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.

Using Body Mass Index to Predict Needle Length in Fluoroscopy-Guided Lumbar Punctures.

BACKGROUND AND PURPOSE: Predicting the appropriate needle length to use in oblique interlaminar-approach fluoroscopy-guided lumbar punctures in patients with a large body mass index is difficult. Using the wrong needle length can lead to an increased radiation dose and patient discomfort. We hypothesized that body mass index could help determine the appropriate needle length to use in patients. MATERIALS AND METHODS: We randomly selected patients who underwent oblique interlaminar-approach fluoroscopy-guided lumbar punctures and had cross-sectional imaging of the lumbar spine within 1 year of imaging (n = 50). The distance from the skin to the midlumbar spinal canal (skin-canal distance) at the level of the lumbar puncture was measured by using an oblique angle of 8.6°, which is an average of angles most often used to perform the procedure. A formula was devised using the skin-canal distance and body mass index to predict the appropriate needle length, subsequently confirmed in 45 patients. RESULTS: The body mass index and skin-canal distance were significantly higher (P < .001) in patients who underwent fluoroscopy-guided lumbar puncture with 5- or 7-inch needles (n = 22) than in patients requiring 3.5-inch needles (n = 28). Using linear regression, we determined the formula to predict the needle length as Skin-Canal Distance (inches) = 0.077 × Body Mass Index + 0.88. We found a strong correlation (P < .001) between the predicted and actual skin canal distance in 45 patients, and our formula better predicted the skin-canal distance than others. CONCLUSIONS: We designed a formula that uses body mass index to predict the appropriate needle length in oblique interlaminar-approach fluoroscopy-guided lumbar punctures and validated it by demonstrating a strong correlation between the predicted and actual skin-canal distance.

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation.

BACKGROUND AND PURPOSE: Fluorine-18 florbetapir is a recently developed ß-amyloid plaque positron-emission tomography imaging agent with high sensitivity, specificity, and accuracy in the detection of moderate-to-frequent cerebral cortical ß-amyloid plaque. However, the FDA has expressed concerns about the consistency of interpretation of [(18)F] florbetapir PET brain scans. We hypothesized that incorporating automated cerebral-to-whole-cerebellar standardized uptake value ratios into [(18)F] florbetapir PET brain scan interpretation would reduce this interreader variability. MATERIALS AND METHODS: This randomized, blinded-reader study used previously acquired [(18)F] florbetapir scans from 30 anonymized patients who were enrolled in the Alzheimer's Disease Neuroimaging Initiative 2. In 4 separate, blinded-reading sessions, 5 readers classified 30 cases as positive or negative for significant ß-amyloid deposition either qualitatively alone or qualitatively with additional adjunct software that determined standardized uptake value ratios. A κ coefficient was used to calculate interreader agreement with and without the use of standardized uptake value ratios. RESULTS: There was complete interreader agreement on 20/30 cases of [(18)F] florbetapir PET brain scans by using qualitative interpretation and on 27/30 scans interpreted with the adjunct use of standardized uptake value ratios. The κ coefficient for the studies read with standardized uptake value ratios (0.92) was significantly higher compared with the qualitatively read studies (0.69, P = .006). CONCLUSIONS: Use of standardized uptake value ratios improves interreader agreement in the interpretation of [(18)F] florbetapir images.

Multiple sclerosis: identification of temporal changes in brain lesions with computer-assisted detection software.

Multiple sclerosis (MS) is a chronic disease with a progressing and evolving course. Serial imaging with MRI is the mainstay in monitoring and managing MS patients. In this work we demonstrate the performance of a locally developed computer-assisted detection (CAD) software used to track temporal changes in brain MS lesions. CAD tracks changes in T2-bright MS lesions between two time points on a 3D high-resolution isotropic FLAIR MR sequence of the brain acquired at 3 Tesla. The program consists of an image-processing pipeline, and displays scrollable difference maps used as an aid to the neuroradiologist for assessing lesional change. To assess the value of the software we have compared diagnostic accuracy and duration of interpretation of the CAD-assisted and routine clinical interpretations in 98 randomly chosen, paired MR examinations from 88 patients (68 women, 20 men, mean age 43.5, age range 21-75) with a diagnosis of definite MS. The ground truth was determined by a three-expert panel. In case-wise analysis, CAD interpretation showed higher sensitivity than a clinical report (87% vs 77%, respectively). Lesion-wise analysis demonstrated improved sensitivity of CAD over a routine clinical interpretation of 40%-48%. Mean software-assisted interpretation time was 2.7 min. Our study demonstrates the potential of including CAD software in the workflow of neuroradiology practice for the detection of MS lesional change. Automated quantification of temporal change in MS lesion load may also be used in clinical research, e.g., in drug trials.

