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The AGES-Reykjavik Study suggests that change in kidney measures is associated with subclinical brain pathology in older community-dwelling persons.

https://arctichealth.org/en/permalink/ahliterature292670
Source
Kidney Int. 2018 Jun 27; :
Publication Type
Journal Article
Date
Jun-27-2018
Author
Sanaz Sedaghat
Jie Ding
Gudny Eiriksdottir
Mark A van Buchem
Sigurdur Sigurdsson
M Arfan Ikram
Osorio Meirelles
Vilmundur Gudnason
Andrew S Levey
Lenore J Launer
Author Affiliation
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Source
Kidney Int. 2018 Jun 27; :
Date
Jun-27-2018
Language
English
Publication Type
Journal Article
Abstract
Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min per 1.73m2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology.
PubMed ID
29960746 View in PubMed
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The AGES-Reykjavik Study suggests that change in kidney measures is associated with subclinical brain pathology in older community-dwelling persons.

https://arctichealth.org/en/permalink/ahliterature300494
Source
Kidney Int. 2018 09; 94(3):608-615
Publication Type
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Date
09-2018
Author
Sanaz Sedaghat
Jie Ding
Gudny Eiriksdottir
Mark A van Buchem
Sigurdur Sigurdsson
M Arfan Ikram
Osorio Meirelles
Vilmundur Gudnason
Andrew S Levey
Lenore J Launer
Author Affiliation
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Source
Kidney Int. 2018 09; 94(3):608-615
Date
09-2018
Language
English
Publication Type
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Keywords
Aged
Albuminuria - physiopathology - urine
Cerebral Small Vessel Diseases - diagnosis - epidemiology
Creatinine - urine
Disease Progression
Female
Follow-Up Studies
Glomerular Filtration Rate - physiology
Humans
Incidence
Independent living
Kidney - physiopathology
Magnetic Resonance Imaging
Male
Prospective Studies
Renal Insufficiency, Chronic - physiopathology - urine
Risk factors
Serum Albumin
White Matter - diagnostic imaging - pathology
Abstract
Decreased glomerular filtration rate (GFR) and albuminuria may be accompanied by brain pathology. Here we investigated whether changes in these kidney measures are linked to development of new MRI-detected infarcts and microbleeds, and progression of white matter hyperintensity volume. The study included 2671 participants from the population-based AGES-Reykjavik Study (mean age 75, 58.7% women). GFR was estimated from serum creatinine, and albuminuria was assessed by urinary albumin-to-creatinine ratio. Brain MRI was acquired at baseline (2002-2006) and 5 years later (2007-2011). New MRI-detected infarcts and microbleeds were counted on the follow-up scans. White matter hyperintensity progression was estimated as percent change in white matter hyperintensity volumes between the two exams. Participants with a large eGFR decline (over 3 ml/min/1.73m2 per year) had more incident subcortical infarcts (odds ratio 1.53; 95% confidence interval 1.05, 2.22), and more marked progression of white matter hyperintensity volume (difference: 8%; 95% confidence interval: 4%, 12%), compared to participants without a large decline. Participants with incident albuminuria (over 30 mg/g) had 21% more white matter hyperintensity volume progression (95% confidence interval: 14%, 29%) and 1.86 higher odds of developing new deep microbleeds (95% confidence interval 1.16, 2.98), compared to participants without incident albuminuria. The findings were independent of cardiovascular risk factors. Changes in kidney measures were not associated with occurrence of cortical infarcts. Thus, larger changes in eGFR and albuminuria are associated with increased risk for developing manifestations of cerebral small vessel disease. Individuals with larger changes in these kidney measures should be considered as a high risk population for accelerated brain pathology.
PubMed ID
29960746 View in PubMed
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Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer's disease: Pooled analysis from 5 cohorts.

https://arctichealth.org/en/permalink/ahliterature298160
Source
PLoS One. 2019; 14(2):e0212293
Publication Type
Journal Article
Date
2019
Author
Galit Weinstein
Kendra L Davis-Plourde
Sarah Conner
Jayandra J Himali
Alexa S Beiser
Anne Lee
Andreea M Rawlings
Sanaz Sedaghat
Jie Ding
Erin Moshier
Cornelia M van Duijn
Michal S Beeri
Elizabeth Selvin
M Arfan Ikram
Lenore J Launer
Mary N Haan
Sudha Seshadri
Author Affiliation
School of Public Health, University of Haifa, Haifa, Israel.
Source
PLoS One. 2019; 14(2):e0212293
Date
2019
Language
English
Publication Type
Journal Article
Abstract
To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties.
Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis.
After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (ß = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity.
Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.
PubMed ID
30768625 View in PubMed
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Carotid Arterial Stiffness and Risk of Incident Cerebral Microbleeds in Older People: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study.

https://arctichealth.org/en/permalink/ahliterature264207
Source
Arterioscler Thromb Vasc Biol. 2015 Jun 25;
Publication Type
Article
Date
Jun-25-2015
Author
Jie Ding
Gary F Mitchell
Michiel L Bots
Sigurdur Sigurdsson
Tamara B Harris
Melissa Garcia
Gudny Eiriksdottir
Mark A van Buchem
Vilmundur Gudnason
Lenore J Launer
Source
Arterioscler Thromb Vasc Biol. 2015 Jun 25;
Date
Jun-25-2015
Language
English
Publication Type
Article
Abstract
Age and high blood pressure are major risk factors for cerebral microbleeds (CMBs). However, the underlying mechanisms remain unclear and arterial stiffness may be important. We investigated whether carotid arterial stiffness is associated with incidence and location of CMBs.
In the prospective, population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik study, 2512 participants aged 66 to 93 years underwent a baseline brain MRI examination and carotid ultrasound in 2002 to 2006 and returned for a repeat brain MRI in 2007 to 2011. Common carotid arterial stiffness was assessed using a standardized protocol and expressed as carotid arterial strain, distensibility coefficient, and Young elastic modulus. Modified Poisson regression was applied to relate carotid arterial stiffness parameters to CMB incidence. During a mean follow-up of 5.2 years, 463 people (18.4%) developed new CMBs, of whom 292 had CMBs restricted to lobar regions and 171 had CMBs in a deep or infratentorial region. After adjusting for age, sex, and follow-up interval, arterial stiffness measures were associated with incident CMBs (risk ratio per SD decrease in carotid arterial strain, 1.11 [95% confidence interval, 1.01-1.21]; per SD decrease in natural log-transformed distensibility coefficient, 1.14 [1.05-1.24]; and per SD increase in natural log-transformed Young elastic modulus, 1.13 [1.04-1.23]). These measures were also significantly associated with incident deep CMBs (1.18 [1.02-1.37]; 1.24 [1.08-1.42]; and 1.23 [1.07-1.42]) but not with lobar CMBs. When further adjusted for blood pressure and other baseline vascular risk factors, carotid plaque, prevalent CMBs, subcortical infarcts, and white matter hyperintensities, the associations persisted.
Our findings support the hypothesis that localized increases in carotid arterial stiffness may contribute to the development of CMBs, especially in a deep location attributable to hypertension.
PubMed ID
26112009 View in PubMed
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Cerebral Small Vessel Disease and Association With Higher Incidence of Depressive Symptoms in a General Elderly Population: The AGES-Reykjavik Study.

https://arctichealth.org/en/permalink/ahliterature260900
Source
Am J Psychiatry. 2015 Mar 3;:appiajp201414050578
Publication Type
Article
Date
Mar-3-2015
Author
Thomas T van Sloten
Sigurdur Sigurdsson
Mark A van Buchem
Caroline L Phillips
Palmi V Jonsson
Jie Ding
Miranda T Schram
Tamara B Harris
Vilmundur Gudnason
Lenore J Launer
Source
Am J Psychiatry. 2015 Mar 3;:appiajp201414050578
Date
Mar-3-2015
Language
English
Publication Type
Article
Abstract
Objective: The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) leads to depressive symptoms by disruption of brain structures involved in mood regulation. However, longitudinal data on the association between CSVD and depressive symptoms are scarce. The authors investigated the association between CSVD and incident depressive symptoms. Method: Longitudinal data were taken from the Age, Gene/Environment Susceptibility-Reykjavik Study of 1,949 participants free of dementia and without baseline depressive symptoms (mean age: 74.6 years [SD=4.6]; women, 56.6%). MRI markers of CSVD, detected at baseline (2002-2006) and follow-up (2007-2011), included white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces, and total brain parenchyma volume. Incident depressive symptoms were defined by a score =6 on the 15-item Geriatric Depression Scale and/or use of antidepressant medication. Results: Depressive symptoms occurred in 10.1% of the participants. The association for a greater onset of depressive symptoms was significant for participants with 1 standard deviation increase in white matter hyperintensity volume over time, new subcortical infarcts, new Virchow-Robin spaces, 1 standard deviation lower total brain volume at baseline, and 1 standard deviation decreased total brain volume over time, after adjustments for cognitive function and sociodemographic and cardiovascular factors. Results were qualitatively similar when change in the Geriatric Depression Scale score over time was used as the outcome instead of incident depressive symptoms. Conclusions: Most markers of progression of CSVD over time and some markers of baseline CSVD are associated with concurrently developing new depressive symptoms. These findings support the vascular depression hypothesis.
PubMed ID
25734354 View in PubMed
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Differential associations between retinal signs and CMBs by location: The AGES-Reykjavik Study.

