Intensive Blood Pressure Management Preserves Functional Connectivity in Patients with Hypertension from the Systolic Blood Pressure Intervention Randomized Trial.

BACKGROUND AND PURPOSE: The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure. MATERIALS AND METHODS: Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample t test, followed by a voxelwise t test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics. RESULTS: Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group (P = .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities (P = .013). CONCLUSIONS: Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network.

White Matter Lesion Penumbra Shows Abnormalities on Structural and Physiologic MRIs in the Coronary Artery Risk Development in Young Adults Cohort.

BACKGROUND AND PURPOSE: White matter lesions are 1 age-related manifestation of cerebrovascular disease, but subthreshold abnormalities have been identified in nonlesional WM. We hypothesized that structural and physiologic MR imaging findings of early cerebrovascular disease can be measured in middle-aged subjects in tissue adjacent to WM lesions, termed "penumbra." MATERIALS AND METHODS: WM lesions were defined using automated segmentation in 463 subjects, 43-56 years of age, from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal observational cohort study. We described 0- to 2-mm and 2- to 4-mm-thick spatially defined penumbral WM tissue ROIs as rings surrounding WM lesions. The remaining WM was defined as distant normal-appearing WM. Mean signal intensities were measured for FLAIR, T1-, and T2-weighted images, and from fractional anisotropy, mean diffusivity, CBF, and vascular reactivity maps. Group comparisons were made using Kruskal-Wallis and pair-wise t tests. RESULTS: Lesion volumes averaged 0.738 ± 0.842 cm3 (range, 0.005-7.27 cm3). Mean signal intensity for FLAIR, T2, and mean diffusivity was increased, while T1, fractional anisotropy, and CBF were decreased in white matter lesions versus distant normal-appearing WM, with penumbral tissues showing graded intermediate values (corrected P < .001 for all group/parameter comparisons). Vascular reactivity was significantly elevated in white matter lesions and penumbral tissue compared with distant normal-appearing white matter (corrected P ≤ .001). CONCLUSIONS: Even in relatively healthy 43- to 56-year-old subjects with small white matter lesion burden, structural and functional MR imaging in penumbral tissue reveals significant signal abnormalities versus white matter lesions and other normal WM. Findings suggest that the onset of WM injury starts by middle age and involves substantially more tissue than evident from focal white matter lesions visualized on structural imaging.

Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

OBJECTIVE: To assess the evidence for the use of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) in the diagnosis of patients with acute ischemic stroke. METHODS: We systematically analyzed the literature from 1966 to January 2008 to address the diagnostic and prognostic value of DWI and PWI. RESULTS AND RECOMMENDATIONS: DWI is established as useful and should be considered more useful than noncontrast CT for the diagnosis of acute ischemic stroke within 12 hours of symptom onset. DWI should be performed for the most accurate diagnosis of acute ischemic stroke (Level A); however, the sensitivity of DWI for the diagnosis of ischemic stroke in a general sample of patients with possible acute stroke is not perfect. The diagnostic accuracy of DWI in evaluating cerebral hemorrhage is outside the scope of this guideline. On the basis of Class II and III evidence, baseline DWI volumes probably predict baseline stroke severity in anterior territory stroke (Level B) but possibly do not in vertebrobasilar artery territory stroke (Level C). Baseline DWI lesion volumes probably predict (final) infarct volumes (Level B) and possibly predict early and late clinical outcome measures (Level C). Baseline PWI volumes predict to a lesser degree the baseline stroke severity compared with DWI (Level C). There is insufficient evidence to support or refute the value of PWI in diagnosing acute ischemic stroke (Level U).

Automated Bayesian segmentation of microvascular white-matter lesions in the ACCORD-MIND study.

PURPOSE: Automatic brain-lesion segmentation has the potential to greatly expand the analysis of the relationships between brain function and lesion locations in large-scale epidemiologic studies, such as the ACCORD-MIND study. In this manuscript we describe the design and evaluation of a Bayesian lesion-segmentation method, with the expectation that our approach would segment white-matter brain lesions in MR images without user intervention. MATERIALS AND METHODS: Each ACCORD-MIND subject has T1-weighted, T2-weighted, spin-density-weighted, and FLAIR sequences. The training portion of our algorithm first registers training images to a standard coordinate space; then, it collects statistics that capture signal-intensity information, and residual spatial variability of normal structures and lesions. The classification portion of our algorithm then uses these statistics to segment lesions in images from new subjects, without the need for user intervention. We evaluated this algorithm using 42 subjects with primarily white-matter lesions from the ACCORD-MIND project. RESULTS: Our experiments demonstrated high classification accuracy, using an expert neuroradiologist as a standard. CONCLUSIONS: A Bayesian lesion-segmentation algorithm that collects multi-channel signal-intensity and spatial information from MR images of the brain shows potential for accurately segmenting brain lesions in images obtained from subjects not used in training.