Multiple Sclerosis Lesions in the Brain: Computer-Assisted Assessment of Lesion Load Dynamics on 3D FLAIR MR Images.

The detection and monitoring of brain lesions caused by multiple sclerosis is commonly performed with the use of magnetic resonance imaging. Analysis of a large number of images is a time-consuming challenge to the neuroradiologist, that can be accelerated with the assistance of computer-detection software. In 98 baseline and follow-up brain magnetic resonance studies from 88 patients with a diagnosis of multiple sclerosis, we employed locally developed lesion-detection software to assess temporal change in the load of brain lesions and compared its results to routine clinical reports. Analyzing the differences between the follow-up study and the baseline study, the software displays the results in the form of a scrollable axial volume, with the changed lesions highlighted in different colors and superimposed on the baseline reference scan. Disagreements between the software and the clinical readers in the detection of changed lesions were observed only in 11 (11.2%) cases, and the difference did not reach statistical significance (p=0.07). The mean interpretation time with assistance of the software was 2.7±2.2 minutes. We conclude that the performance of the software-assisted interpretation in the analysis of change over time in multiple sclerosis brain lesions is comparable to the performance of clinical readers, with a possibly shorter assessment time. Our study demonstrates the potential of including lesion-detection software in the workflow of neuroradiology practice.

Errata Corrige: The Neuroradiology Journal 25: 17-21, 2012. Multiple Sclerosis Lesions in the Brain: Computer-Assisted Assessment of Lesion Load Dynamics on 3D FLAIR MR Images.

The detection and monitoring of brain lesions caused by multiple sclerosis is commonly performed with the use of magnetic resonance imaging. Analysis of a large number of images is a time-consuming challenge to the neuroradiologist, that can be accelerated with the assistance of computer-detection software. In 98 baseline and follow-up brain magnetic resonance studies from 88 patients with a diagnosis of multiple sclerosis, we employed locally developed lesion-detection software to assess temporal change in the load of brain lesions and compared its results to routine clinical reports. Analyzing the differences between the follow-up study and the baseline study, the software displays the results in the form of a scrollable axial volume, with the changed lesions highlighted in different colors and superimposed on the baseline reference scan. Although disagreements between the software and the clinical readers in the detection of changed lesions were observed only in 12 (12.2%) cases, the difference reached statistical significance (p=0.04). The mean interpretation time with assistance of the software was 2.7±2.2 minutes. We conclude that the performance of the software-assisted interpretation in the analysis of change over time in multiple sclerosis brain lesions is different from the performance of clinical readers, with a possibly shorter assessment time. The software detected more changes from baseline than clinical readers, suggesting a higher sensitivity, which will have to be confirmed on further analysis.

Brain, eye, and face defects as a result of ectopic localization of Sonic hedgehog protein in the developing rostral neural tube.

BACKGROUND: Normal development of the face, eyes, and brain requires the coordinated expression of many genes. One gene that has been implicated in the development of each of these structures encodes the secreted protein, Sonic hedgehog (Shh). During central nervous system development, Shh is required for ventral specification along the entire neural axis. To further explore the role of Shh in chick brain and craniofacial development, we overexpressed Shh in the developing rostral neural tube METHODS: In order to determine if Shh is sufficient to ventralize the forebrain, we localized ectopically recombinant Shh protein to the rostral neural tube of chick embryos. The resulting embryos were evaluated morphologically and by assaying gene expression. RESULTS: Disruption in normal gene expression patterns was observed with a reduction or loss in expression of genes normally expressed in the dorsal forebrain (wnt-3a, wnt-4, and Pax-6) and expansion of ventrally expressed genes dorsally (HNF-3beta, Ptc). In addition to the genetic alterations observed in the neural tube, a craniofacial phenotype characterized by a reduction in many cranial neural crest-derived structures was observed. The eyes of Shh-treated embryos were also malformed. They were small with expansion of the retinal pigmented epithelium, enlarged optic stalks, and a reduction of neural retina. DISCUSSION: The ectopic localization of recombinant Shh protein in the rostral neural tube resulted in severe craniofacial anomalies and alterations of gene expression predicted by other studies. The system employed appears to be a model for studying the embryogenesis of malformations that involve the brain, eyes, and face.

Human cytoplasmic serine hydroxymethyltransferase is an mRNA binding protein.

