Comparing Vascular Brain Injury and Stroke by Cranial Magnetic Resonance Imaging, Physician-Adjudication, and Self-Report: Data from the Strong Heart Study.

BACKGROUND: Epidemiologic studies often use self-report as proxy for clinical history. However, whether self-report correctly identifies prevalence in minority populations with health disparities and poor health-care access is unknown. Furthermore, overlap of clinical vascular events with covert vascular brain injury (VBI), detected by imaging, is largely unexamined. METHODS: The Strong Heart Study recruited American Indians from 3 regions, with surveillance and adjudication of stroke events from 1989 to 2013. In 2010-2013, all 817 survivors, aged 65-95 years, underwent brain imaging, neurological history interview, and cognitive testing. VBI was defined as imaged infarct or hemorrhage. RESULTS: Adjudicated stroke was prevalent in 4% of participants and separately collected, self-reported stroke in 8%. Imaging-defined VBI was detected in 51% and not associated with any stroke event in 47%. Compared with adjudication, self-report had 76% sensitivity and 95% specificity. Participants with adjudicated or self-reported stroke had the poorest performance on cognitive testing; those with imaging-only (covert) VBI had intermediate performance. CONCLUSION: In this community-based cohort, self-report for prior stroke had good performance metrics. A majority of participants with VBI did not have overt, clinically recognized events but did have neurological or cognitive symptoms. Data collection methodology for studies in a resource-limited setting must balance practical limitations in costs, accuracy, feasibility, and research goals.

Cognitive Correlates of MRI-defined Cerebral Vascular Injury and Atrophy in Elderly American Indians: The Strong Heart Study.

OBJECTIVE: American Indians experience substantial health disparities relative to the US population, including vascular brain aging. Poorer cognitive test performance has been associated with cranial magnetic resonance imaging findings in aging community populations, but no study has investigated these associations in elderly American Indians. METHODS: We examined 786 American Indians aged 64 years and older from the Cerebrovascular Disease and its Consequences in American Indians study (2010-2013). Cranial magnetic resonance images were scored for cortical and subcortical infarcts, hemorrhages, severity of white matter disease, sulcal widening, ventricle enlargement, and volumetric estimates for white matter hyperintensities (WMHs), hippocampus, and brain. Participants completed demographic, medical history, and neuropsychological assessments including testing for general cognitive functioning, verbal learning and memory, processing speed, phonemic fluency, and executive function. RESULTS: Processing speed was independently associated with the presence of any infarcts, white matter disease, and hippocampal and brain volumes, independent of socioeconomic, language, education, and clinical factors. Other significant associations included general cognitive functioning with hippocampal volume. Nonsignificant, marginal associations included general cognition with WMH and brain volume; verbal memory with hippocampal volume; verbal fluency and executive function with brain volume; and processing speed with ventricle enlargement. CONCLUSIONS: Brain-cognition associations found in this study of elderly American Indians are similar to those found in other racial/ethnic populations, with processing speed comprising an especially strong correlate of cerebrovascular disease. These findings may assist future efforts to define opportunities for disease prevention, to conduct research on diagnostic and normative standards, and to guide clinical evaluation of this underserved and overburdened population.

Midlife Smaller and Larger Infarctions, White Matter Hyperintensities, and 20-Year Cognitive Decline: A Cohort Study.

Background: Smaller (<3-mm) infarctions are associated with stroke and stroke mortality, but relationships with cognitive decline are unknown. Objective: To characterize the relationships of smaller, larger, and both smaller and larger infarctions in middle age with 20-year cognitive decline. Design: Longitudinal cohort study. Setting: Two ARIC (Atherosclerosis Risk in Communities) study sites with magnetic resonance imaging data (1993 to 1995) and up to 5 cognitive assessments over 20 years. Participants: Stroke-free participants aged 50 years or older. Measurements: Infarctions were categorized as none, smaller only, larger only (3 to 20 mm), or both smaller and larger. Global cognitive Z scores were derived from 3 cognitive tests administered up to 5 times. Mixed-effects models estimated adjusted associations between infarctions and cognitive decline. Results are the average difference in standardized cognitive decline associated with infarctions versus no infarctions. Results: Among 1884 participants (mean age, 62 years; 60% women; 50% black), 1611 (86%) had no infarctions, 50 (3%) had smaller infarctions only, 185 (10%) had larger infarctions only, and 35 (2%) had both. Participants with both smaller and larger infarctions had steeper cognitive decline by more than half an SD (difference, -0.57 SD [95% CI, -0.89 to -0.26 SD]) compared with those who had no infarctions. Amounts of cognitive decline associated with only smaller infarctions and only larger infarctions were similar and were not statistically different from that associated with no infarctions. Limitation: Few participants had only smaller infarctions or both smaller and larger infarctions, and the data lacked counts of smaller infarctions and volumes of white matter hyperintensities. Conclusion: The substantial cognitive decline from middle age associated with having both smaller and larger infarctions, but not larger infarctions alone, suggests that the combination of smaller and larger infarctions may escalate risk for cognitive decline later in life in stroke-free persons. Primary Funding Source: National Institutes of Health.

