Automating Quantitative Measures of an Established Conventional MRI Scoring System for Preterm-Born Infants Scanned between 29 and 47 Weeks' Postmenstrual Age.

BACKGROUND AND PURPOSE: Conventional MR imaging scoring is a valuable tool for risk stratification and prognostication of outcomes, but manual scoring is time-consuming, operator-dependent, and requires high-level expertise. This study aimed to automate the regional measurements of an established brain MR imaging scoring system for preterm neonates scanned between 29 and 47 weeks' postmenstrual age. MATERIALS AND METHODS: This study used T2WI from the longitudinal Prediction of PREterm Motor Outcomes cohort study and the developing Human Connectome Project. Measures of biparietal width, interhemispheric distance, callosal thickness, transcerebellar diameter, lateral ventricular diameter, and deep gray matter area were extracted manually (Prediction of PREterm Motor Outcomes study only) and automatically. Scans with poor quality, failure of automated analysis, or severe pathology were excluded. Agreement, reliability, and associations between manual and automated measures were assessed and compared against statistics for manual measures. Associations between measures with postmenstrual age, gestational age at birth, and birth weight were examined (Pearson correlation) in both cohorts. RESULTS: A total of 652 MRIs (86%) were suitable for analysis. Automated measures showed good-to-excellent agreement and good reliability with manual measures, except for interhemispheric distance at early MR imaging (scanned between 29 and 35 weeks, postmenstrual age; in line with poor manual reliability) and callosal thickness measures. All measures were positively associated with postmenstrual age (r = 0.11-0.94; R2 = 0.01-0.89). Negative and positive associations were found with gestational age at birth (r = -0.26-0.71; R2 = 0.05-0.52) and birth weight (r = -0.25-0.75; R2 = 0.06-0.56). Automated measures were successfully extracted for 80%-99% of suitable scans. CONCLUSIONS: Measures of brain injury and impaired brain growth can be automatically extracted from neonatal MR imaging, which could assist with clinical reporting.

A combined tract-based spatial statistics and voxel-based morphometry study of the first MRI scan after diagnosis of amyotrophic lateral sclerosis with subgroup analysis.

BACKGROUND AND PURPOSE: This study aims to compare the cortical and subcortical deep gray matter (GM) and white matter (WM) of ALS subjects and controls and to compare ALS subjects with (ALScog) and without (ALSnon-cog) cognitive impairment. MATERIALS AND METHODS: The study was performed in 30 ALS subjects, and 19 healthy controls. Structural T1- and diffusion-weighted MRI data were analyzed using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS). RESULTS: All DTI measures and GM volume differed significantly between ALS subjects and controls. Compared to controls, greater DTI changes were present in ALScog than ALSnon-cog subjects. GM results showed reduction in the caudate nucleus volume in ALScog subjects compared to ALSnon-cog. and comparing all ALS with controls, there were changes on the right side and in a small region in the left middle frontal gyrus. CONCLUSION: This combined DTI and VBM study showed changes in motor and extra-motor regions. The DTI changes were more extensive in ALScog than ALSnon-cog subjects. It is likely that the inclusion of ALS subjects with cognitive impairment in previous studies resulted in extra-motor WM abnormalities being reported in ALS subjects.

Validation of an MRI Brain Injury and Growth Scoring System in Very Preterm Infants Scanned at 29- to 35-Week Postmenstrual Age.

BACKGROUND AND PURPOSE: The diagnostic and prognostic potential of brain MR imaging before term-equivalent age is limited until valid MR imaging scoring systems are available. This study aimed to validate an MR imaging scoring system of brain injury and impaired growth for use at 29 to 35 weeks postmenstrual age in infants born at <31 weeks gestational age. MATERIALS AND METHODS: Eighty-three infants in a prospective cohort study underwent early 3T MR imaging between 29 and 35 weeks' postmenstrual age (mean, 32+2 ± 1+3 weeks; 49 males, born at median gestation of 28+4 weeks; range, 23+6-30+6 weeks; mean birthweight, 1068 ± 312 g). Seventy-seven infants had a second MR scan at term-equivalent age (mean, 40+6 ± 1+3 weeks). Structural images were scored using a modified scoring system which generated WM, cortical gray matter, deep gray matter, cerebellar, and global scores. Outcome at 12-months corrected age (mean, 12 months 4 days ± 1+2 weeks) consisted of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley III), and the Neuro-Sensory Motor Developmental Assessment. RESULTS: Early MR imaging global, WM, and deep gray matter scores were negatively associated with Bayley III motor (regression coefficient for global score ß = -1.31; 95% CI, -2.39 to -0.23; P = .02), cognitive (ß = -1.52; 95% CI, -2.39 to -0.65; P < .01) and the Neuro-Sensory Motor Developmental Assessment outcomes (ß = -1.73; 95% CI, -3.19 to -0.28; P = .02). Early MR imaging cerebellar scores were negatively associated with the Neuro-Sensory Motor Developmental Assessment (ß = -5.99; 95% CI, -11.82 to -0.16; P = .04). Results were reconfirmed at term-equivalent-age MR imaging. CONCLUSIONS: This clinically accessible MR imaging scoring system is valid for use at 29 to 35 weeks postmenstrual age in infants born very preterm. It enables identification of infants at risk of adverse outcomes before the current standard of term-equivalent age.

