Publications by authors named "Sigurdur Sigurdsson"

161 Publications

Soft tissue radiodensity parameters mediate the relationship between self-reported physical activity and lower extremity function in AGES-Reykjavík participants.

Sci Rep 2021 Oct 11;11(1):20173. Epub 2021 Oct 11.

Institute for Biomedical and Neural Engineering, Reykjavík University, Reykjavík, Iceland.

Although previous studies have highlighted the association between physical activity and lower extremity function (LEF) in elderly individuals, the mechanisms underlying this relationship remain debated. Our recent work has recognized the utility of nonlinear trimodal regression analysis (NTRA) parameters in characterizing changes in soft tissue radiodensity as a quantitative construct for sarcopenia in the longitudinal, population-based cohort of the AGES-Reykjavík study. For the present work, we assembled a series of prospective multivariate regression models to interrogate whether NTRA parameters mediate the 5-year longitudinal relationship between physical activity and LEF in AGES-Reykjavík participants. Healthy elderly volunteers from the AGES-Reykjavík cohort underwent mid-thigh X-ray CT scans along with a four-part battery of LEF tasks: normal gait speed, fastest-comfortable gait speed, isometric leg strength, and timed up-and-go. These data were recorded at two study timepoints which were separated by approximately 5 years: AGES-I (n = 3157) and AGES-II (n = 3098). Participants in AGES-I were likewise administered a survey to approximate their weekly frequency of engaging in moderate-to-vigorous physical activity (PA). Using a multivariate mediation analysis framework, linear regression models were assembled to test whether NTRA parameters mediated the longitudinal relationship between PA and LEF; all models were covariate-adjusted for age, sex, BMI, and baseline LEF, and results were corrected for multiple statistical comparisons. Our first series of models confirmed that all four LEF tasks were significantly related to PA; next, modelling the relationship between PA and NTRA identified muscle amplitude (N) and location (μ) as potential mediators of LEF to test. Finally, adding these two parameters into our PA → LEF models attenuated the prior effect of PA; bootstrapping confirmed N and μ as significant partial mediators of the PA → LEF relationship, with the strongest effect found in isometric leg strength. This work describes a novel approach toward clarifying the mechanisms that underly the relationship between physical activity and LEF in aging individuals. Identifying N and μ as significant partial mediators of this relationship provides strong evidence that physical activity protects aging mobility through the preservation of both lean tissue quantity and quality.
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http://dx.doi.org/10.1038/s41598-021-99699-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505499PMC
October 2021

Finite element derived femoral strength is a better predictor of hip fracture risk than aBMD in the AGES Reykjavik study cohort.

Bone 2021 Sep 25;154:116219. Epub 2021 Sep 25.

Institute for Biomechanics, ETH Zürich, Zürich, Switzerland; Future Health Technologies, Singapore-ETH Centre, Campus for Research Excellence And Technological Enterprise (CREATE), Singapore.

Hip fractures associated with a high economic burden, loss of independence, and a high rate of post-fracture mortality, are a major health concern for modern societies. Areal bone mineral density is the current clinical metric of choice when assessing an individual's future risk of fracture. However, this metric has been shown to lack sensitivity and specificity in the targeted selection of individuals for preventive interventions. Although femoral strength derived from computed tomography based finite element models has been proposed as an alternative based on its superior femoral strength prediction ex vivo, such predictions have only shown marginal or no improvement for assessing hip fracture risk. This study compares finite element derived femoral strength to aBMD as a metric for hip fracture risk assessment in subjects (N = 601) from the AGES Reykjavik Study cohort and analyses the dependence of femoral strength predictions and classification accuracy on the material model and femoral loading alignment. We found hip fracture classification based on finite element derived femoral strength to be significantly improved compared to aBMD. Finite element models with non-linear material models performed better at classifying hip fractures compared to finite element models with linear material models and loading alignments with low internal rotation and adduction, which do not correspond to weak femur alignments, were found to be most suitable for hip fracture classification.
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http://dx.doi.org/10.1016/j.bone.2021.116219DOI Listing
September 2021

Contributions of Cerebral Blood Flow to Associations Between Blood Pressure Levels and Cognition: The Age, Gene/Environment Susceptibility-Reykjavik Study.

Hypertension 2021 Jun 19;77(6):2075-2083. Epub 2021 Apr 19.

From the Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, National Institute of Health, Baltimore, MD (J.E.M., O.M., L.J.L.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119347PMC
June 2021

Exploratory assessment of pineal gland volume, composition, and urinary 6-sulfatoxymelatonin levels on prostate cancer risk.

Prostate 2021 Jun 16;81(8):487-496. Epub 2021 Apr 16.

Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

Introduction: Melatonin levels are partially driven by the parenchyma volume of the pineal gland. Low urinary levels of 6-sulfatoxymelatonin have been associated with increased risk of advanced prostate cancer, but the relationship between pineal gland volume and composition and prostate cancer risk has not been examined.

Materials And Methods: We utilized data from 864 men from the AGES-Reykjavik Study with complete pineal gland volumes and urinary 6-sulfatoxymelatonin measurements. Pineal parenchyma, calcification, and cyst volumes were calculated from brain magnetic resonance imaging. Levels of 6-sulfatoxymelatonin were assayed from prediagnostic urine samples. We calculated Pearson correlation coefficients between parenchyma volume and urinary 6-sulfatoxymelatonin levels. We used Cox proportional hazards regression to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) comparing prostate cancer risk across parenchyma volume tertiles and across categories factoring in parenchyma volume, gland composition, and urinary 6-sulfatoxymelatonin level.

