@article {788, title = {White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke.}, journal = {Stroke}, volume = {35}, year = {2004}, month = {2004 Aug}, pages = {1821-5}, abstract = {

BACKGROUND AND PURPOSE: We have previously reported that several "silent" infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG > or =2 was a predictor of risk for stroke, independent of other risk factors.

METHODS: We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade=0) to most severe (grade=9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8\% per year for participants with high WMG (grades > or =5), compared with only 0.6\% for participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.

}, keywords = {Aged, Brain, Female, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Radiography, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000132193.35955.69}, author = {Kuller, Lewis H and Longstreth, W T and Arnold, Alice M and Bernick, Charles and Bryan, R Nick and Beauchamp, Norman J} } @article {812, title = {Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {36}, year = {2005}, month = {2005 Jan}, pages = {56-61}, abstract = {

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) scans in the elderly commonly show white matter findings that may raise concerns. We sought to document incidence, manifestations, and predictors of worsening white matter grade on serial imaging.

METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people aged 65 years and older, of whom 1919 have had extensive initial and follow-up evaluations, including 2 MRI scans separated by 5 years. Scans were read without clinical information in standard side-by-side fashion to determine worsening white matter grade.

RESULTS: Worsening was evident in 538 participants (28\%), mostly (85\%) by 1 grade. Although similar at initial scan, participants with worsening white matter grade, compared with those without, experienced greater decline on modified Mini-Mental State examination and Digit-Symbol Substitution test (both P< or =0.001) after controlling for potential confounding factors, including occurrence of transient ischemic attack or stroke between scans. Independent predictors of worsening white matter grade included cigarette smoking before initial scan and infarct on initial scan. Otherwise, predictors differed according to white matter grade on initial scan. For low initial grade, increased age, increased diastolic blood pressure, increased high-density lipoprotein cholesterol, and decreased low-density lipoprotein cholesterol were associated with increased risk of worsening. For high initial grade, any cardiovascular disease and low ankle-arm index were associated with decreased risk of worsening, whereas use of diuretics and statins were associated with increased risk.

CONCLUSIONS: Worsening white matter grade on serial MRI scans in elderly is common, is associated with cognitive decline, and has complex relations with cardiovascular risk factors.

}, keywords = {Aged, Brain, Cardiovascular Diseases, Cognition Disorders, Female, Humans, Incidence, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/01.STR.0000149625.99732.69}, author = {Longstreth, W T and Arnold, Alice M and Beauchamp, Norman J and Manolio, Teri A and Lefkowitz, David and Jungreis, Charles and Hirsch, Calvin H and O{\textquoteright}Leary, Daniel H and Furberg, Curt D} } @article {921, title = {Associations between findings on cranial magnetic resonance imaging and retinal photography in the elderly: the Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {165}, year = {2007}, month = {2007 Jan 01}, pages = {78-84}, abstract = {

Associations between findings on cranial magnetic resonance imaging (MRI) and retinal photographs have been described mostly in middle-aged people. In the Cardiovascular Health Study, 1,717 elderly participants underwent MRI and retinal photography between 1991 and 1999. Associations were sought between MRI findings and four findings of retinal microvascular disease: retinopathy, focal arteriolar narrowing, arteriovenous nicking, and the arteriovenous ratio--the last based upon semiautomated measurements of arterioles and venules. After controlling for age and gender, the authors found associations between MRI findings and the smaller arteriovenous ratio (per standard deviation decrease): prevalent infarcts (odds ratio = 1.18, 95\% confidence interval: 1.05, 1.34; p = 0.007), white matter grade (regression coefficient, 0.093; p = 0.011), incident infarct (odds ratio = 1.26, 95\% confidence interval: 1.09, 1.46; p = 0.002), and worsening white matter grade (odds ratio = 1.12, 95\% confidence interval: 0.98, 1.29; p = 0.09). Arteriovenous nicking was also associated with prevalent (odds ratio = 1.84, 95\% confidence interval: 1.23, 2.76; p = 0.003) and incident (odds ratio = 1.84, 95\% confidence interval: 1.15, 2.94; p = 0.011) infarcts. Adjustment for hypertension and diabetes had minimal effect. Evidence of small vessel disease in the retina increases the likelihood of finding it in the brain. Associations were less prominent in this elderly population than have been described in middle-aged people.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Arteriosclerosis, Cerebral Infarction, Female, Humans, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Microcirculation, Photography, Retina, Retinal Diseases, Retinal Vessels, Risk Assessment, Risk Factors}, issn = {0002-9262}, doi = {10.1093/aje/kwj350}, author = {Longstreth, Wt and Larsen, Emily K Marino and Klein, Ronald and Wong, Tien Yin and Sharrett, A Richey and Lefkowitz, David and Manolio, Teri A} } @article {1054, title = {Anemia is associated with the progression of white matter disease in older adults with high blood pressure: the cardiovascular health study.}, journal = {J Am Geriatr Soc}, volume = {56}, year = {2008}, month = {2008 Oct}, pages = {1867-72}, abstract = {