The prognostic utility of MRI in clinically isolated syndrome: a literature review.

For patients presenting with clinically isolated syndrome, the treating clinician needs to advise the patient on the probability of conversion to clinically definite multiple sclerosis. MR imaging may give useful prognostic information, and there is large body of literature pertaining to the use of MR imaging in assessing patients presenting with clinically isolated syndrome. This literature review evaluates the accuracy of MR imaging in predicting which patients with clinically isolated syndrome will go on to develop long-term disease and/or disability. New and emerging MR imaging technologies and their applicability to patients with clinically isolated syndrome are also considered.

Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma differentially.

The increasing prevalence of immune-related diseases, including multiple sclerosis, may be partly explained by reduced microbial burden during childhood. Within a multi-centre case-control study population, we examined: (i) the co-morbid immune diseases profile of adults with a first clinical diagnosis of central nervous system demyelination (FCD) and (ii) sibship structure in relation to an autoimmune (FCD) and an allergic (asthma) disease. FCD cases (n = 282) were aged 18-59 years; controls (n = 558) were matched on age, sex and region. Measures include: history of doctor-diagnosed asthma; sibling profile (number; dates of birth); and regular childcare attendance. FCD cases did not differ from controls with regard to personal or family history of allergy, but had a greater likelihood of chronic fatigue syndrome [odds ratio (OR) = 3·11; 95% confidence interval (CI) 1·11, 8·71]. Having any younger siblings showed reduced odds of FCD (OR = 0·68; 95% CI: 0·49, 0·95) but not asthma (OR = 1·47; 95% CI: 0·91, 2·38). In contrast, an increasing number of older siblings was associated with reduced risk of asthma (P trend = 0·04) but not FCD (P trend = 0·66). Allergies were not over-represented among people presenting with FCD. Sibship characteristics influence both FCD and asthma risk but the underlying mechanisms differ, possibly due to the timing of the putative 'sibling effect'.

Occupational exposure and risk of central nervous system demyelination.

Inconsistent evidence exists regarding the association between work-related factors and risk of multiple sclerosis (MS). We examined the association between occupational exposures and risk of a first clinical diagnosis of central nervous system demyelination (FCD), which is strongly associated with progression to MS, in a matched case-control study of 276 FCD cases and 538 controls conducted in Australia (2003-2006). Using a personal residence and work calendar, information on occupational history and exposure to chemicals and animals was collected through face-to-face interviews. Few case-control differences were noted. Fewer cases had worked as professionals (≥6 years) than controls (adjusted odds ratio (AOR) = 0.60, 95% confidence interval (CI): 0.37, 0.96). After further adjustment for number of children, cases were more likely to have ever been exposed to livestock than controls (AOR = 1.54, 95% CI: 1.03, 2.29). Among women, there was an increase in FCD risk associated with 10 or more years of exposure to livestock (AOR = 2.78, 95% CI: 1.22, 6.33) or 6 or more years of farming (AOR = 2.00, 95% CI: 1.23, 3.25; also adjusted for number of children). Similar findings were not evident among men. Thus, farming and exposure to livestock may be important factors in the development of FCD among women, with this finding further revealed after the confounding effect of parity or number of children is considered.

Correlation of MRI-derived apparent diffusion coefficients in newly diagnosed gliomas with [18F]-fluoro-L-dopa PET: what are we really measuring with minimum ADC?

