Magnetic resonance imaging-based tumour perfusion parameters are biomarkers predicting response after radiation to brain metastases.

PURPOSE: To investigate whether early relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF) and permeability (Ktrans(2)) measurements may serve as magnetic resonance imaging (MRI) biomarkers of radiation response or progression for brain metastases. MATERIALS AND METHODS: Seventy brain metastases in 44 patients treated with either stereotactic radiosurgery or whole brain radiotherapy were imaged with dynamic susceptibility and dynamic contrast enhancement MRI at baseline, 1 week and 1 month after treatment. The final response status was determined according to volume criteria derived from a 1 year post-treatment MRI or last available follow-up MRI. Tumours were characterised as responders, non-responders, progressors and non-progressors and compared for Ktrans(2), rCBF and rCBV differences. Uni- and multivariate analysis evaluated factors associated with tumour response and progression at 1 week and 1 month. A generalised estimating equations (GEE) model accounted for multiple tumours per subject. Receiver operator characteristic (ROC) analysis identified optimal cut-off values, sensitivity and specificity for response or progression. RESULTS: Tumour responders showed lower Ktrans(2) and reduced rCBF at 1 week (P < 0.05 each). Progressive disease showed lower rCBF and reduced rCBV at 1 month (P < 0.05 each). GEE and multivariate analysis revealed lower Ktrans(2) at 1 week, an absence of prior radiation predicted response. At 1 month only lower rCBV predicted progressive disease on GEE and multivariate analysis. Optimal cut-off points for Ktrans(2) and rCBV were 1.37 and 2.03 with sensitivity and specificity of 61.5 and 81.1% and 73.9 and 81.8%, respectively. CONCLUSION: Lower Ktrans(2) at 1 week and rCBV at 1 month discriminated responders and progressive disease, respectively.

Extensive white matter dysfunction in cognitively impaired patients with secondary-progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment is a common, disabling symptom of MS. We investigated the association between cognitive impairment and WM dysfunction in secondary-progressive multiple sclerosis using DTI. MATERIALS AND METHODS: Cognitive performance was assessed with a standard neuropsychological battery, the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Cognitive impairment was defined as scoring >1.5 standard deviations below healthy controls on ≥2 subtests. Fractional anisotropy maps were compared against cognitive status using tract-based spatial statistics with threshold-free cluster enhancement. RESULTS: Forty-five patients with secondary-progressive multiple sclerosis (median age: 55 years, female/male: 27/18, median Expanded Disability Status Scale Score: 6.5) were prospectively recruited. Cognitively impaired patients (25/45) displayed significantly less normalized global GM and WM volumes (P = .001, P = .024), more normalized T2-weighted and T1-weighted WM lesion volumes (P = .002, P = .006), and lower WM skeleton fractional anisotropy (P < .001) than non-impaired patients. Impaired patients also had significantly lower fractional anisotropy (p(corr) < .05) in over 50% of voxels within every major WM tract. The most extensively impinged tracts were the left posterior thalamic radiation (100.0%), corpus callosum (97.8%), and right sagittal stratum (97.5%). No WM voxels had significantly higher fractional anisotropy in patients with cognitive impairment compared with their non-impaired counterparts (p(corr) > .05). After the inclusion of confounders in a multivariate logistic regression, only fractional anisotropy remained a significant predictor of cognitive status. CONCLUSIONS: Cognitively impaired patients with secondary-progressive multiple sclerosis exhibited extensive WM dysfunction, though preferential involvement of WM tracts associated with cognition, such as the corpus callosum, was apparent. Multivariate analysis revealed that only WM skeleton fractional anisotropy was a significant predictor of cognitive status.

Non Tumor Perfusion Changes Following Stereotactic Radiosurgery to Brain Metastases.

