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ABSTRACT: OBJECTIVES: To evaluate the relationship between patent foramen ovale (PFO), ischemic stroke and subclinical cerebrovascular disease in the general population. BACKGROUND: PFO is more frequently found in stroke patients than in stroke-free controls. However, the PFO-related stroke risk in the general population is not well established, and the relationship between PFO and silent brain infarcts (SBI) is not known. METHODS: PFO presence was assessed by transthoracic echocardiography with saline contrast injection in 1,100 stroke-free individuals over age 39 of a community-based sample followed for a mean of 11 years. In addition, 360 participants underwent brain magnetic resonance imaging (MRI) for SBI detection. We evaluated the risk of stroke associated with PFO after adjusting for established stroke risk factors, and examined the odds of having SBI among those with and without PFO. RESULTS: A PFO was present in 164 participants (14.9%). Over a mean follow up of 11.0 ± 4.5 years, 111 ischemic strokes occurred (10.1%), 15 (9.2%) in the PFO + and 96 (10.3%) in the PFO - groups. The 12.5 year cumulative risk of stroke was 10.1% (standard error 2.5%) in the PFO+ and 10.4% (standard error 1.1%) in the PFO- group (p=0.46). The adjusted hazard ratio for PFO and stroke was 1.10 (95% confidence interval 0.64-1.91). In the MRI subcohort, PFO was not associated with SBI (adjusted odds ratio 1.15, 95% CI 0.50-2.62). CONCLUSIONS: - In this community-based cohort, PFO was not associated with an increased risk of clinical stroke or subclinical cerebrovascular disease.
Journal of the American College of Cardiology 05/2013; · 14.16 Impact Factor
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Natalie L Marchant,
Bruce R Reed,
Nerses Sanossian,
Cindee M Madison,
Stephen Kriger,
Roxana Dhada,
Wendy J Mack, Charles Decarli,
Michael W Weiner,
Dan M Mungas,
Helena C Chui,
William J Jagust
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ABSTRACT: IMPORTANCE β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI's influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD). OBJECTIVE To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition. DESIGN AND SETTING A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors. PARTICIPANTS Clinically normal (mean age, 77.1 years [N = 30]), cognitively impaired (mean age, 78.0 years [N = 24]), and mildly demented (mean age, 79.8 years [N = 7]) participants. INTERVENTIONS Magnetic resonance imaging, Aβ (Pittsburgh Compound B-positron emission tomographic [PiB-PET]) imaging, and cognitive testing. MAIN OUTCOME MEASURES Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory. RESULTS Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P < .05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI. CONCLUSIONS AND RELEVANCE In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
JAMA neurology. 04/2013;
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Cesare Russo,
Zhezhen Jin,
Rui Liu,
Shinichi Iwata,
Aylin Tugcu,
Mitsuhiro Yoshita,
Shunichi Homma,
Mitchell S V Elkind,
Tatjana Rundek, Charles Decarli,
Clinton B Wright,
Ralph L Sacco,
Marco R Di Tullio
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ABSTRACT: The purpose of this study was to assess the relationship of left atrial (LA) phasic volumes and LA reservoir function with subclinical cerebrovascular disease in a stroke-free community-based cohort.
An increase in LA size is associated with cardiovascular events including stroke. However, it is not known whether LA phasic volumes and reservoir function are associated with subclinical cerebrovascular disease.
The LA minimum (LAV) and maximum (LAV) volumes, and LA reservoir function, measured as total emptying volume (LAEV) and total emptying fraction (LAEF), were assessed by real-time 3-dimensional echocardiography in 455 stroke-free participants from the community-based CABL (Cardiovascular Abnormalities and Brain Lesions) study. Subclinical cerebrovascular disease was assessed as silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV) by brain magnetic resonance imaging.
Prevalence of SBI was 15.4%; mean WMHV was 0.66 ± 0.92%. Participants with SBI showed greater LAV (17.1 ± 9.3 ml/m vs. 12.5 ± 5.6 ml/m, p < 0.01) and LAV (26.6 ± 8.8 ml/m vs. 23.3 ± 7.0 ml/m, p < 0.01) compared to those without SBI. The LAEV (9.5 ± 3.4 ml/m vs. 10.8 ± 3.9 ml/m, p < 0.01) and LAEF (38.7 ± 14.7% vs. 47.0 ± 11.9%, p < 0.01) were also reduced in participants with SBI. In univariate analyses, greater LA volumes and smaller reservoir function were significantly associated with greater WMHV. In multivariate analyses, LAV remained significantly associated with SBI (adjusted odds ratio per SD increase: 1.37, 95% confidence interval: 1.04 to 1.80, p < 0.05) and with WMHV (β = 0.12, p < 0.01), whereas LAV was not independently associated with either. Smaller LAEF was independently associated with SBI (adjusted odds ratio: 0.67, 95% confidence interval: 0.50 to 0.90, p < 0.01) and WMHV (β = -0.09, p < 0.05).
Greater LA volumes and reduced LA reservoir function are associated with subclinical cerebrovascular disease detected by brain magnetic resonance imaging in subjects without history of stroke. In particular, LAV and LAEF are more strongly associated with SBI and WMHV than the more commonly measured LAV, and their relationship with subclinical brain lesions is independent of other cardiovascular risk factors.
JACC. Cardiovascular imaging 03/2013; 6(3):313-23. · 14.29 Impact Factor
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ABSTRACT: Previous work examining Alzheimer's Disease Neuroimaging Initiative (ADNI) normal controls using cluster analysis identified a subgroup characterized by substantial brain atrophy and white matter hyperintensities (WMH). We hypothesized that these effects could be related to vascular damage. Fifty-three individuals in the suspected vascular cluster (Normal 2) were compared with 31 individuals from the cluster characterized as healthy/typical (Normal 1) on a variety of outcomes, including magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers, vascular risk factors and outcomes, cognitive trajectory, and medications for vascular conditions. Normal 2 was significantly older but did not differ on ApoE4+ prevalence. Normal 2 differed significantly from Normal 1 on all MRI measures but not on Amyloid-Beta1-42 or total tau protein. Normal 2 had significantly higher body mass index (BMI), Hachinksi score, and creatinine levels, and took significantly more medications for vascular conditions. Normal 2 had marginally significantly higher triglycerides and blood glucose. Normal 2 had a worse cognitive trajectory on the Rey's Auditory Verbal Learning Test (RAVLT) 30-min delay test and the Functional Activity Questionnaire (FAQ). Cerebral atrophy associated with multiple vascular risks is common among cognitively normal individuals, forming a distinct subgroup with significantly increased cognitive decline. Further studies are needed to determine the clinical impact of these findings. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Psychology and Aging 03/2013; 28(1):191-201. · 2.73 Impact Factor
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ABSTRACT: BACKGROUND: Amnestic mild cognitive impairment (aMCI) is associated with an elevated risk of progressing to Alzheimer's disease. Much less is known about the course of dysexecutive mild cognitive impairment (dMCI). The goals of this study were to determine how the profile of cognitive deficits differs over time between patients with dMCI and aMCI, and control subjects; if the type of dementia differs between dMCI and aMCI in patients who progress to dementia; and if dMCI is more associated with stroke and white matter hyperintensity on magnetic resonance imaging (MRI) than aMCI. METHODS: The authors undertook a prospective evaluation of an inception cohort of 1167 ethnically diverse elders recruited from an urban community-based sample monitored with clinical and neuropsychological testing for an average of 4.5 years (standard deviation, 0.8 year). A subset of the subjects underwent MRI. We compared four groups of MCI patients: single-domain amnestic and dysexecutive MCI, and multiple-domain MCI with and without executive dysfunction. RESULTS: Compared with aMCI, dMCI was less likely to involve other areas of cognition over time and progress to dementia. None of the 33 single-domain dMCI patients progressed to dementia. The presence of executive dysfunction in multiple-domain MCI did not increase risk of progression to dementia. Patients with multiple-domain MCI with executive dysfunction who progressed to dementia were less likely to have an Alzheimer's-type dementia than MCI patients without executive dysfunction. Patients with dMCI were more likely to experience stroke, but not white matter hyperintensity, detected via MRI than patients with aMCI. CONCLUSIONS: dMCI appears to follow a different course, and is less associated with Alzheimer's disease and more associated with stroke than aMCI.
Alzheimer's & dementia: the journal of the Alzheimer's Association 02/2013; · 5.90 Impact Factor
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ABSTRACT: The purpose of this study was to evaluate how demographic variables relate to cognitive change and address whether cross-sectional demographic effects on cognitive tests are mirrored in differences in longitudinal trajectories of cognitive decline. We hypothesized that race and ethnicity, education, and language of test administration would relate to cross-sectional status and that the rate of cognitive decline would differ among African Americans, Hispanics, and Caucasians, across levels of educational attainment, and according to linguistic background. Participants were 404 educationally, ethnically, and cognitively diverse older adults enrolled in an ongoing longitudinal study of cognition. Mixed-effects regression analysis was used to measure baseline status and longitudinal change in episodic memory, executive functioning, and semantic memory. Results showed that ethnicity and education were strongly associated with baseline scores, but were, at most, weakly associated with change in cognition over time after accounting for confounding variables. There was evidence that the episodic-memory scores of Spanish-speaking Hispanic participants with limited education underestimated their true abilities in the initial evaluation, which may reflect lack of familiarity with the testing environment. These results-consistent with other reports in the literature-suggest that cross-sectional effects of demographic variables on cognitive-test scores result from differences in life experiences that directly influence test performance and do not indicate greater disease effects on cognition in minorities and those with limited education. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
Psychology and Aging 02/2013; · 2.73 Impact Factor
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ABSTRACT: BACKGROUND AND PURPOSE: Parental stroke has been related to an increased risk of stroke in the offspring. This study examines whether parental stroke is also associated with increased vascular brain injury and poorer cognitive performance among offspring free of clinical stroke. METHODS: Multivariable regression analyses were used to relate parental stroke to cross-sectional and change in brain magnetic resonance imaging measures and cognitive function among the offspring, with and without adjustment for vascular risk factors. RESULTS: Stroke- and dementia-free Framingham Offspring (n=1297, age, 61±9 years, 54% women) were studied. Parental stroke by age 65 years was associated with a higher baseline white matter hyperintensity volume (β=0.17±0.08; P=0.027) and with lower visual memory performance (β= -0.80±0.34; P=0.017). During a 6-year follow-up, parental stroke was also associated with increase in white matter hyperintensity volume (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.03-3.38) and decline in executive function (Trails B-A; OR, 1.81; 95% CI, 1.06-3.09). The associations with white matter hyperintensity volume and visual memory attenuated after additional adjustment for concomitant vascular risk factors. CONCLUSIONS: Parental stroke by age 65 years is associated with increased vascular brain injury and lower memory in offspring equivalent to 3 and 7 years of brain aging, respectively. This may be partly attributed to inheritance of vascular risk factors.
Stroke 01/2013; · 5.73 Impact Factor
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ABSTRACT: OBJECTIVE: To examine the association of perceived stress with magnetic resonance imaging (MRI) markers of subclinical cerebrovascular disease in an elderly cohort. METHODS: Using a cross-sectional study of a community-based cohort in Chicago, 571 adults (57% women; 58.1% African American; 41.9% non-Hispanic white; mean [SD] age: 79.8 [5.9] years) from the Chicago Health and Aging Project, an epidemiologic study of aging, completed questionnaires on perceived stress, medical history, and demographics as part of an in-home assessment and 5 years later underwent a clinical neurologic examination and MRI of the brain. Outcome measures were volumetric MRI assessments of white matter hyperintensity volume (WMHV), total brain volume (TBV), and cerebral infarction. RESULTS: Stress was measured with six items from the Perceived Stress Scale (PSS); item responses, ranging from never (0) to often (3), were summed to create an overall stress score (mean [SD]: 4.9 [3.3]; range: 0-18). Most participants had some evidence of vascular disease on MRI, with 153 participants (26.8%) having infarctions. In separate linear and logistic regression models adjusted for age, sex, education, race, and time between stress assessment and MRI, each one-point increase in PSS score was associated with significantly lower TBV (coefficient = -0.111, SE = 0.049, t[563] = -2.28, p = 0.023) and 7% greater odds of infarction (odds ratio: 1.07; 95% confidence interval: 1.01, 1.13; Wald χ(2)[1] = 4.90; p = 0.027). PSS scores were unrelated to WMHV. Results were unchanged with further adjustment for smoking, body mass index, physical activity, history of heart disease, stroke, diabetes, hypertension, depressive symptoms, and dementia. CONCLUSIONS: Greater perceived stress was significantly and independently associated with cerebral infarction and lower brain volume assessed 5 years later in this elderly cohort.
The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry 01/2013; · 3.35 Impact Factor
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Christian Habeck,
Shannon Risacher,
Grace J Lee,
M Maria Glymour,
Elizabeth Mormino,
Shubhabrata Mukherjee,
Sungeun Kim,
Kwangsik Nho, Charles Decarli,
Andrew J Saykin,
Paul K Crane
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ABSTRACT: Differences in brain metabolism as measured by FDG-PET in prodromal and early Alzheimer's disease (AD) have been consistently observed, with a characteristic parietotemporal hypometabolic pattern. However, exploration of brain metabolic correlates of more nuanced measures of cognitive function has been rare, particularly in larger samples. We analyzed the relationship between resting brain metabolism and memory and executive functioning within diagnostic group on a voxel-wise basis in 86 people with AD, 185 people with mild cognitive impairment (MCI), and 86 healthy controls (HC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We found positive associations within AD and MCI but not in HC. For MCI and AD, impaired executive functioning was associated with reduced parietotemporal metabolism, suggesting a pattern consistent with known AD-related hypometabolism. These associations suggest that decreased metabolic activity in the parietal and temporal lobes may underlie the executive function deficits in AD and MCI. For memory, hypometabolism in similar regions of the parietal and temporal lobes were significantly associated with reduced performance in the MCI group. However, for the AD group, memory performance was significantly associated with metabolism in frontal and orbitofrontal areas, suggesting the possibility of compensatory metabolic activity in these areas. Overall, the associations between brain metabolism and cognition in this study suggest the importance of parietal and temporal lobar regions in memory and executive function in the early stages of disease and an increased importance of frontal regions for memory with increasing impairment.
Brain Imaging and Behavior 11/2012; · 1.66 Impact Factor
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David C Whitcomb,
Jessica Larusch,
Alyssa M Krasinskas,
Lambertus Klei,
Jill P Smith,
Randall E Brand,
John P Neoptolemos,
Markus M Lerch,
Matt Tector,
Bimaljit S Sandhu, [......],
Frank Ulrich Weiss,
C Mel Wilcox,
Narcis Octavian Zarnescu,
Stephen R Wisniewski,
Michael R O'Connell,
Michelle L Kienholz,
Kathryn Roeder,
M Michael Barmada,
Dhiraj Yadav,
Bernie Devlin
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ABSTRACT: Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12)) and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
Nature Genetics 11/2012; · 35.53 Impact Factor
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ABSTRACT: BACKGROUND: Previous studies have identified effects of age and vascular risk factors on brain injury in elderly individuals. We aimed to establish whether the effects of high blood pressure in the brain are evident as early as the fifth decade of life. METHODS: In an investigation of the third generation of the Framingham Heart Study, we approached all participants in 2009 to ask whether they would be willing to undergo MRI. Consenting patients underwent clinical assessment and cerebral MRI that included T1-weighted and diffusion tensor imaging to obtain estimates of fractional anisotropy, mean diffusivity, and grey-matter volumes. All images were coregistered to a common minimum deformation template for voxel-based linear regressions relating fractional anisotropy, mean diffusivity, and grey-matter volumes to age and systolic blood pressure, with adjustment for potential confounders. FINDINGS: 579 (14·1%) of 4095 participants in the third-generation cohort (mean age 39·2 years, SD 8·4) underwent brain MRI between June, 2009 and June, 2010. Age was associated with decreased fractional anisotropy and increased mean diffusivity in almost all cerebral white-matter voxels. Age was also independently associated with reduced grey-matter volumes. Increased systolic blood pressure was linearly associated with decreased regional fractional anisotropy and increased mean diffusivity, especially in the anterior corpus callosum, the inferior fronto-occipital fasciculi, and the fibres that project from the thalamus to the superior frontal gyrus. It was also strongly associated with reduced grey-matter volumes, particularly in Brodmann's area 48 on the medial surface of the temporal lobe and Brodmann's area 21 of the middle temporal gyrus. INTERPRETATION: Our results suggest that subtle vascular brain injury develops insidiously during life, with discernible effects even in young adults. These findings emphasise the need for early and optimum control of blood pressure. FUNDING: National Institutes of Health and National Heart, Lung, and Blood Institute; National Institute on Aging; and National Institute of Neurological Disorders and Stroke.
The Lancet Neurology 11/2012; · 23.46 Impact Factor
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Bradley T Wyman,
Danielle J Harvey,
Karen Crawford,
Matt A Bernstein,
Owen Carmichael,
Patricia E Cole,
Paul K Crane, Charles Decarli,
Nick C Fox,
Jeffrey L Gunter,
Derek Hill,
Ronald J Killiany,
Chahin Pachai,
Adam J Schwarz,
Norbert Schuff,
Matthew L Senjem,
Joyce Suhy,
Paul M Thompson,
Michael Weiner,
Clifford R Jack
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ABSTRACT: The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T(1)-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12-month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2-year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI-GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly.
Alzheimer's & dementia: the journal of the Alzheimer's Association 10/2012; · 5.90 Impact Factor
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Kwangsik Nho,
Shannon L Risacher,
Paul K Crane, Charles Decarli,
M Maria Glymour,
Christian Habeck,
Sungeun Kim,
Grace J Lee,
Elizabeth Mormino,
Shubhabrata Mukherjee,
Li Shen,
John D West,
Andrew J Saykin
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ABSTRACT: Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are associated with a progressive loss of cognitive abilities. In the present report, we assessed the relationship of memory and executive function with brain structure in a sample of 810 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, including 188 AD, 396 MCI, and 226 healthy older adults (HC). Composite scores of memory (ADNI-Mem) and executive function (ADNI-Exec) were generated by applying modern psychometric theory to item-level data from ADNI's neuropsychological battery. We performed voxel-based morphometry (VBM) and surface-based association (SurfStat) analyses to evaluate relationships of ADNI-Mem and ADNI-Exec with grey matter (GM) density and cortical thickness across the whole brain in the combined sample and within diagnostic groups. We observed strong associations between ADNI-Mem and medial and lateral temporal lobe atrophy. Lower ADNI-Exec scores were associated with advanced GM and cortical atrophy across broadly distributed regions, most impressively in the bilateral parietal and temporal lobes. We also evaluated ADNI-Exec adjusted for ADNI-Mem, and found associations with GM density and cortical thickness primarily in the bilateral parietal, temporal, and frontal lobes. Within-group analyses suggest these associations are strongest in patients with MCI and AD. The present study provides insight into the spatially unbiased associations between brain atrophy and memory and executive function, and underscores the importance of structural brain changes in early cognitive decline.
Brain Imaging and Behavior 10/2012; · 1.66 Impact Factor
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José Rafael Romero,
Sarah R Preis,
Alexa S Beiser, Charles Decarli,
Dong Young Lee,
Anand Viswanathan,
Emelia J Benjamin,
Joao Fontes,
Rhoda Au,
Aleksandra Pikula,
Jimmy Wang,
Carlos S Kase,
Philip A Wolf,
Michael C Irrizary,
Sudha Seshadri
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ABSTRACT: Cerebral microbleeds (CMB) attributable to cerebral amyloid angiopathy generally occur in lobar regions, whereas those attributable to hypertensive vasculopathy are deep. Inflammation may be an underlying mechanism for CMB, with varying associations according to CMB location. Lipoprotein phospholipase-A2 (Lp-PLA2) is a circulating enzyme marker of vascular inflammation associated with risk of ischemic stroke and dementia. We hypothesized that higher Lp-PLA2 levels would be related to higher prevalence of CMB, with possible regional specificity.
Framingham Offspring participants aged 65 years or older with available Lp-PLA2 measures and brain magnetic resonance imaging were included. Logistic regression models were used to relate Lp-PLA2 activity and mass to presence of CMB, adjusted for age, sex, medication use (aspirin, anticoagulants, and statins), systolic blood pressure, APOE, current smoking, and diabetes.
Eight-hundred nineteen participants (mean age, 73 years; 53% women) were included; 106 (13%) had CMB, 82 (10%) were lobar, and 27 (3%) were deep. We did not observe significant associations of CMB and LpPLA2 measures in multivariable adjusted analyses. However, there was a significant interaction between APOE genotype and Lp-PLA2 activity in their relation to presence of deep CMB (P interaction=0.01). Among persons with APOE ε3/ε3, the odds ratio for deep CMB was 0.95 (confidence interval, 0.59-1.53; P=0.83), whereas among those with at least 1 ε2 or ε4 allele, odds ratio was 3.46 (confidence interval, 1.43-8.36; P=0.006).