Results: Parenchyma volume was moderately correlated with urinary 6-sulfatoxymelatonin level (r = .24; p < .01). There was no statistically significant association between parenchyma volume tertile and prostate cancer risk. Men with high parenchyma volume, pineal cysts and calcifications, and low urinary 6-sulfatoxymelatonin levels had almost twice the risk of total prostate cancer as men with low parenchyma volume, no pineal calcifications or cysts, and low urinary 6-sulfatoxymelatonin levels (HR: 1.98; 95% CI: 1.02, 3.84; p: .04).

Conclusions: Although parenchyma volume is not associated with prostate cancer risk, pineal gland composition and other circadian dynamics may influence risk for prostate cancer. Additional studies are needed to examine the interplay of pineal gland volume, composition, and melatonin levels on prostate cancer risk.
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http://dx.doi.org/10.1002/pros.24130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194005PMC
June 2021

Accelerated decline in quadriceps area and Timed Up and Go test performance are associated with hip fracture risk in older adults with impaired kidney function.

Exp Gerontol 2021 07 16;149:111314. Epub 2021 Mar 16.

National Institute on Aging, Intramural Research Program, Laboratory of Epidemiology and Population Sciences, Bethesda, MD, USA.

Objective: This study aimed to examine whether an accelerated decline in quadriceps cross-sectional area (CSA), attenuation (a surrogate of quality), and strength, as well as lower limb muscular function, are associated with hip fractures in older adults with impaired kidney function.

Design: Prospective population-based study.

Setting: Community-dwelling old population in Reykjavik, Iceland.

Subjects: A total of 875 older adults (mean baseline age 76 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study with impaired kidney function.

Methods: Quadriceps CSA and density were determined using computed tomography (CT), knee extension strength was measured with an isometric dynamometer chair, and muscular function was assessed using the Timed Up and Go (TUG) test. All muscle-related measurements were assessed twice over a mean follow-up of 5.2 years. Data on hip fracture incidence was obtained from medical records during a maximum of 8.4 years of follow-up time.

Results: Fully adjusted cox-proportional hazard regression models showed that a faster decline in quadriceps CSA and TUG test performance were significantly associated with increased hip fracture risk (HR = 1.55, 95% CI = 1.02-2.36, and HR = 1.80, 95% CI = 1.19-2.72, respectively). A faster decrease in quadriceps density and isometric knee extension strength were not associated with fracture risk.

Conclusions: Accelerated decline in CT-derived quadriceps CSA and muscular function, as measured by the TUG test's performance, are predictive of hip fracture risk in older adults with impaired kidney function. TUG test is a simple measure and easily included in routine medical examinations, compared to CT scans, which seems to be useful for identifying a subgroup of individuals with high risk of fracture.
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http://dx.doi.org/10.1016/j.exger.2021.111314DOI Listing
July 2021

Computed tomography-based skeletal muscle and adipose tissue attenuation: Variations by age, sex, and muscle.

Exp Gerontol 2021 07 10;149:111306. Epub 2021 Mar 10.

Laboratory of Epidemiology and Population Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Objective: This study aimed to investigate how skeletal muscle attenuation and adipose tissue (AT) attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle vary according to the targeted muscles, sex, and age.

Design: Population-based cross-sectional study.

Setting: Community-dwelling old population in Reykjavik, Iceland.

Subjects: A total of 5331 older adults (42.8% women), aged 66-96 years from the Age, Gene/Environment Susceptibility (AGES)- Reykjavik Study, who participated in the baseline visit (between 2002 and 2006) and had valid thigh and abdominal computed tomography (CT) scans were studied.

Methods: Muscle attenuation and AT attenuation of the quadriceps, hamstrings, paraspinal muscle groups and the psoas muscle were determined using CT. Linear mixed model analysis of variance was performed for each sex, with skeletal muscle or AT attenuation as the dependent variable.

Results: Muscle attenuation decreased, and AT attenuation increased with age in both sexes, and these differences were specific for each muscle, although not in all age groups. Age-related differences in muscle and AT attenuation varied with specific muscle. In general, for both sexes, skeletal muscle attenuation of the hamstrings declined more than average with age. Men and women displayed a different pattern in the age differences in AT attenuation for each muscle.

Conclusions: Our data support the hypotheses that skeletal muscle attenuation decreases, and AT attenuation increases with aging. In addition, our data add new evidence, supporting that age-related differences in skeletal muscle and AT attenuation vary between muscles.
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http://dx.doi.org/10.1016/j.exger.2021.111306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096682PMC
July 2021

Wave Reflection at the Origin of a First-Generation Branch Artery and Target Organ Protection: The AGES-Reykjavik Study.

Hypertension 2021 04 10;77(4):1169-1177. Epub 2021 Mar 10.

From the Cardiovascular Engineering, Inc, Norwood, MA (M.A.H., J.D.G., G.F.M.).

[Figure: see text].
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16696DOI Listing
April 2021

Radiological, vascular osteochondrosis occurs in the distal tarsus, and may cause osteoarthritis.

Equine Vet J 2021 Feb 3. Epub 2021 Feb 3.

Faculty of Veterinary Medicine, Department of Companion Animal Clinical Sciences, Equine Section, Norwegian University of Life Sciences, Oslo, Norway.

Background: Osteochondrosis occurs due to failure of the blood supply to growth cartilage. Osteochondrosis lesions have been identified in small tarsal bones and suggested to cause distal tarsal osteoarthritis; however, it has not been determined whether distal tarsal osteochondrosis lesions were the result of vascular failure.

Objectives: To perform post-mortem arterial perfusion and micro-computed tomography (CT) of the central (CTB) and third tarsal bones (TIII) of fetuses and foals up to 5 months old, to describe tarsal development and any lesions detected.

Study Design: Descriptive, nonconsecutive case series.

