Publications by authors named "Donald J Hagler"

226 Publications

Long-term Associations of Cigarette Smoking in Early Midlife with Predicted Brain Aging from Midlife to Late Life.

Addiction 2021 Oct 4. Epub 2021 Oct 4.

Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

Background And Aims: Smoking is associated with increased risk for brain aging/atrophy and dementia. Few studies have examined early associations with brain aging. This study aimed to measure whether adult men with a history of heavier smoking in early midlife would have older than predicted brain age 16 to 28 years later.

Design: Prospective cohort observational study, utilizing smoking pack years data from average age 40 (early midlife) predicting predicted brain age difference scores (PBAD) at average ages 56, 62 (later midlife) and 68 (early old age). Early midlife alcohol use was also evaluated.

Setting: Population-based United States sample.

Participants/cases: Participants were male twins of predominantly European ancestry who served in the United States military sometime between 1965 and 1975. Structural magnetic resonance imaging (MRI) began at average age 56. Subsequent study waves included most baseline participants; attrition replacement subjects were added at later waves.

Measurements: Self-reported smoking information was used to calculate pack years smoked at ages 40, 56, 62, and 68. MRIs were processed with the BARACUS program to create PBAD scores (chronological age - predicted brain age) acquired at average ages 56 (N=493; 2002-08), 62 (N=408; 2009-14), and 68 (N=499; 2016-19).

Findings: In structural equation modelling, age 40 pack years predicted more advanced age 56 PBAD (β = -0.144, p = 0.012, 95% confidence interval (CI) -0.257, -0.032). Age 40 pack years did not additionally predict PBAD at later ages. Age 40 alcohol consumption, but not a smoking-by-alcohol interaction, predicted more advanced PBAD at age 56 (β = -0.166, p=0.001, 95%CI -0.261,-0.070) with additional influences at age 62 (β = -0.115, p = 0.005, 95%CI -0.195,-0.036). Age 40 alcohol did not predict age 68 PBAD. Within-twin pair analyses suggested some genetic mechanism partially underlying effects of alcohol, but not smoking, on PBAD.

Conclusions: Heavier smoking and alcohol consumption by age 40 appears to predict advanced brain aging by age 56 in men.
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http://dx.doi.org/10.1111/add.15710DOI Listing
October 2021

Vertex-wise multivariate genome-wide association study identifies 780 unique genetic loci associated with cortical morphology.

Neuroimage 2021 Sep 21;244:118603. Epub 2021 Sep 21.

NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Building 48, Oslo University Hospital, Ullevål, PO Box 4956 Nydalen, Oslo 0424, Norway; Department of Neurosciences, University of California San Diego, La Jolla, CA 92037, USA; Department of Radiology, University of California San Diego, La Jolla, CA 92037, USA; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA 92037, USA. Electronic address:

Brain morphology has been shown to be highly heritable, yet only a small portion of the heritability is explained by the genetic variants discovered so far. Here we extended the Multivariate Omnibus Statistical Test (MOSTest) and applied it to genome-wide association studies (GWAS) of vertex-wise structural magnetic resonance imaging (MRI) cortical measures from N=35,657 participants in the UK Biobank. We identified 695 loci for cortical surface area and 539 for cortical thickness, in total 780 unique genetic loci associated with cortical morphology robustly replicated in 8,060 children of mixed ethnicity from the Adolescent Brain Cognitive Development (ABCD) Study®. This reflects more than 8-fold increase in genetic discovery at no cost to generalizability compared to the commonly used univariate GWAS methods applied to region of interest (ROI) data. Functional follow up including gene-based analyses implicated 10% of all protein-coding genes and pointed towards pathways involved in neurogenesis and cell differentiation. Power analysis indicated that applying the MOSTest to vertex-wise structural MRI data triples the effective sample size compared to conventional univariate GWAS approaches. The large boost in power obtained with the vertex-wise MOSTest together with pronounced replication rates and highlighted biologically meaningful pathways underscores the advantage of multivariate approaches in the context of highly distributed polygenic architecture of the human brain.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118603DOI Listing
September 2021

Lifestyle and the aging brain: interactive effects of modifiable lifestyle behaviors and cognitive ability in men from midlife to old age.

Neurobiol Aging 2021 Aug 19;108:80-89. Epub 2021 Aug 19.