https://arctichealth.org/en/permalink/ahliterature287583
Source
Neurology. 2017 Dec 13;
Publication Type
Article
Date
Dec-13-2017
Author
Chengxuan Qiu
Jie Ding
Sigurdur Sigurdsson
Diana E Fisher
Qian Zhang
Gudny Eiriksdottir
Ronald Klein
Mark A van Buchem
Vilmundur Gudnason
Mary Frances Cotch
Lenore J Launer
Source
Neurology. 2017 Dec 13;
Date
Dec-13-2017
Language
English
Publication Type
Article
Abstract
To test the hypothesis that age-related macular degeneration (AMD) and retinal microvascular signs are differentially associated with lobar and deep cerebral microbleeds (CMBs).
CMBs in lobar regions indicate cerebral amyloid angiopathy (CAA). ß-Amyloid deposits are implicated in both CAA and AMD. Deep CMBs are associated with hypertension, a major risk factor for retinal microvascular damage. This population-based cohort study included 2,502 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who undertook binocular digital retinal photographs at baseline (2002-2006) to assess retinal microvascular signs and AMD and brain MRI scan at both baseline and follow-up (2007-2011) to assess CMBs. We assessed retinal microvascular lesion burden by counting the 3 retinal microvascular signs (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) concurrently present in the participant. We used multiple logistic models to examine the association of baseline retinal pathology to incident CMBs detected at follow-up.
During an average 5.2 years of follow-up, 461 people (18.3%) developed new CMBs, including 293 in exclusively lobar regions and 168 in deep regions. Pure geographic atrophy was significantly associated with strictly lobar CMBs (multivariable-adjusted odds ratio 2.59, 95% confidence interval [CI] 1.01-6.65) but not with deep CMBs. Concurrently having =2 retinal microvascular signs was associated with a 3-fold (95% CI 1.73-5.20) increased likelihood for deep CMBs but not exclusively lobar CMBs.
Retinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people. These results have implications for further research to define the role of small vessel disease in cognitive impairment.
PubMed ID
29237799 View in PubMed
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Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia: The Age, Gene/Environment Susceptibility-Reykjavik Study.

https://arctichealth.org/en/permalink/ahliterature284082
Source
JAMA Neurol. 2017 Jul 17;
Publication Type
Article
Date
Jul-17-2017
Author
Jie Ding
Sigurður Sigurðsson
Pálmi V Jónsson
Gudny Eiriksdottir
Andreas Charidimou
Oscar L Lopez
Mark A van Buchem
Vilmundur Guðnason
Lenore J Launer
Source
JAMA Neurol. 2017 Jul 17;
Date
Jul-17-2017
Language
English
Publication Type
Article
Abstract
With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown.
To examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia.
The prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017.
The presence, number, and location of L-PVSs.
Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines.
Of the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers.
Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.
PubMed ID
28715552 View in PubMed
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Risk Factors Associated With Incident Cerebral Microbleeds According to Location in Older People: The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study.