Magnocellular and parvocellular visual pathways have different blood oxygen level-dependent signal time courses in human primary visual cortex.

PURPOSE: The magnocellular and parvocellular pathways (M and P pathways) are the major pathways of the visual system, with distinct histologic and physiologic properties that may also have different metabolic characteristics. We hypothesize that the differences of the 2 visual pathways would also manifest as differences in the signal time course of blood oxygen level-dependent functional MR imaging (BOLD fMRI). The differences in BOLD signal time course may provide insight into the metabolic requirements of the 2 pathways. METHODS: Eleven fMRI sessions on 6 subjects were performed using stimuli that preferentially activated the 2 pathways. Regions commonly activated by both the M and P stimuli in the primary visual cortex (V1) were determined, and the contrast elicited by the stimulus, time-to-peak (TTP), and the full width at half maximum (FWHM) of the BOLD signal time course were measured. RESULTS: The functional stimuli activated cortical regions described previously in the literature, such as V1, V4, and V5. Within V1, the TTP of the signal time course of the 2 stimuli were statistically different, with the P stimulus generating TTPs that were on average 12% faster than the M stimulus (P = .0037). CONCLUSION: We have demonstrated the ability to functionally differentiate the M and P stimuli in a commonly activated anatomic region. Because the BOLD response is dependent on the ratio of oxyhemoglobin and deoxyhemoglobin in the blood, the difference in the BOLD time course between the 2 stimuli suggests that the oxygen demand of the 2 pathways may be different.

Cognitive correlates of human brain aging: a quantitative magnetic resonance imaging investigation.

The relations between age-related changes in brain structure and neuropsychological test performance in 320 elderly nonclinical volunteers (ages 66-90) were examined by using quantitative MRI data and measures of attention, information processing speed, language, memory, and visuospatial ability. Final path analyses revealed significant brain-behavior relationships for two of the six cognitive measures: the Trail Making Test part B and visual delayed memory. Poorer performance on Trails B was associated with smaller cerebral hemisphere volumes and larger volumes of peripheral CSF, lateral ventricles, and third ventricle. Poorer recall on visual delayed memory was associated with larger volumes of the lateral ventricles and third ventricle. The findings demonstrate a relationship between age-related changes in brain structure and an age-related decline in attention, psychomotor speed, and visual delayed memory. The neurobiological basis for this relationship requires further investigation.

Quantitative proton MR spectroscopic imaging in acute disseminated encephalomyelitis.

Serial MR imaging and quantitative proton MR spectroscopic imaging (MRSI) findings of a 4-year-old boy with acute disseminated encephalomyelitis (ADEM) are reported. Over a 2-month period characterized by an initial illness and two relapses, each with full recovery, MR imaging exhibited the appearance and disappearance of multifocal lesions throughout the CNS that correlated only partly with the neurologic impairment. During one relapse, MRSI revealed low levels of N-acetylaspartate (NAA) within the regions of prolonged T2 signal intensity. All other metabolites were normal. At follow-up, the MR imaging and MRSI abnormalities had fully resolved. MRSI might play an important role in the diagnosis of ADEM, as well as in the elucidation of underlying pathophysiologic processes in this poorly defined disorder of children. This case demonstrates that reduced levels of NAA are not always associated with neuronal loss, irreversible tissue damage, or poor neurologic outcome.

Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure. METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified. RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension. CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.

One-year age changes in MRI brain volumes in older adults.

Longitudinal studies indicate that declines in cognition and memory accelerate after age 70 years. The neuroanatomic and neurophysiologic underpinnings of cognitive change are unclear, as there is little information on longitudinal brain changes. We are conducting a longitudinal neuroimaging study of nondemented older participants in the Baltimore Longitudinal Study of Aging. This report focuses on age and sex differences in brain structure measured by magnetic resonance imaging during the first two annual evaluations. Cross-sectional results from 116 participants aged 59-85 years reveal significantly larger ventricular volumes and smaller gray and white matter volumes in older compared with younger participants and in men compared with women. Regional brain volumes show that the effects of age and sex are not uniform across brain regions. Age differences are greatest for the parietal region. Sex differences tend to be larger for frontal and temporal than parietal and occipital regions. Longitudinal analysis demonstrates an increase of 1526 mm(3) in ventricular volume over 1 year, but no detectable change in total or regional brain volumes. Definition of the pattern and rate of longitudinal brain changes will facilitate the detection of pathological brain changes, which may be predictors of dementia.

CPT-EIA assays for the detection of vancomycin resistant vanA and vanB genes in enterococci.