In our community-based sample of older adults, there was no significant association of Lp-PLA2 with total or lobar CMB. The association of higher levels of Lp-PLA2 activity with deep CMB among those with at least 1 APOE ε2 or ε4 allele merits replication.
Stroke 09/2012; 43(11):3091-4. · 5.73 Impact Factor
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ABSTRACT: The time and space complexities of Markov random field (MRF) algorithms for image segmentation increase with the number of edges that represent statistical dependencies between adjacent pixels. This has made MRFs too computationally complex for cutting-edge applications such as joint segmentation of longitudinal sequences of many high-resolution magnetic resonance images (MRIs). Here, we show that simply removing edges from full MRFs can reduce the computational complexity of MRF parameter estimation and inference with no notable decrease in segmentation performance. In particular, we show that for segmentation of white matter hyperintensities in 88 brain MRI scans of elderly individuals, as many as 66% of MRF edges can be removed without substantially degrading segmentation accuracy. We then show that removing edges from MRFs makes MRF parameter estimation and inference computationally tractable enough to enable modeling statistical dependencies within and across a larger number of brain MRI scans in a longitudinal series; this improves segmentation performance compared to separate segmentations of each individual scan in the series.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2012; 2012:2684-7.
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ABSTRACT: We present a method that significantly improves magnetic resonance imaging (MRI) based brain tissue segmentation by modeling the topography of boundaries between tissue compartments. Edge operators are used to identify tissue interfaces and thereby more realistically model tissue label dependencies between adjacent voxels on opposite sides of an interface. When applied to a synthetic MRI template corrupted by additive noise, it provided more consistent tissue labeling across noise levels than two commonly used methods (FAST and SPM5). When applied to longitudinal MRI series it provided lesser variability in individual trajectories of tissue change, suggesting superior ability to discriminate real tissue change from noise. These results suggest that this method may be useful for robust longitudinal brain tissue change estimation.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2012; 2012:5319-22.
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ABSTRACT: To investigate the effects of baseline white matter hyperintensity (WMH) and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function).
A total of 150 individuals including cognitively normal elderly individuals and those with Alzheimer disease and mild cognitive impairment completed serial episodic memory and executive function evaluations and serial MRI scans sufficient for longitudinal measurement of WMH (mean delay 4.0 years). Incident WMH voxels were categorized as extended (baseline WMH that grew larger) or emergent (newly formed WMH). We used a stepwise regression approach to investigate the effects of baseline WMH and rates of WMH extension and emergence on rate of change in cognition (episodic memory and executive function).
WMH burden significantly increased over time, and approximately 80% of incident WMH voxels represented extensions of existing lesions. Each 1 mL/y increase in WMH extension was associated with an additional 0.70 SD/y of subsequent episodic memory decrease (p = 0.0053) and an additional 0.55 SD/y of subsequent executive function decrease (p = 0.022). Emergent WMHs were not found to be associated with a change in cognitive measures.
Aging-associated WMHs evolve significantly over a 4-year period. Most of this evolution represents worsening injury to the already compromised surround of existing lesions. Increasing WMH was also significantly associated with declining episodic memory and executive function. This finding supports the view that white matter disease is an insidious and continuously evolving process whose progression has clinically relevant cognitive consequences.
