The Profiles and Correlates of Psychopathology in Adolescents and Adults with Williams, Fragile X and Prader-Willi Syndromes.

Psychopathology is prevalent in Williams (WS), fragile X (FXS) and Prader-Willi (PWS) syndromes. However, little is known about the potential correlates of psychopathology in these groups. A questionnaire study was completed by 111 caregivers of individuals with WS (n = 35); FXS (n = 50) and PWS (n = 26). Mean age was 26 years (range 12-57 years); 74 (67%) were male. Multiple regression analyses indicated that higher rates of health problems and sensory impairments predicted higher psychopathology in WS (p < .0001). In PWS, poorer adaptive ability predicted higher overall psychiatric disturbance (p = .001), generalised anxiety (p = .006) and hyperactivity (p = .003). There were no significant predictors in FXS. This study highlights dissociations in the potential risk markers of psychopathology between genetic syndromes. Implications for intervention are discussed.

The assessment of fetal brain growth in diabetic pregnancy using in utero magnetic resonance imaging.

AIM: To assess fetal brain growth over the third trimester in pregnant women with diabetes using in utero magnetic resonance imaging (iuMRI) to determine if greater brain growth occurs in type 1 (T1DM) when compared to gestational (GDM) diabetes mellitus. MATERIALS AND METHODS: Each consented participant was scanned at three fixed times during the third trimester using iuMRI. One hundred and fifty-seven patients were approached, 48 participants were recruited, and 36 complete data sets were analysed. Three-dimensional (3D) iuMRI volume data sets were manually segmented using software to construct models of the fetal brain from which brain volumes could be calculated. Inter-rater analysis was performed, and volume differences and growth rates were compared between T1DM and GDM. RESULTS: Recruitment proved difficult with low uptake and high attrition rates (77.1%). Inter-rater analysis revealed excellent correlation (intraclass correlation coefficient=0.93, p<0.001) and agreement with no significant difference between operators (p=0.194). There was no evidence of increased brain volume in the T1DM group. Growth rates between visit 1 and 3 for T1DM and GDM were not significantly different (p=0.095). CONCLUSION: T1DM brain volumes were not significantly larger than GDM volumes and there was no significant divergence of brain growth over the third trimester. Constructing volume models from 3D iuMRI acquisitions is a novel technique that can be used to assess fetal brain growth. No specialist software or knowledge is required. Larger studies attempting to recruit pregnant women in the later stages of pregnancy should employ multicentre recruitment to overcome recruitment difficulties and high attrition rates.

Surface reconstructions of foetal brain abnormalities using ultrafast steady state 3D acquisitions.

MRI of the foetal brain in utero is performed in routine clinical practice using sequences that produce two-dimensional (2D) images. Recent developments in image post-processing have allowed the construction of three-dimensional (3D) volume data sets from 2D images acquired in different anatomical planes, but these have limitations due to the unpredictable nature of foetal movement. These limitations have been overcome by development of several different advanced computer techniques, which require specialist knowledge, software, and processing methods, which are rarely available in routine clinical settings. Our aim was to develop a technique that can be used in routine clinical situations without the need for custom-developed or expensive software by utilizing MRI sequences that can produce a 3D data set in "ultrafast" timescales. The 3D dataset, combined with versatile image post-processing and visualization techniques, has resulted in the production of high-resolution images of foetal brain surfaces in utero. The aim of this paper is to demonstrate our methods and early results by way of a pictorial review illustrating a range of developmental brain disease in utero.

MRI of the foetal brain using a rapid 3D steady-state sequence.