Department of Psychiatry, University of California San Diego, San Diego, CA, USA; Center for Behavior Genetics of Aging, University of California San Diego, San Diego, CA, USA.

We examined the influence of lifestyle on brain aging after nearly 30 years, and tested the hypothesis that young adult general cognitive ability (GCA) would moderate these effects. In the community-dwelling Vietnam Era Twin Study of Aging (VETSA), 431 largely non-Hispanic white men completed a test of GCA at mean age 20. We created a modifiable lifestyle behavior composite from data collected at mean age 40. During VETSA, MRI-based measures at mean age 68 included predicted brain age difference (PBAD), Alzheimer's disease (AD) brain signature, and abnormal white matter scores. There were significant main effects of young adult GCA and lifestyle on PBAD and the AD signature (ps ≤ 0.012), and a GCA-by-lifestyle interaction on both (ps ≤ 0.006). Regardless of GCA level, having more favorable lifestyle behaviors predicted less advanced brain age and less AD-like brain aging. Unfavorable lifestyles predicted advanced brain aging in those with lower age 20 GCA, but did not affect brain aging in those with higher age 20 GCA. Targeting early lifestyle modification may promote dementia risk reduction, especially among lower reserve individuals.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.08.007DOI Listing
August 2021

Hot topics in interventional cardiology: Proceedings from the society for cardiovascular angiography and interventions (SCAI) 2021 think tank.

Catheter Cardiovasc Interv 2021 Aug 16. Epub 2021 Aug 16.

Department of Cardiology, Piedmont Heart Institute, Atlanta, Georgia, USA.

The Society for Cardiovascular Angiography and Interventions (SCAI) Think Tank is a collaborative venture that brings together interventional cardiologists, administrative partners, and select members of the cardiovascular industry community annually for high-level field-wide discussions. The 2021 Think Tank was organized into four parallel sessions reflective of the field of interventional cardiology: (a) coronary intervention, (b) endovascular medicine, (c) structural heart disease, and (d) congenital heart disease. Each session was moderated by a senior content expert and co-moderated by a member of SCAI's Emerging Leader Mentorship program. This document presents the proceedings to the wider cardiovascular community in order to enhance participation in this discussion, create additional dialog from a broader base, and thereby aid SCAI, the industry community and external stakeholders in developing specific action items to move these areas forward.
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http://dx.doi.org/10.1002/ccd.29898DOI Listing
August 2021

12-year prediction of mild cognitive impairment aided by Alzheimer's brain signatures at mean age 56.

Brain Commun 2021 23;3(3):fcab167. Epub 2021 Jul 23.

Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA 92093, USA.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (s = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%;  = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.
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http://dx.doi.org/10.1093/braincomms/fcab167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361427PMC
July 2021

Sex Differences in Children and Young Adults With Bicuspid Aortic Valve Disease in First Two Decades of Life.

Mayo Clin Proc 2021 07;96(7):1874-1887

Division of Pediatric Cardiology, Department of Pediatrics, Mayo Clinic, Rochester, MN; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To elucidate sex differences in valve morphology, disease phenotype, progression, and outcomes among children and young adults with bicuspid aortic valve (BAV).

Patients And Methods: This is a retrospective cohort study examining all children and young adults (aged ≤22 years) with isolated BAV diagnosed, by excluding patients with concomitant congenital heart defects or genetic syndromes, from January 1, 1990, through December 1, 2016, at Mayo Clinic in Rochester, Minnesota.

Results: Of 1010 patients with BAV, 558 had isolated BAV. Distributions of morphology were right-left in 65.8% (n=367), right-noncoronary in 34% (n=190), and left-noncoronary cusp fusion in 0.2% (n=1) of patients; with no sex differences. Male to female ratio was 3:1. At the first echocardiographic evaluation in the study, there were no sex differences in terms of frequency of aortic valve stenosis or regurgitation. However, males had significantly higher grades of aortic valve regurgitation at 17 years of age onward (P<.0001). Males had significantly larger mid-ascending aorta (P=.01) and sinus of Valsalva dimensions (z score; P=.0001) as compared with females, with a novel finding of peak aortic dimensions around 8 years of age. Males also had more than 2-fold higher risk for sinus of Valsalva dilation (z score >2) as compared with females (odds ratio, 2.3; 95% CI, 1.2 to 4.2; P=.01). There were no significant sex differences in the primary cardiac outcomes of interventions on aortic valve and/or aorta, aortic dissection, or death.

