Plasma EFEMP1 Is Associated with Brain Aging and Dementia: The Framingham Heart Study

Background: Epidermal growth factor containing fibulin extracellular matrix protein-1 (EFEMP1) has been associated with increased white matter hyperintensities (WMH) burden and disorders of premature aging and may have a shared pathophysiological role in the development of WMH and dementia. Objective: To determine the association between plasma EFEMP1 levels and MRI markers of vascular brain injury and incident all-cause and Alzheimer’s disease (AD) dementia. Methods: We measured plasma EFEMP1 levels in 1597 [53% women, mean age 68.7 (SD 5.7) years] dementia-free Framingham Offspring cohort participants between 1998–2001 and subsequently followed them for incident dementia. Secondary outcomes included stroke, structural MRI brain measures and neurocognitive test performance. Results: During a median 11.8 [Q1, Q3 : 7.1, 13.3] year follow-up, 131 participants developed dementia. The highest quintile of plasma EFEMP1, compared to the bottom four quintiles, was associated with an increased risk of time to incident all-cause dementia (HR 1.77, 95% CI 1.18–2.64) and AD dementia (HR 1.76, 95% CI 1.11–2.81) but not with markers of vascular brain injury (WMH, covert brain infarcts or stroke). Higher circulating EFEMP1 concentrations were also cross-sectionally associated with lower total brain (β±SE, –0.28±0.11, p = 0.01) and hippocampal volumes (–0.006±0.003, p = 0.04) and impaired abstract reasoning (Similarities test, –0.18±0.08, p = 0.018 per standard deviation increment in EFEMP1). Conclusion: Elevated circulating EFEMP1 is associated with an increased risk of all-cause and AD dementia, smaller hippocampal and total brain volumes, and poorer cognitive performance. EFEMP1 may play an important biological role in the development of AD dementia. Further studies to validate these findings are warranted.

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Abstract 36: Association of Parental Stroke with Cognitive and Brain MRI Measures in Offspring - The Framingham Heart Study

Stroke ◽

10.1161/str.43.suppl_1.a36 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

GALIT WEINSTEIN ◽

Alexa Beiser ◽

Rhoda Au ◽

Charles DeCarli ◽

Philip A Wolf ◽

...

Keyword(s):

Executive Function ◽

Brain Injury ◽

Verbal Learning ◽

Brain Mri ◽

Abstract Reasoning ◽

Parental History ◽

Brain Volumes ◽

Regional Brain ◽

Increased Risk ◽

History Of

Objectives- Parental stroke is related to an increased risk of stroke among the offspring. Vascular related brain changes, however, often occur before clinical stroke and the association of parental history of stroke and structural brain measures and cognition has not been fully explored. We hypothesized that prospectively verified parental stroke will be associated with increased vascular brain injury and poorer cognitive performance. Methods- A total of 1,297 Framingham offspring (mean age: 61 ± 9 years, 54% women) were studied. Of these, 9.9% had prospectively identified stroke in one or both parents before age 65. Volumetric brain MRI measures of total cerebral brain volume (TCBV), regional brain volumes, white matter hyperintensity volume (WMHV), and covert brain infarcts (CBI) and performance on tests of verbal memory, abstract reasoning, verbal learning and visuospatial memory (VRd) were compared for offspring with and without parental history of stroke. All measures were assessed cross-sectionally and longitudinally (mean duration of follow-up was 6.1±1.2 years). We used models adjusted only for age, sex, education and also additionally adjusted for vascular risk factors and for WMHV as an index of subclinical vascular brain injury. GEE models were used to adjust for sibling relationships among offspring. Results- Higher WMHV (β±SE=0.17±0.08;p=0.027) and lower VRd scores (β±SE=-0.80±0.34; p=0.017) at baseline were found in offspring with parental history of stroke. In addition, participants with parental stroke by age 65 years were more likely to be in the highest quintile of increase in WMHV (OR=1.87;p=0.04) as well as worsening executive function (Trails B-A) (OR:1.81;p=0.03). Parental stroke was not associated with total and regional brain volumes or with memory, abstract reasoning and verbal learning. Conclusions- In our community-based sample of middle-aged asymptomatic subjects, the occurrence of parental stroke by age 65 years is associated with higher baseline WMHV and with a more rapid increase in WMHV. Further, parental stroke is also associated with poorer performance on VRd and a decline in executive function. The effects on baseline WMH and VRd were substantial equivalent to 2.8 and 7 years of brain aging, respectively.

