Abnormal cerebral hemodynamics and blood-brain barrier permeability detected with perfusion MRI in systemic lupus erythematosus patients.

OBJECTIVE: Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) has previously shown alterations in cerebral perfusion in patients with systemic lupus erythematosus (SLE). However, the results have been inconsistent, in particular regarding neuropsychiatric (NP) SLE. Thus, we investigated perfusion-based measures in different brain regions in SLE patients with and without NP involvement, and additionally, in white matter hyperintensities (WMHs), the most common MRI pathology in SLE patients. MATERIALS AND METHODS: We included 3 T MRI images (conventional and DSC) from 64 female SLE patients and 19 healthy controls (HC). Three different NPSLE attribution models were used: the Systemic Lupus International Collaborating Clinics (SLICC) A model (13 patients), the SLICC B model (19 patients), and the American College of Rheumatology (ACR) case definitions for NPSLE (38 patients). Normalized cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were calculated in 26 manually drawn regions of interest and compared between SLE patients and HC, and between NPSLE and non-NPSLE patients. Additionally, normalized CBF, CBV and MTT, as well as absolute values of the blood-brain barrier leakage parameter (K2) were investigated in WMHs compared to normal appearing white matter (NAWM) in the SLE patients. RESULTS: After correction for multiple comparisons, the most prevalent finding was a bilateral significant decrease in MTT in SLE patients compared to HC in the hypothalamus, putamen, right posterior thalamus and right anterior insula. Significant decreases in SLE compared to HC were also found for CBF in the pons, and for CBV in the bilateral putamen and posterior thalamus. Significant increases were found for CBF in the posterior corpus callosum and for CBV in the anterior corpus callosum. Similar patterns were found for both NPSLE and non-NPSLE patients for all attributional models compared to HC. However, no significant perfusion differences were revealed between NPSLE and non-NPSLE patients regardless of attribution model. The WMHs in SLE patients showed a significant increase in all perfusion-based metrics (CBF, CBV, MTT and K2) compared to NAWM. CONCLUSION: Our study revealed perfusion differences in several brain regions in SLE patients compared to HC, independently of NP involvement. Furthermore, increased K2 in WMHs compared to NAWM may indicate blood-brain barrier dysfunction in SLE patients. We conclude that our results show a robust cerebral perfusion, independent from the different NP attribution models, and provide insight into potential BBB dysfunction and altered vascular properties of WMHs in female SLE patients. Despite SLE being most prevalent in females, a generalization of our conclusions should be avoided, and future studies including all sexes are needed.

MTT and Blood-Brain Barrier Disruption within Asymptomatic Vascular WM Lesions.

BACKGROUND AND PURPOSE: White matter lesions of presumed ischemic origin are associated with progressive cognitive impairment and impaired BBB function. Studying the longitudinal effects of white matter lesion biomarkers that measure changes in perfusion and BBB patency within white matter lesions is required for long-term studies of lesion progression. We studied perfusion and BBB disruption within white matter lesions in asymptomatic subjects. MATERIALS AND METHODS: Anatomic imaging was followed by consecutive dynamic contrast-enhanced and DSC imaging. White matter lesions in 21 asymptomatic individuals were determined using a Subject-Specific Sparse Dictionary Learning algorithm with manual correction. Perfusion-related parameters including CBF, MTT, the BBB leakage parameter, and volume transfer constant were determined. RESULTS: MTT was significantly prolonged (7.88 [SD, 1.03] seconds) within white matter lesions compared with normal-appearing white (7.29 [SD, 1.14] seconds) and gray matter (6.67 [SD, 1.35] seconds). The volume transfer constant, measured by dynamic contrast-enhanced imaging, was significantly elevated (0.013 [SD, 0.017] minutes-1) in white matter lesions compared with normal-appearing white matter (0.007 [SD, 0.011] minutes-1). BBB disruption within white matter lesions was detected relative to normal white and gray matter using the DSC-BBB leakage parameter method so that increasing BBB disruption correlated with increasing white matter lesion volume (Spearman correlation coefficient = 0.44; P < .046). CONCLUSIONS: A dual-contrast-injection MR imaging protocol combined with a 3D automated segmentation analysis pipeline was used to assess BBB disruption in white matter lesions on the basis of quantitative perfusion measures including the volume transfer constant (dynamic contrast-enhanced imaging), the BBB leakage parameter (DSC), and MTT (DSC). This protocol was able to detect early pathologic changes in otherwise healthy individuals.

