Localized components analysis (LoCA) is a new method for describing surface shape variation in an ensemble of objects using a linear subspace of spatially localized shape components. In contrast to ...earlier methods, LoCA optimizes explicitly for localized components and allows a flexible trade-off between localized and concise representations, and the formulation of locality is flexible enough to incorporate properties such as symmetry. This paper demonstrates that LoCA can provide intuitive presentations of shape differences associated with sex, disease state, and species in a broad range of biomedical specimens, including human brain regions and monkey crania.
Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in ...the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
The purpose of this study was to examine the incidence of mild cognitive impairment (MCI) and patterns of progression from incident MCI to dementia in 285 cognitively normal subjects (mean age, 78.9 ...years) in the Cardiovascular Health Study-Cognition Study from 1998-1999 to 2010-2011.
Two hundred (70%) of the participants progressed to MCI; the age-adjusted incidence of MCI was 111.09 (95% confidence interval, 88.13-142.95) per 1,000 person-years. A total of 107 (53.5%) of the incident MCI subjects progressed to dementia. The mean time from MCI to dementia was 2.8 ± 1.8 years. Forty (20%) of the incident MCI cases had an "unstable" course: 19 (9.5%) converted to MCI and later returned to normal; 10 (5%) converted to MCI, to normal, and later back to MCI; 7 (3.5%) converted to MCI, to normal, to MCI, and later to dementia; and 4 (2%) converted to MCI, to normal, and later to dementia. There was an increased mortality rate among the cognitively normal group (110.10 per 1,000 person-years) compared to those with incident MCI who converted to dementia (41.32 per 1,000 person-years).
The majority of the subjects aged >80 years developed an MCI syndrome, and half of them progressed to dementia. Once the MCI syndrome was present, the symptoms of dementia appeared within 2 to 3 years. Progression from normal to MCI or from normal to MCI to dementia is not always linear; subjects who developed MCI and later returned to normal can subsequently progress to dementia. Competing mortality and morbidity influence the study of incident MCI and dementia in population cohorts.
We present the rationale and design of a double-blind placebo-controlled feasibility trial combining intranasal insulin (INI) with dulaglutide, a GLP-1 receptor agonist, to improve cognition in older ...adults with metabolic syndrome (MetS) and mild cognitive impairment (MCI). Since both INI and dulaglutide have beneficial effects on the cerebrovascular disease (CVD), we anticipate that improved CVD will underlie the hypothesized cognitive benefits.
This 12-months trial will include 80 older adults aged > 60 with MetS and MCI, randomized to 4 groups: INI/dulaglutide injection, intranasal placebo/dulaglutide injection, INI/placebo injection, and intranasal placebo/placebo injection. Feasibility of combining INI with dulaglutide will be tested by examining the ease of use of INI (20IU, twice/day) with dulaglutide (1.5 mg/week), adherence, and safety profile are the efficacy of combination therapy on global cognition and neurobiological markers: cerebral blood flow, cerebral glucose utilization, white matter hyperintensities, Alzheimer's related blood biomarkers and expression of insulin signaling proteins measured in brain-derived exosomes. Efficacy will be assessed for the intent-to-treat sample.
This feasibility study is anticipated to provide the basis for a multi-center large-scale randomized clinical trial of the cognitive benefits of the combination of INI with dulaglutide in individuals enriched for CVD and at high dementia risk.
Abstract
Introduction
African Americans are at a greater risk for cardiovascular disease and inadequate sleep than are corresponding whites. Age-associated declines in sleep duration, cardiovascular ...health, and physical activity highlight the need to understand the relationship among these variables in this population. While physical activity is thought to be beneficial for promoting sleep quality, it remains unknown how habitual short sleep during a physical activity intervention influences the intervention response in this population.
Methods
Sedentary older African Americans (n=27; 65-85 years old; 74% female) participating in the intervention arm of a 12-week randomized controlled physical activity trial (NCT03474302) were categorized as short (n= 15) or adequate (n=12) sleepers, defined as sleeping <6 hours/night or >6 hours/night on average during the intervention. Participants wore validated activity monitors at baseline and 12 weeks, and commercially available sleep monitors were worn daily. Differences in cardiovascular outcomes at baseline and 12 weeks were assessed between sleep categories using sex-adjusted linear mixed models.
