Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration.

BACKGROUND AND PURPOSE: Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. METHODS: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. RESULTS: In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (ß = -3.5, 95% confidence interval [CI] = -5.4 to -1.7), total gray matter (ß = -1.9, 95% CI = -3.4 to -0.3), and total cortical gray matter (ß = -1.9, 95% CI = -3.7 to -0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (ß = -7.3, 95% CI = -11.1 to -3.5). Heterogeneity between studies was low. CONCLUSIONS: NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.

Long Non-Coding RNAs: New Insights in Neurodegenerative Diseases.

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.

Research on aging during the Venezuelan humanitarian crisis: the experience of the Maracaibo aging study.

BACKGROUND: Venezuela is in the throes of a complex humanitarian crisis that is one of the worst in decades to impact any country outside of wartime. This case analysis describes the challenges faced by the ongoing Maracaibo Aging Study (MAS) during the deteriorating conditions in Venezuela. When the MAS began in 1997, it focused on memory-related disorders. Since then, strategic planning and proactive community participation allowed us to anticipate and address logistical, funding, and ethical challenges, and facilitated the enrollment and retention of more than 2500 subjects over 55 years of age. All participants, who are residents of the city of Maracaibo, Venezuela, underwent various assessments on several occasions. Here, we discuss how our approach to implementing a longitudinal, population-based study of age-related conditions has allowed our research program to continue throughout this period of political, economic, and social upheaval. DISCUSSION: As the social context in Venezuela became more complicated, new challenges emerged, and strategies to sustain the study and participation were refined. We identified five main mechanisms through which the evolving humanitarian crisis has affected implementation of the MAS: 1) community dynamics; 2) morale of researchers, staff, and participants; 3) financial feasibility; 4) components of the research process; and 5) impact on the health of staff, participants, and their families. Strategies to compensate for the impact on these components were implemented, based on inputs from community members and staff. Improved communication, greater involvement of stakeholders, broadening the scope of the project, and strengthening international collaboration have been the most useful strategies. Particular demands emerged, related to the increased mortality and comorbidities of participants and staff, and deterioration of basic services and safety. CONCLUSION: Although the MAS has faced numerous obstacles, it has been possible to continue a longitudinal research project throughout the humanitarian crisis, because our research team has engaged the community deeply and developed a sense of mutual commitment, and also because our project has provided funding to help keep researchers employed, somewhat attenuating the brain drain.

Urinary proteomics combined with home blood pressure telemonitoring for health care reform trial: rational and protocol.

BACKGROUND: Hypertension and diabetes cause chronic kidney disease (CKD) and diastolic left ventricular dysfunction (DVD) as forerunners of disability and death. Home blood pressure telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling prevention. METHODS: UPRIGHT-HTM (Urinary Proteomics Combined with Home Blood Pressure Telemonitoring for Health Care Reform [NCT04299529]) is an investigator-initiated 5-year clinical trial with patient-centred design, which will randomise 1148 patients to be recruited in Europe, sub-Saharan Africa and South America. During the whole study, HTM data will be collected and freely accessible for patients and caregivers. The UPP, measured at enrolment only, will be communicated early during follow-up to 50% of patients and their caregivers (intervention), but only at trial closure in 50% (control). The hypothesis is that early knowledge of the UPP risk profile will lead to more rigorous risk factor management and result in benefit. Eligible patients, aged 55-75 years old, are asymptomatic, but have ≥5 CKD- or DVD-related risk factors, preferably including hypertension, type-2 diabetes, or both. The primary endpoint is a composite of new-onset intermediate and hard cardiovascular and renal outcomes. Demonstrating that combining UPP with HTM is feasible in a multicultural context and defining the molecular signatures of early CKD and DVD are secondary endpoints. EXPECTED OUTCOMES: The expected outcome is that application of UPP on top of HTM will be superior to HTM alone in the prevention of CKD and DVD and associated complications and that UPP allows shifting emphasis from treating to preventing disease, thereby empowering patients.

Association of Office and Ambulatory Blood Pressure With Mortality and Cardiovascular Outcomes.