Conclusion: In children and young adults with BAV, males have a higher grade of aortic regurgitation in late adolescence, significantly larger aortic dimensions, different patterns of aortic growth, and more frequent sinus of Valsalva dilation as compared with females. Overall, the rate of primary cardiac events is lower in young patients, with no significant sex differences.
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http://dx.doi.org/10.1016/j.mayocp.2020.12.033DOI Listing
July 2021

Brain structure associations with phonemic and semantic fluency in typically-developing children.

Dev Cogn Neurosci 2021 08 21;50:100982. Epub 2021 Jun 21.

Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark; Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital - Amager and Hvidovre, Kettegaard Allé 30, DK-2650, Hvidovre, Denmark; Radiography, Department of Technology, University College Copenhagen, Sigurdsgade 26, DK-2200, Copenhagen N., Denmark. Electronic address:

Verbal fluency is the ability to retrieve lexical knowledge quickly and efficiently and develops during childhood and adolescence. Few studies have investigated associations between verbal fluency performance and brain structural variation in children. Here we examined associations of verbal fluency performance with structural measures of frontal and temporal language-related brain regions and their connections in 73 typically-developing children aged 7-13 years. Tract-based spatial statistics was used to extract fractional anisotropy (FA) from the superior longitudinal fasciculus/arcuate fasciculus (SLF/AF), and the white matter underlying frontal and temporal language-related regions. FreeSurfer was used to extract cortical thickness and surface area. Better semantic and phonemic fluency performance was associated with higher right SLF/AF FA, and phonemic fluency was also modestly associated with lower left SLF/AF FA. Explorative voxelwise analyses for semantic fluency suggested associations with FA in other fiber tracts, including corpus callosum and right inferior fronto-occipital fasciculus. Overall, our results suggest that verbal fluency performance in children may rely on right hemisphere structures, possibly involving both language and executive function networks, and less on solely left hemisphere structures as often is observed in adults. Longitudinal studies are needed to clarify whether these associations are mediated by maturational processes, stable characteristics and/or experience.
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http://dx.doi.org/10.1016/j.dcn.2021.100982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242963PMC
August 2021

Periventricular and deep abnormal white matter differ in associations with cognitive performance at midlife.

Neuropsychology 2021 Mar;35(3):252-264

Center for Behavior Genetics of Aging, University of California.

Abnormal white matter (AWM) on magnetic resonance imaging is associated with cognitive performance in older adults. We explored cognitive associations with AWM during late-midlife. Participants were community-dwelling men ( = 242; = 61.90 years; range = 56-66). Linear-mixed effects regression models examined associations of total, periventricular, and deep AWM with cognitive performance, controlling for multiple comparisons. Models considering specific cognitive domains controlled for current general cognitive ability (GCA). We hypothesized that total AWM would be associated with worse processing speed, executive function, and current GCA; deep AWM would correlate with GCA and periventricular AWM would relate to specific cognitive abilities. We also assessed the potential influence of cognitive reserve by examining a moderation effect of early life (mean age of 20) cognition. Greater total and deep AWM were associated with poorer current GCA. Periventricular AWM was associated with worse executive function, working memory, and episodic memory. When periventricular and deep AWM were modeled simultaneously, both retained their respective significant associations with cognitive performance. Cognitive reserve did not moderate associations. Our findings suggest that AWM contributes to poorer cognitive function in late-midlife. Examining only total AWM may obscure the potential differential impact of regional AWM. Separating total AWM into subtypes while controlling for current GCA revealed a dissociation in relationships with cognitive performance; deep AWM was associated with nonspecific cognitive ability whereas periventricular AWM was associated with specific frontal-related abilities and memory. Management of vascular or other risk factors that may increase the risk of AWM should begin during or before early late-midlife. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500190PMC
March 2021

Bicuspid Aortic Valve in Infants, Children, and Adolescents: A Review for Primary Care Providers.

Pediatr Rev 2021 05;42(5):233-244

Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, and.

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http://dx.doi.org/10.1542/pir.2019-0307DOI Listing
May 2021

Is MYBPC3 linked to bicuspid aortic valve?