Purpose: To evaluate early perfusion changes in normal tissue following stereotactic radiosurgery (SRS). Methods: Nineteen patients harboring twenty-two brain metastases treated with SRS were imaged with dynamic susceptibility magnetic resonance imaging (DSC MRI) at baseline, 1 week and 1 month post SRS. Relative cerebral blood volume and flow (rCBV and rCBF) ratios were evaluated outside of tumor within a combined region of interest (ROI) and separately within gray matter (GM) and white matter (WM) ROIs. Three-dimensional dose distribution from each SRS plan was divided into six regions: (1) <2 Gy; (2) 2-5 Gy; (3) 5-10 Gy; (4) 10-12 Gy; (5) 12-16 Gy; and (6) >16 Gy. rCBV and rCBF ratio differences between baseline, 1 week and 1 month were compared. Best linear fit plots quantified normal tissue dose-dependency. Results: Significant rCBV ratio increases were present between baseline and 1 month for all ROIs and dose ranges except for WM ROI receiving <2 Gy. rCBV ratio for all ROIs was maximally increased from baseline to 1 month with the greatest changes occurring within the 5-10 Gy dose range (53.1%). rCBF ratio was maximally increased from baseline to 1 month for all ROIs within the 5-10 Gy dose range (33.9-45.0%). Both rCBV and rCBF ratios were most elevated within GM ROIs. A weak, positive but not significant association between dose, rCBV and rCBF ratio was demonstrated. Progressive rCBV and rCBF ratio increased with dose up to 10 Gy at 1 month. Conclusion: Normal tissue response following SRS can be characterized by dose, tissue, and time specific increases in rCBV and rCBF ratio.

Toward patient-tailored perfusion thresholds for prediction of stroke outcome.

BACKGROUND AND PURPOSE: Multiple patient-specific clinical and radiologic parameters impact traditional perfusion thresholds used to classify/determine tissue outcome. We sought to determine whether modified baseline perfusion thresholds calculated by integrating baseline perfusion and clinical factors better predict tissue fate and clinical outcome. MATERIALS AND METHODS: CTP within 4.5 hours of acute anterior circulation stroke onset and 5- to 7-day MR imaging were performed for 203 patients with stroke, divided into derivation (n = 114) and validation (n = 89) data bases. Affected regions were operationally classified as infarct and noninfarct according to baseline CTP and follow-up FLAIR imaging. Perfusion thresholds were derived for each of the infarct and noninfarct regions, without and with transformation by baseline clinical and radiologic variables by using a general linear mixed model. Performance of transformed and nontransformed perfusion thresholds for tissue fate and 90-day clinical outcome prediction was then tested in the derivation data base. Reproducibility of models was verified by using bootstrapping and validated in an independent cohort. RESULTS: Perfusion threshold transformation by clinical and radiologic baseline parameters significantly improved tissue fate prediction for both gray matter and white matter (P < .001). Transformed thresholds improved the 90-day outcome prediction for CBF and time-to-maximum (P < .001). Transformed relative CBF and absolute time-to-maximum values demonstrated maximal GM and WM accuracies in the derivation and validation cohorts (relative CBF GM: 91%, 86%; WM: 86%, 83%; absolute time-to-maximum 88%, 79%, and 80%, 76% respectively). CONCLUSIONS: Transformation of baseline perfusion parameters by patient-specific clinical and radiologic parameters significantly improves the accuracy of tissue fate and clinical outcome prediction.

Normal-appearing white matter permeability distinguishes poor cognitive performance in processing speed and working memory.

