More Rapid Increase in BMI from Age 5–15 is Associated with Elevated Weight Status at Age 24 among Non-Hispanic White Females

Background: A rapidly increasing BMI trajectory throughout childhood is associated with negative health outcomes in adulthood such as obesity, cardiovascular disease, and diabetes. The purpose of the current study was to assess whether BMI trajectories from age 5–15 predicted changes in weight and BMI from adolescence to adulthood, and dieting-related behaviors in young adulthood. Methods: Non-Hispanic White female participants from Early Dieting in Girls (n=182), a longitudinal cohort study, were followed from age 5 to 15 and completed a follow-up survey at age 24. Participants were classified by age 5–15 BMI trajectory groups: UPC, accelerated weight gain from age 5–9; DDPC, accelerated weight gain from 5 to 9 followed by a decrease; 60PT, weight tracked along 60th percentile; 50PT, weight tracked along 50th percentile. Data at age 24 included self-reported weight, height, dietary restraint, disinhibition, and dieting. Results: Majority of participants (80.8%) completed the follow-up survey; of these participants, 60% in UPC group had obesity at age 24, compared to\u3c10% in the other 3 groups. Participants in the UPC group had greater increases in BMI since age 15, compared to the 50PT group, and trend-level greater weight increases than those in the DDPC and 60PT groups. Dietary restraint, but not disinhibition, differed across the groups. Conclusions: Children with accelerated weight gain continued to have the greatest weight gain from adolescence to adulthood and the highest prevalence of obesity in adulthood

The relationship between white matter microstructure and self-perceived cognitive decline

Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer's disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included [n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 ± 7 years, 37% female]. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-β(CSF Aβ42), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE ε4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF Aβ42. FW-corrected radial diffusivity (RDT) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF Aβ42 was related to SCD scores in our cohort (Radj2 = 39.03%; β = −0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD scores beyond CSF Aβ42 (Radj2 = 44.35% and Radj2 = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RDT, fornix RDT, and UF FW were best associated with SCD scores (Radj2 = 46.69%; p = 6.37 × 10-12). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline

A longitudinal implementation evaluation of a physical activity program for cancer survivors: LIVESTRONG(R) at the YMCA

Purpose: Increased physical activity (PA) levels in cancer survivors are associated with decreased risk of recurrence and mortality as well as additional positive health outcomes. PA interventions have shown to be efficacious, though many lack translation to and sustainability in community settings. We used dimensions of the RE-AIM framework to evaluate LIVESTRONG(R) at the YMCA, a nation-wide community-based PA program for cancer survivors delivered at Ys. Methods: This was a longitudinal study design using national LIVESTRONG at the YMCA data compiled between 2010 and 2018. Data is from all YMCAs who deliver LIVESTRONG at the YMCA, submitted by Program Directors to the YMCA-USA. We assessed reach (number of participants), adoption (associations offering the program), implementation (conducting 3 fidelity checks), and organizational level maintenance (associations recently offering program). We also examined relationships between organizational characteristics (years of program existence and association area household income) and program implementation factors with member conversion rates. Results: As of 2018, LIVESTRONG at the YMCA has reached 62,044 survivors and 245 of the 840 (29.2%) of Y associations have adopted the program. Among the adopters, 91% were aware of fidelity checks; implementation of observational (62.3%), goal setting (49.9%), and functional (64.6%) checklists varied. Most (95.1%) adopters reported offering \u3e /= 1 LIVESTRONG session per year (organizational-level maintenance) and a facility-level mean membership conversion percentage of 46.9 +/- 31.2%. Fewer years implementing the program and higher association area household income were significantly associated with a greater membership conversion rate vs their comparison. In a multiple regression model controlling for organizational characteristics, conducting the fidelity checks independently (observational, beta = 8.41; goal-setting, beta = 9.70; and functional, beta = 9.61) and collectively (beta = 10.82; 95% CI 5.90-16.80) was positively associated with higher membership conversion rates. Conclusions: LIVESTRONG at the YMCA, in its early years, has shown promise for high reach, while adoption at more associations could be facilitated. Implementing fidelity checks along with organizational characteristics were associated with membership conversion rate. Identification of association-level strategies to increase reach, adoption, implementation, and maintenance may increase the impact of this community-based PA program

Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

INTRODUCTION: While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. METHODS: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. RESULTS: Stages differed at baseline on APOE-ε4 status (early middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03). DISCUSSION: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets

Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

Introduction Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Methods Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Results Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. Discussion Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI

The cis/trans interconversion of the calcium regulating hormone calcitonin is catalyzed by cyclophilin

AbstractThe cytosolic peptidyl-prolyl cis/trans isomerase cyclophilin from pig kidney can accelerate catalytically the cis/trans isomerization of prolyl peptide bonds. One- and two-dimensional 1H NMR spectroscopy was used to prove that the polypeptide hormone calcitonin is a substrate for cyclophilin. Isomerization of only one of the two prolyl peptide bonds is catalyzed significantly. The efficiency of catalysis was calculated by lineshape analysis and NOESY spectroscopy. Cyclosporin A completely blocks the effect of the enzyme on the conformational dynamics of the polypeptide

Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults

BACKGROUND: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration. OBJECTIVE: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. METHODS: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognitive (NC), mild cognitive impairment (MCI)). RESULTS: Higher LVEF related to decreased CSF Aβ42 levels (β= -6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= -9.74, p = 0.01) and p-tau in the NC (β= -1.41, p = 0.003) but not MCI participants (p-values>0.13). CONCLUSIONS: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life

Using Unoccupied Aerial Vehicles to Map and Monitor Changes in Emergent Kelp Canopy after an Ecological Regime Shift

Kelp forests are complex underwater habitats that form the foundation of many nearshore marine environments and provide valuable services for coastal communities. Despite their ecological and economic importance, increasingly severe stressors have resulted in declines in kelp abundance in many regions over the past few decades, including the North Coast of California, USA. Given the significant and sustained loss of kelp in this region, management intervention is likely a necessary tool to reset the ecosystem and geospatial data on kelp dynamics are needed to strategically implement restoration projects. Because canopy-forming kelp forests are distinguishable in aerial imagery, remote sensing is an important tool for documenting changes in canopy area and abundance to meet these data needs. We used small unoccupied aerial vehicles (UAVs) to survey emergent kelp canopy in priority sites along the North Coast in 2019 and 2020 to fill a key data gap for kelp restoration practitioners working at local scales. With over 4,300 hectares surveyed between 2019 and 2020, these surveys represent the two largest marine resource-focused UAV surveys conducted in California to our knowledge. We present remote sensing methods using UAVs and a repeatable workflow for conducting consistent surveys, creating orthomosaics, georeferencing data, classifying emergent kelp and creating kelp canopy maps that can be used to assess trends in kelp canopy dynamics over space and time. We illustrate the impacts of spatial resolution on emergent kelp canopy classification between different sensors to help practitioners decide which data stream to select when asking restoration and management questions at varying spatial scales. Our results suggest that high spatial resolution data of emergent kelp canopy from UAVs have the potential to advance strategic kelp restoration and adaptive management

Exploring common genetic contributors to neuroprotection from amyloid pathology

Preclinical Alzheimer’s disease describes some individuals who harbor Alzheimer’s pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer’s-related neurodegeneration. We therefore conducted a genome-wide association study using 5,891,064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analyzed genotype, biomarker, and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal aging studies (n=1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency > 0.01), including APOE-ε4 and APOE-ε2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analyzed an independent dataset (n=808) where amyloid burden was assessed by Pittsburgh Compound B ([{11}^C]-PiB) PET. In this study, we found that APOE-ε4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ε4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene, (p=1.46x10^{-8}; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 x amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (p=0.0112) where amyloid burden was assessed by PET. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis

Axonal Injury Partially Mediates Associations Between Increased Left Ventricular Mass Index and White Matter Damage

BACKGROUND AND PURPOSE: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. METHODS: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE-ε4 positive, LV mass index 51.4±8.1 g/m2, NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE-ε4. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. RESULTS: Among all participants, LV mass index was unrelated to CSF biomarkers (P>0.33). LV mass index interacted with MCI (P=0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE-ε4 carriers (P=0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. CONCLUSIONS: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE-ɛ4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage