Norman J. Beauchamp

Incidence, manifestations, and predictors of worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.

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≤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. Conclusion— 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.

Silent MRI infarcts and the risk of future stroke The cardiovascular health study

Background: Silent infarcts are commonly discovered on cranial MRI in the elderly. Objective: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors. Methods: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts. Results: Approximately 28% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes). Conclusion: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.

White Matter Hyperintensity on Cranial Magnetic Resonance Imaging A Predictor of Stroke

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 ≥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 ≥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.

Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study.

Background and Purpose— MRI-defined infarcts are common in the elderly. We sought to explore incidence, manifestations, and predictors of such infarcts. Methods— The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of 5888 people aged ≥65 years. Participants have had extensive baseline and follow-up evaluations; 1433 participants underwent 2 MRI scans separated by 5 years and had no infarcts on initial MRI. Results— On follow-up MRI, 254 participants (17.7%) had 1 or more infarcts. Most were single (75.6%), subcortical (79.9%), and small (3 to 20 mm in 87.0%). Only 11.4% of those with infarcts experienced a documented transient ischemic attack or stroke between the scans. Although participants were similar at initial MRI, those with MRI-defined infarcts on follow-up experienced greater decline than those without infarcts on the Modified Mini-Mental State Examination and Digit-Symbol Substitution test (both P <0.01). Severity of white matter changes on initial MRI was the strongest predictor of incident infarcts. When it was excluded from stepwise multivariable models, predictors were serum creatinine, age, and ankle-arm index. Conclusions— Incident MRI-defined infarcts commonly affect the elderly. Most are small, subcortical, and not associated with acute symptoms recognized as a transient ischemic attack or stroke. Nonetheless, they cannot be considered silent because of their association with subtle cognitive deficits. These covert infarcts are associated with white matter changes, which may share a common pathophysiology. Whether control of vascular risk factors, such as blood pressure, would reduce the risk of developing these infarcts and associated cognitive decline deserves further investigation.

Risk Factors for Dementia in the Cardiovascular Health Cognition Study

Background: The Cardiovascular Health Cognition Study has evaluated the determinants of dementia among 3,608 participants that had a magnetic resonance imaging (MRI) of the brain in 1991 and were followed to 1998–1999. Methods: There were 480 incident dementia cases, 330 (69%) were classified as Alzheimer’s disease (AD). Results: In univariate analysis, low scores on the Modified Mini-Mental State Examination (3MSE) and on the Digit Symbol Substitution Test as well as declines in scores over time prior to the development of dementia were significant predictors of dementia. A high ventricular grade on the MRI (atrophy) as well as high white matter grade, a number of brain infarcts on the MRI were all determinants of dementia. Apolipoprotein E Ε4 (ApoE-4) was also a powerful predictor of dementia. In a multivariate Cox proportional hazards model controlling for race, gender and grade, the hazard ratios for age (1.1), 3MSE score (0.9), ventricular size (1.4), white matter grade (1.8), presence of large infarcts >3 mm (1.3) and ApoE-4 (2.1) were significant predictors of dementia. The combination of an ApoE-4 genotype, 3MSE score <90, ≧5 ventricular grade, ≧3 white matter grade at the time of the MRI were associated with a 17-fold increased risk (95% CI: 8.6–34.9) of dementia as compared to individuals with none of the above attributes. Conclusions: Measures of cognition, ApoE-4 and MRI of the brain are strong predictors of both dementia and of AD.

Evaluation of Dementia in the Cardiovascular Health Cognition Study

Objective: To describe a methodology to evaluate dementia and frequency of different types of dementia and prevalence of the Cardiovascular Health Study (CHS). Methods: The CHS is a longitudinal study of cardiovascular disease among community-dwelling individuals over the age of 65. Of the 5,888 participants in the original study, 3,608 had a magnetic resonance imaging (MRI) of the brain in 1991, and formed the cohort for the dementia study. The CHS included yearly measures of cognitive function and, from 1998 to 2000, participants were evaluated for dementia by detailed neurological, and neuropsychological examinations. The possible cases of dementia and mild cognitive impairment (MCI) were adjudicated by a review committee of neurologists and psychiatrists. Results: There were 480 cases of (13.3%) incident dementia in the total sample, 227 (6.3%) prevalent dementia, 577 (16.0%) MCI, and 2,318 (64.4%) normal. The adjudication committee classified 69% of the incident dementia as Alzheimer’s disease (AD), 11% as vascular dementia (VaD), 16% as both, and 4% as other types. There was a substantial agreement between pre- and postMRI diagnosis of types of dementia. The frequency of dementia within the CHS cohort which survived to the end of the study in 1998–1999, was 13.5% for white men, 14.5% for white women, 22.2% for black men and 23.4% for black women. Conclusion: The CHS has developed a methodology for longitudinal studies of dementia in large cohorts and represents the largest study of dementia including cognitive testing, MRI and genetic markers.