Methods: Twenty-three animals that died or were euthanased from 228 days of gestation to 5 months old were collected, comprising two fetuses and nine foals of miscellaneous breeds and 12 Icelandic Horse foals, a breed with high prevalence of distal tarsal osteoarthritis. One hindlimb from each foal was perfused arterially with barium, and the CTB and TIII were examined with micro-CT.

Results: Perfusion yielded partial information from 41% of the animals. The CTB and TIII were supplied by nutrient arteries and perichondrial vessels with vertical, transverse and circumferential configurations. Fourteen of the 23 (61%) animals had focal defects in the ossification front, that is, radiological osteochondrosis. The majority of lesions matched the configuration and development of vertical vessels. Additionally, full-thickness, cylindrical defects matched transverse vessels, and the long axes of some dorsal lesions matched circumferential vessels.

Main Limitations: Lack of histological validation.

Conclusions: Post-mortem perfusion was poor for examination of the blood supply to the growth cartilage of the CTB and TIII. Radiological osteochondrosis lesions were compatible with vascular failure because they were focal, and because lesion geometry matched vessel configuration. The relationship between osteochondrosis and distal tarsal osteoarthritis warrants further investigation.
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http://dx.doi.org/10.1111/evj.13432DOI Listing
February 2021

Training non-intensivist doctors to work with COVID-19 patients in intensive care units.

Acta Anaesthesiol Scand 2021 05 3;65(5):664-673. Epub 2021 Mar 3.

Copenhagen Academy for Medical Education and Simulation, Centre for Human Resources and Education, Copenhagen, Denmark.

Background: Due to an expected surge of COVID-19 patients in need of mechanical ventilation, the intensive care capacity was doubled at Rigshospitalet, Copenhagen, in March 2020. This resulted in an urgent need for doctors with competence in working with critically ill COVID-19 patients. A training course and a theoretical test for non-intensivist doctors were developed. The aims of this study were to gather validity evidence for the theoretical test and explore the effects of the course.

Methods: The 1-day course was comprised of theoretical sessions and hands-on training in ventilator use, hemodynamic monitoring, vascular access, and use of personal protective equipment. Validity evidence was gathered for the test by comparing answers from novices and experts in intensive care. Doctors who participated in the course completed the test before (pretest), after (posttest), and again within 8 weeks following the course (retention test).

Results: Fifty-four non-intensivist doctors from 15 different specialties with a wide range in clinical experience level completed the course. The test consisted of 23 questions and demonstrated a credible pass-fail standard at 16 points. Mean pretest score was 11.9 (SD 3.0), mean posttest score 20.6 (1.8), and mean retention test score 17.4 (2.2). All doctors passed the posttest.

Conclusion: Non-intensivist doctors, irrespective of experience level, can acquire relevant knowledge for working in the ICU through a focused 1-day evidence-based course. This knowledge was largely retained as shown by a multiple-choice test supported by validity evidence. The test is available in appendix and online.
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http://dx.doi.org/10.1111/aas.13789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013477PMC
May 2021

Central and peripheral nervous system complications of COVID-19: a prospective tertiary center cohort with 3-month follow-up.

J Neurol 2021 Sep 13;268(9):3086-3104. Epub 2021 Jan 13.

Departments of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objective: To systematically describe central (CNS) and peripheral (PNS) nervous system complications in hospitalized COVID-19 patients.

Methods: We conducted a prospective, consecutive, observational study of adult patients from a tertiary referral center with confirmed COVID-19. All patients were screened daily for neurological and neuropsychiatric symptoms during admission and discharge. Three-month follow-up data were collected using electronic health records. We classified complications as caused by SARS-CoV-2 neurotropism, immune-mediated or critical illness-related.

Results: From April to September 2020, we enrolled 61 consecutively admitted COVID-19 patients, 35 (57%) of whom required intensive care (ICU) management for respiratory failure. Forty-one CNS/PNS complications were identified in 28 of 61 (45.9%) patients and were more frequent in ICU compared to non-ICU patients. The most common CNS complication was encephalopathy (n = 19, 31.1%), which was severe in 13 patients (GCS ≤ 12), including 8 with akinetic mutism. Length of ICU admission was independently associated with encephalopathy (OR = 1.22). Other CNS complications included ischemic stroke, a biopsy-proven acute necrotizing encephalitis, and transverse myelitis. The most common PNS complication was critical illness polyneuromyopathy (13.1%), with prolonged ICU stay as independent predictor (OR = 1.14). Treatment-related PNS complications included meralgia paresthetica. Of 41 complications in total, 3 were para/post-infectious, 34 were secondary to critical illness or other causes, and 4 remained unresolved. Cerebrospinal fluid was negative for SARS-CoV-2 RNA in all 5 patients investigated.

Conclusion: CNS and PNS complications were common in hospitalized COVID-19 patients, particularly in the ICU, and often attributable to critical illness. When COVID-19 was the primary cause for neurological disease, no signs of viral neurotropism were detected, but laboratory changes suggested autoimmune-mediated mechanisms.
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http://dx.doi.org/10.1007/s00415-020-10380-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803470PMC
September 2021

Serum FSH Is Associated With BMD, Bone Marrow Adiposity, and Body Composition in the AGES-Reykjavik Study of Older Adults.

J Clin Endocrinol Metab 2021 03;106(3):e1156-e1169

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Context: Follicle-stimulating hormone (FSH) concentrations increase during the perimenopausal transition and remain high after menopause. Loss of bone mineral density (BMD) and gain of bone marrow adiposity (BMA) and body fat mass also occur during this time. In mice, blocking the action of FSH increases bone mass and decreases fat mass.

Objective: To investigate the associations between endogenous FSH levels and BMD, BMA, and body composition in older adults, independent of estradiol and testosterone levels.