The 5' untranslated region (UTR) of the human cytoplasmic serine hydroxymethyltransferase (cSHMT) message is alternatively spliced, creating a full-length 5' UTR (LUTR) encoded within exons 1-3 and a shorter UTR (SUTR) that results from excision of exon 2. The role of the 5' UTRs in cSHMT expression was investigated by fusing the cSHMT 5' UTRs to the 5' end of the luciferase gene. Human cSHMT protein at 10 microM inhibits in vitro translation of cSHMT 5' UTR-luciferase fusion mRNA templates by more than 90%, but does not inhibit translation of the luciferase message lacking the UTR. Translation inhibition is independent of amino acid and folate substrate binding to the cSHMT enzyme. The cSHMT SUTR-luciferase mRNA binds to the cSHMT.glycine.5-formyltetrahydrofolate ternary complex with an apparent K(d) of 10 microM. Gel mobility shift assays demonstrate that the human cSHMT protein binds to the cSHMT LUTR-luciferase fusion mRNA in the presence and absence of glycine and 5-formyltetrahydrofolate pentaglutamate. The fusion cSHMT SUTR-luciferase message at 65 microM inhibits the cSHMT-catalyzed cleavage of allothreonine as a partial mixed type inhibitor, reducing both k(cat) and K(m) by 40 and 75%, respectively, while tRNA has no effect on cSHMT catalysis. These studies indicate that the cSHMT protein can bind mRNA, and displays increased affinity for the 5' untranslated region of its mRNA.

Mimosine is a cell-specific antagonist of folate metabolism.

Iron deficiency and iron chelators are known to alter folate metabolism in mammals, but the underlying biochemical mechanisms have not been established. Although many studies have demonstrated that the iron chelators mimosine and deferoxamine inhibit DNA replication in mammalian cells, their mechanism of action remains controversial. The effects of mimosine on folate metabolism were investigated in human MCF-7 cells and SH-SY5Y neuroblastoma. Our findings indicate that mimosine is a folate antagonist and that its effects are cell-specific. MCF-7 cells cultured in the presence of 350 microm mimosine were growth-arrested, whereas mimosine had no effect on SH-SY5Y cell proliferation. Mimosine altered the distribution of folate cofactor forms in MCF-7 cells, indicating that mimosine targets folate metabolism. However, mimosine does not influence folate metabolism in SH-SY5Y neuroblastoma. The effect of mimosine on folate metabolism is associated with decreased cytoplasmic serine hydroxymethyltransferase (cSHMT) expression in MCF-7 cells but not in SH-SY5Y cells. MCF-7 cells exposed to mimosine for 24 h have a 95% reduction in cSHMT protein, and cSHMT promoter activity is reduced over 95%. Transcription of the cSHMT gene is also inhibited by deferoxamine in MCF-7 cells, indicating that mimosine inhibits cSHMT transcription by chelating iron. Analyses of mimosine-resistant MCF-7 cell lines demonstrate that although the effect of mimosine on cell cycle is independent of its effects on cSHMT expression, it inhibits both processes through a common regulatory mechanism.

Molecular cloning, characterization and alternative splicing of the human cytoplasmic serine hydroxymethyltransferase gene.

The human cytoplasmic serine hydroxymethyltransferase (CSHMT) gene was isolated, sequenced and its expression characterized in human MCF-7 mammary carcinoma and SH_5Y5Y neuroblastoma cells. The 23-kb gene contains 12 introns and 13 exons; all splice junctions conform to the gt/ag rule. The open reading frame is interrupted by 10 introns, two of which are positionally conserved within the human mitochondrial SHMT gene. The gene is expressed with 330 nucleotides of 5' untranslated message within three exons. The 5' promoter region does not contain a consensus TATA, and primer extension and 5'-RACE studies suggest that transcription initiation occurs at multiple sites. Consensus motifs for several regulatory proteins, including SP1, mammary and neuronal-specific elements, NF1, a Y-box, and two steroid hormone response elements, are present within the first 408 nucleotides of the 5' promoter region. The human gene is expressed as multiple splice variants in both the 5' untranslated region and within the open reading frame, all due to exon excision. The splicing pattern is cell-specific. At least six CSHMT mRNA splice forms are present in MCF-7 cells; the gene is expressed as a full-length message as well as splice forms that lack exon(s) 2, 9 and 10. In 5Y cells, the predominant form of the message lacks exon 2, which encodes part of the 5' untranslated region, but does not contain deletions within the open reading frame. Western analysis suggests that the CSHMT gene is expressed as a single full-length protein in 5Y cells, but as multiple forms in MCF-7 cells. Multiple tissue Northern blots suggest that the CSHMT message levels and alternative splicing patterns display tissue-specific variations.