OBJECTIVES: To investigate whether anemia predicts worsening white matter hyperintensities (WMHs) in older community-dwellers.

DESIGN: Prospective cohort study.

SETTING: Older community-dwellers.

PARTICIPANTS: One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7 +/- 4.4, 41\% male, 15.6\% African American).

MEASUREMENTS: Participants had hemoglobin measured and brain magnetic resonance imaging (MRI) in 1992/93 and a second brain MRI in 1997/98. Anemia was defined according to World Health Organization criteria (hemoglobin <12 g/dL in women and <13 g/dL in men). Worsening WMHs were determined according to standardized side-by-side readings.

RESULTS: After 5 years, WMHs worsened in 517 participants (28\%). Progression was not associated with anemia in the whole sample, in sex or race strata, or in other prespecified subgroups (participants with renal dysfunction or diabetes mellitus), except in participants with high blood pressure (>or=140/90 mmHg). Of the 678 participants with high blood pressure, those with anemia (10.5\%) had a 1.79 times greater risk of WMHs worsening (95\% confidence interval=1.06-2.98; P for interaction between anemia and high blood pressure=.01) independent of demographics, baseline WMHs, cardiovascular risk factors and comorbidities, medications, renal function, inflammation, and incident stroke (logistic regression models). There was no greater risk in participants with anemia with normal blood pressure.

CONCLUSION: Anemia may contribute to worsening of WMHs in older adults with high blood pressure.

}, keywords = {Aged, Anemia, Brain, Cardiovascular Diseases, Disease Progression, Female, Humans, Hypertension, Leukoaraiosis, Magnetic Resonance Imaging, Male}, issn = {1532-5415}, doi = {10.1111/j.1532-5415.2008.01950.x}, author = {Inzitari, Marco and Studenski, Stephanie and Rosano, Caterina and Zakai, Neil A and Longstreth, William T and Cushman, Mary and Newman, Anne B} } @article {1014, title = {Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.}, journal = {Stroke}, volume = {39}, year = {2008}, month = {2008 Mar}, pages = {857-62}, abstract = {

BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants.

METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables.

RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95\% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95\% CI 1.07 to 2.94).

CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.

}, keywords = {Aged, Antidepressive Agents, Antidepressive Agents, Tricyclic, Cohort Studies, Disease Progression, Female, Follow-Up Studies, Humans, Leukoaraiosis, Magnetic Resonance Imaging, Male, Multivariate Analysis, Risk Assessment, Serotonin Uptake Inhibitors}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.107.498097}, author = {Steffens, David C and Chung, Hyoju and Krishnan, K Ranga R and Longstreth, W T and Carlson, Michelle and Burke, Gregory L} } @article {1381, title = {Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts.}, journal = {Ann Neurol}, volume = {71}, year = {2012}, month = {2012 Apr}, pages = {552-9}, abstract = {

OBJECTIVE: To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.

METHODS: Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.

RESULTS: After adjustment for other IPH risk factors, the hazard ratios (95\% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or >=3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83-4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).

INTERPRETATION: Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.