Design, Setting, And Participants: Older adults from the AGES-Reykjavik Study, an observational cohort study.

Main Outcome Measures: Areal BMD, total body fat, and lean mass were measured with dual-energy x-ray absorptiometry. Lumbar vertebral BMA was measured by 1H-magnetic resonance spectroscopy. Volumetric BMD and visceral and subcutaneous adipose tissue (VAT, SAT) areas were measured with quantitative computed tomography. The least squares means procedure was used to determine sex hormone-adjusted associations between quartiles of serum FSH and BMD, BMA, and body composition.

Results: In women (N = 238, mean age 81 years), those in the highest FSH quartile, compared with the lowest quartile, had lower adjusted mean spine integral BMD (-8.6%), lower spine compressive strength index (-34.8%), higher BMA (+8.4%), lower weight (-8.4%), lower VAT (-17.6%), lower lean mass (-6.1%), and lower fat mass (-11.9%) (all P < 0.05). In men, FSH level was not associated with any outcome.

Conclusions: Older postmenopausal women with higher FSH levels have higher BMA, but lower BMD and lower fat and lean mass, independent of estradiol and testosterone levels. Longitudinal studies are needed to better understand the underlying mechanisms.
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http://dx.doi.org/10.1210/clinem/dgaa922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947831PMC
March 2021

Healthy Aging Within an Image: Using Muscle Radiodensitometry and Lifestyle Factors to Predict Diabetes and Hypertension.

IEEE J Biomed Health Inform 2021 06 3;25(6):2103-2112. Epub 2021 Jun 3.

The strong age dependency of many deleterious health outcomes likely reflects the cumulative effects from a variety of risk and protective factors that occur over one's life course. This notion has become increasingly explored in the etiology of chronic disease and associated comorbidities in aging. Our recent work has shown the robust classification of individuals at risk for cardiovascular pathophysiology using CT-based soft tissue radiodensity parameters obtained from nonlinear trimodal regression analysis (NTRA). Past and present lifestyle influences the incidence of comorbidities like hypertension (HTN), diabetes (DM) and cardiac diseases. 2,943 elderly subjects from the AGES-Reykjavik study were sorted into a three-level binary-tree structure defined by: 1) lifestyle factors (smoking and self-reported physical activity level), 2) comorbid HTN or DM, and 3) cardiac pathophysiology. NTRA parameters were extracted from mid-thigh CT cross-sections to quantify radiodensitometric changes in three tissue types: lean muscle, fat, and loose-connective tissue. Between-group differences were assessed at each binary-tree level, which were then used in tree-based machine learning (ML) models to classify subjects with DM or HTN. Classification scores for detecting HTN or DM based on lifestyle factors were excellent (AUCROC: 0.978 and 0.990, respectively). Finally, tissue importance analysis underlined the comparatively-high significance of connective tissue parameters in ML classification, while predictive models of DM onset from five-year longitudinal data gave a classification accuracy of 94.9%. Altogether, this work serves as an important milestone toward the construction of predictive tools for assessing the impact of lifestyle factors and healthy aging based on a single image.
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http://dx.doi.org/10.1109/JBHI.2020.3044158DOI Listing
June 2021

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

Association of common genetic variants with brain microbleeds: A genome-wide association study.

Neurology 2020 12 10;95(24):e3331-e3343. Epub 2020 Sep 10.

From the Departments of Epidemiology (M.J.K., H.H.H.A., D.V., S.J.v.d.L., P.Y., M.W.V., N.A., C.M.v.D., M.A.I.), Radiology and Nuclear Medicine (H.H.H.A., P.Y., A.v.d.L., M.W.V.), and Clinical Genetics (H.H.H.A.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Stroke Research Group, Department of Clinical Neurosciences (D.L., M.T., J.L., D.J.T., H.S.M.), University of Cambridge, UK; Department of Neurology (J.R.J.R., C.L.S., J.J.H., A.S.B., C.D., S. Seshadri), Boston University School of Medicine; The Framingham Heart Study (J.R.J.R., C.L.S., J.J.H., A.S.B., S. Seshadri), MA; Department of Biostatistics (A.V.S.), University of Michigan, Ann Arbor; Icelandic Heart Association (A.V.S., S. Sigurdsson, V.G.), Kopavogur, Iceland; Brown Foundation Institute of Molecular Medicine, McGovern Medical School (M.F.), and Human Genetics Center, School of Public Health (M.F.), University of Texas Health Science Center at Houston; Clinical Division of Neurogeriatrics, Department of Neurology (E.H., L.P., R.S.), Institute for Medical Informatics, Statistics and Documentation (E.H.), and Gottfried Schatz Research Center, Department of Molecular Biology and Biochemistry (Y.S., H.S.), Medical University of Graz, Austria; Center of Cerebrovascular Diseases, Department of Neurology (J.L.), West China Hospital, Sichuan University, Chengdu; Stroke Research Centre, Queen Square Institute of Neurology (I.C.H., D.W., H.H., D.J.W.), University College London, UK; Department of Neurosurgery (I.C.H.), Klinikum rechts der Isar, University of Munich, Germany; Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology (M.L., D.C.M.L., M.E.B., I.J.D., J.M.W.), and Centre for Clinical Brain Sciences, Edinburgh Imaging, UK Dementia Research Institute (M.E.B., J.M.W.), University of Edinburgh, UK; Department of Internal Medicine, Section of Gerontology and Geriatrics (S.T.), Department of Cardiology (S.T., J.v.d.G., J.W.J.), Section of Molecular Epidemiology, Biomedical Data Sciences (E.B.v.d.A., M.B., P.E.S.), Leiden Computational Biology Center, Biomedical Data Sciences (E.B.v.d.A.), Department of Radiology (J.v.d.G.), and Einthoven Laboratory for Experimental Vascular Medicine (J.W.J.), Leiden University Medical Center, the Netherlands; Department of Neurology (A.-K.G., N.S.R.), Massachusetts General Hospital, Harvard Medical School, Boston; Memory Aging and Cognition Center (S.H., C.C.), National University Health System, Singapore; Department of Pharmacology (S.H., C.C.) and Saw Swee Hock School of Public Health (S.H.), National University of Singapore and National University Health System, Singapore; Pattern Recognition & Bioinformatics (E.B.v.d.A.), Delft University of Technology, the Netherlands; Department of Biostatistics (S.L., J.J.H., Q.Y., A.S.B.), Boston University School of Public Health, MA; Department of Radiology (C.R.J., K.K.), Mayo Clinic, Rochester, MN; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases (C.L.S., S. Seshadri), UT Health San Antonio, TX; Department of Medicine, Division of Geriatrics (B.G.W., T.H.M), and Memory Impairment and Neurodegenerative Dementia (MIND) Center (T.H.M.), University of Mississippi Medical Center, Jackson; Singapore Eye Research Institute (C.Y.C., J.Y.K., T.Y.W.); Department of Neuroradiology (Z.M., J.M.W.), NHS Lothian, Edinburgh; Institute of Cardiovascular and Medical Sciences (D.J.S.), College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; Division of Cerebrovascular Neurology (R.F.G.), Johns Hopkins University, Baltimore, MD; Department of Neuroradiology (A.D.M.), Atkinson Morley Neurosciences Centre, St George's NHS Foundation Trust, London, UK; Department of Neurology (C.D.), University of California at Davis; Nuffield Department of Population Health (C.M.v.D.), University of Oxford, UK; Laboratory of Epidemiology and Population Sciences (L.J.L.), National Institute on Aging, Baltimore, MD; and Faculty of Medicine (V.G.), University of Iceland, Reykjavik, Iceland.