Differentiation between glioblastomas and brain metastases and regarding their primary site of malignancy using dynamic susceptibility contrast MRI at 3T.

BACKGROUND: Differentiation between glioblastoma and brain metastasis may be challenging in conventional contrast-enhanced MRI. PURPOSE: To investigate if perfusion-weighted MRI is able to differentiate glioblastoma from metastasis and, as a second aim was to see if it was possible in the latter group, to predict the primary site of neoplasm. MATERIAL AND METHODS: Hundred and fourteen patients with newly discovered tumor lesion (76 metastases and 38 glioblastomas) underwent conventional contrast-enhanced MRI including dynamic susceptibility contrast perfusion sequence. The calculated relative cerebral blood volumes were analyzed in the solid tumor area, peritumoral area, area adjacent to peritumoral area, and normal appearing white matter in contralateral semioval center. The Student t-test was used to detect statistically significant differences in relative cerebral blood volume between glioblastomas and metastases in the aforementioned areas. Furthermore, the metastasis group was divided in four sub groups (lung-, breast-, melanoma-, and gastrointestinal origin) and using one-way ANOVA test. P-values < 0.05 were considered significant. RESULTS: Relative cerebral blood volume (rCBV) in the peritumoral edema was significantly higher in glioblastomas than in metastases (mean 3.2 ± 1.4 and mean 0.9 ± 0.7), respectively, (P < 0.0001). No significant differences in the solid tumor area or the area adjacent to edema were found, (P = 0.28 and 0.21 respectively). There were no significant differences among metastases in the four groups. CONCLUSION: It is possible to differentiate glioblastomas from metastases by measuring the CBV in the peritumoral edema. It is not possible to differentiate between brain metastases from different primaries (lung-, breast-, melanoma or gastrointestinal) using CBV-measurements in the solid tumor area, peritumoral edema or area adjacent to edema.

Invasive melanoma in vivo can be distinguished from basal cell carcinoma, benign naevi and healthy skin by canine olfaction: a proof-of-principle study of differential volatile organic compound emission.

BACKGROUND: Volatile organic compounds (VOCs) are continuously released by the body during normal metabolic processes, but their profiles change in the presence of cancer. Robust evidence that invasive melanoma in vivo emits a characteristic VOC signature is lacking. OBJECTIVES: To conduct a canine olfactory, proof-of-principle study to investigate whether VOCs from invasive melanoma are distinguishable from those of basal cell carcinoma (BCC), benign naevi and healthy skin in vivo. METHODS: After a 13-month training period, the dog's ability to discriminate melanoma was evaluated in 20 double-blind tests, each requiring selection of one melanoma sample from nine controls (three each of BCC, naevi and healthy skin; all samples new to the dog). RESULTS: The dog correctly selected the melanoma sample on nine (45%) occasions (95% confidence interval 0·23-0·68) vs. 10% expected by chance alone. A one-sided exact binomial test gave a P-value of < 0·01, supporting the hypothesis that samples were not chosen at random but that some degree of VOC signal from the melanoma samples significantly increased the probability of their detection. Use of a discrete-choice model confirmed melanoma as the most influential of the recorded medical/personal covariates in determining the dog's choice of sample. Accuracy rates based on familiar samples during training were not a reliable indicator of the dog's ability to distinguish melanoma, when confronted with new, unknown samples. CONCLUSIONS: Invasive melanoma in vivo releases odorous VOCs distinct from those of BCC, benign naevi and healthy skin, adding to the evidence that the volatile metabolome of melanoma contains diagnostically useful biomarkers.

Cerebral perfusion imaging in hemodynamic stroke: be aware of the pattern.