The ability of magnetic resonance black blood vessel wall imaging to evaluate blunt cerebrovascular injury following acute trauma.

BACKGROUND AND PURPOSE: Blunt cerebrovascular injury (BCVI) is associated with a significant risk of ischemic stroke when left untreated. Cross-sectional imaging is vital to early BCVI diagnosis and treatment; however, conventional luminal vessel imaging is limited in its ability to evaluate for vessel wall pathology. The purpose of this study is to evaluate the ability of vessel wall magnetic resonance imaging (VWI) to detect and evaluate BCVI in acutely injured trauma patients relative to neck computed tomographic angiography (CTA). MATERIALS AND METHODS: Trauma patients with suspected BCVI on initial neck CTA were prospectively recruited for VWI evaluation. Two neuroradiologists blinded to patient clinical history and CTA findings evaluated each artery independently on VWI and noted the presence and grade of BCVI. These results were subsequently compared to neck CTA findings relative to expert clinical consensus review. Interrater reliability of VWI for detecting BCVI was evaluated using a weighted Cohen κ-statistic. RESULTS: Ten trauma patients (40 cervical arteries) were prospectively evaluated using both CTA and VWI. Out of 18 vascular lesions identified as suspicious for BCVI on CTA, six lesions were determined to represent true BCVI by expert consensus review. There was almost perfect agreement between VWI and expert consensus regarding the presence and grade of BCVI (κ=0.82). This agreement increased when considering only low grade BCVI. There was only fair agreement between CTA and expert clinical consensus (κ=0.36). This agreement decreased when considering only low grade BCVI. CONCLUSIONS: VWI can potentially accurately identify and evaluate BCVI in acutely injured trauma patients with excellent inter-rater reliability.

Lifestyle Risk Factors and Findings on Brain Magnetic Resonance Imaging of Older Adult American Indians: The Strong Heart Study.

BACKGROUND: Clinical stroke is prevalent in American Indians, but the lifestyle risk factors for vascular brain injury have not been well-studied in this population. The purpose of this study was to correlate brain magnetic resonance imaging (MRI) findings with obesity, alcohol use, and smoking behaviors in elderly American Indians from the Strong Heart Study. METHODS: Cranial MRI scans (n = 789) were analyzed for dichotomous measures of infarcts, hemorrhages, white matter hyperintensities (WMH), and cerebral atrophy and continuous measures of total brain, WMH, and hippocampal volume. Poisson regression was used to estimate prevalence ratios, and linear regression was used to estimate measures of association for continuous outcomes. Models were adjusted for the risk factors of interest as well as age, sex, study site, income, education, hypertension, diabetes, and low-density lipoprotein cholesterol. RESULTS: Smoking was associated with increased hippocampal atrophy (p = 0.002) and increased prevalence of sulcal widening (p < 0.001). Relative to nonsmokers, smokers with more than 25 pack-years of smoking had a 27% (95% CI 7-47%) increased prevalence of high-grade sulci, p = 0.005. Body mass index was inversely associated with prevalence of nonlacunar infarcts and sulcal widening (all p = 0.004). Alcohol use was not significantly associated with any of the measured MRI findings. CONCLUSIONS: This study found similar associations between smoking and vascular brain injury among American Indians, as seen in other populations. In particular, these findings support the role of smoking as a key correlate for cerebral atrophy.

Vascular Risk Factors and Findings on Brain MRI of Elderly Adult American Indians: The Strong Heart Study.