Importance: Blood pressure (BP) is a known risk factor for overall mortality and cardiovascular (CV)-specific fatal and nonfatal outcomes. It is uncertain which BP index is most strongly associated with these outcomes. Objective: To evaluate the association of BP indexes with death and a composite CV event. Design, Setting, and Participants: Longitudinal population-based cohort study of 11 135 adults from Europe, Asia, and South America with baseline observations collected from May 1988 to May 2010 (last follow-ups, August 2006-October 2016). Exposures: Blood pressure measured by an observer or an automated office machine; measured for 24 hours, during the day or the night; and the dipping ratio (nighttime divided by daytime readings). Main Outcomes and Measures: Multivariable-adjusted hazard ratios (HRs) expressed the risk of death or a CV event associated with BP increments of 20/10 mm Hg. Cardiovascular events included CV mortality combined with nonfatal coronary events, heart failure, and stroke. Improvement in model performance was assessed by the change in the area under the curve (AUC). Results: Among 11 135 participants (median age, 54.7 years, 49.3% women), 2836 participants died (18.5 per 1000 person-years) and 2049 (13.4 per 1000 person-years) experienced a CV event over a median of 13.8 years of follow-up. Both end points were significantly associated with all single systolic BP indexes (P < .001). For nighttime systolic BP level, the HR for total mortality was 1.23 (95% CI, 1.17-1.28) and for CV events, 1.36 (95% CI, 1.30-1.43). For the 24-hour systolic BP level, the HR for total mortality was 1.22 (95% CI, 1.16-1.28) and for CV events, 1.45 (95% CI, 1.37-1.54). With adjustment for any of the other systolic BP indexes, the associations of nighttime and 24-hour systolic BP with the primary outcomes remained statistically significant (HRs ranging from 1.17 [95% CI, 1.10-1.25] to 1.87 [95% CI, 1.62-2.16]). Base models that included single systolic BP indexes yielded an AUC of 0.83 for mortality and 0.84 for the CV outcomes. Adding 24-hour or nighttime systolic BP to base models that included other BP indexes resulted in incremental improvements in the AUC of 0.0013 to 0.0027 for mortality and 0.0031 to 0.0075 for the composite CV outcome. Adding any systolic BP index to models already including nighttime or 24-hour systolic BP did not significantly improve model performance. These findings were consistent for diastolic BP. Conclusions and Relevance: In this population-based cohort study, higher 24-hour and nighttime blood pressure measurements were significantly associated with greater risks of death and a composite CV outcome, even after adjusting for other office-based or ambulatory blood pressure measurements. Thus, 24-hour and nighttime blood pressure may be considered optimal measurements for estimating CV risk, although statistically, model improvement compared with other blood pressure indexes was small.

Correction to: Mind, Brain, and Behavior: an Integrative Approach to Teaching Neuroscience to Medical Students.

This article was updated to correct Ignacio Martinez Escobedo's name.

Glaucomatous Optic Neuropathy Associated with Nocturnal Dip in Blood Pressure: Findings from the Maracaibo Aging Study.

PURPOSE: To determine which nocturnal blood pressure (BP) parameters (low levels or extreme dipper status) are associated with an increased risk of glaucomatous damage in Hispanics. DESIGN: Observational cross-sectional study. PARTICIPANTS: A subset (n = 93) of the participants from the Maracaibo Aging Study (MAS) who met the study eligibility criteria were included. These participants, who were at least 40 years of age, had measurements for optical tomography coherence, visual field (VF) tests, 24-hour BP, office BP, and intraocular pressure <22 mmHg. METHODS: Univariate and multivariate logistic regression analyses under the generalized estimating equations (GEE) framework were used to examine the relationships between glaucomatous damage and BP parameters, with particular attention to decreases in nocturnal BP. MAIN OUTCOME MEASURES: Glaucomatous optic neuropathy (GON) based on the presence of optic nerve damage and VF defects. RESULTS: The mean age was 61.9 years, and 87.1% were women. Of 185 eyes evaluated, 19 (26.5%) had signs of GON. Individuals with GON had significantly lower 24-hour and nighttime diastolic BP levels than those without. However, results of the multivariate GEE models indicated that the glaucomatous damage was not related to the average systolic or diastolic BP levels measured over 24 hours, daytime, or nighttime. In contrast, extreme decreases in nighttime systolic and diastolic BP (>20% compared with daytime BP) were significant risk factors for glaucomatous damage (odds ratio, 19.78 and 5.55, respectively). CONCLUSIONS: In this population, the link between nocturnal BP and GON is determined by extreme dipping effects rather than low nocturnal BP levels alone. Further studies considering extreme decreases in nocturnal BP in individuals at high risk of glaucoma are warranted.