BACKGROUND AND PURPOSE: There is significant interest in whether diffusion-weighted MR imaging indices, such as the minimum apparent diffusion coefficient, may be useful clinically for preoperative tumor grading and treatment planning. To help establish the pathologic correlate of minimum ADC, we undertook a study investigating the relationship between minimum ADC and maximum FDOPA PET uptake in patients with newly diagnosed glioblastoma multiforme. MATERIALS AND METHODS: MR imaging and FDOPA PET data were acquired preoperatively from 15 patients who were subsequently diagnosed with high-grade brain tumor (WHO grade III or IV) by histopathologic analysis. ADC and SUVR normalized FDOPA PET maps were registered to the corresponding CE MR imaging. Regions of minimum ADC within the FDOPA-defined tumor volume were anatomically correlated with areas of maximum FDOPA SUVR uptake. RESULTS: Minimal anatomic overlap was found between regions exhibiting minimum ADC (a putative marker of tumor cellularity) and maximum FDOPA SUVR uptake (a marker of tumor infiltration and proliferation). FDOPA SUVR measures for tumoral regions exhibiting minimum ADC (1.36±0.22) were significantly reduced compared with those with maximum FDOPA uptake (2.45±0.88, P=.0001). CONCLUSIONS: There was a poor correlation between minimum ADC and the most viable/aggressive component of high-grade gliomas. This study suggests that other factors, such as tissue compression and ischemia, may be contributing to restricted diffusion in GBM. Caution should be exercised in the clinical use of minimum ADC as a marker of tumor grade and the use of this index for guiding tumor biopsies preoperatively.

Structural hemispheric asymmetries in the human precentral gyrus hand representation.

The superior region of the precentral gyrus (preCG) is known to be actively involved with hand function and has been proposed as a possible neural correlate of handedness. To test this hypothesis, we used a combined voxel-based morphometric (VBM) asymmetry analysis of structural MRI, along with diffusion MRI (dMRI) tractography to investigate laterality indices of corticomotor white matter (WM) pathways, based on measures of fractional anisotropy (FA). The relationship between measures of motor performance and FA laterality indices was also investigated. In a cohort of 14 right-handed healthy participants, the VBM asymmetry analysis revealed an area within the preCG associated with hand representation. The tractography analysis revealed that this region possessed a number of major WM intrahemispheric connections to the brain stem, thalamus, cerebellum, postcentral, caudal middle and superior frontal, and superior and inferior parietal corticomotor regions. Within the corticospinal tracts, we found FA was significantly higher in the left hemisphere compared with the right. Furthermore, significant correlations were found between FA asymmetry measures projecting from this region, namely corticospinal tracts and those connecting the postcentral gyri, with grip strength and finger-tapping performance, respectively. A number of the motor pathways projecting from this region also exhibited leftward asymmetry of FA distributions. The findings from this study highlight the role of the left motor cortex in skilled motor performance and provide a framework for the study of the relationship between handedness and preCG hand representation in larger normative populations.

Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study.

OBJECTIVE: To examine the association between past pregnancy, offspring number, and first clinical demyelination risk. METHODS: Cases (n = 282) were aged 18-59 years with a first clinical diagnosis of CNS demyelination (first clinical demyelinating event [FCD]) and resident within 1 of 4 Australian centers (from latitudes 27° south to 43° south) from 2003 to 2006. Controls (n = 542) were matched to cases on age, sex, and study region, without first clinical diagnosis of CNS demyelination. RESULTS: Higher offspring number was associated with FCD risk among women (p < 0.001) but not men (p = 0.71); difference in effect; p = 0.001. Among women, higher parity was associated with reduced risk of FCD (adjusted odds ratio 0.51 [95% confidence interval 0.36, 0.72] per birth) with a similar magnitude of effect observed among classic first demyelinating events (adjusted odds ratio 0.47 [95% confidence interval 0.29, 0.74]). The apparent beneficial effect of higher parity was also evident among parous women only (p < 0.001). Among cases, a clear female excess was evident for those with low but not high (4 or more) offspring number. Factors such as human leukocyte antigen DR15 genotype did not appear to modify the association between higher parity and a reduced FCD risk among women. CONCLUSIONS: These findings are consistent with a cumulative beneficial effect of pregnancy. Temporal changes toward an older maternal age of parturition and reduced offspring number may partly underlie the increasing female excess among MS cases over time.

Current and past Epstein-Barr virus infection in risk of initial CNS demyelination.