BACKGROUND: Clinical stroke is prevalent in American Indians, but the risk factors for cerebrovascular pathology have not been well-studied in this population. The purpose of this study was to correlate abnormalities on brain magnetic resonance imaging (MRI) with clinical risk factors in a cohort of elderly American Indians. METHODS: Brain MRI scans from 789 participants of the Strong Heart Study were analyzed for infarcts, hemorrhage, white matter disease, and measures of cerebral atrophy including ventricular and sulcal grade and total brain volume. Clinical risk factors included measures of hypertension, diabetes, and high levels of low-density lipoprotein (LDL) cholesterol. Regression models adjusted for potential confounders were used to estimate associations between risk factors and brain MRI outcomes. RESULTS: -Hypertension was associated with the presence of infarcts (p = 0.001), ventricle enlargement (p = 0.01), and increased white matter hyperintensity volume (p = 0.01). Diabetes was associated with increased prevalence of cerebral atrophy (p < 0.001), ventricular enlargement (p = 0.001), and sulcal widening (p = 0.001). High LDL was not significantly associated with any of the measured cranial imaging outcomes. CONCLUSIONS: This study found risk factors for cerebrovascular disease in American Indians similar to those seen in other populations and provides additional evidence for the important roles of hypertension and diabetes in promoting cerebral infarcts and brain atrophy, respectively.

Telomere Length and Magnetic Resonance Imaging Findings of Vascular Brain Injury and Central Brain Atrophy: The Strong Heart Study.

Telomeres are repeating regions of DNA that cap chromosomes. They shorten over the mammalian life span, especially in the presence of oxidative stress and inflammation. Telomeres may play a direct role in cell senescence, serving as markers of premature vascular aging. Leukocyte telomere length (LTL) may be associated with premature vascular brain injury and cerebral atrophy. However, reports have been inconsistent, especially among minority populations with a heavy burden of illness related to vascular aging. We examined associations between LTL and magnetic resonance imaging in 363 American Indians aged 64-93 years from the Strong Heart Study (1989-1991) and its ancillary study, Cerebrovascular Disease and Its Consequences in American Indians (2010-2013). Our results showed significant associations of LTL with ventricular enlargement and the presence of white matter hyperintensities. Secondary models indicated that renal function may mediate these associations, although small case numbers limited inference. Hypertension and diabetes showed little evidence of effect modification. Results were most extreme among participants who evinced the largest decline in LTL. Although this study was limited to cross-sectional comparisons, it represents (to our knowledge) the first consideration of associations between telomere length and brain aging in American Indians. Findings suggest a relationship between vascular aging by cell senescence and severity of brain disease.

Cortisol is More Important than Metanephrines in Driving Changes in Leukocyte Counts after Stroke.

BACKGROUND: There are notable changes in the number of white blood cells (WBCs) after stroke, but the primary mediators of these changes are unclear. In this study, we assessed the role of the neuroendocrine and sympathetic nervous systems in stroke-induced changes of WBCs within distinct leukocyte subsets, as well as the effect of these changes on stroke outcomes. METHODS: Patients were recruited within 72 hours after ischemic stroke; complete blood count with differential was obtained at set time points. The relationships among leukocyte numbers, cortisol, adrenocorticotropic hormone, interleukin-6, and metanephrines were assessed at 72 hours after stroke. Associations between abnormal leukocyte counts at 72 hours, poststroke infection, and 3-month outcomes were determined. RESULTS: A total of 114 subjects were enrolled. Severe stroke was associated with leukocytosis, neutrophilia, monocytosis, lymphopenia, and eosinopenia. At 72 hours after stroke, increased serum cortisol was independently associated with neutrophilia and lymphopenia. Abnormal leukocyte counts were not independently predictive of poststroke infection, but lymphopenia was associated with poor outcome (modified Rankin score >3) at 3 months after stroke (odds ratio = 22.86 [1.95, 267.65]; P = .01). CONCLUSIONS: Increased serum cortisol is independently associated with neutrophilia and lymphopenia after stroke. Lymphopenia is not an independent predictor of infections but is independently associated with worse outcome.

Added Value of Vessel Wall Magnetic Resonance Imaging for Differentiation of Nonocclusive Intracranial Vasculopathies.

BACKGROUND AND PURPOSE: Our goal is to determine the added value of intracranial vessel wall magnetic resonance imaging (IVWI) in differentiating nonocclusive vasculopathies compared with luminal imaging alone. METHODS: We retrospectively reviewed images from patients with both luminal and IVWI to identify cases with clinically defined intracranial vasculopathies: atherosclerosis (intracranial atherosclerotic disease), reversible cerebral vasoconstriction syndrome, and inflammatory vasculopathy. Two neuroradiologists blinded to clinical data reviewed the luminal imaging of defined luminal stenoses/irregularities and evaluated the pattern of involvement to make a presumed diagnosis with diagnostic confidence. Six weeks later, the 2 raters rereviewed the luminal imaging in addition to IVWI for the pattern of wall involvement, presence and pattern of postcontrast enhancement, and presumed diagnosis and confidence. Analysis was performed on per-lesion and per-patient bases. RESULTS: Thirty intracranial atherosclerotic disease, 12 inflammatory vasculopathies, and 12 reversible cerebral vasoconstriction syndrome patients with 201 lesions (90 intracranial atherosclerotic disease, 64 reversible cerebral vasoconstriction syndrome, and 47 inflammatory vasculopathy lesions) were included. For both per-lesion and per-patient analyses, there was significant diagnostic accuracy improvement with luminal imaging+IVWI when compared with luminal imaging alone (per-lesion: 88.8% versus 36.1%; P<0.001 and per-patient: 96.3% versus 43.5%; P<0.001, respectively). There was substantial interrater diagnostic agreement for luminal imaging+IVWI (κ=0.72) and only slight agreement for luminal imaging (κ=0.04). Although there was a significant correlation for both luminal and IVWI pattern of wall involvement with diagnosis, there was a stronger correlation for IVWI finding of lesion eccentricity and intracranial atherosclerotic disease diagnosis than for luminal imaging (κ=0.69 versus 0.18; P<0.001). CONCLUSIONS: IVWI can significantly improve the differentiation of nonocclusive intracranial vasculopathies when combined with traditional luminal imaging modalities.

Findings of Vascular Brain Injury and Structural Loss from Cranial Magnetic Resonance Imaging in Elderly American Indians: The Strong Heart Study.

BACKGROUND: The Cerebrovascular Disease and its Consequences in American Indians study conducted cranial MRI examination of surviving participants of the Strong Heart Study, a longitudinal cohort of elderly American Indians. METHODS: Of the 1,033 recruited participants, some were unable to complete the MRI (n = 22), some scans were unusable due to participant motion or technical errors (n = 13), and one community withdrew consent after data collection (n = 209), leaving 789 interpretable MRI scan images. Six image sequences were obtained in contiguous slices on 1.5T scanners. Neuroradiologists graded white matter hyperintensities (WMH), sulci, and ventricles on a 0- to 9-point scale, and recorded the presence of infarcts and hemorrhages. Intracranial, brain, hippocampal, and WMH volumes were estimated by automated image processing. RESULTS: The median scores for graded measures were 2 (WMH) and 3 (sulci, ventricles). About one-third of participants had lacunar (20%) or other infarcts (13%); few had hemorrhages (5.7%). Findings of cortical atrophy were also prevalent. Statistical analyses indicated significant associations between older age and findings of vascular injury and atrophy; male gender was associated with findings of cortical atrophy. CONCLUSIONS: Vascular brain injury is the likely explanation in this elderly American Indian population for brain infarcts, hemorrhages, WMH grade, and WMH volume. Although vascular brain injury may play a role in other findings, independent degenerative other disease processes may underlie abnormal sulcal widening, ventricular enlargement, hippocampal volume, and total brain volume. Further examination of risk factors and outcomes with these findings may expand the understanding of neurological conditions in this understudied population.

Total Brain and Hippocampal Volumes and Cognition in Older American Indians: The Strong Heart Study.

BACKGROUND: Estimates of hippocampal volume by magnetic resonance imaging have clinical and cognitive correlations and can assist in early Alzheimer disease diagnosis. However, little is known about the relationship between global or regional brain volumes and cognitive test performance in American Indians. MATERIALS AND METHODS: American Indian participants (N=698; median age, 72 y) recruited for the Cerebrovascular Disease and its Consequences in American Indians study, an ancillary study of the Strong Heart Study cohort, were enrolled. Linear regression models assessed the relationship between magnetic resonance imaging brain volumes (total brain and hippocampi) and cognitive measures of verbal learning and recall, processing speed, verbal fluency, and global cognition. RESULTS: After controlling for demographic and clinical factors, all volumetric measurements were positively associated with processing speed. Total brain volume was also positively associated with verbal learning, but not with verbal recall. Conversely, left hippocampal volume was associated with both verbal learning and recall. The relationship between hippocampal volume and recall performance was more pronounced among those with lower scores on a global cognitive measure. Controlling for APOE ε4 did not substantively affect the associations. CONCLUSIONS: These results support further investigation into the relationship between structural Alzheimer disease biomarkers, cognition, genetics, and vascular risk factors in aging American Indians.