BACKGROUND AND PURPOSE: Secondary-progressive MS is characterized by reduced acute inflammation and contrast enhancement but with increased axonal degeneration and cognitive/clinical disability that worsens with advanced disease. Relative recirculation, extracted from DSC is a surrogate measure of BBB integrity. We hypothesized that normal-appearing white matter relative recirculation is reduced in cognitively impaired compared with nonimpaired secondary-progressive MS, reflecting more advanced disease. MATERIALS AND METHODS: Cognitive performance was classified as impaired or nonimpaired by use of Minimal Assessment of Cognitive Function In MS test components. Demographic data, brain parenchymal fraction, WM lesion fraction, and weighted mean normal-appearing white matter relative recirculation were compared in cognitively dichotomized groups. Univariate and multivariate logistic regressions were used to study the association between cognitive test results and normal-appearing white matter relative recirculation. RESULTS: The mean (SD) age of 36 patients with secondary-progressive MS studied was 55.9 ± 9.3 years; 13 of 36 (36%) patients were male. A highly significant difference between normal-appearing white matter relative recirculation and WM lesion relative recirculation was present for all patients (P < .001). Normal-appearing white matter relative recirculation in impaired patients was significantly lower than in nonimpaired subjects for the Symbol Digit Modalities Test (P = .007), Controlled Word Association Test (P = .008), and Paced Auditory Serial Addition Test (P = .024). The Expanded Disability Status Scale demonstrated an inverse correlation with normal-appearing white matter relative recirculation (r = -0.319, P = .075). After adjustment for confounders, significant normal-appearing white matter relative recirculation reduction persisted for the Symbol Digit Modalities Test (P = .023) and the Paced Auditory Serial Addition Test (P = .047) but not for the Controlled Word Association Test (P = .13) in impaired patients. CONCLUSIONS: Significant normal-appearing white matter relative recirculation reduction exists in cognitively impaired patients with secondary-progressive MS, localizing to the domains of processing speed and working memory.

Robust perfusion deficits in cognitively impaired patients with secondary-progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment is a common, disabling symptom of MS. We investigated the impact of cerebral perfusion and brain and lesion volumetry on cognitive performance in 45 patients with SPMS by using MR imaging. MATERIALS AND METHODS: Cognition was assessed by using a standard battery, the Minimal Assessment of Cognitive Function in Multiple Sclerosis. qCBF and qCBV maps were analyzed by using SPM and PLS. SPM was also used to conduct the GM, WM, and WML volumetric analyses. RESULTS: Both SPM and PLS demonstrated significantly reduced qCBV in the superior medial frontal cortex of impaired patients. PLS also revealed significantly lower qCBV in the bilateral thalami and caudate nuclei of impaired patients and identified a pattern of significantly attenuated qCBF similar to that of qCBV. Performance on the Symbol Digit Modalities Test, which assesses information-processing speed, correlated most strongly overall with cerebral perfusion. Focal (ie, voxelwise) analyses of GM, WM, and WML volume revealed no significant differences between patients with and without cognitive impairment, though global GM volume was significantly decreased and global WML volume was significantly increased in impaired patients. CONCLUSIONS: These results suggest that cognitively impaired patients with SPMS exhibit robust perfusion deficits in cortical and subcortical GM and impaired processing speed.

CT perfusion spot sign improves sensitivity for prediction of outcome compared with CTA and postcontrast CT.

BACKGROUND AND PURPOSE: Recent studies have recommended both early and late imaging to increase spot sign detection. However optimal acquisition timing for spot detection and impact on outcome prediction is uncertain. Our aim was to assess the utility of CTP in spot sign detection and characterization with emphasis on its impact on the prediction of outcome in patients with acute primary ICH. MATERIALS AND METHODS: A retrospective review of 28 patients presenting within 6 hours of ICH, studied with CTA, CTP, and postcontrast CT, was performed. CTA, CTP, and postcontrast CT spot sign characteristics were recorded according to predefined radiologic criteria. A combined primary outcome of hematoma expansion or poor clinical outcome was used and defined as hematoma expansion ≥6 mL or ≥30%, need for surgical drainage, or in-hospital mortality. Associations with the primary outcome and spot sign presence were examined against baseline clinical, laboratory, and radiographic variables. Predictive ability of CTA, CTP, and postcontrast CT spot characteristics were compared among modalities. RESULTS: Primary outcome criteria were met in 18 patients (61%). CTP spot sign presence was an independent predictor of hematoma expansion or poor outcome (P = .040) and demonstrated greater sensitivity (78%) than spots detected on CTA (44%, P = .034) and postcontrast CT (50%, P = .025). Specificity and positive predictive value of the spot sign was high (100%) on all modalities. CTP detected the greatest number of spots (80%) with peak spot attenuation demonstrated at a median (interquartile range) time of 50 seconds (range, 34-63 seconds) after contrast bolus injection. CTP spot appearance was later than CTA-detected spots (P = .002) and earlier than postcontrast CT spots (P < .001). CONCLUSIONS: CTP spot sign detection improves the sensitivity for prediction of outcome compared with CTA or postcontrast CT-detected spots.

