Summary
It has been increasingly recognized at the basic science level that perturbations in ceramide metabolism are associated with the development and progression of many age‐related diseases. ...However, the translation of this work to the clinic has lagged behind. Understanding the factors longitudinally associated with plasma ceramides and dihydroceramides (DHCer) at the population level and how these lipid levels change with age, and by sex, is important for the clinical development of future therapeutics and biomarkers focused on ceramide metabolism. We, therefore, examined factors cross‐sectionally and longitudinally associated with plasma concentrations of ceramides and DHCer among Baltimore Longitudinal Study of Aging participants (n = 992; 3960 total samples), aged 55 years and older, with plasma at a mean of 4.1 visits (range 2–6). Quantitative analyses were performed on a high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometer. Linear mixed models were used to assess the relationships between plasma ceramide and DHCer species and demographics, diseases, medications, and lifestyle factors. Women had higher plasma concentrations of most ceramide and DHCer species and showed steeper trajectories of age‐related increases compared to men. Ceramides and DHCer were more associated with waist–hip ratio than body mass index. Plasma cholesterol and triglycerides, prediabetes, and diabetes were associated with ceramides and DHCer, but the relationship showed specificity to the acyl chain length and saturation. These results demonstrate the importance of examining the individual species of ceramides and DHCer, and of establishing whether intra‐individual age‐ and sex‐specific changes occur in synchrony to disease onset and progression.
US rural, compared to non-rural, populations have diabetes health disparities. However, it is unknown if there are rural disparities in incident diabetes. We used CDC data on incidence of diagnosed ...diabetes in adults aged ≥20 years, available for 97.5% of US counties (n=3145/3226) . Trends in the annual age-adjusted incident diabetes rate per 1000 adults (AADR) were assessed by weighted least squares regression. Year was fitted nonlinearly with a spline function, and AADR fold-change was tested by a model-based contrast of 20vs. 2018. The average AADR of 8.7 (95% CI 8.6-8.7) ranged from 9.3 (in 2011) to 8.3 (in 2013) and 8.9 (in 2018) , and concealed subnational disparities based on rurality (Figure) . In 2018, compared with 2011, the AADR decreased for large central metro counties (most urban) with AADR fold-change of 0.92 (0.91-0.93) but increased for noncore counties (most rural) with AADR fold-change of 1. (1.01-1.08) (both P<.01) . The AADR declined in counties with intermediate rurality except for micropolitan counties (no change; P=.56) . When stratified by region, the largest rural disparity in AADR was observed in the South, with smaller disparities in other regions.
In summary, from 2011-2018, rural counties had the highest overall AADR. The overall disparity in trends based on county rurality and the disparity in incidence in the rural South and rural West highlight areas for diabetes primary prevention interventions.
Disclosure
K.R. Bailey: None. M.M. Mielke: Consultant; Biogen, LabCorp. A. Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S. Other Relationship; Novo Nordisk.
Funding
National Institute on Minority Health and Health Disparities (NIH K23 MD016230)
Abstract Background The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimer’s disease (AD). The aims of the present study ...were to: (1) examine the cross-sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy FA, mean diffusivity MD, axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia. Methods Twenty-three mild cognitive impairment participants for whom hippocampal volumetry and DTI were conducted at baseline received detailed evaluations at baseline; 3, 6, and 12 months; and 2.5 years. Six participants converted to AD over the follow-up period. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the Mini-Mental State Examination, Clinical Dementia Rating-sum of boxes, and memory z scores; receiver operating characteristic analyses examined the predictive value for conversion to AD. Results There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, radial diffusivity, and axial diffusivity) were cross-sectionally correlated with memory z scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression, with likelihood ratios >83, and better than 90% accuracy. Conclusion Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually drawn region of interest within the fornix shows promise comparable with hippocampal volume as a predictive biomarker of progression, and this finding warrants replication in a larger study.
OBJECTIVE:To determine risk and protective factors for mild cognitive impairment (MCI) among persons 85 years and older.
METHODS:Participants in the population-based prospective Mayo Clinic Study of ...Aging were comprehensively evaluated at baseline and at 15 monthly intervals to determine incident MCI. At baseline, lifestyle factors in midlife and late life were assessed by self-reported questionnaire; vascular and comorbid conditions were abstracted from participantsʼ medical records.
RESULTS:Of 256 participants who were cognitively normal at enrollment (median age 87.3 years, 62% women), 121 developed MCI at a median 4.1 years of follow-up. Predictors of MCI were APOE ε4 allele (hazard ratio HR 1.89; p = 0.008), current depressive symptoms (HR 1.78; p = 0.02), midlife onset of hypertension (HR 2.43; p = 0.005), increasing number of vascular diseases (HR 1.13; p = 0.02), and chronic conditions from the Charlson Comorbidity Index (HR 1.08; p = 0.006). Models were adjusted for sex and education, with age as the time variable. The risk of MCI was reduced for participants who reported engagement in artistic (HR 0.27; p = 0.03), craft (HR 0.55; p = 0.02), and social (HR 0.45; p = 0.005) activities in both midlife and late life, and in the use of a computer in late life (HR 0.47; p = 0.008).
CONCLUSIONS:Chronic disease burden increases risk of MCI, whereas certain lifestyle factors reduce risk in persons 85 years and older. This implies that preventive strategies for MCI may need to begin in midlife and should persist throughout late life.
Hypertensive disorders of pregnancy (HDP) have been associated with an increased risk of chronic hypertension for both mothers and offspring. We sought to quantify the incidence of chronic ...hypertension in offspring from HDP-affected pregnancies in a large, population-based cohort study. Furthermore, we evaluate the association of HDP exposure in utero and maternal chronic hypertension in offspring.