A Pilot Randomized Trial of Induced Blood Pressure Elevation: Effects on Function and Focal Perfusion in Acute and Subacute Stroke

Background: Small, unrandomized studies have indicated that pharmacologically induced blood pressure elevation may improve function in ischemic stroke, presumably by improving blood flow to ischemic, but noninfarcted tissue (which may be indicated by diffusion-perfusion mismatch on MRI). We conducted a pilot, randomized trial to evaluate effects of pharmacologically induced blood pressure elevation on function and perfusion in acute stroke. Methods: Consecutive series of patients with large diffusion-perfusion mismatch were randomly assigned to induced blood pressure elevation (‘treated’ patients, n = 9) or conventional management (‘untreated’ patients, n = 6). Results: There were no significant differences between groups at baseline. NIH Stroke Scale (NIHSS) scores were lower (better) in treated versus untreated patients at day 3 (mean 5.6 vs. 12.3; p = 0.01) and week 6–8 (mean 2.8 vs. 9.7; p < 0.04). Treated (but not untreated) patients showed significant improvement from day 1 to day 3 in NIHSS score (from mean 10.2 to 5.6; p < 0.002), cognitive score (from mean 58.7 to 27.9% errors; p < 0.002), and volume of hypoperfused tissue (mean 132 to 58 ml; p < 0.02). High Pearson correlations between the mean arterial pressure (MAP) and accuracy on daily cognitive tests indicated that functional changes were due to changes in MAP. Conclusion: Results warrant a full-scale, double-blind clinical trial to evaluate the efficacy and risk of induced blood pressure elevation in selective patients with acute/subacute stroke.

Absolute Quantitation of Diffusion Constants in Human Stroke

BACKGROUND AND PURPOSE Animal studies have shown that MR diffusion imaging can outline acute ischemic regions before irreversible damage (infarction) occurs. To study evolution of ischemic lesions in humans, it is therefore important to quantify absolute diffusion constants (D values), but quantitation has not been reproducible among different clinics. These problems are explained, and a method for reproducible quantitation is suggested. METHODS Diffusion-weighted and absolute diffusion images were acquired, and the absolute apparent diffusion constants in three orthogonal spatial directions (Dxx, Dyy, and Dzz) were measured. These were combined to calculate images of the orientation-independent apparent diffusion parameter Dav = 1/3 Trace[D] = 1/3(Dxx + Dyy + Dzz). Values of the individual diffusion constants and Dav were evaluated in 6 patients and 6 normal volunteers. RESULTS Patient data show that comparison of diffusion constants between contralateral and ipsilateral hemispheres after ischemia may give results varying by more than 100% depending on orientation. Findings in normal-appearing regions containing a mixture of gray and white matter in patients (n = 5) and in normal volunteers (n = 6) show that Dav = (0.92+/-0.11) x 10(-3) mm2/s, with a small intersubject variation, whereas Dxx, Dyy, and Dzz vary strongly. Hemispheric ratios (ipsilateral/contralateral [I/C]) in these subjects were (I/C)Dav = 1.00+/-0.05, (I/C)Dxx = 1.02+/-0.15, (I/C)Dyy = 1.07+/-0.24, and (I/C)Dzz = 0.96+/-0.28. The individual subjects in this group all had an (I/C)Dav within 10% of unity, while the other three ratios showed intersubject variations as large as 100%. CONCLUSIONS (I/C)Dav ratios are a reliable means to quantitate changes in absolute diffusion constants for the study of stroke evolution independent of tissue orientation, gradient orientation, and diffusion time. The use of these ratios will enable reproducible intersubject and interclinic quantitation.

Relationships of Cerebral MRI Findings to Ultrasonographic Carotid Atherosclerosis in Older Adults: The Cardiovascular Health Study

Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults. While these findings are generally believed to be related to ischemia and atherosclerosis, their relationship to atherosclerosis in the carotid arteries remains to be explored. Study subjects were part of the multicenter Cardiovascular Health Study, a cross-sectional study of 3502 women and men >/=65 years of age undergoing cranial MRI and carotid ultrasonography. MRI infarcts were detected in 1068 participants (29.3%) and measurable carotid plaque in 2745 (75.3%). MRI infarcts, ventricular and sulcal widening, and white matter score were strongly associated with carotid intimal-medial thickness (IMT) and stenosis degree after adjustment for age and sex (all P<0. 01). Associations with plaque characteristics were less strong and less consistent; MRI infarcts were weakly associated only with surface irregularity, and ventricular size was weakly associated only with lesion density (both P<0.04). In contrast, sulcal widening was strongly related to plaque characteristics, with scores being higher in those with heterogeneous and irregular plaque (both P<0. 009). Adjustment for other risk factors, and for carotid IMT/stenosis, removed associations of MRI findings with plaque characteristics except for weak relationships remaining between MRI infarcts and surface irregularity and between sulcal score and heterogeneous plaque (both P<0.03). MRI abnormalities show strong and consistent relationships with increasing carotid IMT and stenosis degree but less strong associations with plaque characteristics, especially after adjusting for IMT and stenosis.

Hypoperfusion of Wernicke's area predicts severity of semantic deficit in acute stroke

Based on earlier findings that the presence of word comprehension impairment (a deficit in the meaning of words, or lexical semantics) in acute stroke was strongly associated with the presence of hypoperfusion or infarct in Wernickes area, we tested the hypothesis that the severity of word comprehension impairment was correlated with the magnitude of delay in perfusion of Wernickes area on magnetic resonance perfusion‐weighted imaging. Eighty patients were prospectively studied within 24 hours of onset or progression of acute left hemisphere stroke symptoms, with diffusion‐weighted imaging, perfusion‐weighted imaging, and detailed language tests. For 50 patients without infarct in Wernickes area, we found a strong Pearson correlation between the rate of errors on a word comprehension test and the mean number of seconds of delay in time‐to‐peak concentration of contrast in Wernickes area, relative to the homologous region on the right. These results add further evidence for the crucial role of Wernickes area (Brodmanns area 22) in word comprehension and indicate that the magnitude of delay on PWI may be a gross indicator of tissue dysfunction.