjects were randomized into the study [mean (standard deviation, SD) age 78.5 (5.4) years; 46.3% female; mean (SD) short physical performance battery 7.9 (1.2); mean (SD) vitamin D 18.7 (6.4) ng/mL]. After the intervention period both groups demonstrated improvements in muscle strength, body composition, and thigh composition. Nutritional supplementation lead to further losses of intermuscular fat (p = .049) and increased normal muscle density (p = .018). CONCLUSIONS: Six months of physical activity resulted in improvements in body composition, subcutaneous fat, intermuscular fat, and strength measures. The addition of nutritional supplementation resulted in further declines in intermuscular fat and improved muscle density compared to placebo. These results suggest nutritional supplementation provides additional benefits to mobility-limited older adults undergoing exercise training. ClinicalTrials.gov Identifier: NCT01542892.
Assuntos
Suplementos Nutricionais , Exercício Físico/fisiologia , Limitação da Mobilidade , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Treinamento Resistido/métodos , Sarcopenia/terapia , Absorciometria de Fóton , Idoso , Proteínas Alimentares/administração & dosagem , Método Duplo-Cego , Ingestão de Energia , Feminino , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Cooperação do Paciente , Sarcopenia/metabolismo , Sarcopenia/fisiopatologiaRESUMO
This cluster-randomized trial was designed to determine the efficacy of a 6-month exercise-nutritional supplement program (ENP) on physical function and nutritional status for older adults and the feasibility of implementing this program in a senior living setting. Twenty senior-living facilities were randomized to either a 3 day per week group-based ENP led by a trained facility staff member or a health education program (SAP). Participants (N = 121) completed a short physical performance battery, 400-m walk, handgrip strength test, and mini-nutrition assessment. 25-hydroxyvitamin D [25(OH)D], insulin-like growth-factor 1 (IGF-1), and activity level were also measured. The ENP did not significantly improve physical function or nutritional status compared with the SAP. Compared with baseline, participants in the ENP engaged in 39 min less physical activity per week at 6 months. Several facility characteristics hindered implementation of the ENP. This study highlights the complexity of implementing an evidence-based program in a field setting.