Incidence of dementia in elderly Latin Americans: Results of the Maracaibo Aging Study.

INTRODUCTION: There are few longitudinal studies of dementia in developing countries. We used longitudinal data from the Maracaibo Aging Study to accurately determine the age- and sex-specific incidence of dementia in elderly Latin Americans. METHODS: The Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) was used to diagnose dementia, which was classified as Alzheimer's disease, vascular dementia, or other. Age- and sex-specific incidence was estimated as the number of new cases of dementia divided by person-years (p-y) of follow-up. RESULTS: The incidence of all dementia diagnoses was 9.10 per 1000 p-y (95% confidence interval [CI] 7.13-11.44; 8026 total p-y), 5.18 for Alzheimer's disease (95% CI 3.72-7.03; 7916 total p-y), and 3.35 for vascular dementia (95% CI 2.19-4.91; 7757 total p-y). DISCUSSION: Among Maracaibo Aging Study participants younger than 65 years, the incidence of dementia was higher than that of US Whites. Among individuals older than 65 years, the incidence was comparable to the mean of previous incidence estimates for other populations worldwide.

Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations.

BACKGROUND: Data on risk associated with 24-hour ambulatory diastolic (DBP24) versus systolic (SBP24) blood pressure are scarce. METHODS AND RESULTS: We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP24≥80 mm Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs≤1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P≤0.0054). Isolated systolic hypertension (SBP24≥130 mm Hg) and mixed diastolic plus systolic hypertension were associated with increased risks of all aforementioned end points (P≤0.0012). Below age 50, DBP24 was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP24 (HR≤0.92; P≥0.068); above age 50, SBP24 predicted all end points (HR≥1.19; P≤0.0002) with a nonsignificant contribution of DBP24 (0.96≤HR≤1.14; P≥0.10). The interactions of age with SBP24 and DBP24 were significant for all cardiovascular and coronary events (P≤0.043). CONCLUSIONS: The risks conferred by DBP24 and SBP24 are age dependent. DBP24 and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP24 and isolated systolic and mixed hypertension are the predominant risk factors.

Sickle cell in Latin America and the United States [corrected].

Latin Americans are an underappreciated population affected by sickle cell disease (SCD). Sickle trait and SCD exist throughout Latin America and U.S. Latino communities. We describe the epidemiology and genetic heterogeneity of SCD among Latin Americans, and fetal hemoglobin expression. National population-based newborn screening for SCD is limited to Brazil, Costa Rica, and the U.S. Available and extrapolated data suggest that over 6,000 annual births and 100,000-150,000 Latin Americans are affected by SCD. This comprehensive review highlights the substantial numbers and population distribution of SCD and sickle trait in Latin America, and where national newborn screening programs for SCD exist.

Edentulism associates with worse cognitive performance in community-dwelling elders in rural Ecuador: results of the Atahualpa project.