Aluminium and strontium in calcium supplements and antacids: a concern to haemodialysis patients?

Trace elements, most notably aluminium and strontium, have been noted for their role in the development of secondary bone disorders in haemodialysis patients. Due to the large dosages of calcium required for the maintenance of dialysis patients, this study investigated whether the source of calcium chosen for supplementation, including the form of administration (i.e. chewable forms or capsules), has an influence on the total amount of strontium and aluminium ingested daily. A convenience sample of various calcium supplement tablets and antacids was acquired, and strontium and aluminium quantification was performed by wavelength-dispersive X-ray fluorescence spectrometry. The use of readily available oyster shell-based calcium was found potentially to increase the total amount of ingested strontium substantially with concentrations reaching (2.26 +/- 0.05) (mg Sr).(g Ca)(-1), while the use of antacids or chewable supplements was found to contain concentrations reaching as high as (1.2 +/- 0.3) (mg Al).(g Ca)(-1) in the supplements analysed within this work. It is recommended that the choice of calcium supplement prescribed to individuals undergoing haemodialysis be closely regulated and noted as a possible factor in the prevalence of bone disorders reported in these patients.

Chronic psychological effects of exposure to mercury vapour among chlorine-alkali plant workers.

BACKGROUND: Quantitative assessment of nervous system function is essential in characterising the nature and extent of impairment in individuals experiencing symptoms following work-place mercury vapour exposure. OBJECTIVES: The purpose of this study was the application of standardised tests of behavioural, psychomotor and memory function to understand the neuropsychological effects of mercury in occupationally exposed chlorine-alkali plant workers. SUBJECTS AND METHODS: The study comprised 45 workers at a chlorine-alkali plant with the mean age of 39.36 +/- 5.94 years, who had been exposed to daily inhalation of mercury vapour over long-term employment of 16.06 +/- 4.29 years. The cumulative mercury index was 155.32 +/- 95.02 micrograms/g creatinine, the mean of urinary mercury concentrations on the first day of the study was 119.50 +/- 157.24 micrograms/g creatinine, and the mean of urinary mercury concentrations 120 days after cessation of exposure was 21.70 +/- 26.07 micrograms/g creatinine. The analysis included tests of behavioural, psychomotor and memory function. The behavioural test battery consisted of: Environmental Worry Scale (EWS), Minnesota Modified Personal Inventory (MMPI-2), Purdue standard 25 minute test, and adapted, 10 minutes test, Bender's Visual-Motor Gestalt test (BGT), and Eysenck Personality Inventory (EPQ). The data were compared to a control group of 32 not directly exposed workers. RESULTS: In the mercury vapour exposed workers with relatively high level exposure to inorganic mercury vapour (TWA/TLV = 0.12 mg/m3/0.025 mg/m3) we identified somatic depression-hypochondria symptoms with higher scores for scales: hysteria (P < 0.001), schizoid and psycho-asthenia (MMPI-2). The mercury-exposed workers had introvert behaviour (EPQ, MMPI-2). The cognitive disturbances in mercury-exposed workers were identified as: concentration difficulty, psychomotor, perceptual and motor coordination disturbances, and brain effects. We identified fine tremor of the hands in 34 out of 45 mercury-exposed workers (BGT). CONCLUSIONS: The results point to a relationship between the duration of mercury exposure and the long-term, probably irreversible, psychological disturbances.