Cycling Probe Technology (CPT) was combined with a colorimetric enzyme-immuno assay (EIA) to develop two assays for the detection of vanA and vanB genes in vancomycin resistant enterococci (VRE). The CPT-EIA assay employs a gene-specific fluorescein labeled DNA-RNA-DNA probe that gets cleaved within the probe : target duplex. The cleaved DNA probe fragments dissociate from the target, making it available for further cycling. Following the separation of cleaved probe fragments, anti-fluorescein-horseradish peroxidase antibodies are used for the detection of uncleaved probes. The two CPT-EIA assays were used to screen a collection of 440 clinical isolates (Modrusan et al., 1999). All of the 154 VanA and 131 VanB isolates were correctly identified in the vanA and vanB CPT-EIA, respectively. The VanA and VanB isolates were differentiated from vancomycin sensitive enterococci (VSE) and also from the VanC isolates. In addition, an accurate VRE detection in the CPT-EIA assay was shown with cultures grown on eight different media.

Neuroimaging variables related to development of Secondary Attention Deficit Hyperactivity Disorder after closed head injury in children and adolescents.

OBJECTIVE: To characterize children who develop Secondary Attention Deficit Hyperactivity Disorder (S-ADHD) after severe and moderate closed head injury (CHI) according to neuroimaging variables. METHOD: Ninety-nine children from 4-19 years who suffered severe and moderate CHI were prospectively followed for a year after injury. Premorbid psychiatric status was determined by administration to the parent of a structured psychiatric interview. This interview was readministered 1 year after injury to determine the presence of post-closed head injury S-ADHD. An MRI was performed 3 months after injury to define lesion locations and volumes. RESULTS: A set of multiple logistic regression models determined that the odds of developing S-ADHD were 3.64 times higher among children with thalamus injury, and 3.15 times higher among children with basal ganglia injury. There was no significant difference in lesion volumes in any of the locations of interest between the group who developed S-ADHD and the group who did not develop S-ADHD. CONCLUSION: The data support an association between S-ADHD and injury in either or both the thalamus and basal ganglia, but they do not definitively demonstrate whether injury in either structure has an effect on S-ADHD in the absence of injury in the other.

Is the spatial distribution of brain lesions associated with closed-head injury predictive of subsequent development of attention-deficit/hyperactivity disorder? Analysis with brain-image database.

PURPOSE: To determine whether there is an association between the spatial distribution of lesions detected at magnetic resonance (MR) imaging of the brain in children after closed-head injury and the development of secondary attention-deficit/hyperactivity disorder (ADHD). MATERIALS AND METHODS: Data obtained from 76 children without prior history of ADHD were analyzed. MR images were obtained 3 months after closed-head injury. After manual delineation of lesions, images were registered to the Talairach coordinate system. For each subject, registered images and secondary ADHD status were integrated into a brain-image database, which contains depiction (visualization) and statistical analysis software. Using this database, we assessed visually the spatial distributions of lesions and performed statistical analysis of image and clinical variables. RESULTS: Of the 76 children, 15 developed secondary ADHD. Depiction of the data suggested that children who developed secondary ADHD had more lesions in the right putamen than children who did not develop secondary ADHD; this impression was confirmed statistically. After Bonferroni correction, we could not demonstrate significant differences between secondary ADHD status and lesion burdens for the right caudate nucleus or the right globus pallidus. CONCLUSION: Closed-head injury-induced lesions in the right putamen in children are associated with subsequent development of secondary ADHD. Depiction software is useful in guiding statistical analysis of image data.

Neuroanatomic and functional correlates of depressed mood: the Cardiovascular Health Study.

Although a number of studies suggest an association between stroke and depression, few have examined the relation between magnetic resonance imaging (MRI)-identified lesions and depression among community-dwelling older adults. This cross-sectional study sought to assess the association between MRI infarcts in the basal ganglia and non-basal-ganglia areas, potential functional consequences of these lesions, and depressive symptomatology in 3,371 US men and women aged 65 years or older who participated in the Cardiovascular Health Study between 1992 and 1994. By using multiple linear regression models, the authors found that after adjustment for age, gender, and stroke history, Center for Epidemiologic Studies Depression Scale scores were independently associated with non-basal-ganglia lesions (p = 0.04) but were not independently associated with basal ganglia lesions (p = 0.11). When measures of physical disability and cognitive impairment were added to the models, these measures displaced MRI-identified infarcts in their association with depressive symptoms. In additional models, hemispheric location and size of the basal ganglia lesion were found to have no relation to depression levels. These results suggest that the functional consequences of cerebrovascular disease may be the causal pathway by which basal ganglia and non-basal-ganglia lesions are associated with depressive symptomatology.