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Increased Brain Age Gap Estimate (BrainAGE) in Young Adults After Premature Birth

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.653365 ◽

2021 ◽

Vol 13 ◽

Author(s):

Dennis M. Hedderich ◽

Aurore Menegaux ◽

Benita Schmitz-Koep ◽

Rachel Nuttall ◽

Juliana Zimmermann ◽

...

Keyword(s):

Premature Birth ◽

Brain Aging ◽

Structural Mri ◽

Full Term ◽

Intracranial Volume ◽

Age Gap ◽

Increased Risk ◽

Aging Rates ◽

Brain Age ◽

Premature Born

Recent evidence suggests increased metabolic and physiologic aging rates in premature-born adults. While the lasting consequences of premature birth on human brain development are known, its impact on brain aging remains unclear. We addressed the question of whether premature birth impacts brain age gap estimates (BrainAGE) using an accurate and robust machine-learning framework based on structural MRI in a large cohort of young premature-born adults (n = 101) and full-term (FT) controls (n = 111). Study participants are part of a geographically defined population study of premature-born individuals, which have been followed longitudinally from birth until young adulthood. We investigated the association between BrainAGE scores and perinatal variables as well as with outcomes of physical (total intracranial volume, TIV) and cognitive development (full-scale IQ, FS-IQ). We found increased BrainAGE in premature-born adults [median (interquartile range) = 1.4 (−1.3–4.7 years)] compared to full-term controls (p = 0.002, Cohen’s d = 0.443), which was associated with low Gestational age (GA), low birth weight (BW), and increased neonatal treatment intensity but not with TIV or FS-IQ. In conclusion, results demonstrate elevated BrainAGE in premature-born adults, suggesting an increased risk for accelerated brain aging in human prematurity.

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Association of Social Engagement with Brain Volumes Assessed by Structural MRI

Journal of Aging Research ◽

10.1155/2012/512714 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Bryan D. James ◽

Thomas A. Glass ◽

Brian Caffo ◽

Jennifer F. Bobb ◽

Christos Davatzikos ◽

...

Keyword(s):

Social Engagement ◽

Structural Mri ◽

Population Based ◽

Magnetic Resonance Images ◽

Intracranial Volume ◽

Linear Regression Models ◽

Brain Volumes ◽

Total Brain ◽

Summary Scale ◽

Control Versus

We tested the hypothesis that social engagement is associated with larger brain volumes in a cohort study of 348 older male former lead manufacturing workers () and population-based controls (), age 48 to 82. Social engagement was measured using a summary scale derived from confirmatory factor analysis. The volumes of 20 regions of interest (ROIs), including total brain, total gray matter (GM), total white matter (WM), each of the four lobar GM and WM, and 9 smaller structures were derived from T1-weighted structural magnetic resonance images. Linear regression models adjusted for age, education, race/ethnicity, intracranial volume, hypertension, diabetes, and control (versus lead worker) status. Higher social engagement was associated with larger total brain and GM volumes, specifically temporal and occipital GM, but was not associated with WM volumes except for corpus callosum. A voxel-wise analysis supported an association in temporal lobe GM. Using longitudinal data to discern temporal relations, change in ROI volumes over five years showed null associations with current social engagement. Findings are consistent with the hypothesis that social engagement preserves brain tissue, and not consistent with the alternate hypothesis that persons with smaller or shrinking volumes become less socially engaged, though this scenario cannot be ruled out.