Cranial Magnetic Resonance Imaging in Elderly American Indians: Design, Methods, and Implementation of the Cerebrovascular Disease and Its Consequences in American Indians Study.

The Cerebrovascular Disease and its Consequences in American Indians (CDCAI) Study recruited surviving members of a 20-year, longitudinal, population-based cohort of American Indians focused on cardiovascular disease, its risk factors, and its consequences. The goal of the CDCAI Study is to characterize the burden, risk factors, and manifestations of vascular brain injury identified on cranial MRI. The CDCAI Study investigators enrolled 1,033 participants aged 60 and older from 11 American Indian communities and tribes in the Northern Plains, Southern Plains, and Southwestern United States. In addition to cranial MRI performed according to standardized protocols, participants underwent extensive medical interview, clinical examination, neurocognitive testing, physical function evaluation, electrocardiogram, and provided blood and urine specimens. Participants also self-administered questionnaires covering demographics, quality of life, and medical history. This report describes the design, implementation, and some of the unique challenges of this study and data collection.

Small Brain Lesions and Incident Stroke and Mortality: A Cohort Study.

BACKGROUND: Although cerebral lesions 3 mm or larger on imaging are associated with incident stroke, lesions smaller than 3 mm are typically ignored. OBJECTIVE: To examine stroke risks associated with subclinical brain lesions (<3 mm only, ≥3 mm only, and both sizes) and white matter hyperintensities (WMHs). DESIGN: Community cohort from the ARIC (Atherosclerosis Risk in Communities) Study. SETTING: Two ARIC sites with magnetic resonance imaging (MRI) data from 1993 to 1995. PARTICIPANTS: 1884 adults aged 50 to 73 years with MRI, no prior stroke, and average follow-up of 14.5 years. MEASUREMENTS: Lesions on MRI (by size), WMH score (scale of 0 to 9), incident stroke, all-cause mortality, and stroke-related mortality. Hazard ratios (HRs) were estimated with proportional hazards models. RESULTS: Compared with no lesions, stroke risk tripled with lesions smaller than 3 mm only (HR, 3.47 [95% CI, 1.86 to 6.49]), doubled with lesions 3 mm or larger only (HR, 1.94 [CI, 1.22 to 3.07]), was 8-fold higher with lesions of both sizes (HR, 8.59 [CI, 4.69 to 15.73]), and doubled with a WMH score of at least 3 (HR, 2.14 [CI, 1.45 to 3.16]). Risk for stroke-related death tripled with lesions smaller than 3 mm only (HR, 3.05 [CI, 1.04 to 8.94]) and was 7 times higher with lesions of both sizes (HR, 6.97 [CI, 2.03 to 23.93]). LIMITATION: Few strokes (especially hemorrhagic) and few participants with lesions smaller than 3 mm only or lesions of both sizes. CONCLUSION: Very small cerebrovascular lesions may be associated with increased risks for stroke and death; presence of lesions smaller than 3 mm and 3 mm or larger may result in a particularly striking risk increase. Larger studies are needed to confirm findings and provide more precise estimates. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies. RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden. CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