Objective: To identify common genetic variants associated with the presence of brain microbleeds (BMBs).

Methods: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.

Results: BMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the region reached genome-wide significance for its association with BMB (lead rs769449; odds ratio [OR] [95% confidence interval (CI)] 1.33 [1.21-1.45]; = 2.5 × 10). ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; = 1.0 × 10) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; = 0.68). ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.

Conclusions: Genetic variants in the region are associated with the presence of BMB, most likely due to the ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.
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http://dx.doi.org/10.1212/WNL.0000000000010852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836652PMC
December 2020

Type 2 Diabetes, Change in Depressive Symptoms Over Time, and Cerebral Small Vessel Disease: Longitudinal Data of the AGES-Reykjavik Study.

Diabetes Care 2020 08 11;43(8):1781-1787. Epub 2020 Jun 11.

Intramural Research Program, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD

Objective: Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms.

Research Design And Methods: We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose-lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up.

Results: Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (β = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association.

Conclusions: Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association.
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http://dx.doi.org/10.2337/dc19-2437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372064PMC
August 2020

No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

J Renin Angiotensin Aldosterone Syst 2019 Jul-Sep;20(3):1470320319874615

Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Denmark.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin-angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na) and low (0.004% Na) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.
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http://dx.doi.org/10.1177/1470320319874615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732866PMC
June 2020

Assessing cardiovascular risks from a mid-thigh CT image: a tree-based machine learning approach using radiodensitometric distributions.

Sci Rep 2020 02 18;10(1):2863. Epub 2020 Feb 18.

Institute for Biomedical and Neural Engineering, Reykjavík University, Reykjavík, Iceland.

The nonlinear trimodal regression analysis (NTRA) method based on radiodensitometric CT distributions was recently developed and assessed for the quantification of lower extremity function and nutritional parameters in aging subjects. However, the use of the NTRA method for building predictive models of cardiovascular health was not explored; in this regard, the present study reports the use of NTRA parameters for classifying elderly subjects with coronary heart disease (CHD), cardiovascular disease (CVD), and chronic heart failure (CHF) using multivariate logistic regression and three tree-based machine learning (ML) algorithms. Results from each model were assembled as a typology of four classification metrics: total classification score, classification by tissue type, tissue-based feature importance, and classification by age. The predictive utility of this method was modelled using CHF incidence data. ML models employing the random forests algorithm yielded the highest classification performance for all analyses, and overall classification scores for all three conditions were excellent: CHD (AUCROC: 0.936); CVD (AUCROC: 0.914); CHF (AUCROC: 0.994). Longitudinal assessment for modelling the prediction of CHF incidence was likewise robust (AUCROC: 0.993). The present work introduces a substantial step forward in the construction of non-invasive, standardizable tools for associating adipose, loose connective, and lean tissue changes with cardiovascular health outcomes in elderly individuals.
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http://dx.doi.org/10.1038/s41598-020-59873-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029006PMC
February 2020

Utilizing Group-Based Contingencies to Increase Hand Washing in a Large Human Service Setting.

Behav Anal Pract 2019 Sep 23;12(3):600-611. Epub 2019 Jan 23.

1Neurobehavioral Unit, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD 21205 USA.

Hand washing is the most important preventative measure for the reduction of contagious disease. Although hand washing is easy to perform, non-adherence is a ubiquitous problem. Several studies have demonstrated the effectiveness of multi-component intervention packages to improve hand washing among employees; however, interventions are limited to acute settings, are often implemented for a short period of time, and rarely, if ever, include information on long-term effectiveness. The purpose of the current study was to utilize a behavior analytic approach to determine the stimulus conditions under which hand washing should occur, and to assess and then implement a long-term monitoring system among direct care workers in a large, non-acute inpatient unit. A single-case repeated measures reversal design was used to evaluate the effectiveness of two interventions aimed at improving hand washing adherence. A lottery was found to be effective in increasing hand hygiene for 2-years with 170 staff.
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http://dx.doi.org/10.1007/s40617-018-00328-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743514PMC
September 2019

Improved brain perfusion after electrical cardioversion of atrial fibrillation.