Results
The intervention increased accelerometer derived steps (p=0.04) with no between group differences (p=0.78). Moderate to vigorous activity (MVA) duration increased (p<0.001), but change was greater in adequate sleepers (9 minutes; p<0.05). Body weight did not significantly change (-0.71 kg; p=0.11) and changes were similar between groups (p=0.55). Total (p=0.046) and LDL cholesterol (p=0.04) decreased over time. Adequate sleepers experienced improvements in systolic blood pressure (-10 ± 4.5 mmHg; p=0.03), total cholesterol (-30 ± 11 mg/dL; p=0.01), and LDL cholesterol (-23 ± 9 mg/dL; p=0.01) from baseline while short sleepers did not (all p>0.05). Significant differences or trends between adequate and poor sleepers were observed (-10.5 mmHg; p=0.096; -30 mg/dL p=0.044; -21 mg/dL; p=0.095, respectively).
Conclusion
Adequate sleep during a physical activity intervention may be important to elicit cardiovascular benefits. Thus, research evaluating sleep extension complementary to increased physical activity is warranted in short sleepers.
Support
BrightFocus (A20175472); National Institute of General Medical Sciences of the National Institutes of Health (U54-GM104940)
Abstract There is growing interest in the influence of early-life development on clinical manifestations of late-life diseases. Latent variable modeling was used to investigate how maximal brain ...volume (measured by intracranial volume ICV) and current brain volumes uniquely contribute to domain-specific cognitive performance in a group of 401 cognitively and ethnically diverse older adults. Individual effects of volumetric magnetic resonance imaging (MRI) measures including ICV were examined as predictors of episodic memory, semantic memory, spatial ability, and executive function. Total brain matter volume related to all cognitive domains; hippocampal volume was associated primarily with episodic memory; white matter hyperintensity volume was related to executive function and episodic memory. Maximal brain size as measured by ICV was related to semantic memory, executive function, and spatial ability independent of current brain volumes ( p s < 0.01). Relationships between magnetic resonance imaging (MRI) variables and cognition did not differ substantially across groups defined by ethnicity, gender, and with minor exceptions, clinical diagnosis. Results suggest maximal brain development and measures of brain injury/atrophy jointly contribute to cognitive function in older people.
Tensor-based morphometry is a powerful tool for automatically computing longitudinal change in brain structure. Because of bias in images and in the algorithm itself, however, a penalty term and ...inverse consistency are needed to control the over-reporting of nonbiological change. These may force a tradeoff between the intrinsic sensitivity and specificity, potentially leading to an under-reporting of authentic biological change with time. We propose a new method incorporating prior information about tissue boundaries (where biological change is likely to exist) that aims to keep the robustness and specificity contributed by the penalty term and inverse consistency while maintaining localization and sensitivity. Results indicate that this method has improved sensitivity without increased noise. Thus it will have enhanced power to detect differences within normal aging and along the spectrum of cognitive impairment.
Emerging evidence suggests that a number of factors can influence blood-based biomarker levels for Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD). We examined the associations that ...demographic and clinical characteristics have with AD/ADRD blood-based biomarker levels in an observational continuation of a clinical trial cohort of older individuals with type 2 diabetes and overweight or obesity.
Participants aged 45-76 years were randomized to a 10-year Intensive Lifestyle Intervention (ILI) or a diabetes support and education (DSE) condition. Stored baseline and end of intervention (8-13 years later) plasma samples were analyzed with the Quanterix Simoa HD-X Analyzer. Changes in Aβ42, Aβ40, Aβ42/Aβ40, ptau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were evaluated in relation to randomization status, demographic, and clinical characteristics.
In a sample of 779 participants from the Look AHEAD cohort, we found significant associations between blood-based biomarkers for AD/ADRD and 15 of 18 demographic (age, gender, race and ethnicity, education) and clinical characteristics (APOE, depression, alcohol use, smoking, body mass index, HbA1c, diabetes duration, diabetes treatment, estimated glomerular filtration rate, hypertension, and history of cardiovascular disease) .
Blood-based biomarkers of AD/ADRD are influenced by common demographic and clinical characteristics. These factors should be considered carefully when interpreting these AD/ADRD blood biomarker values for clinical or research purposes.
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