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Meta-analysis of Magnetic Resonance Imaging Studies in Velocardiofacial Syndrome (VCFS)

European Psychiatry ◽

10.1016/s0924-9338(09)70936-8 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

G. Tan ◽

D. Arnone ◽

A.M. McIntosh ◽

K.P. Ebmeier

Keyword(s):

Meta Analysis ◽

Genetic Disorder ◽

Velocardiofacial Syndrome ◽

Original Data ◽

Brain Regions ◽

Significant Heterogeneity ◽

Total Brain Volume ◽

Brain Volumes ◽

Total Brain ◽

Increased Risk

Introduction:Velocardiofacial syndrome (VCFS) is a common genetic disorder due to a micro deletion on chromosome 22q11. This region includes several risk-associated genetic variants, including COMT, and VCFS is associated with a substantially increased risk for schizophrenia. As such, VCFS may serve as a valuable model for clarifying the neuroanatomical changes associated with genetic risk for psychosis.Methods:A systematic literature search was conducted. Studies were included if they presented original data and were published by March 2008, compared subjects with VCFS and healthy controls and reported measures of brain regions according to SI units as mean and standard deviation. Data extracted from the studies included diagnosis, demographic variables and IQ. Statistical analysis was conducted using STATA 8.0 supplemented by ‘Metan’ software.Results:Twenty studies were retrieved. All measures were expressed in volumes apart from the corpus callosum (area). Subjects with VCFS showed reduced total brain volume (N=156 versus N=138), ([ES]=1.04, 95% CI:1.40, -0.67), with no significant heterogeneity or publication bias. This reduction was reflected in total hemisphere grey and white matter. Prefrontal, parieto-occipital and temporal cortices appeared to be particularly affected. A number of sub-cortical areas also showed decreased volumes including the hippocampus and putamen. In contrast, callosal areas were increased in VCFS.Conclusion:In relation to controls, subjects with VCFS present with an overall reduction in brain volumes and specific abnormalities in multiple cortical and subcortical brain regions. These abnormalities may explain partly why VCFS is associated with a greatly increased risk of psychosis and other psychiatric disorders.

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Lack of association between proton pump inhibitor use and brain aging: a cross-sectional study

European Journal of Clinical Pharmacology ◽

10.1007/s00228-020-03068-8 ◽

2021 ◽

Author(s):

Nayeon Ahn ◽

Stefan Frenzel ◽

Katharina Wittfeld ◽

Robin Bülow ◽

Henry Völzke ◽

...

Keyword(s):

Cognitive Function ◽

Proton Pump ◽

Brain Aging ◽

Verbal Learning ◽

Brain Magnetic Resonance Imaging ◽

Primary Analysis ◽

Cross Sectional ◽

Brain Volumes ◽

Increased Risk ◽

Brain Age

Abstract Purpose Due to conflicting scientific evidence for an increased risk of dementia by intake of proton pump inhibitors (PPIs), this study investigates associations between PPI use and brain volumes, estimated brain age, and cognitive function in the general population. Methods Two surveys of the population-based Study of Health in Pomerania (SHIP) conducted in Northeast Germany were used. In total, 2653 participants underwent brain magnetic resonance imaging (MRI) and were included in the primary analysis. They were divided into two groups according to their PPI intake and compared with regard to their brain volumes (gray matter, white matter, total brain, and hippocampus) and estimated brain age. Multiple regression was used to adjust for confounding factors. Cognitive function was evaluated by the Verbal Learning and Memory Test (VLMT) and the Nuremberg Age Inventory (NAI) and put in relation to PPI use. Results No association was found between PPI use and brain volumes or the estimated brain age. The VLMT score was 1.11 lower (95% confidence interval: − 2.06 to − 0.16) in immediate recall, and 0.72 lower (95% CI: − 1.22 to − 0.22) in delayed recall in PPI users than in non-users. PPI use was unrelated to the NAI score. Conclusions The present study does not support a relationship between PPI use and brain aging.