Europace 2020 04;22(4):530-537

Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

Aims: Atrial fibrillation (AF) has been associated with reduced brain volume, cognitive impairment, and reduced cerebral blood flow. The causes of reduced cerebral blood flow in AF are unknown, but no reduction was seen in individuals without the arrhythmia in a previous study. The aim of this study was to test the hypothesis that brain perfusion, measured with magnetic resonance imaging (MRI), improves after cardioversion of AF to sinus rhythm (SR).

Methods And Results: All patients undergoing elective cardioversion at our institution were invited to participate. A total of 44 individuals were included. Magnetic resonance imaging studies were done before and after cardioversion with both brain perfusion and cerebral blood flow measurements. However, 17 did not complete the second MRI as they had a recurrence of AF during the observation period (recurrent AF group), leaving 17 in the SR group and 10 in the AF group to complete both measurements. Brain perfusion increased after cardioversion to SR by 4.9 mL/100 g/min in the whole brain (P < 0.001) and by 5.6 mL/100 g/min in grey matter (P < 0.001). Cerebral blood flow increased by 58.6 mL/min (P < 0.05). Both brain perfusion and cerebral blood flow remained unchanged when cardioversion was unsuccessful.

Conclusion: In this study of individuals undergoing elective cardioversion for AF, restoration, and maintenance of SR for at least 10 weeks after was associated with an improvement of brain perfusion and cerebral blood flow measured by both arterial spin labelling and phase contrast MRI. In those individuals where cardioversion was unsuccessful, there was no change in perfusion or blood flow.
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http://dx.doi.org/10.1093/europace/euz336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132536PMC
April 2020

SegAE: Unsupervised white matter lesion segmentation from brain MRIs using a CNN autoencoder.

Neuroimage Clin 2019 9;24:102085. Epub 2019 Nov 9.

Department of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland; Department of Electrical and Computer Engineering, The Johns Hopkins University, Baltimore, MD, USA. Electronic address:

White matter hyperintensities (WMHs) of presumed vascular origin are frequently observed in magnetic resonance images (MRIs) of the elderly. Detection and quantification of WMHs is important to help doctors make diagnoses and evaluate prognosis of their elderly patients, and once quantified, these can act as biomarkers in clinical research studies. Manual delineation of WMHs can be both time-consuming and inconsistent, hence, automatic segmentation methods are often preferred. However, fully automatic methods can be challenging to construct due to the variability in lesion load, placement of lesions, and voxel intensities. Several state-of-the-art lesion segmentation methods based on supervised Convolutional Neural Networks (CNNs) have been proposed. These approaches require manually delineated lesions for training the parameters of the network. Here we present a novel approach for WMH segmentation using a CNN trained in an unsupervised manner, by reconstructing multiple MRI sequences as weighted sums of segmentations of WMHs and tissues present in the images. After training, our method can be used to segment new images that are not part of the training set to provide fast and robust segmentation of WMHs in a matter of seconds per subject. Comparisons with state-of-the-art WMH segmentation methods evaluated on ground truth manual labels from two distinct data sets and six different scanners indicate that the proposed method works well at generating accurate WMH segmentations without the need for manual delineations.
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http://dx.doi.org/10.1016/j.nicl.2019.102085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861597PMC
September 2020

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Nat Genet 2019 11 28;51(11):1580-1587. Epub 2019 Oct 28.

National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, MA, USA.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.
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http://dx.doi.org/10.1038/s41588-019-0514-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858575PMC
November 2019

Greater Bone Marrow Adiposity Predicts Bone Loss in Older Women.

J Bone Miner Res 2020 02 14;35(2):326-332. Epub 2019 Nov 14.

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.

Bone marrow adiposity (BMA) is associated with aging and osteoporosis, but whether BMA can predict bone loss and fractures remains unknown. Using data from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study, we investigated the associations between H-MRS-based measures of vertebral bone marrow adipose tissue (BMAT), annualized change in bone density/strength by quantitative computed tomography (QCT) and DXA, and secondarily, with incident clinical fractures and radiographic vertebral fractures among older adults. The associations between BMAT and annualized change in bone density/strength were evaluated using linear regression models, adjusted for age, body mass index (BMI), diabetes, estradiol, and testosterone. Cox proportional hazards models were used to evaluate the associations between baseline BMAT and incident clinical fractures, and logistic regression models for incident vertebral fractures. At baseline, mean ± SD age was 80.9 ± 4.2 and 82.6 ± 4.2 years in women (n = 148) and men (n = 150), respectively. Mean baseline BMAT was 55.4% ± 8.1% in women and 54.1% ± 8.2% in men. Incident clinical fractures occurred in 7.4% of women over 2.8 years and in 6.0% of men over 2.2 years. Incident vertebral fractures occurred in 12% of women over 3.3 years and in 17% of men over 2.7 years. Each 1 SD increase in baseline BMAT was associated with a 3.9 mg /cm /year greater loss of spine compressive strength index (p value = .003), a 0.9 mg/cm /year greater loss of spine trabecular BMD (p value = .02), and a 1.2 mg/cm /year greater loss of femoral neck trabecular BMD (p value = .02) in women. Among men, there were no associations between BMAT and changes in bone density/strength. There were no associations between BMAT and incident fractures in women or men. In conclusion, we found greater BMAT is associated with greater loss of trabecular bone at the spine and femoral neck, and greater loss of spine compressive strength, in older women. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3895DOI Listing
February 2020

Association Between Unrecognized Myocardial Infarction and Cerebral Infarction on Magnetic Resonance Imaging.