Transl Pediatr 2021 Feb;10(2):223-224

Division of Pediatric Cardiology, Department of Pediatrics, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.21037/tp-20-477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944166PMC
February 2021

Case Report: A Rare Case of Right-Sided Papillary Fibroelastoma in a 1-Year-Old With Congenital Heart Disease.

Front Cardiovasc Med 2020 27;7:624219. Epub 2021 Jan 27.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States.

Cardiac papillary fibroelastomas (PFEs) are the most common primary benign cardiac tumors, although they are somewhat unusual in children and typically seen on the left-sided cardiac valves. A 10-week-old patient was found to have a partial atrioventricular canal defect, with associated tricuspid and mitral regurgitation. He was medically managed until 1 year of age, when surgical correction was done. During the procedure, a PFE was found incidentally on the TV. This is one of the youngest patients to be reported with PFE, thus adding to the literature of these unusual cases in children.
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http://dx.doi.org/10.3389/fcvm.2020.624219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873290PMC
January 2021

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

Alzheimers Dement 2021 06 13;17(6):1017-1025. Epub 2021 Feb 13.

Department of Psychiatry, University of California San Diego, La Jolla, California, USA.

Introduction: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.

Methods: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LC ). We examined LC , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.

Results: Heritability of LC was .48. Participants with aMCI showed greater daytime dysfunction. Lower LC was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.

Discussion: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.
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http://dx.doi.org/10.1002/alz.12261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248066PMC
June 2021

Brain microstructure mediates sex-specific patterns of cognitive aging.

Aging (Albany NY) 2021 01 28;13(3):3218-3238. Epub 2021 Jan 28.

Department of Radiology, University of California, San Diego, La Jolla, CA 92093, USA.

Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.
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http://dx.doi.org/10.18632/aging.202561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906181PMC
January 2021

Age and Sex Differences in the Associations of Pulse Pressure With White Matter and Subcortical Microstructure.

Hypertension 2021 03 19;77(3):938-947. Epub 2021 Jan 19.

Department of Family Medicine and Public Health (G.A.L., L.K.M.), University of California, San Diego.

Midlife vascular disease increases risk for dementia and effects of vascular dysfunction on brain health differ between men and women. Elevated pulse pressure, a surrogate for arterial stiffness, contributes to cerebrovascular pathology and white matter damage that may advance cognitive aging; however, it remains unclear how associations between pulse pressure and neural integrity differ by sex and age. This study used restriction spectrum imaging to examine associations between pulse pressure and brain microstructure in community-dwelling women (N=88) and men (N=55), aged 56 to 97 (mean, 76.3) years. Restricted isotropic (presumed intracellular), hindered isotropic (presumed extracellular), neurite density, and free water diffusion were computed in white matter tracts and subcortical regions. After adjustment for age and sex, higher pulse pressure correlated with lower restricted isotropic diffusion in global white matter, with more pronounced associations in parahippocampal cingulum, as well as in thalamus and hippocampus. Subgroup analyses demonstrated stronger correlations between pulse pressure and restricted isotropic diffusion in association fibers for participants ≤75 years than for older participants, with stronger effects for women than men of this age group. Microstructure in parahippocampal cingulum and thalamus differed by pulse pressure level regardless of antihypertensive treatment. Increased pulse pressure may lead to widespread injury to white matter and subcortical structures, with greatest vulnerability for women in late middle to early older age. Restriction spectrum imaging could be useful for monitoring microstructural changes indicative of neuronal loss or shrinkage, demyelination, or inflammation that accompany age-related cerebrovascular dysfunction.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878422PMC
March 2021

Biophysically detailed forward modeling of the neural origin of EEG and MEG signals.

Neuroimage 2021 01 17;225:117467. Epub 2020 Oct 17.

Faculty of Science and Technology, Norwegian University of Life Sciences, 1432 Ås, Norway. Electronic address:

Electroencephalography (EEG) and magnetoencephalography (MEG) are among the most important techniques for non-invasively studying cognition and disease in the human brain. These signals are known to originate from cortical neural activity, typically described in terms of current dipoles. While the link between cortical current dipoles and EEG/MEG signals is relatively well understood, surprisingly little is known about the link between different kinds of neural activity and the current dipoles themselves. Detailed biophysical modeling has played an important role in exploring the neural origin of intracranial electric signals, like extracellular spikes and local field potentials. However, this approach has not yet been taken full advantage of in the context of exploring the neural origin of the cortical current dipoles that are causing EEG/MEG signals. Here, we present a method for reducing arbitrary simulated neural activity to single current dipoles. We find that the method is applicable for calculating extracranial signals, but less suited for calculating intracranial electrocorticography (ECoG) signals. We demonstrate that this approach can serve as a powerful tool for investigating the neural origin of EEG/MEG signals. This is done through example studies of the single-neuron EEG contribution, the putative EEG contribution from calcium spikes, and from calculating EEG signals from large-scale neural network simulations. We also demonstrate how the simulated current dipoles can be used directly in combination with detailed head models, allowing for simulated EEG signals with an unprecedented level of biophysical details. In conclusion, this paper presents a framework for biophysically detailed modeling of EEG and MEG signals, which can be used to better our understanding of non-inasively measured neural activity in humans.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117467DOI Listing
January 2021

Nucleus accumbens cytoarchitecture predicts weight gain in children.

Proc Natl Acad Sci U S A 2020 10 12;117(43):26977-26984. Epub 2020 Oct 12.

Department of Psychology, Yale University, New Haven, CT 06511;

The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.
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http://dx.doi.org/10.1073/pnas.2007918117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604478PMC
October 2020

Prevalence of pulmonary hypertension in adults after atrial switch and role of ventricular filling pressures.

Heart 2020 Oct 7. Epub 2020 Oct 7.

Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.

Objective: To assess the prevalence of elevated systemic right ventricular (sRV) end-diastolic pressure and pulmonary arterial hypertension in adults with transposition of the great arteries (TGA) who have undergone atrial switch operation.

Methods: Forty-two adults (aged ≥18 years) with complete TGA and atrial switch palliation undergoing cardiac catheterisation between 2004 and 2018 at Mayo Clinic, MN, were identified. Clinical, echocardiographic and invasive haemodynamic data were abstracted from the medical charts and procedure logs.

Results: Mean age was 37.6±7.9 years; 28 were male (67%). The Mustard operation was performed in 91% of individuals. Mean estimated sRV ejection fraction by echocardiography was 33.3%±10.9% and ≥moderate tricuspid (systemic atrioventricular valve) regurgitation was present in 15 patients (36%). Mean sRV end-diastolic pressure was 13.2±5.4 mm Hg. An sRV end-diastolic pressure >15 mm Hg was present in 35% of individuals whereas a pulmonary artery wedge pressure (PAWP) >15 mm Hg was seen in 59%. Mean pulmonary artery pressure ≥25 mm Hg was seen in 47.5% of patients with PAWP being >15 mm Hg in all but one patient.

Conclusion: In adults after atrial switch, elevated sRV end-diastolic pressure was present in only one-third of patients whereas increased PAWP was seen in almost 60%. These findings are most likely related to a combination of decreased pulmonary atrial (functional left atrium) compliance and, in a subset of patients, pulmonary venous baffle obstruction. Elevation in pulmonary pressures was highly prevalent with concomitant elevation in PAWP being present in essentially all patients.
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http://dx.doi.org/10.1136/heartjnl-2020-317111DOI Listing
October 2020

Radiation dose reduction for 3D angiography images in pediatric and congenital cardiology.

Catheter Cardiovasc Interv 2021 03 5;97(4):E502-E509. Epub 2020 Oct 5.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.

Objectives: The purpose of this study was to investigate the influence of simulated reduced-dose three-dimensional angiography (3DA) on the accuracy and precision of linear measurements derived from 3DA datasets.

Background: Three-dimensional angiography is performed during X-ray guided interventional procedures to aid diagnosis and inform treatment strategies for children and adults with congenital heart disease. However, 3DA contributes substantially to patient radiation dose and may lead to an increased radiation-induced cancer risk.

Methods: Reduced-dose patient 3DA images were simulated by adding quantum noise to the 2D projection angiograms, then reconstructing the projection angiograms into the 3DA dataset. Dose reduction in the range 33-72% was simulated. Five observers performed 46 vessel diameter measurements along prespecified axes within 23 vessel segments from 11 patient 3DA datasets. Statistical tests were performed to assess the influence of radiation dose reduction on the accuracy and precision of vessel diameter measurements.

Results: Vessel diameter measurements were in the range 5.9- 22.7 mm. Considering all vessel segments and observers, the influence of dose level on the accuracy of diameter measurements was in the range 0.02 - 0.15 mm (p .05-.8). Interobserver variability increased modestly with vessel diameter, but was not influence by dose level (p = .52). The statistical test for observer recall bias was negative (p = .51).