https://arctichealth.org/en/permalink/ahliterature261725
Source
JAMA Neurol. 2015 Apr 13;
Publication Type
Article
Date
Apr-13-2015
Author
Jie Ding
Sigurdur Sigurdsson
Melissa Garcia
Caroline L Phillips
Gudny Eiriksdottir
Vilmundur Gudnason
Mark A van Buchem
Lenore J Launer
Source
JAMA Neurol. 2015 Apr 13;
Date
Apr-13-2015
Language
English
Publication Type
Article
Abstract
The spatial distribution of cerebral microbleeds (CMBs), which are asymptomatic precursors of intracerebral hemorrhage, reflects specific underlying microvascular abnormalities of cerebral amyloid angiopathy (lobar structures) and hypertensive vasculopathy (deep brain structures). Relatively little is known about the occurrence of and modifiable risk factors for developing CMBs, especially in a lobar location, in the general population of older people.
To investigate whether lifestyle and lipid factors predict new CMBs in relation to their anatomic location.
We enrolled 2635 individuals aged 66 to 93 years from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study in a brain imaging study. Participants underwent a baseline magnetic resonance imaging (MRI) examination of the brain from September 1, 2002, through February 28, 2006, and returned for a second MRI examination from April 1, 2007, through September 30, 2011.
Lifestyle and lipid factors assessed at baseline included smoking, alcohol consumption, body mass index, and serum levels of total cholesterol, high- and low-density lipoprotein cholesterol, and triglycerides.
Incident CMBs detected on MRIs, which were further categorized as exclusively lobar or as deep.
During a mean follow-up of 5.2 years, 486 people (18.4%) developed new CMBs, of whom 308 had lobar CMBs only and 178 had deep CMBs. In the multivariate logarithm-binomial regression model adjusted for baseline cardiovascular risk factors, including blood pressure, antihypertensive use, prevalent CMBs, and markers of cerebral ischemic small-vessel disease, heavy alcohol consumption (vs light to moderate consumption; relative risk [RR], 2.94 [95% CI, 1.23-7.01]) was associated with incident CMBs in a deep location. Baseline underweight (vs normal weight; RR, 2.41 [95% CI, 1.21-4.80]), current smoking (RR, 1.47 [95% CI, 1.11-1.94]), an elevated serum level of high-density lipoprotein cholesterol (RR per 1-SD increase, 1.13 [95% CI, 1.02-1.25]), and a decreased triglyceride level (RR per 1-SD decrease in natural logarithm-transformed triglyceride level, 1.17 [95% CI, 1.03-1.33]) were significantly associated with an increased risk for lobar CMBs exclusively but not for deep CMBs.
Lifestyle and lipid risk profiles for CMBs were similar to those for symptomatic intracerebral hemorrhage and differed for lobar and deep CMBs. Modification of these risk factors could have the potential to prevent new-onset CMBs, particularly those occurring in a lobar location.
PubMed ID
25867544 View in PubMed
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Space and location of cerebral microbleeds, cognitive decline, and dementia in the community.

https://arctichealth.org/en/permalink/ahliterature282194
Source
Neurology. 2017 May 03;
Publication Type
Article
Date
May-03-2017
Author
Jie Ding
Sigurður Sigurðsson
Pálmi V Jónsson
Gudny Eiriksdottir
Osorio Meirelles
Olafur Kjartansson
Oscar L Lopez
Mark A van Buchem
Vilmundur Gudnason
Lenore J Launer
Source
Neurology. 2017 May 03;
Date
May-03-2017
Language
English
Publication Type
Article
Abstract
To assess the association of the number and anatomic location of cerebral microbleeds (CMBs), visible indicators of microvascular damage on MRI, with incident cognitive disease in the general population of older people.
In the longitudinal population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 2,602 participants 66 to 93 years of age and free of prevalent dementia underwent brain MRI and cognitive testing of verbal memory, processing speed, and executive function at baseline and a mean of 5.2 years later. Adjudicated incident dementia cases were diagnosed according to international guidelines.
In the multiple linear regression models adjusted for demographic, genetic, cardiovascular risk, and other cerebrovascular MRI markers, the presence of CMBs located in deep or mixed (deep and lobar) areas was associated with a greater decline in all 3 cognitive domains. Mixed CMBs were the strongest correlate for decline in memory and speed. Compared to those with no CMBs, participants with =3 CMBs had a steeper decline in a composite measure of global cognitive function, memory, and speed. Among those with =3 deep or mixed CMBs, associations were strongest for memory; the association with speed was strongest in those having =3 strictly lobar CMBs. People with =3 CMBs, regardless of their locations, had a higher incidence of all-cause dementia and vascular dementia.
Mixed or a higher load of CMBs, with some specificity for location, is associated with accelerated cognitive decline in older people. These findings suggest a role for hypertensive vasculopathy and the combined effect of hypertensive and cerebral amyloid angiopathy in the pathogenesis of cognitive deterioration.
PubMed ID
28468844 View in PubMed
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9 records – page 1 of 1.