JAMA Neurol 2019 Aug;76(8):956-961

Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland.

Importance: It is uncertain whether unrecognized myocardial infarction (MI) is a risk factor for cerebral infarction.

Objective: To determine whether unrecognized MI detected by cardiac magnetic resonance imaging (MRI) is associated with cerebral infarction.

Design, Setting, And Participants: This is a cross-sectional study of ICELAND MI, a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study conducted in Iceland. Enrollment occurred from January 2004 to January 2007 from a community-dwelling cohort of older Icelandic individuals. Participants aged 67 to 93 years who underwent both brain MRI and late gadolinium enhancement cardiac MRI were included. Data analysis was performed from September 2018 to March 2019.

Exposures: Unrecognized MI identified by cardiac MRI.

Main Outcomes And Measures: Unrecognized MI was defined as cardiac MRI evidence of MI without a history of clinically evident MI. Recognized MI was defined as cardiac MRI evidence of MI with a history of clinically evident MI. Cerebral infarctions on brain MRI were included regardless of associated symptoms. Multiple logistic regression was used to evaluate the association between MI status (no MI, unrecognized MI, or recognized MI) and cerebral infarction after adjustment for demographic factors and vascular risk factors. In addition, we evaluated the association between unrecognized MI and embolic infarcts of undetermined source.

Results: Five enrolled participants had nondiagnostic brain MRI studies and were excluded. Among 925 participants, 480 (51.9%) were women; the mean (SD) age was 75.9 (5.3) years. There were 221 participants (23.9%) with cardiac MRI evidence of MI, of whom 68 had recognized MI and 153 unrecognized MI. There were 308 participants (33.3%) with brain MRI evidence of cerebral infarction; 93 (10.0%) had embolic infarcts of undetermined source. After adjustment for demographic factors and vascular risk factors, the likelihood (odds ratio) of having cerebral infarction was 2.0 (95% CI, 1.2-3.4; P = .01) for recognized MI and 1.5 (95% CI, 1.02-2.2; P = .04) for unrecognized MI. After adjustment for demographics and vascular risk factors, unrecognized MI was also associated with embolic infarcts of undetermined source (odds ratio, 2.0 [95% CI, 1.1-3.5]; P = .02).

Conclusions And Relevance: In a population-based sample, we found an association between unrecognized MI and cerebral infarction. These findings suggest that unrecognized MI may be a novel risk factor for cardiac embolism and cerebral infarction.
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http://dx.doi.org/10.1001/jamaneurol.2019.1226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537766PMC
August 2019

Cigarette Smoking Is Associated With Lower Quadriceps Cross-sectional Area and Attenuation in Older Adults.

Nicotine Tob Res 2020 05;22(6):935-941

Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD.

Introduction: In addition to well-established links with cardiovascular and respiratory diseases, cigarette smoking may affect skeletal muscle; however, associations with quadriceps atrophy, density, and function are unknown. This study explored the associations of current and former smoking with quadriceps muscle area and attenuation as well as muscle force (assessed as knee extension peak torque) and rate of torque development-a measure of muscle power in older adults.

Methods: Data from 4469 older adults, aged 66-95 years at baseline in the Age, Gene/Environment Susceptibility-Reykjavik Study with measurements of thigh computed tomography, isometric knee extension testing, self-reported smoking history, and potential covariates were analyzed.

Results: Sex differences were observed in these data; therefore, our final analyses are stratified by sex. In men, both former smokers and current smokers had lower muscle area (with β= -0.10, 95% confidence interval [CI] = -0.17 to -0.03 and β = -0.19, 95% CI = -0.33 to -0.05, respectively) and lower muscle attenuation (ie, higher fat infiltration, β = -0.08, 95% CI = -0.16 to -0.01 and β = -0.17, 95% CI = -0.34 to -0.01, respectively) when compared with never smokers. Smoking status was not associated with male peak torque or rate of torque development. In women, current smoking was associated with lower muscle attenuation (β = -0.24, 95% CI = -0.34 to -0.13) compared to never smoking. Among female smokers (current and former), muscle attenuation and peak torque were lower with increasing pack-years.

Conclusions: Results suggest that cigarette smoking is related to multiple muscle properties at older age and that these relationships may be different among men and women.

Implications: This article presents novel data, as it examined for the first time the relationship between smoking and computed tomography-derived quadriceps muscle size (cross-sectional area) and attenuation. This study suggests that current cigarette smoking is related to higher muscle fat infiltration, which may have significant health implications for the older population, because of its known association with poor physical function, falls, and hip fractures.
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http://dx.doi.org/10.1093/ntr/ntz081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249920PMC
May 2020

Structural covariability hubs in old age.

Neuroimage 2019 04 19;189:307-315. Epub 2019 Jan 19.

Department of Neuroscience, Karolinska Institutet, S-17177, Stockholm, Sweden.

Studies have shown that inter-individual differences in grey matter, as measured by voxel-based morphometry, are coordinated between voxels. This has been done by studying covariance maps based on a limited number of seed regions. Here, we used GPU-based (Graphics Processing Unit) accelerated computing to calculate, for the first time, the aggregated map of the total structural topographical organisation in the brain on voxel level in a large sample of 960 healthy individuals in the age range 68-83 years. This map describes for each voxel the number of significant correlations with all other grey matter voxels in the brain. Voxels that correlate significantly with many other voxels are called hubs. A majority of these hubs were found in the basal ganglia, the thalamus, the brainstem, and the cerebellum; subcortical regions that have been preserved through vertebrate evolution, interact with large portions of the neocortex and play fundamental roles for the control of a wide range of behaviours. No significant difference in the level of covariability could be found with increasing age or between men and women in these hubs.
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http://dx.doi.org/10.1016/j.neuroimage.2019.01.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438381PMC
April 2019

Association of Unrecognized Myocardial Infarction With Long-term Outcomes in Community-Dwelling Older Adults: The ICELAND MI Study.

