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.

bcl-2 antisense therapy chemosensitizes human melanoma in SCID mice.

Malignant melanoma is a prime example of cancers that respond poorly to various treatment modalities including chemotherapy. A number of chemotherapeutic agents have been shown recently to act by inducing apoptosis, a type of cell death antagonized by the bcl-2 gene. Human melanoma expresses Bcl-2 in up to 90% of all cases. In the present study we demonstrate that bcl-2 antisense oligonucleotide treatment improves the chemosensitivity of human melanoma grown in severe combined immunodeficient (SCID) mice. Our findings suggest that reduction of Bcl-2 in melanoma, and possibly also in a variety of other tumors, may be a novel and rational approach to improve chemosensitivity and treatment outcome.

Retrograde amnesia: effects of handling and microwave radiation.

Rats that were irradiated with microwaves immediately after the training trial in a one-trial shock-avoidance learning task retained the conditioned avoidance response 24 hours later. However, rats that were handled a few minutes each day for 3 days before the experiment did not retain the response, although they were capable of learning in a later test.

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.

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.

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.

Autistic features in Joubert syndrome: a genetic disorder with agenesis of the cerebellar vermis.

Recent reports in the literature have suggested a link between abnormalities of the cerebellar vermis and the behavioral syndrome of autism. Joubert syndrome is an autosomal recessive disorder characterized by partial or complete agenesis of the cerebellar vermis. However, there is little behavioral or psychiatric description of patients with this genetic condition. In this report, the neuropsychiatric characteristics of two children with Joubert syndrome are described in detail. One child met DSM-III-R diagnostic criteria for autistic disorder, while the other displayed autistic features. The female child displayed stereotypic behavior and impairments in social interaction and communication, had a markedly restricted repertoire of interests, and showed distress over changes in the environment. The male child demonstrated perseveration and preoccupation with sounds and textures, but had no abnormalities in social interaction. Although both children showed developmental disabilities, the degree of cognitive delay was significantly less than that described in previous reports of children with Joubert syndrome. This report adds to the growing body of evidence implicating cerebellar involvement in developmental disabilities and autistic behavior.

Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects.

Accuracy in in vivo quantitation of brain function with positron emission tomography (PET) has often been limited by partial volume effects. This limitation becomes prominent in studies of aging and degenerative brain diseases where partial volume effects vary with different degrees of atrophy. The present study describes how the actual gray matter (GM) tracer concentration can be estimated using an algorithm that relates the regional fraction of GM to partial volume effects. The regional fraction of GM was determined by magnetic resonance imaging (MRI). The procedure is designated as GM PET. In computer simulations and phantom studies, the GM PET algorithm permitted a 100% recovery of the actual tracer concentration in neocortical GM and hippocampus, irrespective of the GM volume. GM PET was applied in a test case of temporal lobe epilepsy revealing an increase in radiotracer activity in GM that was undetected in the PET image before correction for partial volume effects. In computer simulations, errors in the segmentation of GM and errors in registration of PET and MRI images resulted in less than 15% inaccuracy in the GM PET image. In conclusion, GM PET permits accurate determination of the actual radiotracer concentration in human brain GM in vivo. The method differentiates whether a change in the apparent radiotracer concentration reflects solely an alteration in GM volume or rather a change in radiotracer concentration per unit volume of GM.

Dominant-side intracarotid amobarbital spares comprehension of word meaning.

Abolition of speech production after intracarotid amobarbital injection is generally considered evidence for language laterality. However, complex auditory comprehension may be preserved after injection of the dominant (left) side. The possibility that this sparing may be due to the intracarotid amobarbital injection not adequately deactivating some of the areas responsible for speech comprehension in the posterior part of the hemisphere was tested with a task known to be critically dependent on the left posterotemporal-inferoparietal region, one assessing visuo-verbal semantic relatedness. Even when the intracarotid injection of the left side produced marked deficits of speech production, comprehension of semantic relations was still intact in eight of 15 patients. Ten of these 15 patients also received right carotid injections, none of which affected comprehension of semantic relatedness. These data indicate that the intracarotid amobarbital injection cannot always specify the laterality of all language functions, an important concern when considering surgical procedures in the dominant posterotemporal-inferoparietal region.

Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome.

OBJECTIVE: To provide the first comprehensive magnetic resonance imaging (MRI) assessment of brain in a series of patients with Lesch-Nyhan syndrome (LNS), with emphasis on basal ganglia measurements. DESIGN: Routine readings of MRI studies, repeated reading in random order blinded to subject diagnosis, and 3-dimensional volumetric measures of basal ganglia regions. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Seven patients with LNS who have hypoxanthine guanine phosphoribosyltransferase levels less than 1.6% and characteristic clinical features of the disorder, which include hyperuricemia, cognitive impairment, and dystonic movement disorder, were compared with 7 age-matched control subjects. Five of the 7 patients demonstrated self-injurious behavior. MRI studies were performed using general anesthesia because of the severity of the movement disorder. MAIN OUTCOME MEASURES: Measurement of brain regions from MRI-obtained images. RESULTS: Routine readings described mild cerebral atrophy in 2 of 7 patients, but no caudate or putamen abnormalities were reported. However, on the directed blinded rereading, small caudates were suspected in 5 of 7 cases, and abnormalities in cerebral size and cranium were identified. Volumetric studies of the patients with LNS confirmed a 34% decrease in caudate volume (P<.001), a 17% decrease in total cerebral volume (P<.03), and a 12% decrease in putamen volume (P=.19). CONCLUSIONS: To our knowledge, this is the first demonstration of consistent neuroanatomic abnormalities in LNS. The findings of reduced basal ganglia volume are consistent with the dystonic movement disorder.