SUMMARY: Reduction of the cerebral perfusion pressure caused by vessel occlusion or stenosis is a cause of neurological symptoms and border-zone infarctions. The aim of this article is to describe perfusion patterns in hemodynamic stroke, to give a practical approach for the assessment of colour encoded CT- and MR-perfusion maps and to demonstrate the clinical use of comprehensive imaging in the workup of patients with hemodynamic stroke. Five patients with different duration cause and degree of hemodynamic stroke were selected. The patients shared the typical presentation with fluctuating and transient symptoms. All were examined by MR or CT angiography and MR or CT perfusion in the symptomatic phase. All patients were examined with diffusion weighted imaging. All five cases showed the altered perfusion patterns of hemodynamic insufficiency with a slight or marked increase in CBV in the supply area of the affected vessel and only slightly reduced or maintained CBF. The perfusion disturbances were most easily detected on the MTT maps. Border-zone infarctions were seen in all cases. The typical pattern for hemodynamic insufficiency is characterized by increased CBV, normal or decreased CBF and prolonged MTT in the affected areas. The increased CBV is the hallmark of stressed autoregulation. Reading the color-encoded perfusion maps enables a quick and robust assessment of the cerebral perfusion and its characteristic patterns. Internal border-zone infarctions can be regarded as a marker for hemodynamic insufficiency. Finding of the typical rosary-like pattern of DWI lesions should call for further work up.

Attempts to improve absolute quantification of cerebral blood flow in dynamic susceptibility contrast magnetic resonance imaging: a simplified T1-weighted steady-state cerebral blood volume approach.

BACKGROUND: Attempts to retrieve absolute values of cerebral blood flow (CBF) by dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) have typically resulted in overestimations. PURPOSE: To improve DSC-MRI CBF estimates by calibrating the DSC-MRI-based cerebral blood volume (CBV) with a corresponding T1-weighted (T1W) steady-state (ss) CBV estimate. MATERIAL AND METHODS: 17 volunteers were investigated by DSC-MRI and 133Xe SPECT. Steady-state CBV calculation, assuming no water exchange, was accomplished using signal values from blood and tissue, before and after contrast agent, obtained by T1W spin-echo imaging. Using steady-state and DSC-MRI CBV estimates, a calibration factor K = CBV(ss)/CBV(DSC) was obtained for each individual. Average whole-brain CBF(DSC) was calculated, and the corrected MRI-based CBF estimate was given by CBF(ss) = K x CBF(DSC). RESULTS: Average whole-brain SPECT CBF was 40.1+/-6.9 ml/min x 100 g, while the corresponding uncorrected DSC-MRI-based value was 69.2+/-13.8 ml/min x 100 g. After correction with the calibration factor, a CBF(ss) of 42.7+/-14.0 ml/min x 100 g was obtained. The linear fit to CBF(ss)-versus-CBF(SPECT) data was close to proportionality (R = 0.52). CONCLUSION: Calibration by steady-state CBV reduced the population average CBF to a reasonable level, and a modest linear correlation with the reference 133Xe SPECT technique was observed. Possible explanations for the limited accuracy are, for example, large-vessel partial-volume effects, low post-contrast signal enhancement in T1W images, and water-exchange effects.

Hand-arm-vibration syndrome (HAVS): is there a central nervous component? An fMRI study.

Hand-held vibrating tools may result in neuromuscular dysfunction and vasospastic problems of the hand. Sensory and motor dysfunction can be explained by injury to peripheral structures, but could also be due to changes in cortical somatotopic mapping of the hand in the brain. The purpose of the present study was to use functional magnetic resonance imaging (fMRI) to assess the somatotopic cortical representation of the hands of workers subjected to occupational vibration. The study included six men with severe vibration exposures who were suffering from hand-arm-vibration syndrome (HAVS) and six controls. The analysis focused on the pattern and degree of activation of contra- and ipsilateral hemispheres of the brain with tactile stimulation and motor activation of the hand. These stimulations resulted in well-defined activation of the contralateral, and to a lesser extent the ipsilateral hemisphere. Statistical analysis of this limited patient material did not indicate any significant somatotopic cortical changes following long-term exposure to vibrating hand-held tools, although there was a tendency to a shift of activation towards the more cranial parts of the cortex in the patient group.