OBJECTIVES: To assess risk of a first clinical diagnosis of CNS demyelination (FCD) in relation to measures of Epstein-Barr virus (EBV) infection within the context of other known risk factors. METHODS: This was a multicenter incident case-control study. FCD cases (n = 282) aged 18-59 years and controls (n = 558, matched on age, sex, and region) were recruited from 4 Australian centers between November 1, 2003, and December 31, 2006. A nested study (n = 215 cases, n = 216 controls) included measurement of whole blood quantitative EBV DNA load and serum EBV-specific antibodies. Conditional logistic regression was used to analyze case-control differences. RESULTS: There were no significant case-control differences in the proportion with detectable EBV DNA (55.8% vs 50.5%, respectively, p = 0.28), or in quantitative EBV DNA load (p = 0.33). Consistent with previous work, higher anti-EBV-specific immunoglobulin G (IgG) titers and a history of infectious mononucleosis were associated with increased FCD risk and there was an additive interaction with HLA-DRB1*1501 status. We found additional interactions between high anti-EBNA IgG titer and SNPs in HLA-A (adjusted odds ratios [AOR] = 19.84 [95% confidence interval (CI) 5.95 to 66.21] for both factors compared to neither) and CTLA-4 genes (AOR = 0.31 [95% CI 0.13 to 0.76] for neither factor compared to both). EBV DNA load was lower at higher serum 25-hydroxyvitamin D concentrations in controls (r = -0.17, p = 0.01). An adverse effect of higher EBV DNA load on FCD risk was increased with higher 25-hydroxyvitamin D concentration (p[interaction] = 0.02). CONCLUSION: Past infection with EBV, but not current EBV DNA load in whole blood, is significantly associated with increased FCD risk. These associations appear to be modified by immune-related gene variants.

Sun exposure and vitamin D are independent risk factors for CNS demyelination.

OBJECTIVES: To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D [25(OH)D] levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the contribution of these factors to the latitudinal gradient in FDE incidence in Australia. METHODS: This was a multicenter incident case-control study. Cases (n = 216) were aged 18-59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status. RESULTS: Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval [CI] 0.53-0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m(2) (range 508-6,397 kJ/m(2)). Higher actinic skin damage (AOR = 0.39 [95% CI 0.17-0.92], highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 [95% CI 0.86-1.00] per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions. CONCLUSIONS: Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.

Characterisation of a refined rat model of respiratory infection with Pseudomonas aeruginosa and the effect of ciprofloxacin.

BACKGROUND: We sought to characterise a refined rat model of respiratory infection with P. aeruginosa over an acute time course and test the antibiotic ciprofloxacin. METHODS: Agar beads were prepared ± SPAN(®)80. Rats were inoculated with sterile agar beads or those containing 10(5) colony forming units (cfu) P. aeruginosa via intra-tracheal dosing. Bacterial load and inflammatory parameters were measured. RESULTS: Differing concentrations of SPAN(®) 80 modified median agar bead diameter and reduced particle size distribution. Beads prepared with 0.01% v/v SPAN(®)80 were evaluated in vivo. A stable lung infection up to 7 days post infection was achieved and induced BALF neutrophilia 2 and 5 days post infection. Ciprofloxacin (50mg/kg) significantly attenuated infection without affecting the inflammatory parameters measured. CONCLUSION: SPAN(®) 80 can control the particle size and lung distribution of agar beads and P. aeruginosa-embedded beads prepared with 0.01%v/v SPAN(®)80 can induce infection and inflammation over 7 days.

Improved language performance subsequent to low-frequency rTMS in patients with chronic non-fluent aphasia post-stroke.

BACKGROUND: Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential tool for neurorehabilitation and remediation of language in chronic non-fluent aphasia post-stroke. Inhibitory (1 Hz) rTMS has been applied to homologous language sites to facilitate behavioural language changes. Improvements in picture-naming performance and speech output over time have been reported. METHODS: Low-frequency (1 Hz) rTMS was applied to six real stimulation and six sham placebo patients for 20 min per day, for 10 days, and behavioural language outcome measures were taken at baseline (pre-stimulation) and 2 months post-stimulation. RESULTS: The findings demonstrate treatment-related changes observed in the stimulation group when compared to the placebo control group at 2 months post-stimulation on naming performance as well as other aspects of expressive language and auditory comprehension. CONCLUSIONS: These findings provide considerable evidence to support the theory of rTMS modulating mechanisms of transcallosal disinhibition in the aphasic brain and highlight the potential clinical applications for language rehabilitation post-stroke.

Joint factor and kinetic analysis of dynamic FDOPA PET scans of brain cancer patients.

Kinetic analysis is an essential tool of Positron Emission Tomography image analysis. However it requires a pure tissue time activity curve (TAC) in order to calculate the system parameters. Pure tissue TACs are particularly difficult to obtain in the brain as the low resolution of PET means almost all voxels are a mixture of tissues. Factor analysis explicitly accounts for mixing but is an underdetermined problem that can give arbitrary results. A joint factor and kinetic analysis is proposed whereby factor analysis explicitly accounts for mixing of tissues. Hence, more meaningful parameters are obtained by the kinetic models, which also ensure a less ambiguous solution to the factor analysis. The method was tested using a cylindrical phantom and the 18F-DOPA data of a brain cancer patient.

Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent.

BACKGROUND: CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity. METHODS: This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours. RESULTS: Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles. CONCLUSIONS: CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.