Studies in industrialized nations suggest that severe edentulism correlates with cognitive impairment, but there is little information on this association in underserved populations. We conducted a community-based study to assess whether edentulism associates with cognitive impairment in elders living in rural Ecuador. Atahualpa residents aged ≥60 years were identified during a door-to-door census and evaluated using the Montreal Cognitive Assessment (MoCA). Persons were classified into two groups according to whether they have severe edentulism (<10 remaining teeth) or not. In addition, a questionnaire allowed self-rating of oral health. A total of 274 persons (mean age 69.6 ± 7.7 years; 59% women) were included. Persons with <10 remaining teeth (n = 116) have significantly lower MoCA scores than those with ≥10 teeth (n =158), after adjusting for demographics, cardiovascular risk factors, depression and dementia (ß = -1.06, p = 0.03). Self-rated poor oral health was more prevalent among persons with <10 teeth (p < 0.0001), but did not correlate with MoCA scores (good vs. poor, ß = -0.89, p = 0.89). Severe edentulism is associated with poor cognitive performance in elders living in rural Ecuador. Public health campaigns directed to improve oral health may facilitate early recognition of persons with cognitive impairment in underserved populations.

The Relevance of Arterial Blood Pressure in the Management of Glaucoma Progression: A Systematic Review.

BACKGROUND: Glaucoma is one of the leading causes of global blindness and is expected to co-occur more frequently with vascular morbidities in the upcoming years, as both are aging-related diseases. Yet, the pathogenesis of glaucoma is not entirely elucidated and the interplay between intraocular pressure, arterial blood pressure (BP) and ocular perfusion pressure is poorly understood. OBJECTIVES: This systematic review aims to provide clinicians with the latest literature regarding the management of arterial BP in glaucoma patients. METHODS: A systematic search was performed in Medline, Embase, Web of Science and Cochrane Library. Articles written in English assessing the influence of arterial BP and systemic antihypertensive treatment of glaucoma and its management were eligible for inclusion. Additional studies were identified by revising references included in selected articles. RESULTS: 80 Articles were included in this systemic review. A bimodal relation between BP and glaucoma progression was found. Both high and low BP increase the risk of glaucoma. Glaucoma progression was, possibly via ocular perfusion pressure variation, strongly associated with nocturnal dipping and high variability in the BP over 24 h. CONCLUSIONS: We concluded that systemic BP level associates with glaucomatous damage and provided recommendations for the management and study of arterial BP in glaucoma. Prospective clinical trials are needed to further support these recommendations.

Association of Variability and Hypertensive Loads in 24-h Blood Pressure With Mortality and Cardiovascular Risk.

BACKGROUND: Evidence shows that high 24-h blood pressure (BP) variability increases cardiovascular risk. We investigated whether 24-h BP variability relates to mortality and cardiovascular risk due to inherent variability and/or hypertensive loads in 24-h BP. METHODS: A total of 1,050 participants from the Maracaibo Aging Study (mean age, 66 years; women, 67.2%) underwent 24-h ambulatory BP monitoring and were followed between 2001 and 2016. To evaluate inherent BP variability, we used average real variability (ARV) as it captures variability among consecutive BP readings. 24-h systolic BP load was the proportion (%) of systolic BP readings ≥130 mm Hg during the daytime and ≥110 during the nighttime. Our primary endpoint was total mortality and major adverse cardiovascular endpoints (MACE). Statistics included Cox proportional models. RESULTS: During a median follow-up of 8.3 years, 299 participants died and 210 experienced MACE. Each +2 mm Hg (corresponding to 1-standard deviation) higher 24-h systolic ARV (mean value, 9.0 ±â€…2.0 mm Hg) was associated with higher hazard ratios (HRs) for mortality by 1.28-fold (95% confidence interval [CI], 1.14-1.43) and for MACE by 1.24-fold (95% CI, 1.08-1.42). Each 30% higher 24-h systolic BP load (median value, 63%) was associated with mortality and MACE with HRs of 1.29 (95% CI, 1.15-1.46) and 1.28 (95% CI, 1.10-1.48); respectively. After models were additionally adjusted by BP level, only ARV was associated with mortality (HR, 1.17; 95% CI, 1.04-1.33) and MACE (HR, 1.16; 95% CI, 1.00-1.34). CONCLUSIONS: High ARV and hypertensive loads in 24-h systolic BP were associated with mortality and cardiovascular risk, however, only ARV is associated independently of the BP level.

Corrigendum: Progression of functional and structural glaucomatous damage in relation to diurnal and nocturnal dips in mean arterial pressure.