OBJECTIVE: To evaluate the capacity of a rapid T2 weighted three-dimensional (3D) sequence to diagnose foetal brain abnormalities by comparing the results with current two-dimensional (2D) methods. We have also made assessments of the estimates of energy deposition using those methods. METHODS: 50 pregnant females were included in this study under the guidance of the institutional review board. All their foetuses had suspected brain abnormalities on antenatal ultrasonography or were at increased risk of a brain malformation based on the results of an earlier pregnancy. All the foetuses had a routine MR protocol that includes three orthogonal plane single-shot fast-spin echoes and 2D steady-state sequences. In addition, a 3D rapid steady-state sequence of the foetal brain was performed (acquisition time approximately 40 s), and the standard and 3D sequences were reported independently and the results were compared. The specific absorption rate (SAR) predicted by the scanner was recorded in 12 cases in order to estimate the energy deposited by the three sequences. RESULTS: The 3D rapid steady-state sequences produced diagnostic-quality images in 41/50 (82%) cases. All the failures were in second trimester foetuses (9/26-35% failure rate). There was a discrepancy between the standard report and findings using the 3D sequence in 2/41 of the foetuses with good-quality 3D imaging. The predicted SAR deposition of the 3D steady-state sequences was comparable with the single-shot fast-spin echo sequence. CONCLUSION: Our initial assessments of a 3D rapid steady-state sequence to image the foetus are encouraging in terms of diagnostic information and acceptable energy deposition values. The high failure rate in second trimester foetuses probably relates to the greater mobility of the smaller foetuses, and improvements in the 3D sequence are required in terms of reduced acquisition time and higher resolution. ADVANCES IN KNOWLEDGE: We have shown that 3D T2 weighted images of the foetal brain can be acquired in a clinical setting and produce diagnostic-quality imaging in a high proportion of cases. The success rate in acquiring diagnostic-quality images is related to gestational age. Good-quality images were obtained in all third trimester foetuses but only in approximately two-thirds of second trimester foetuses. This probably reflects the problem of the greater mobility of second trimester foetuses. 3D T2 weighted acquisitions have great potential for improving the antenatal diagnosis of foetal brain abnormalities and may reduce the time that a pregnant female needs to spend on the MR scanner.

Note: A robust low-cost high-sensitivity subangstrom bidirectional displacement sensor.

The design of a simple, robust, low-cost, and bidirectional displacement sensor with subangstrom resolution is described. A small gold plate is attached to the object, whose displacement is to be measured, and a small gold tip is brought into contact with the plate, establishing a reference current between the two. Movements of the gold plate away from the tip lead to a change in the tip-plate current; the reference current is then re-established by moving the tip using a simple magnetic actuator. The resolution of the sensor has been calibrated using an interferometer and was shown to be as high as 0.3 Å per system count. Potential applications of the sensor are numerous, including microbar air pressure measurement, motion and infrasound detection, thermal sensing, and gravitational field and relativistic gravity wave measurement.

Brain choline concentration. Early quantitative marker of ischemia and infarct expansion?

OBJECTIVE: Better prediction of tissue prognosis in acute stroke might improve treatment decisions. We hypothesized that there are metabolic ischemic disturbances measurable noninvasively by proton magnetic resonance spectroscopy ((1)H MRS) that occur earlier than any structural changes visible on diffusion-tensor imaging (DTI), which may therefore serve for territorial identification of tissue at risk. METHODS: We performed multivoxel (1)H MRS plus DTI within a maximum of 26 hours, and DTI at 3-7 days, after ischemic stroke. We compared choline, lactate, N-acetylaspartate, and creatine concentrations in normal-appearing voxels that became infarcted (infarct expansion) with normal-appearing voxels around the infarct that remained "healthy" (nonexpansion) on follow-up DTI. Each infarct expansion voxel was additionally classified as either complete infarct expansion (infarcted tissue on follow-up DTI covered > or =50% of the voxel) or partial infarct expansion (<50% of voxel). RESULTS: In 31 patients (NIH Stroke Scale score 0-28), there were 108 infarct nonexpansion voxels and 113 infarct expansion voxels (of which 80 were complete expansion and 33 partial expansion voxels). Brain choline concentration increased for each change in expansion category from nonexpansion, via partial expansion to complete expansion (2,423, 3,843, 4,158 IU; p < 0.05). Changes in lactate, N-acetylaspartate, and creatine concentrations in expansion category were insignificant although for lactate there was a tendency to such association. CONCLUSIONS: Choline concentration measurable with (1)H MRS was elevated in peri-ischemic normal-appearing brain that became infarcted by 3-7 days. The degree of elevation was associated with the amount of infarct expansion. (1)H MRS might identify DTI-normal-appearing tissue at risk of conversion to infarction in early stroke.

A practical assessment of magnetic resonance diffusion-perfusion mismatch in acute stroke: observer variation and outcome.

MR diffusion/perfusion mismatch may help identify patients for acute stroke treatment, but mixed results from clinical trials suggest that further evaluation of the mismatch concept is required. To work effectively, mismatch should predict prognosis on arrival at hospital. We assessed mismatch duration and associations with functional outcome in acute stroke. We recruited consecutive patients with acute stroke, recorded baseline clinical variables, performed MR diffusion and perfusion imaging and assessed 3-month functional outcome. We assessed practicalities, agreement between mismatch on mean transit time (MTT) or cerebral blood flow (CBF) maps, visually and with lesion volume, and the relationship of each to functional outcome. Of 82 patients starting imaging, 14 (17%) failed perfusion imaging. Overall, 42% had mismatch (56% at <6 h; 41% at 12-24 h; 23% at 24-48 h). Agreement for mismatch by visual versus volume assessment was fair using MTT (kappa 0.59, 95% CI 0.34-0.84) but poor using CBF (kappa 0.24, 95% CI 0.01-0.48). Mismatch by either definition was not associated with functional outcome, even when the analysis was restricted to just those with mismatch. Visual estimation is a reasonable proxy for mismatch volume on MTT but not CBF. Perfusion is more difficult for acute stroke patients than diffusion imaging. Mismatch is present in many patients beyond 12 h after stroke. Mismatch alone does not distinguish patients with good and poor prognosis; both can do well or poorly. Other factors, e.g. reperfusion, may influence outcome more strongly, even in patients without mismatch.

Development and initial testing of normal reference MR images for the brain at ages 65-70 and 75-80 years.

Interpretation of brain images from older patients requires knowledge of changes that occur with healthy ageing. We constructed and tested a reference template for older subjects. We used MR images from normal subjects aged 65-70 and 75-80 to generate average age-specific images. We ranked the T2-weighted images by worsening brain tissue loss to create a diagram of key centiles. Two neuroradiologists tested the template during routine reporting; eight radiologists read 99 MR examinations without and then with the template. Fifty-four subjects (65-70 years) and 25 subjects (75-80 years) formed the reference images. For the two neuroradiologists, the reference template reduced the abnormal scan reporting from 28/42 without to 3/42 with the template. Of 99 MR examinations assessed by eight radiologists, 39/58 scans (67%) reported as moderate or severe atrophy without the template were reported as normal with the template (p = 0.00011). Reference templates of the brain at older ages can "calibrate" radiology reporting. They could also be useful for research into ageing and related conditions. Larger numbers of examinations from more diverse populations and at different ages are required to increase the versatility of these templates.

Changes in NAA and lactate following ischemic stroke: a serial MR spectroscopic imaging study.

OBJECTIVE: Although much tissue damage may occur within the first few hours of ischemic stroke, the duration of tissue injury is not well defined. We assessed the temporal pattern of neuronal loss and ischemia after ischemic stroke using magnetic resonance spectroscopic imaging (MRSI) and diffusion-weighted imaging (DWI). METHODS: We measured N-acetylaspartate (NAA) and lactate in 51 patients with acute ischemic stroke at five time points, from admission to 3 months, in voxels classified as normal, possibly or definitely abnormal (ischemic) according to the appearance of the stroke lesion on the admission DWI. We compared changes in NAA and lactate in different voxel classes using linear mixed models. RESULTS: NAA was significantly reduced from admission in definitely and possibly abnormal (p < 0.01) compared to contralateral normal voxels, reaching a nadir by 2 weeks and remaining reduced at 3 months. Lactate was significantly increased in definitely and possibly abnormal voxels (p < 0.01) during the first 5 days, falling to normal at 2 weeks, rising again later in these voxels. CONCLUSION: The progressive fall in N-acetylaspartate suggests that some additional neuronal death may continue beyond the first few hours for up to 2 weeks or longer. The mechanism is unclear but, if correct, then it is possible that interventions to limit this ongoing subacute tissue damage might add to the benefit of hyperacute treatment, making further improvements in outcome possible.

MR diffusion-weighted imaging and outcome prediction after ischemic stroke.

BACKGROUND: MR diffusion-weighted imaging (DWI) shows acute ischemic lesions early after stroke so it might improve outcome prediction and reduce sample sizes in stroke treatment trials. Previous studies of DWI and outcome produced conflicting results. OBJECTIVE: To determine whether DWI lesion characteristics independently predict outcome in a broad range of patients with acute stroke. METHODS: The authors recruited hospital-admitted patients with all severities of suspected stroke, assessed stroke severity on the NIH Stroke Scale (NIHSS), performed early brain DWI, and assessed outcome at 3 months (modified Rankin Scale). Clinical data and DWI lesion parameters were evaluated in a logistic regression model to identify independent predictors of outcome at 3 months and a previously described "Three-Item Scale" (including DWI) was tested for outcome prediction. RESULTS: Among 82 patients (mean NIHSS 7.1 [+/-6.3 SD]), the only independent outcome predictors were age and stroke severity. Neither DWI lesion volume nor apparent diffusion coefficient nor the previously described Three-Item Scale predicted outcome independently. Comparison with previous studies suggested that DWI may predict outcome only in patients with more severe cortical ischemic strokes. CONCLUSIONS: Across a broad range of stroke severities, diffusion-weighted imaging (DWI) did not predict outcome beyond that of key clinical variables. Thus, DWI is unlikely to reduce sample sizes in acute stroke trials assessing functional outcome, especially where estimated treatment effects are modest.

Effects of dexamethasone on cerebral perfusion and water diffusion in patients with high-grade glioma.

BACKGROUND AND PURPOSE: The mechanisms by which the glucocorticoid dexamethasone produces its therapeutic action in patients with intracranial tumors still remain unclear. The purpose of this study was to investigate whether dexamethasone affects cerebral perfusion and water molecule diffusion by using quantitative dynamic susceptibility contrast perfusion MR imaging (DSC-MR imaging) and diffusion tensor MR imaging (DT-MR imaging). METHODS: Ten consecutive patients with glioblastoma multiforme underwent DSC-MR imaging and DT-MR imaging before and 48-72 hours after dexamethasone treatment (16 mg/day). Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and water mean diffusivity () were measured for enhancing tumor, nonenhancing peritumoral edematous brain, and normal-appearing contralateral white matter before and after steroid therapy. The percentage change in CBF, CBV, MTT, and for the 3 tissue types was calculated for each patient, a mean value obtained for the population, and the statistical significance determined by using a paired-samples Student t test. RESULTS: After dexamethasone treatment, there was no significant change in tumor CBF, CBV, or MTT. Edematous brain CBV and MTT were also unchanged. There was, however, an increase in edematous brain CBF (11.6%; P = .05). was reduced in both enhancing tumor (-5.8%; P = .001) and edematous brain (-6.0%; P < .001). There was no significant change in CBF, CBV, MTT, or for normal-appearing contralateral white matter after treatment. CONCLUSION: These data suggest that dexamethasone does not significantly affect tumor blood flow but may, by reducing peritumoral water content and local tissue pressure, subtly increase perfusion in the edematous brain.

The effects of sediment size fraction and associated algal biofilms on the kinetics of phosphorus release.