Conclusions: Simulated dose reduction up to 72% did not affect the accuracy or precision of the diameter measurements acquired from 3DA images. These findings may embolden 3DA radiation dose reduction for pediatric and congenital heart disease patients.
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http://dx.doi.org/10.1002/ccd.29272DOI Listing
March 2021

Associations between age and brain microstructure in older community-dwelling men and women: the Rancho Bernardo Study.

Neurobiol Aging 2020 11 15;95:94-103. Epub 2020 Jul 15.

Department of Radiology, University of California, San Diego, La Jolla, CA, USA; Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.

Cytoarchitectural brain changes during normal aging remain poorly characterized, and it is unclear whether patterns of brain aging differ by sex. This study used restriction spectrum imaging to examine associations between age and brain microstructure in 147 community-dwelling participants (aged 56-99 years). Widespread associations with age in multiple diffusion compartments, including increased free water, decreased restricted and hindered diffusion, and reduced neurite complexity, were observed in the cortical gray matter, the white matter tracts, and the hippocampus. Age differences in cortical microstructure were largely independent of atrophy. Associations were mostly global, although foci of stronger effects emerged in the fornix, anterior thalamic radiation and commissural fibers, and the medial temporal, orbitofrontal, and occipital cortices. Age differences were stronger and more widespread for women than men, even after adjustment for education, hypertension, and body mass index. Restriction spectrum imaging may be a convenient, noninvasive tool for monitoring changes in diffusion properties that are thought to reflect reduced cellular fractions and neurite density or complexity, which occur with typical aging, and for detecting sex differences in patterns of brain aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609610PMC
November 2020

Management of adults with coarctation of aorta.

World J Cardiol 2020 May;12(5):167-191

Department of Cardiovascular Diseases, Mayo Clinic, Scottsdale, AZ 85259, United States.

Coarctation of the aorta (CoA) is a relatively common congenital cardiac defect often causing few symptoms and therefore can be challenging to diagnose. The hallmark finding on physical examination is upper extremity hypertension, and for this reason, CoA should be considered in any young hypertensive patient, justifying measurement of lower extremity blood pressure at least once in these individuals. The presence of a significant pressure gradient between the arms and legs is highly suggestive of the diagnosis. Early diagnosis and treatment are important as long-term data consistently demonstrate that patients with CoA have a reduced life expectancy and increased risk of cardiovascular complications. Surgical repair has traditionally been the mainstay of therapy for correction, although advances in endovascular technology with covered stents or stent grafts permit nonsurgical approaches for the management of older children and adults with native CoA and complications. Persistent hypertension and vascular dysfunction can lead to an increased risk of coronary disease, which, remains the greatest cause of long-term mortality. Thus, blood pressure control and periodic reassessment with transthoracic echocardiography and three-dimensional imaging (computed tomography or cardiac magnetic resonance) for should be performed regularly as cardiovascular complications may occur decades after the intervention.
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http://dx.doi.org/10.4330/wjc.v12.i5.167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284000PMC
May 2020

Clinical history and management of bicuspid aortic valve in children and adolescents.

Prog Cardiovasc Dis 2020 Jul - Aug;63(4):425-433. Epub 2020 Jun 1.

Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, United States of America; Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States of America. Electronic address:

Bicuspid aortic valve (BAV) is one of the most common congenital heart defects in children, adolescents and adults. BAV can occur as an isolated lesion or in association with other congenital heart defects, such as coarctation of the aorta or genetic syndromes like Turner syndrome. Although the majority of long term complications associated with BAV manifest later in life, children and adolescents may present with early onset valvular dysfunction or dilation of the aorta. BAV is a heterogeneous disease with a wide array of presentations at various ages, depending on the degree of aortic valve dysfunction, aortic dilation and presence of associated lesions. Aortic valve stenosis and/or regurgitation are the primary indications for intervention in children and adolescents with BAV. Although a majority of young patients with BAV also have some aortic dilation, interventions on the aorta are very rare during this time frame. Children and adolescents with BAV benefit from comprehensive assessment of their risk profile to determine follow-up surveillance intervals, sports recommendations, and timing of surgical intervention. The morphologic phenotype of BAV is important to identify, as it may predict future complications and prognosis.
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http://dx.doi.org/10.1016/j.pcad.2020.05.012DOI Listing
October 2020

Behavioral and Neural Signatures of Working Memory in Childhood.