}, keywords = {Cerebral Infarction, Cohort Studies, Female, Humans, Incidence, Intracranial Hemorrhages, Leukoaraiosis, Magnetic Resonance Imaging, Male, Middle Aged, Risk Factors}, issn = {1531-8249}, doi = {10.1002/ana.22690}, author = {Folsom, Aaron R and Yatsuya, Hiroshi and Mosley, Thomas H and Psaty, Bruce M and Longstreth, W T} } @article {1333, title = {White matter lesions and brain gray matter volume in cognitively normal elders.}, journal = {Neurobiol Aging}, volume = {33}, year = {2012}, month = {2012 Apr}, pages = {834.e7-16}, abstract = {

Cerebral white matter lesions (WMLs) reflect small vessel disease, are common in elderly individuals, and are associated with cognitive impairment. We sought to determine the relationships between WMLs, age, gray matter (GM) volume, and cognition in the Cardiovascular Health Study (CHS). From the Cardiovascular Health Study we selected 740 cognitively normal controls with a 1.5 T magnetic resonance imaging (MRI) scan of the brain and a detailed diagnostic evaluation. WML severity was determined using a standardized visual rating system. GM volumes were analyzed using voxel-based morphometry implemented in the Statistical Parametric Mapping software. WMLs were inversely correlated with GM volume, with the greatest volume loss in the frontal cortex. Age-related atrophy was observed in the hippocampus and posterior cingulate cortex. Regression analyses revealed links among age, APOE*4 allele, hypertension, WMLs, GM volume, and digit symbol substitution test scores. Both advancing age and hypertension predict higher WML load, which is itself associated with GM atrophy. Longitudinal data are needed to confirm the temporal sequence of events leading to a decline in cognitive function.

}, keywords = {Aged, Aged, 80 and over, Aging, Apolipoprotein E4, Brain, Cognition Disorders, Female, Humans, Imaging, Three-Dimensional, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Memory Disorders, Mental Status Schedule, Neuropsychological Tests, Regression Analysis, Retrospective Studies}, issn = {1558-1497}, doi = {10.1016/j.neurobiolaging.2011.08.010}, author = {Raji, Cyrus A and Lopez, Oscar L and Kuller, Lewis H and Carmichael, Owen T and Longstreth, William T and Gach, H Michael and Boardman, John and Bernick, Charles B and Thompson, Paul M and Becker, James T} } @article {6581, title = {Brain imaging findings in elderly adults and years of life, healthy life, and able life over the ensuing 16 years: the Cardiovascular Health Study.}, journal = {J Am Geriatr Soc}, volume = {62}, year = {2014}, month = {2014 Oct}, pages = {1838-43}, abstract = {

OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes.

DESIGN: Longitudinal cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses.

MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses.

RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38\%) and not able (38\%).

CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease.

}, keywords = {Activities of Daily Living, Aged, Atrophy, Brain, Brain Infarction, Cohort Studies, Disability Evaluation, Female, Health Status, Humans, Leukoaraiosis, Longevity, Longitudinal Studies, Magnetic Resonance Imaging, Male, Prognosis, Regression Analysis, United States}, issn = {1532-5415}, doi = {10.1111/jgs.13068}, author = {Longstreth, W T and Diehr, Paula H and Yee, Laura M and Newman, Anne B and Beauchamp, Norman J} } @article {7466, title = {Blood Pressure and Heart Rate Measures Associated With Increased Risk of Covert Brain Infarction and Worsening Leukoaraiosis in Older Adults.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {37}, year = {2017}, month = {2017 Aug}, pages = {1579-1586}, abstract = {

OBJECTIVE: In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings.

APPROACH AND RESULTS: In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15\% and worsening white matter grade in 27\%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95\% confidence interval, 1.12-1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95\% confidence interval, 1.24-1.69). These findings persisted in secondary and sensitivity analyses.

CONCLUSIONS: Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ.

}, keywords = {Age Factors, Aged, Antihypertensive Agents, Blood Pressure, Cerebral Infarction, Disease Progression, Female, Heart Rate, Humans, Hypertension, Incidence, Leukoaraiosis, Longitudinal Studies, Magnetic Resonance Imaging, Male, Prospective Studies, Pulsatile Flow, Risk Factors, Time Factors, United States}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.117.309298}, author = {Leung, Lester Y and Bartz, Traci M and Rice, Kenneth and Floyd, James and Psaty, Bruce and Gutierrez, Jose and Longstreth, W T and Mukamal, Kenneth J} }