Retinal microvascular abnormalities predict progression of brain microvascular disease: an atherosclerosis risk in communities magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Brain microvascular disease leads to leukoaraiosis and lacunar infarcts and contributes to risk of stroke and cognitive decline. Given a shared pathophysiology, retinal microvascular signs are expected to predict brain microvascular disease progression. We investigated if either leukoaraiosis volume progression measured continuously or combined with incident lacunar infarcts would better demonstrate expected associations with retinal disease than has previously been shown. METHODS: Eight hundred thirty participants in the Atherosclerosis Risk in Communities (ARIC) study aged ≥55 years and without previous stroke received an initial brain magnetic resonance imaging, retinal photography, and, 10 years later, a follow up magnetic resonance imaging. We evaluated retinal vascular sign phenotypes as predictors of (1) leukoaraiosis volume increase, and (2) a new score combining leukoaraiosis volume change and incident lacunar infarcts. Hypertension and diabetes mellitus were evaluated as confounders and effect modifiers. RESULTS: Individuals with any retinopathy (3.34 cm3; 95% confidence interval [CI], 0.74-5.96) or with arteriovenous nicking (2.61 cm3; 95% CI, 0.80-4.42) each had greater progression of leukoaraiosis compared with those without these conditions. Any retinopathy (odds ratio [OR], 3.18; 95% CI, 1.71-5.89) or its components-microaneurysms (OR, 3.06; 95% CI, 1.33-7.07) and retinal hemorrhage (OR, 3.02; 95% CI, 1.27-7.20)-as well as arteriovenous nicking (OR, 1.93; 95%, CI 1.24-3.02) and focal arteriolar narrowing (OR, 1.76; 95% CI, 1.19-2.59), were associated with a higher quartile of a novel brain microvascular disease score combining leukoaraiosis progression with incident subclinical lacunes. CONCLUSIONS: A novel scoring method revealed associations of retinal signs with leukoaraiosis progression and brain microvascular disease, which have not been shown before.

Stroke, IL-1ra, IL1RN, infection and outcome.

BACKGROUND: Infection is a common phenomenon following stroke, and adversely affects outcome. Previous studies suggest that interleukin-1 receptor antagonist (IL-1ra) and single nucleotide polymorphisms (SNPs) in the IL1RN gene might influence the risk of post-stroke infection and outcome. In this study, we addressed the effects of the rs4251961 SNP in IL1RN on infection risk and outcome. METHODS: Subjects with acute ischemic stroke were enrolled within 72 h of symptom onset and followed up to 1 year. Plasma IL-1ra was measured at multiple time points and outcome assessed at 1, 3, 6, and 12 months. Active surveillance for infection occurred while subjects were hospitalized. Subjects were genotyped for the IL1RN rs4251961 polymorphism. RESULTS: In the population of 113 subjects for this study, those with the minor C allele of rs4251961 polymorphism in IL1RN were more likely to be Caucasian, hypertensive, and to be afflicted with coronary heart disease. Higher plasma IL-1ra was associated with an increased risk of infection (other than pneumonia), and the minor C allele of rs4251961 was independently associated with a decreased risk of infection (other than pneumonia). Initial plasma IL-1ra was not predictive of long-term outcome, but patients with the minor C allele of rs4251961 were more likely to experience good (modified Rankin Score <2) long-term outcome. CONCLUSIONS: These data indicate that IL-1ra and IL1RN may influence the risk of infection after stroke, but this influence seems limited to infections other than pneumonia. Further studies are needed to better understand the complexities of immune regulation on infection and outcome after stroke.

Longitudinal Relationship Between Brain Atrophy Patterns, Cognitive Decline, and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease Explored by Orthonormal Projective Non-Negative Matrix Factorization.

Background: Longitudinal magnetic resonance imaging (MRI) has been proposed for tracking the progression of Alzheimer's disease (AD) through the assessment of brain atrophy. Objective: Detection of brain atrophy patterns in patients with AD as the longitudinal disease tracker. Methods: We used a refined version of orthonormal projective non-negative matrix factorization (OPNMF) to identify six distinct spatial components of voxel-wise volume loss in the brains of 83 subjects with AD from the ADNI3 cohort relative to healthy young controls from the ABIDE study. We extracted non-negative coefficients representing subject-specific quantitative measures of regional atrophy. Coefficients of brain atrophy were compared to subjects with mild cognitive impairment and controls, to investigate the cross-sectional and longitudinal associations between AD biomarkers and regional atrophy severity in different groups. We further validated our results in an independent dataset from ADNI2. Results: The six non-overlapping atrophy components represent symmetric gray matter volume loss primarily in frontal, temporal, parietal and cerebellar regions. Atrophy in these regions was highly correlated with cognition both cross-sectionally and longitudinally, with medial temporal atrophy showing the strongest correlations. Subjects with elevated CSF levels of TAU and PTAU and lower baseline CSF Aß42 values, demonstrated a tendency toward a more rapid increase of atrophy. Conclusions: The present study has applied a transferable method to characterize the imaging changes associated with AD through six spatially distinct atrophy components and correlated these atrophy patterns with cognitive changes and CSF biomarkers cross-sectionally and longitudinally, which may help us better understand the underlying pathology of AD.