J Neurosci 2020 06 25;40(26):5090-5104. Epub 2020 May 25.

Department of Psychology, Yale University, New Haven, CT 06511

Working memory function changes across development and varies across individuals. The patterns of behavior and brain function that track individual differences in working memory during human development, however, are not well understood. Here, we establish associations between working memory, other cognitive abilities, and functional MRI (fMRI) activation in data from over 11,500 9- to 10-year-old children (both sexes) enrolled in the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing longitudinal study in the United States. Behavioral analyses reveal robust relationships between working memory, short-term memory, language skills, and fluid intelligence. Analyses relating out-of-scanner working memory performance to memory-related fMRI activation in an emotional -back task demonstrate that frontoparietal activity during a working memory challenge indexes working memory performance. This relationship is domain specific, such that fMRI activation related to emotion processing during the emotional -back task, inhibitory control during a stop-signal task (SST), and reward processing during a monetary incentive delay (MID) task does not track memory abilities. Together, these results inform our understanding of individual differences in working memory in childhood and lay the groundwork for characterizing the ways in which they change across adolescence. Working memory is a foundational cognitive ability that changes over time and varies across individuals. Here, we analyze data from over 11,500 9- to 10-year-olds to establish relationships between working memory, other cognitive abilities, and frontoparietal brain activity during a working memory challenge, but not during other cognitive challenges. Our results lay the groundwork for assessing longitudinal changes in working memory and predicting later academic and other real-world outcomes.
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http://dx.doi.org/10.1523/JNEUROSCI.2841-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314411PMC
June 2020

Not to worry (most of the time).

Authors:
Donald J Hagler

Catheter Cardiovasc Interv 2020 04;95(5):937-938

Division of Pediatric Cardiology and Department of Cardiovascular Diseases, Mayo Clinic College of Medicine and science, Rochester, Minnesota, USA.

Most (87.6%) of residual atrial L-R shunts after Gore Cardioform septal occluder implant disappear by 12 months. Residual leaks at implantation were more common in larger defects with smaller retro-aortic rims, and multiple fenestrations. While most residual defects close in 12 months, we unfortunately do not yet have a clear idea why or which of the 13% do not close.
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http://dx.doi.org/10.1002/ccd.28877DOI Listing
April 2020

Cardiovascular surgery in Turner syndrome - early outcome and long-term follow-up.

World J Cardiol 2020 Mar;12(3):97-106

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, United States.

Background: Cardiovascular disease is the leading cause of death in patients with Turner syndrome (TS), and cardiovascular surgery is frequently required for management of these patients. TS is associated with medical comorbidities than can complicate the care of this patient population.

Aim: To describe the cardiovascular surgical outcomes of patients with TS.

Methods: A retrospective case series was compiled of 51 consecutive TS patients who had at least one cardiovascular surgery at Mayo Clinic Rochester from 1977-2017. The baseline clinical data of these patients were reviewed including demographics, medical comorbidities, congenital heart disease history, and medications. Echocardiographic reports were analyzed in detail. Operative reports and surgical hospital courses were reviewed. Long-term mortality was determined using medical records and the Social Security Death Index. Survival analysis was performed with the Kaplan Meier method.

Results: The cohort comprised 51 TS patients, average age at the time of surgery at Mayo Clinic was 28 (8-41) years, and 23 (45%) patients were under the age of 18. At the time of first Mayo Clinic surgery, 18 (35%) patients had previously undergone cardiac surgery at another institution. The most common procedures were repair of aortic coarctation in 14 (28%) patients, aortic valve replacement in 6 (12%) patients, and composite aortic root/ascending aorta replacement in 7 (14%) patients, with 7 patients undergoing repair of more than one lesion. Aortic dissection required operative intervention in 5 patients. After initial Mayo Clinic surgery, subsequent operations were required in 6 (13%) patients. Average hospital length of stay was 6 ± 2 d. There were 4 (8%) early surgical deaths. Freedom from death was 97% and 89% at 10 and 20 years, and the freedom from reoperation was 93% and 81% at 10 and 20 years.