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451 - Estimating “Brain Age Gaps” in patients with brain injury: Applying machine learning to advanced neuroimaging techniques

International Psychogeriatrics ◽

10.1017/s1041610220003038 ◽

2020 ◽

Vol 32 (S1) ◽

pp. 171-171

Keyword(s):

Machine Learning ◽

Older Adults ◽

Brain Injury ◽

Brain Aging ◽

High Rate ◽

Intracranial Volume ◽

Increased Risk ◽

Age Range ◽

Brain Age ◽

The Brain

Introduction:A single moderate or severe TBI is associated with accelerated brain aging and increased risk for dementia. Despite the high rate of falls that result in brain injury in older adults, numerous factors such as genetic predisposition to Alzheimer’s disease, sex, education, age are also known to affect multiple age-sensitive neuroimaging markers.METHODS:Here we use the “brain age” metric being tested by the global consortium, Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA), that employs machine learning to predict a person’s age from multiple age-sensitive imaging markers (e.g., hippocampal volume, regional cortical gray matter thickness, intracranial volume (ICV)), while also taking into account their sex and educational level. We will discuss results from brain injured patients ( n = 60; age range: 20-75 years) and healthy age-matched controls (n = 20 (20-75 years). We will compute the “brain age gap” – between a person’s actual chronological age and that predicted from their brain scan – and test relations between this measure and injury characteristics.RESULTS:In our pilot work, we predicted a person’s age from their MRI scan with a mean absolute error of about 5 years. ENIGMA’s current best model includes: (1) non-normalized brain volumetric measures as predictors including ICV, (2) separate models for males and females, (3) use of a large age range (12-80), and (4) Gaussian process regression (GPR).CONCLUSION:This “overall” marker of accelerated brain aging offers a metric that taps diverse sources of information, weighted by their relevance to brain aging, and is associated with decreased functionality in older adults.

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Structural MRI markers of brain aging early after ischemic stroke

Neurology ◽

10.1212/wnl.0000000000004086 ◽

2017 ◽

Vol 89 (2) ◽

pp. 116-124 ◽

Cited By ~ 21

Author(s):

Emilio Werden ◽

Toby Cumming ◽

Qi Li ◽

Laura Bird ◽

Michele Veldsman ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Brain Aging ◽

Infarct Volume ◽

Hippocampal Volume ◽

Vascular Risk Factors ◽

Vascular Risk ◽

Total Brain Volume ◽

Brain Volumes ◽

Total Brain

Objective:To examine associations between ischemic stroke, vascular risk factors, and MRI markers of brain aging.Methods:Eighty-one patients (mean age 67.5 ± 13.1 years, 31 left-sided, 61 men) with confirmed first-ever (n = 66) or recurrent (n = 15) ischemic stroke underwent 3T MRI scanning within 6 weeks of symptom onset (mean 26 ± 9 days). Age-matched controls (n = 40) completed identical testing. Multivariate regression analyses examined associations between group membership and MRI markers of brain aging (cortical thickness, total brain volume, white matter hyperintensity [WMH] volume, hippocampal volume), normalized against intracranial volume, and the effects of vascular risk factors on these relationships.Results:First-ever stroke was associated with smaller hippocampal volume (p = 0.025) and greater WMH volume (p = 0.004) relative to controls. Recurrent stroke was in turn associated with smaller hippocampal volume relative to both first-ever stroke (p = 0.017) and controls (p = 0.001). These associations remained significant after adjustment for age, sex, education, and, in stroke patients, infarct volume. Total brain volume was not significantly smaller in first-ever stroke patients than in controls (p = 0.056), but the association became significant after further adjustment for atrial fibrillation (p = 0.036). Cortical thickness and brain volumes did not differ as a function of stroke type, infarct volume, or etiology.Conclusions:Brain structure is likely to be compromised before ischemic stroke by vascular risk factors. Smaller hippocampal and total brain volumes and increased WMH load represent proxies for underlying vascular brain injury.

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Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00411.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. L951-L957 ◽

Cited By ~ 24

Author(s):

Curtis Kuo ◽

Sam Lim ◽

Nicholas J. C. King ◽

Sebastian L. Johnston ◽

Janette K. Burgess ◽

...