[This corrects the article DOI: 10.3389/fcvm.2022.1024044.].

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Relationship Between Cognitive Performance, Physical Activity, and Socio-Demographic/Individual Characteristics Among Aging Americans.

BACKGROUND: Physical activity (PA) has emerged as a promising approach to delay Alzheimer's disease and related dementias, but the optimal intensity of PA to improve cognitive health remains unknown. OBJECTIVE: To evaluate the association between duration and intensity of PA and cognitive domains (executive function, processing speed, and memory) in aging Americans. METHODS: Linear regressions in hierarchical blocks for variable adjustment and the size of effect (η2) were analyzed by using the data of 2,377 adults (age = 69.3±6.7 years) from the NHANES 2011-2014. RESULTS: Participants with 3-6 h/week of vigorous- and > 1 h/week of moderate-intensity PA scored significantly higher in executive function and processing speed domains of cognition compared to inactive peers (η2 = 0.005 & 0.007 respectively, p < 0.05). After adjustment, the beneficial effects of 1-3 h /week of vigorous-intensity PA became trivial for delayed recall memory domain test scores (ß= 0.33; 95% CI: -0.01,0.67; η2 = 0.002; p = 0.56). There was no linear dose-response relationship between the cognitive test scores and weekly moderate-intensity of PA. Interestingly, higher handgrip strength and higher late-life body mass index were associated with a higher performance across all cognitive domains. CONCLUSION: Our study supports habitual PA with superior cognition health in some but not all domains among older adults. Furthermore, increased muscle strength and higher late-life adiposity may also impact cognition.

Effect of 24-h blood pressure dysregulations and reduced ocular perfusion pressure in open-angle glaucoma progression.

BACKGROUND: Low ocular perfusion pressure (OPP), which depends on the mean arterial pressure (MAP) and intraocular pressure (IOP), is associated with glaucoma. We studied 24-h MAP dysregulations and OPP in relation to the progression of glaucoma damage. METHODS: We retrospectively analyzed 155 normal-tension glaucoma (NTG) and 110 primary open-angle glaucoma (POAG) patients aged 18 years old followed at the University Hospital Leuven with repeated visual field tests ( n  = 7000 measures, including both eyes) who underwent 24-h ambulatory blood pressure monitoring. Twenty-four-hour MAP dysregulations were variability independent of the mean (VIM), and the five lowest dips in MAP readings over 24 h. OPP was the difference between 2/3 of the MAP and IOP. Glaucoma progression was the deterioration of the visual field, expressed as decibel (dB) changes in mean deviation analyzed by applying multivariable linear mixed regression models. RESULTS: The mean age was 68 years (53% were women). High 24-h VIMmap was associated with glaucoma progression in POAG ( P  < 0.001) independently of the 24-h MAP level. The estimated changes in mean deviation in relation to dip MAP measures ranged from -2.84 dB [95% confidence interval (CI) -4.12 to -1.57] to -2.16 dB (95% CI -3.46 to -0.85) in POAG. Reduced OPP along with high variability and dips in MAP resulted in worse mean deviation deterioration. CONCLUSION: The progression of glaucoma damage associates with repetitive and extreme dips in MAP caused by high variability in MAP throughout 24 h. This progression exacerbates if 24-h MAP dysregulations occur along with reduced OPP.

Assessing dementia in resource-poor regions.

The numbers and proportions of elderly are increasing rapidly in developing countries, where prevalence of dementia is often high. Providing cost-effective services for dementia sufferers and their caregivers in these resource-poor regions poses numerous challenges; developing resources for diagnosis must be the first step. Capacity building for diagnosis involves training and education of healthcare providers, as well as the general public, development of infrastructure, and resolution of economic and ethical issues. Recent progress in some low-to-middle-income countries (LMICs) provides evidence that partnerships between wealthy and resource-poor countries, and between developing countries, can improve diagnostic capabilities. Without the involvement of the mental health community of developed countries in such capacity-building programs, dementia in the developing world is a disaster waiting to happen.