Conclusion: Cardiovascular surgery is associated with 8% early mortality given the medical complexity of TS patients. Those who survive to dismissal have good survival. Later cardiovascular reoperations are not rare.
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http://dx.doi.org/10.4330/wjc.v12.i3.97DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138866PMC
March 2020

Feasibility, reproducibility and accuracy of electrical velocimetry for cardiac output assessment in congenital heart disease.

Int J Cardiol Heart Vasc 2020 Feb 9;26:100464. Epub 2020 Jan 9.

Division of Pediatric Cardiology, Mayo Clinic Rochester, MN 55905, United States.

Background: Noninvasive cardiac output assessment is important for prognostication in patients with heart failure. Electrical velocimetry (EV), an impedance cardiography technique, can be used for noninvasive cardiac output assessment. The purpose of this study was to determine the feasibility, reproducibility and accuracy of cardiac output assessment by EV in adults with congenital heart disease (CHD).

Methods: Cross-sectional study of CHD patients that had simultaneous cardiac output assessment by Fick and EV (using Cardiotronic monitor, Osypka Medical). We divided the cohort into: Group 1 patients (n = 54) had hemodynamic assessment at rest only, while Group 2 patients (n = 7) had assessment both at rest and peak exercise.

Results: EV cardiac output assessment was feasible in 100% of the patients. There was good correlation between Fick-derived and EV-derived cardiac index (r = 0.89, p < 0.001) in Group 1. Among 26 patients in Group 1 that underwent cardiac output assessment pre- and post-intervention, there was no difference in the strength of correlation of Fick and EV cardiac output pre- and post-intervention (p-interaction 0.244) indicating good reproducibility of the technique. There was also modest correlation between Fick-derived and EV-derived cardiac index at rest (r = 0.68, p = 0.032), and peak exercise (r = 0.62, p = 0.055), in Group 2.

Conclusion: In this study, we demonstrated the feasibility and accuracy of EV cardiac output assessment in adults with CHD. We also demonstrated, for the first time, that EV cardiac output assessment was reproducible under different loading conditions, and that EV can be used for the assessment of cardiac output augmentation at peak exercise.
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http://dx.doi.org/10.1016/j.ijcha.2019.100464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956751PMC
February 2020

Associations Between Microstructure, Amyloid, and Cognition in Amnestic Mild Cognitive Impairment and Dementia.

J Alzheimers Dis 2020 ;73(1):347-357

Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.

Background: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer's disease, their independent or synergistic effects on cognitive decline are unclear.

Objective: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia.

Methods: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline.

Results: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF.

Conclusion: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.
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http://dx.doi.org/10.3233/JAD-190871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266036PMC
April 2021

Correction of respiratory artifacts in MRI head motion estimates.

Neuroimage 2020 03 25;208:116400. Epub 2019 Nov 25.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, Washington University, St. Louis, MO, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA; Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Head motion represents one of the greatest technical obstacles in magnetic resonance imaging (MRI) of the human brain. Accurate detection of artifacts induced by head motion requires precise estimation of movement. However, head motion estimates may be corrupted by artifacts due to magnetic main field fluctuations generated by body motion. In the current report, we examine head motion estimation in multiband resting state functional connectivity MRI (rs-fcMRI) data from the Adolescent Brain and Cognitive Development (ABCD) Study and comparison 'single-shot' datasets. We show that respirations contaminate movement estimates in functional MRI and that respiration generates apparent head motion not associated with functional MRI quality reductions. We have developed a novel approach using a band-stop filter that accurately removes these respiratory effects from motion estimates. Subsequently, we demonstrate that utilizing a band-stop filter improves post-processing fMRI data quality. Lastly, we demonstrate the real-time implementation of motion estimate filtering in our FIRMM (Framewise Integrated Real-Time MRI Monitoring) software package.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307712PMC
March 2020

Suprasternal Pulmonary Artery Puncture in the Setting of Right-Sided Mechanical Prostheses: The Radner Technique Redux.

JACC Cardiovasc Interv 2019 11 30;12(22):2320-2321. Epub 2019 Oct 30.

Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1016/j.jcin.2019.05.036DOI Listing
November 2019

Double-Outlet Left Ventricle: The Importance of Echocardiographic and Computed Tomographic Assessment.

CASE (Phila) 2019 Aug 31;3(4):141-144. Epub 2019 May 31.

Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1016/j.case.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710820PMC
August 2019
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