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

Smooth Muscle ◽

Airway Smooth Muscle ◽

Matrix Protein ◽

Viral Infections ◽

Airway Remodeling ◽

Extracellular Matrix Protein ◽

Airway Smooth Muscle Cells ◽

Increased Risk

Airway remodeling, which includes increases in the extracellular matrix (ECM), is a characteristic feature of asthma and is correlated to disease severity. Rhinovirus (RV) infections are associated with increased risk of asthma development in young children and are the most common cause of asthma exacerbations. We examined whether viral infections can increase ECM deposition and whether this increased ECM modulates cell proliferation and migration. RV infection of nonasthmatic airway smooth muscle (ASM) cells significantly increased the deposition of fibronectin (40% increase, n = 12) and perlecan (80% increase, n = 14), while infection of asthmatic ASM cells significantly increased fibronectin (75% increase, n = 9) and collagen IV (15% increase, n = 9). We then treated the ASM cells with the Toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid, imiquimod, and pure RV RNA and were able to show that the mechanism through which RV induced ECM deposition was via the activation of TLR3 and TLR7/8. Finally, we assessed whether the virus-induced ECM was bioactive by measuring the amount of migration and proliferation of virus-naive cells that seeded onto the ECM. Basically, ECM from asthmatic ASM cells induced twofold greater migration of virus-naive ASM cells than ECM from nonasthmatic ASM cells, and these rates of migration were further increased on RV-modulated ECM. Increased migration on the RV-modulated ECM was not due to increased cell proliferation, as RV-modulated ECM decreased the proliferation of virus-naive cells. Our results suggest that viruses may contribute to airway remodeling through increased ECM deposition, which in turn may contribute to increased ASM mass via increased cell migration.

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1280: Increased Susceptibility to Genitovaginal Prolapse Associated with a Polymorphism in the Promoter of the Extracellular Matrix Protein LAMC1

The Journal of Urology ◽

10.1016/s0022-5347(18)31494-0 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 421-422

Author(s):

Ganka Nikolova ◽

Christian O. Twiss ◽

Hane Lee ◽

Nelson Stanley ◽

Janet Sinsheimer ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Increased Susceptibility

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Posttraumatic Stress Disorder Exacerbates Emotional Complaints but not Cognitive Impairments in Individuals Suffering from Postconcussional Disorder after Mild Traumatic Brain Injury

Zeitschrift für Neuropsychologie ◽

10.1024/1016-264x/a000132 ◽

2015 ◽

Vol 26 (1) ◽

pp. 35-50 ◽

Cited By ~ 1

Author(s):

Sara C. Schroeder ◽

Ronald M. Ruff ◽

Lutz Jäncke

Keyword(s):

Traumatic Brain Injury ◽

Posttraumatic Stress Disorder ◽

Brain Injury ◽

Posttraumatic Stress ◽

Mild Traumatic Brain Injury ◽

Test Performance ◽

Stress Disorder ◽

Negative Impact ◽

Neuropsychological Test ◽

Composite Scale

The aim of this study was to examine the effect of posttraumatic stress disorder (PTSD) on (a) neuropsychological test performance and (b) self-reported emotional complaints within individuals suffering from postconcussional disorder (PCD) after a mild traumatic brain injury (MTBI). A two-group comparative research design was employed. Two MTBI samples with and without PTSD were assessed with a neuropsychological test battery and the Ruff Neurobehavioral Inventory (RNBI). On the neurocognitive test performances no significant between group differences were found, but the MTBI group with PTSD endorsed a significantly greater number of emotional complaints, especially in the RNBI subscales of anxiety and depression. The patients with PTSD also endorsed a significantly greater number of premorbid sequelae in the RNBI emotional composite scale as well as the RNBI premorbid subscales of pain, anxiety and abuse. In sum, PTSD has a negative impact on emotional but not cognitive functioning within individuals suffering from PCD after a mild TBI.

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