Pathophysiology of carotid atherosclerosis: Calcification, intraplaque haemorrhage and pulse pressure as key players.

PURPOSE: Intraplaque haemorrhage (IPH) is a well-known risk factor for faster plaque progression (volume increase); however, its etiology is unclear. We aimed at determining what other local plaque- and systemic factors contribute to plaque progression and to the development and progression of IPH. METHODS: We examined 98 asymptomatic participants with carotid plaque using serial multi-contrast magnetic resonance imaging. We measured the percent of wall volume (%WV=100 x [wall volume] / [total vessel volume]) and measured IPH and calcification volumes. We used generalized estimating equations-based regression to analyze predictors of %WV change and new IPH while accounting for covariates (sex, age and statin use), and multiple non-independent observations per participant. RESULTS: Total follow-up was 1.8 ± 0.8 years on average. The presence of IPH (ß: 0.6 %/y, p = 0.033) and calcification (ß: 1.2 %/y, p = 0.028) were each associated with faster plaque progression. New IPH, detected on a subsequent scan in 4 % of arteries that did not initially have IPH, was associated with larger calcification (odds ratio [OR]: 2.6 per 1-SD increase, p = 0.038) and higher pulse pressure (OR: 2.3 per 1-SD increase, p = 0.016). Larger calcification was associated with greater increases in pulse pressure (ß: 1.4 mm Hg/y per 1-SD increase, p = 0.040). CONCLUSIONS: IPH and calcification are each independently associated with faster plaque progression. The association of carotid calcification to increased pulse pressure and new IPH development suggests a possible mechanism by which calcification drives IPH development and plaque progression.

Severe stroke induces long-lasting alterations of high-mobility group box 1.

BACKGROUND AND PURPOSE: The signals that initiate the poststroke inflammatory response are unknown. High-mobility group box (HMGB) 1 protein is a nuclear protein that is passively released from necrotic tissue and is able to activate leukocytes, which in turn secrete HMGB1. HMGB1 is also able to activate antigen-presenting cells and therefore stands at the crossroads of innate and adaptive immunity. METHODS: Plasma HMGB1 concentrations were determined at multiple time points after ischemic stroke (N=110) and correlated to stroke severity and biomarkers of inflammation. The relationships between HMGB1, stroke outcome, and autoimmune responses to brain antigens were also assessed. RESULTS: Stroke resulted in an increase in HMGB1 that persisted for 30 days. Plasma HMGB1 was correlated with the number of circulating leukocytes but was not predictive of either stroke outcome or the development of autoimmune responses to brain antigens. Patients with a Th1(+) response to myelin basic protein at 90 days after stroke, however, had higher plasma HMGB1. CONCLUSIONS: HMGB1 appears to be involved in the postischemic inflammatory response, but it remains unclear whether HMGB1 initiates this response or merely reflects activation of leukocytes by another signal.

Early statin use is associated with increased risk of infection after stroke.

BACKGROUND: Infection after stroke is common and likely detrimental. Given the potent immunomodulatory properties of statins, we hypothesized that early statin use might increase the risk of infection in the immediate post stroke period. METHODS: In a study cohort of 112 patients with ischemic stroke, we assessed the impact of early statin use on the risk of post stroke infection. RESULTS: After controlling for stroke severity and patient age, the odds ratio (OR) and 95% confidence interval (CI) for infection in the first 15 days after stroke among patients on a statin by day 3 after stroke was 7.21 (95% CI 1.40-37.98; P = .018). When controlling for univariate predictors of infection, the OR associated for infection associated with statin use actually increased, but was no longer significant (8.49 [95% CI 0.92-77.98]; P = .059). In addition, early statin use was associated with an increase in plasma interleukin-1 receptor antagonist (IL-1ra); IL-1ra was significantly higher in early statin users than in nonstatin users by day 7 after stroke. CONCLUSIONS: Our data suggest that early statin use appears to be associated with and increased risk of post stroke infection. This risk may, in part, be related to increases in plasma IL-1ra. If these findings are replicated in larger studies, they could have important implications for the timing of statin therapy after stroke.