Sex differences in brain aging: a quantitative magnetic resonance imaging study.

BACKGROUND: Little is known about the effect of sex on age-related changes in brain structure. METHODS: Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained. RESULTS: Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporoparietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex. CONCLUSIONS: Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.

Relation of education to brain size in normal aging: implications for the reserve hypothesis.

OBJECTIVE: To examine the relations between education and age-related changes in brain structure in a nonclinical sample of elderly adults. BACKGROUND: Education may protect against cognitive decline in late life--an observation that has led to the "reserve" hypothesis of brain aging. Little is known, however, about the effect of education on age-related changes in brain structure. METHODS: Quantitative MRI of the brain was performed in 320 elderly volunteers (age range, 66 to 90 years) living independently in the community (Mini-Mental State Examination scores > or =24), all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images using computer-assisted edge detection and trace methodology. High measurement reliabilities were obtained. RESULTS: Regression analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex interactions, and potential confounders) revealed significant main effects of education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each year of education was associated with an increase in peripheral CSF volume of 1.77 mL (p<0.03). As reported previously, main effects of age (but not education) were observed for all of the remaining brain regions examined, including cerebral hemisphere volume, frontal region area, temporoparietal region area, parieto-occipital region area, lateral (Sylvian) fissure volume, lateral ventricular volume, and third ventricle volume. CONCLUSIONS: The authors' findings demonstrate a relation between education and age-related cortical atrophy in a nonclinical sample of elderly persons, and are consistent with the reserve hypothesis as well as with a small number of brain imaging studies in patients with dementia. The neurobiological basis and functional correlates of this education effect require additional investigation.

Volumetric MRI changes in basal ganglia of children with Tourette's syndrome.

To define the site of pathology in Tourette's syndrome (TS), we performed a volumetric MRI study of basal ganglia structures and lateral ventricles on 37 children with this disorder and 18 controls. There were no statistically significant differences in the size of the right or left caudate, putamen, globus pallidus, or ventricles in these populations. In contrast, there were significant differences for measures of symmetry in the putamen and the lenticular region. Virtually all controls (17 right- and one left-handed) had a left-sided predominance of the putamen, whereas in 13 of 37 TS subjects, a right predominance exceeded that of any control. Statistical comparisons among TS patients, with (n = 18) or without (n = 19) attention-deficit hyperactivity disorder (ADHD), and controls showed significant differences for the volume of the left globus pallidus and for lenticular asymmetry. Post hoc evaluations showed that in the TS + ADHD group, the volume of the left globus pallidus was significantly smaller than the volume of the right and that lenticular asymmetry was due to a greater right-sided predominance in the TS+ADHD group. This study lends further support to proposals that claim the basal ganglia is involved in the pathogenesis of TS and also suggests that the comorbid problem of ADHD is related to regional changes that differ from those primarily associated with tics.

Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1.

To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

Neuronal effects of water-soluble contrast agents.

The in vitro rat hippocampus slice preparation has been utilized to examine the direct neurotoxicity of water-soluble contrast agents. Intraneuronal recordings were obtained from pyramidal cells in the CA1 field of rat hippocampus slices. Synaptic activity was evoked by Schaffer's collateral stimulation. The effects of Na-diatrizoate and metrizamide were studied. Test solutions were 300 to 345 mOsm and had iodine concentrations of 22.5 to 30 mg I/ml which are probably near clinical concentrations. The two effects of the contrast agents are apparent within 10 minutes and reversible within 30 to 45 minutes. The first is an epileptogenic property reflected by repetitive action potentials arising from an early prolonged depolarization. The second effect is a depression of electrical activity characterized by hyperpolarization of the resting membrane potential. Na-diatrizoate predominantly produced the first effect. Metrizamide principally produced the second effect. These results indicate that contrast agent seizure activity is not due to hyperosmolarity but a more direct chemical effect. The depression, however, may be related to a hyperosmolar effect. The differences between the dominant effects of the ionic vs. nonionic agents observed in these experiments seem to correlate with clinical experience and may indicate the etiology of central nervous system neurotoxicity of these drugs.

Neurotoxic effects of water-soluble contrast agents on rat hippocampus.