Neurology 07/2012; 79(5):442-8. · 8.31 Impact Factor
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Shubhabrata Mukherjee,
Sungeun Kim,
Laura E Gibbons,
Kwangsik Nho,
Shannon L Risacher,
M Maria Glymour,
Christian Habeck,
Grace J Lee,
Elizabeth Mormino,
Nilüfer Ertekin-Taner,
Thomas J Montine, Charles Decarli,
Andrew J Saykin,
Paul K Crane
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ABSTRACT: The genetic basis of resilience, defined as better cognitive functioning than predicted based on neuroimaging or neuropathology, is not well understood. Our objective was to identify genetic variation associated with executive functioning resilience. We computed residuals from regression models of executive functioning, adjusting for age, sex, education, Hachinski score, and MRI findings (lacunes, cortical thickness, volumes of white matter hyperintensities and hippocampus). We estimated heritability and analyzed these residuals in models for each SNP. We further evaluated our most promising SNP result by evaluating cis-associations with brain levels of nearby (±100 kb) genes from a companion data set, and comparing expression levels in cortex and cerebellum from decedents with AD with those from other non-AD diseases. Complete data were available for 750 ADNI participants of European descent. Executive functioning resilience was highly heritable (H(2) = 0.76; S.E. = 0.44). rs3748348 on chromosome 14 in the region of RNASE13 was associated with executive functioning resilience (p-value = 4.31 × 10(-7)). rs3748348 is in strong linkage disequilibrium (D' of 1.00 and 0.96) with SNPs that map to TPPP2, a member of the α-synuclein family of proteins. We identified nominally significant associations between rs3748348 and expression levels of three genes (FLJ10357, RNASE2, and NDRG2). The strongest association was for FLJ10357 in cortex, which also had the most significant difference in expression between AD and non-AD brains, with greater expression in cortex of decedents with AD (p-value = 7 × 10(-7)). Further research is warranted to determine whether this signal can be replicated and whether other loci may be associated with cognitive resilience.
Brain Imaging and Behavior 06/2012; · 1.66 Impact Factor
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Scott A Melville,
Jacqueline Buros,
Antonio R Parrado,
Badri Vardarajan,
Mark W Logue,
Li Shen,
Shannon L Risacher,
Sungeun Kim,
Gyungah Jun, Charles DeCarli,
Kathryn L Lunetta,
Clinton T Baldwin,
Andrew J Saykin,
Lindsay A Farrer
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ABSTRACT: Large genome-wide association studies (GWASs) have identified many novel genes influencing Alzheimer disease (AD) risk, but most of the genetic variance remains unexplained. We conducted a 2-stage GWAS for AD-related quantitative measures of hippocampal volume (HV), total cerebral volume (TCV), and white matter hyperintensities (WMH).
Brain magnetic resonance imaging measures of HV, TCV, and WMH were obtained from 981 Caucasian and 419 African American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer's Genetic Epidemiology) Study, and from 168 AD cases, 336 individuals with mild cognitive impairment, and 188 controls in the Alzheimer's Disease Neuroimaging Initiative Study. A GWAS for each trait was conducted in the 2 Caucasian data sets in stage 1. Results from the 2 data sets were combined by meta-analysis. In stage 2, 1 single nucleotide polymorphism (SNP) from each region that was nominally significant in each data set (p < 0.05) and strongly associated in both data sets (p < 1.0 × 10(-5)) was evaluated in the African American data set.
Twenty-two markers (14 for HV, 3 for TCV, and 5 for WMH) from distinct regions met criteria for evaluation in stage 2. Novel genome-wide significant associations (p < 5.0 × 10(-8)) were attained for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set. Associations with different SNPs in the same gene (p < 1 × 10(-5) in Caucasians and p < 2.2 × 10(-4) in African Americans) were also observed for PICALM with HV, SYNPR with TCV, and TTC27 with WMH.
Our study demonstrates the efficacy of endophenotypes for broadening our understanding of the genetic basis of AD.
Annals of Neurology 05/2012; 72(1):65-75. · 11.09 Impact Factor
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ABSTRACT: Age-related changes in neural circuits, neural networks, and their plasticity are central to our understanding of age changes in cognition and brain structure and function. This paper summarizes selected findings on these topics presented at the Cognitive Aging Summit II. Specific areas discussed were synaptic vulnerability and plasticity, including the role of different types of synaptic spines, and hormonal effects in the dorsolateral prefrontal cortex of nonhuman primates, the impact of both compensatory processes and dedifferentiation on demand-dependent differences in prefrontal activation in relation to age and performance, the role of vascular disease, indexed by white matter signal abnormalities, on prefrontal activation during a functional magnetic resonance imaging-based cognitive control paradigm, and the influence of amyloid-β neuropathology on memory performance in older adults and the networks of brain activity underlying variability in performance. A greater understanding of age-related changes in brain plasticity and neural networks in healthy aging and in the presence of underlying vascular disease or amyloid pathology will be essential to identify new targets for intervention. Moreover, this understanding will assist in promoting the utilization of existing interventions, such as lifestyle and therapeutic modifiers of vascular disease.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2012; 67(7):747-53. · 4.60 Impact Factor