We performed a population-based cohort study of 8755 individuals born during 1976 to 1982 to 7544 women who all resided in the same community at the time of delivery. HDP was identified using a previously validated algorithm. Diagnosis of chronic hypertension in mothers and their offspring was determined using diagnostic codes. Cox proportional hazards regression was used to assess the association between HDP and chronic hypertension.
HDP exposure (hazard ratio, 1.50 95% CI, 1.18-1.90) and maternal chronic hypertension (hazard ratio, 1.73 95% CI, 1.48-2.02) were both associated with a significant increased risk for chronic hypertension in offspring. Both risk factors remained significantly associated with increased risk of hypertension in offspring when included together in a multivariate model. Having both exposures was associated with a 2.4-fold increase in the risk of hypertension in offspring, suggesting a synergistic additive interaction.
HDP exposure in gestation and maternal hypertension are both independently associated with an increased risk of chronic hypertension in offspring. Our results suggest that HDP exposure in utero, in addition to maternal chronic hypertension, may lead to a greater risk for the development of hypertension in offspring.
The prevalence of midlife cardiovascular conditions and risk factors is higher in men than women. Associations between midlife cardiovascular conditions or risk factors and midlife cognitive decline ...have been reported, but few studies have assessed sex differences in these associations.
We included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging who were 50 to 69 years of age at baseline. Participants were evaluated every 15 months by a coordinator, including neurologic evaluation and neuropsychological testing. The neuropsychological testing used 9 tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills)
scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. Multivariable models adjusted for demographics,
genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex.
Overall, 1,465 (78.9%) participants had at least 1 cardiovascular condition or risk factor; the proportion of men was higher than women (767 83.4% vs 698 74.5%,
< 0.0001). Cross-sectionally, coronary heart disease and ever smoking were associated with a lower visuospatial
score in multivariable models. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and domain-specific z scores but not visuospatial
scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease and other cardiovascular conditions were associated with global cognitive decline only in women (all
< 0.05). In addition, diabetes, dyslipidemia, and coronary heart disease were associated with language
score decline only in women (all
< 0.05). However, congestive heart failure was associated with language
score decline only in men (all
< 0.05).
Midlife cardiovascular conditions and risk factors are associated with midlife cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognitive decline in midlife for women than men despite the higher prevalence of those conditions in men.
Chronic inflammation has been linked with geriatric-related conditions, including dementia. Inflammatory cytokine levels, including interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF) α, in ...the blood have been associated with cognitive impairment and decline. However, evidence has been mixed.
We examined the cross-sectional and longitudinal associations between baseline-measured IL-6, IL-10, and TNFα levels and the ratio of IL-6/IL-10 with cognitive test performance and mild cognitive impairment (MCI) among 1,602 community-dwelling older adults (median age = 72.8) enrolled in the Mayo Clinic Study of Aging. Approximately half (46.5%) of participants were female and 98.6% were white. At baseline and follow-up visits (occurring at 15-month intervals), participants completed neuropsychological testing, blood draws, and had a clinical consensus diagnosis.
In multivariable cross-sectional analyses, we did not observe an association between inflammatory cytokine levels and global or domain-specific cognitive z scores; however, higher IL-6 and IL-10 levels were associated with greater odds of a MCI diagnosis. Longitudinally, we did not observe any association between inflammatory cytokine levels and cognitive test performance or risk of MCI. Sex, age, cognitive status, APOE ε4 genotype, diabetes, depression, and cerebral amyloid-beta deposition were not effect modifiers.
These results suggest that plasma inflammatory markers may not be useful to ascertain risk for cognitive decline and MCI in the general population.
IMPORTANCE: The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a ...prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain. OBJECTIVE: To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers. DESIGN, SETTING, AND PARTICIPANTS: A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated. MAIN OUTCOMES AND MEASURES: Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures. RESULTS: At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB− noncarriers). These associations were largely independent of APOE4. CONCLUSIONS AND RELEVANCE: In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.
Epidemiological studies examining associations between traumatic brain injury (TBI) and Alzheimer's disease and related dementias (ADRD) have yielded conflicting results, which may be due to ...methodological differences.
To examine the relationship between the presence and severity of TBI and risk of ADRD using a population-based cohort with medical record abstraction for confirmation of TBI and ADRD.
All TBI events among Olmsted County, Minnesota residents aged > 40 years from 1985-1999 were confirmed by manual review and classified by severity. Each TBI case was randomly matched to two age-, sex-, and non-head injury population-based referents without TBI. For TBI events with non-head trauma, the Trauma Mortality Prediction Model was applied to assign an overall measure of non-head injury severity and corresponding referents were matched on this variable. Medical records were manually abstracted to confirm ADRD diagnosis. Cox proportional hazards models examined the relationship between TBI and severity with risk of ADRD.
A total of 1,418 residents had a confirmed TBI (865 Possible, 450 Probable, and 103 Definite) and were matched to 2,836 referents. When combining all TBI severities, the risk of any ADRD was significantly higher for those with a confirmed TBI compared to referents (HR = 1.32, 95% CI: 1.11, 1.58). Stratifying by TBI severity, Probable (HR = 1.42, 95% CI: 1.05, 1.92) and Possible (HR = 1.29, 95% CI: 1.02-1.62) TBI was associated with an increased risk of ADRD, but not Definite TBI (HR = 1.22, 95% CI: 0.68, 2.18).
Our analyses support including TBI as a potential risk factor for developing ADRD.
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