Experiments using flumes containing sediment of three different size fractions, from two sites on the River Tame, investigated the influences of sediment particle size, and an associated biofilm, on sediment-water exchanges in heterogeneous sediment deposits. This is the first study undertaken to understand the kinetics of the release of soluble reactive phosphorus from sediments of natural systems to identify which of the size compartments affected those fluxes most. Samples of fine material (<2 mm), gravel (2-20 mm), and stones (>20 mm) were collected over a period of several weeks and brought to a fluvarium where they were placed in artificial, controlled flow, and flume channels. Synthetic solutions of similar ionic strength to the river were prepared using calcium chloride. Temperature, pH, and dissolved oxygen of the solution overlying the sediment were monitored automatically whilst filtered samples were obtained at 2 h intervals over 48 h. The biomass, expressed as mg m(-2) chlorophyll a, of the algal component of the biofilm from the surface of the sediment was estimated using methanol extraction. Differences in the responses were observed between the sediment size fractions and the two sites, where contaminant concentrations varied. The equilibrium phosphate concentration and a phosphorus transfer index were used to establish that there was a net uptake of phosphorus by all three sediment size fractions, from both sites, at the time of sampling. The kinetic results showed very fast initial reactions of phosphorus release from the larger size fractions with a well-developed filamentous algal growth present implying a different mechanism than diffusion being involved. The stones and associated biofilms also released more phosphorus than the fine fraction, e.g. final release concentrations for the most contaminated site were: fines approximately 2.5 microM, gravel approximately 6.5 microM, and stones approximately 65.0 microM (expressed as soluble reactive phosphorus). Phosphorus fluxes, calculated assuming the concentration of phosphorus in the sediment was less than the equilibrium concentration, were a maximum at the most contaminated site, e.g. fines 6.4 nmol m(-2) s(-1), gravel 27 nmol m(-2) s(-1), and stones 109 nmol m(-2) s(-1) (normalised with respect to the river bed area). These results confirm that sediment having a biofilm and associated particulate material results in a greater flux than fine sediment, which does not support a filamentous biomass. Removal of the fine particulates trapped in the algal growth reduced soluble phosphorus release. These factors demonstrate that both gravel and stone substrates have an important control over the release of soluble reactive phosphorus.

Kinetics of phosphorus release from a natural mixed grain-size sediment with associated algal biofilms.

Experiments using flumes containing mixed grain-size sediment with an associated algal biofilm, from two sites on the R. Tame, investigated the sediment-water exchanges in heterogeneous sediment deposits. These results were considered in the light of findings of a companion study [Gainswin BE, et al. The effects of sediment size fraction and associated algal biofilms on the kinetics of phosphorus release. Sci Total Environ, this issue.] by considering this natural system in relation to the effects of the different sizes of material comprising the sediment. Sediment samples were collected in trays installed in the river over a period of one growth cycle (March 2001-April 2002) and placed in flume channels with controlled water flow. The temperature, pH, and dissolved oxygen of the solution overlying the sediment were monitored automatically whilst filtered samples were obtained at 2-0h intervals over 48 h. The biomass, expressed as chlorophyll a, of the algal component of the biofilm from the surface of the sediment was estimated using methanol extraction. The composition of the sediment, viz. size fractions, organic matter and porosity, were determined at the end of the experiments. The equilibrium phosphate concentration and a phosphorus transfer index were used to establish that a net uptake of phosphorus by some of the samples that occurred at the time of sampling. The results were modelled using a Diffusion Boundary Layer model and the maximum flux from the sediment (or limiting diffusion flux) compared for each of the samples. The limiting diffusion flux was highest at the most contaminated site--reaching approximately 180 nmol m(-2) s(-1) (normalised with respect to the river bed area). The limiting diffusion flux calculated for the composite samples was in agreement with the flux estimated from the contributions expected from the individual size fractions [Gainswin BE, et al. The effects of sediment size fraction and associated algal biofilms on the kinetics of phosphorus release. Sci Total Environ, this issue.]. The dominance of the flux contribution from the stones size fraction (>20 mm) confirms that sediment having a filamentous biofilm and associated particulate material results in a greater flux than a silt sediment without such a biomass.

Do acute diffusion- and perfusion-weighted MRI lesions identify final infarct volume in ischemic stroke?