JAMA Cardiol 2018 11;3(11):1101-1106

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.

Importance: Cardiac magnetic resonance (CMR) imaging can identify unrecognized myocardial infarction (UMI) in the general population. Unrecognized myocardial infarction by CMR portends poor prognosis in the short term but, to our knowledge, long-term outcomes are not known.

Objective: To determine the long-term outcomes of UMI by CMR compared with clinically recognized myocardial infarction (RMI) and no myocardial infarction (MI).

Design, Setting, And Participants: Participants of the population-based, prospectively enrolled ICELAND MI cohort study (aged 67-93 years) were characterized with CMR at baseline (from January 2004-January 2007) and followed up for up to 13.3 years. Kaplan-Meier time-to-event analyses and a Cox regression were used to assess the association of UMI at baseline with death and future cardiovascular events.

Main Outcomes And Measures: The primary outcome was all-cause mortality. Secondary outcomes were a composite of major adverse cardiac events (MACE: death, nonfatal MI, and heart failure).

Results: Of 935 participants, 452 (48.3%) were men; the mean (SD) age of participants with no MI, UMI, and RMI was 75.6 (5.3) years, 76.8 (5.2) years, and 76.8 (4.7) years, respectively. At 3 years, UMI and no MI mortality rates were similar (3%) and lower than RMI rates (9%). At 5 years, UMI mortality rates (13%) increased and were higher than no MI rates (8%) but still lower than RMI rates (19%). By 10 years, UMI and RMI mortality rates (49% and 51%, respectively) were not statistically different; both were significantly higher than no MI (30%) (P < .001). After adjusting for age, sex, and diabetes, UMI by CMR had an increased risk of death (hazard ratio [HR], 1.61; 95% CI, 1.27-2.04), MACE (HR, 1.56; 95% CI, 1.26-1.93), MI (HR, 2.09; 95% CI, 1.45-3.03), and heart failure (HR, 1.52; 95% CI, 1.09-2.14) compared with no MI and statistically nondifferent risk of death (HR, 0.99; 95% CI, 0.71-1.38) and MACE (HR, 1.23; 95% CI, 0.91-1.66) vs RMI.

Conclusions And Relevance: In this study, all-cause mortality of UMI was higher than no MI, but within 10 years from baseline evaluation was equivalent with RMI. Unrecognized MI was also associated with an elevated risk of nonfatal MI and heart failure. Whether secondary prevention can alter the prognosis of UMI will require prospective testing.
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http://dx.doi.org/10.1001/jamacardio.2018.3285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353564PMC
November 2018

Chronic Kidney Disease Is Associated With Greater Bone Marrow Adiposity.

J Bone Miner Res 2018 12 27;33(12):2158-2164. Epub 2018 Aug 27.

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.

Bone marrow adiposity is associated with aging, osteoporosis, and reduced hematopoiesis, as well as anorexia nervosa, but little is known about the underlying mechanisms that affect marrow adiposity. Chronic kidney disease (CKD) may influence bone marrow adipose tissue (BMAT), possibly through loss of lean mass or higher circulating levels of sclerostin. To test these hypotheses, we investigated the cross-sectional association between estimated glomerular filtration rate (eGFR) as a measure of kidney function and H-MRS-based measurement of vertebral BMAT (L1 to L4) in 475 older adults from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. Mean BMAT was compared in those with eGFR >60 (n = 297) versus those with eGFR 45 to 60 (n = 120) or eGFR <45 (n = 58) using linear regression models. Participants had a mean age of 81.5 (SD 4.1) years, mean eGFR of 64.3 (SD 16.1) mL/min/1.734 cm , mean BMAT of 54.5% (SD 8.5); 48.2% were women. In unadjusted and adjusted models (age, visit window, gender, diabetes and visceral adipose tissue), BMAT was higher in those with eGFR <45 (adjusted mean 58.5%; 95% CI, 56.2 to 60.7) compared with those with eGFR >60 (adjusted mean 53.8%; 95% CI, 52.8 to 54.8) (p = 0.0002). BMAT did not differ in those with eGFR 45 to 60 (adjusted mean 54.3%; 95% CI, 52.8 to 55.9) compared with those with eGFR >60 (p = 0.58). In a subgroup of participants with serum sclerostin available (n = 253), additional adjustment for sclerostin attenuated the difference in adjusted mean vertebral BMAT between those with eGFR <45 versus >60 from 3.7% (p = 0.04) to 2.4% (p = 0.20). CKD stage 3b or worse was associated with greater bone marrow adiposity; this association may be partially mediated by sclerostin. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702945PMC
December 2018

Co-regulatory networks of human serum proteins link genetics to disease.

Science 2018 08 2;361(6404):769-773. Epub 2018 Aug 2.

Icelandic Heart Association, Holtasmari 1, IS-201 Kopavogur, Iceland.

Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.
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http://dx.doi.org/10.1126/science.aaq1327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190714PMC
August 2018

Exome Chip Analysis Identifies Low-Frequency and Rare Variants in MRPL38 for White Matter Hyperintensities on Brain Magnetic Resonance Imaging.

Stroke 2018 08;49(8):1812-1819

Department of Biochemistry (D.W.B., N.D.P.), Wake Forest School of Medicine, Winston-Salem, NC.

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P=4.5×10) partially independent of known common signal ( P=1.4×10). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P=1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P=2.8×10). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.
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http://dx.doi.org/10.1161/STROKEAHA.118.020689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202149PMC
August 2018
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