Electrical activity in cells directly exposed to water-soluble radiographic contrast agents was investigated by intracellular and extracellular recordings from neurons in in vitro rat hippocampus slices. Measurements included extracellular field potentials, intracellular resting membrane potential and membrane conductance, postsynaptic events, action potential configurations and spontaneous electrical activity. The neurons were exposed to test solutions of an ionic contrast agent, sodium diatrizoate, and a nonionic contrast agent, metrizamide, as well as control solutions. The ionic contrast agent produces bursts of action potentials having epileptogenic characteristics which is temporally followed by a depression of all electrical activity. The nonionic contrast agent produces minimal convulsive-like electrical bursts, but does produce a consistent depression of transmembrane electrical potentials, though in a lesser degree than the ionic contrast agents. The excitatory electrical events appear to be related to large depolarizing post-synaptic events while the later electrical depression is at least partially due to hyperpolarization. The depressing effects may be related to the hyperosmolality of the test solutions; however, no excitatory changes are related to hyperosmolality. These results provide the initial data on the neurotoxicity of water-soluble contrast agents at the intraneuronal level.

Neurotoxic effects of water-soluble contrast agents on rat hippocampus: extracellular recordings.

Synaptically evoked extracellular field potentials were obtained from the pyramidal cell layer of the Cal field of rat hippocampus slices. Synaptic activity was evoked by Schaffer's collateral stimulation. The effects of the water-soluble contrast agents Na-diatrizoate and metrizamide, as well as control solutions of NaCl and sucrose, were studied. Test solutions were 300-345 mOsm and had iodine concentrations of 3-30 mg I/ml. The effects of test solutions are apparent within 10 minutes and reversible within 30-45 minutes. Control recordings have a small positive potential, followed by a large negative spike and a final slow positive wave. Contrast agents have two effects. The first is an epileptogenic property characterized by repetitive negative spikes arising from an extended slow positive field. The second effect is a depression characterized by a reduction in the amplitude of the synaptically evoked fields, particularly the negative spikes. Na-diatrizoate predominately produces the first effect, while metrizamide principally produces the second. Hyperosmolar solutions only produce depression. These results correlate well with the clinical setting where Na-diatrizoate is a potent convulsant, while metrizamide produces symptoms compatible with neuronal depression. These results indicate that contrast agent seizure activity is not due to hyperosmolarity but to a more direct chemical effect. The depression, however, may be related to a hyperosmolar effect.

Effects of radiographic contrast agents on spinal cord physiology.

Segmental reflexes in the spinal cords of cats anesthetized with chloralose were used to evaluate the neurophysiologic effects of radiographic contrast agents. The exposed lumbar spinal cord was bathed with concentrations of ionic and nonionic agents including saline, sodium meglumine diatrizoate, meglumine iothalamate, meglumine iocarmate, and metrizamide. The following responses were evaluated: flexor and extensor monosynaptic reflex; polysynaptic flexion reflexes; spontaneous ventral root activity. Hypertonic solutions generally produced a transient decrease in all reflex activity for up to 1 hour. Isotonic solutions produced no significant changes in the monosynaptic responses, but an increase in amplitude of polysynaptic responses, and increased spontaneous activity. The usual facilitory effects of flexion reflex on the flexor monosynaptic reflex were unchanged, but the expected inhibitory effect of flexion reflex on the extensor monosynaptic reflex was changed to excitatory. The relative ability to produced these effects was sodium meglumine diatrizoate greater than meglumine iothalamate greater than meglumine iocarmate greater than metrizamide.

Iohexol cerebral angiography. Multicenter clinical trial.

Ionic contrast media currently used in cerebral angiography frequently cause discomfort due to hyperosmolality. This double-blind, multicenter trial compared two ionic media, meglumine iothalamate and meglumine-Na diatrizoate, with the new nonionic agent, iohexol, in 277 patients undergoing cerebral angiography. Vital signs, cardiovascular changes, and neurologic status were evaluated before, during, and after injection. Patients were observed for adverse reactions for up to 24 hours following studies. Patient discomfort and image quality were evaluated. Visualization was good or excellent with all media studied. No significant physiological differences were observed between the ionic and iohexol groups, but fewer iohexol patients experienced large increases (greater than 20 mmHg) in systolic blood pressure. Iohexol patients experienced significantly less discomfort; ionic patients reported severe discomfort 21/2 times more often. This finding was attributed to iohexol's low osmolality. Iohexol may be indicated particularly for use in selective angiograms where discomfort is a factor and for patients suspected of having blood-brain barrier disruption.

Rapid diagnosis of Legionella infection by a nonisotopic in situ hybridization method.

The authors report a nonradioactive adaptation of DNA hybridization technology for the direct detection of Legionella organisms in situ in routinely processed histologic specimens. The probe used consisted of synthetic oligodeoxynucleotides, complementary to the ribosomal RNA of all clinically relevant Legionella species, labeled with biotinylated dUTP at their 3' ends. By in situ DNA hybridization and detection with an avidin-alkaline phosphatase complex. Legionella was visualized by light microscopy within the alveoli of lung specimens in 9 of 13 direct fluorescent antibody- or culture-positive cases of Legionnaires' disease. No cross-hybridization was observed in lung specimens infected with Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, or other pathogens. The authors' results illustrate a novel adaptation of in situ DNA hybridization techniques, usually used for viruses, to the detection of a bacterial organism. The method enables direct visualization of bacterial nucleic acid in infected tissues and may facilitate early diagnosis and treatment of legionellosis.