BACKGROUND AND PURPOSE: An acute mismatch on diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) may represent the "tissue-at-risk." It is unclear which "semiquantitative" perfusion parameter most closely identifies final infarct volume. METHODS: Acute stroke patients underwent DWI and PWI (dynamic-susceptibility contrast imaging) on admission (baseline), and T2-weighted imaging (T2WI) at 1 or 3 months after stroke. "Semiquantitative" mean transit time (MTTsq=first moment of concentration/time curve), cerebral blood volume (CBVsq=area under concentration/time curve), and cerebral blood flow (CBFsq=CBVsq/MTTsq) were calculated. DWI and PWI lesions were measured at baseline and final infarct volume on T2WI acquired > or =1 month after stroke. Baseline DWI, CBFsq, and MTTsq lesion volumes were compared with final T2WI lesion volume. RESULTS: Among 46 patients, baseline DWI and CBFsq lesions were not significantly different from final T2WI lesion volume, but baseline MTTsq lesions were significantly larger. The correlation with final T2WI lesion volume was strongest for DWI (Spearman rank correlation coefficient rho=0.68), intermediate for CBFsq (rho=0.55), and weakest for MTTsq (rho=0.49) baseline lesion volumes. Neither DWI/CBFsq nor DWI/MTTsq mismatch predicted lesion growth; lesion growth was equally common in those with and without mismatch. CONCLUSIONS: Of the 2 PWI parameters, CBFsq lesions most closely identifies, and MTTsq overestimates, final T2WI lesion volume. "DWI/PWI mismatch" does not identify lesion growth. Patients without "DWI/PWI mismatch" are equally likely to have lesion growth as those with mismatch and should not be excluded from acute stroke treatment.

Temporal evolution of water diffusion parameters is different in grey and white matter in human ischaemic stroke.

OBJECTIVES: Our purpose was to investigate whether differences exist in the values and temporal evolution of mean diffusivity () and fractional anisotropy (FA) of grey and white matter after human ischaemic stroke. METHODS: Thirty two patients with lesions affecting both grey and white matter underwent serial diffusion tensor magnetic resonance imaging (DT-MRI) within 24 hours, and at 4-7 days, 10-14 days, 1 month, and 3 months after stroke. Multiple small circular regions of interest (ROI) were placed in the grey and white matter within the lesion and in the contralateral hemisphere. Values of [grey], [white], FA[grey] and FA[white] were measured in these ROI at each time point and the ratios of ischaemic to normal contralateral values (R and FAR) calculated. RESULTS: and FA showed different patterns of evolution after stroke. After an initial decline, the rate of increase of [grey] was faster than [white] from 4-7 to 10-14 days. FA[white] decreased more rapidly than FA[grey] during the first week, thereafter for both tissue types the FA decreased gradually. However, FA[white] was still higher than FA[grey] at three months indicating that some organised axonal structure remained. This effect was more marked in some patients than in others. R[grey] was significantly higher than R[white] within 24 hours and at 10-14 days (p<0.05), and FAR[white] was significantly more reduced than FAR[grey] at all time points (p<0.001). CONCLUSIONS: The values and temporal evolution of and FA are different for grey and white matter after human ischaemic stroke. The observation that there is patient-to-patient variability in the degree of white matter structure remaining within the infarct at three months may have implications for predicting patient outcome.

Effects of dexamethasone on peritumoural oedematous brain: a DT-MRI study.

OBJECTIVES: Glucocorticoids (dexamethasone) are thought to reduce peritumoural brain oedema by decreasing the permeability of neoplastic capillaries and/or enhancing the clearance of extracellular water. Diffusion tensor magnetic resonance imaging (DT-MRI) was used to measure the water diffusion parameters of oedematous and normal brain in a group of patients with intracranial tumours before and after steroid treatment. METHODS: Fifteen patients with intracranial tumours (seven with high-grade glioma, four with metastatic carcinoma and four with meningioma) were examined before and 48-72 h after dexamethasone treatment (16 mg/day). The mean diffusivity () and fractional anisotropy (FA) were measured for oedematous brain and apparently normal contralateral white matter before and after steroid therapy. RESULTS: In all three patient groups there was a significant decrease in of oedematous brain after steroid treatment (p<0.01). There was no significant change in FA of oedematous brain after treatment in any of the three groups. There was also no significant change in either or FA of apparently normal contralateral white matter after treatment. CONCLUSION: These data indicate that dexamethasone produces a localised reduction in the magnitude of extracellular water molecule mobility, and hence water content, in peritumoural oedematous brain. Furthermore, the magnitude of these changes is similar for both intra- and extra-axial tumours.