Nonlinear elastic registration of brain images with tumor pathology using a biomechanical model.

A biomechanical model of the brain is presented, using a finite-element formulation. Emphasis is given to the modeling of the soft-tissue deformations induced by the growth of tumors and its application to the registration of anatomical atlases, with images from patients presenting such pathologies. First, an estimate of the anatomy prior to the tumor growth is obtained through a simulated biomechanical contraction of the tumor region. Then a normal-to-normal atlas registration to this estimated pre-tumor anatomy is applied. Finally, the deformation from the tumor-growth model is applied to the resultant registered atlas, producing an atlas that has been deformed to fully register to the patient images. The process of tumor growth is simulated in a nonlinear optimization framework, which is driven by anatomical features such as boundaries of brain structures. The deformation of the surrounding tissue is estimated using a nonlinear elastic model of soft tissue under the boundary conditions imposed by the skull, ventricles, and the falx and tentorium. A preliminary two-dimensional (2-D) implementation is presented in this paper, and tested on both simulated and patient data. One of the long-term goals of this work is to use anatomical brain atlases to estimate the locations of important brain structures in the brain and to use these estimates in presurgical and radiosurgical planning systems.

Detection of nucleic acids by cycling probe technology on magnetic particles: high sensitivity and ease of separation.

Cycling Probe Technology (CPT) is a signal amplification system that allows detection of nucleic acid target sequences without target amplification. CPT employs a sequence specific chimeric probe, typically DNA-RNA-DNA, which hybridizes to a complementary target DNA sequence and becomes a substrate for RNase H. Cleavage occurs at the RNA internucleotide linkages and results in dissociation of the probe from the target, thereby making it available for the next probe molecule. This communication describes the use of oligonucleotides attached to solid supports for target capture and release followed by solution and solid phase cycling. Through the attachment of chimeric probes to Sera-Mag magnetic particles (SMP) a simple and effective method of separating the cleaved probe from non-cycled probe has been developed. By capturing the target DNA on particles and separating it from the extraneous non-specific DNA we are able to dramatically reduce background and thus discriminate between samples of Methicillin Resistant (MRSA) and Methicillin Sensitive (MSSA) Staphylococcus Aureus. We conjugated oligonucleotide probes to SMPs (approximately 1 um) and Nylon beads (NB) which were coated with ID Biomedical's proprietary coating materials (R, patent pending). The general structure of the constructs is shown below: [table: see text]

Prevalence and anatomic characteristics of infarct-like lesions on MR images of middle-aged adults: the atherosclerosis risk in communities study.

BACKGROUND AND PURPOSE: MR imaging has revealed putative evidence of subclinical cerebrovascular disease (CVD) as reflected by white matter signal changes and infarct-like lesions (ILLs). Nonetheless, the prevalence of this condition in the general population has been defined only to a limited extent. We herein report the prevalence and anatomic characteristics of ILLs seen on cranial MR images obtained as part of a population-based study of cardiovascular disease in middle-aged adults. These results are contrasted to those of previous similar studies, particularly those of an elderly population in the Cardiovascular Health Study (CHS). METHODS: This Atherosclerosis Risk in Communities (ARIC) cohort consists of a probability sample of community-living persons who were 55 to 72 years old at the time of MR examination. MR imaging of 1890 participants was performed at two ARIC field centers, based on a common protocol. MR studies were evaluated by trained readers at the MR Reading Center using original digital data displayed on a high-resolution workstation. The measures of lesion size, anatomic location, and signal intensity were collected. The definition for an ILL was a non-mass, hyperintense region with an arterial vascular distribution on spin-density and T2-weighted images. RESULTS: Two hundred ninety participants had ILLs, for an overall prevalence of 15.3%. Eighty-two percent of participants with ILLs had lesions that were 3 mm or larger in maximal dimension, although 87% of these lesions were 20 mm or smaller in maximal dimension. The prevalence of ILLs increased with age, from 7.9% in the 55- to 59-year-old age group to 22.9% in the 65- to 72-year-old age group (P < .001). Lesion prevalence was greater in black (20.7%) than in white persons (10.2% [P < .0001]), but did not differ significantly between male and female participants. The basal ganglia and thalamic region was the most commonly affected anatomic site, accounting for 78.9% of the lesions. CONCLUSION: Considering that the prevalence of self-reported stroke or transient ischemic attack in ARIC participants is 1.5%, these results suggest that there is significantly more subclinical than clinical CVD in the general population. Furthermore, the prevalence of this subclinical disease increases with age, and is greater in black persons. ILLs are dominated by "lacunae" in the basal ganglia and thalamus. These results are, in general, similar to those of a comparable study of elderly participants in the CHS, except for a 60% lower prevalence of ILLs in this younger population.