Enhanced jejunal production of antibodies to Klebsiella and other Enterobacteria in patients with ankylosing spondylitis and rheumatoid arthritis.

OBJECTIVE: To measure gut immunity directly in jejunal fluid in patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). METHODS: Antibodies against three different Enterobacterias were measured in jejunal perfusion fluids (collected by a double balloon perfusion device) of 19 patients with AS, 14 patients with RA, and 22 healthy controls using enzyme linked immunosorbent assay. RESULTS: The AS patients had significantly increased jejunal fluid concentrations of IgM, IgG, and IgA class antibodies against Klebsiella pneumoniae, and IgM and IgA class antibodies against Escherichia coli and Proteus mirabilis compared with healthy controls. When compared with the patients with RA, the AS patients had higher concentrations of IgA and IgG class antibodies only against K pneumoniae. The RA patients had higher IgM class antibody concentrations against all three studied Enterobacterias, when compared with the healthy controls, suggesting an enhanced mucosal immune response in these patients. A three month treatment with sulphasalazine did not decrease enterobacterial antibody concentrations in the 10 patients with AS. CONCLUSION: There is strong direct evidence for an abnormal mucosal humoral immune response particularly to K pneumoniae in patients with AS.

Acute exposure of small intestine to ethanol induces mucosal leakage and prostaglandin E2 synthesis.

The small intestines of healthy volunteers were challenged with ethanol during regional perfusion of a defined jejunal segment. Infusion of 30 mL of 5000 mmol/L ethanol to the perfused jejunal segment gave a maximum ethanol concentration of 973 +/- 98 (SEM) mmol/L in the jejunum lumen. This ethanol challenge induced within 20-30 minutes a 10-fold increase in albumin (P less than 0.001) and a two-fold increase in the glycosaminoglycan hyaluronic acid (P less than 0.05) in the perfusion fluid. Later during the challenge and simultaneously with a decreased jejunal loss of albumin, the jejunal recovery of prostaglandin E2 increased fourfold (P less than 0.01). The jejunal fluid concentrations of histamine and eosinophil cationic protein remained stable during the ethanol challenge. No changes in the jejunal appearance of albumin or other measured substances were seen when the maximum jejunal fluid concentrations of ethanol were less than 400 mmol/L achieved during challenge with smaller amounts of ethanol. The increased jejunal fluid appearance of hyaluronic acid after ethanol challenge indicates increased leakage from the interstitial/lymph fluid of the gut wall due to altered mucosal permeability. The relatively larger jejunal losses of albumin suggest that ethanol induces increased microvascular permeability of the jejunum as well.

Elevation of retinol levels and suppression of alanine aminotransferase activity in the liver of taurine-deficient kittens.

In taurine-deficient cats, the secretion of bile acids is impaired, and this impairment may reduce intestinal uptake of lipophilic vitamins. It was therefore hypothesized that retinol deficiency is involved in the generation of retinal lesions in taurine-deficient kittens. To this end, the concentration of retinol in plasma and liver was determined in taurine-deficient kittens. Further, the effects of taurine deficiency on amino acid concentrations of heart, liver and kidney were investigated. To see whether taurine deficiency adversely affects the liver, hepatic enzymes were measured in plasma and liver of kittens suffering from taurine deficiency. In addition, liver morphology, growth and food intake were studied. Taurine was the only amino acid whose concentration was consistently decreased in plasma of the experimental group. Unexpectedly, retinol level was increased in plasma and liver from taurine-depleted kittens. Several alterations were noted in amino acid concentrations in liver and kidney, but not in heart. Plasma alanine aminotransferase activity was diminished, probably reflecting decreased activity in the liver. Perivenular steatosis was found in both groups. Controls grew linearly, in contrast to deficient animals, which nevertheless consumed more food. The results demonstrate that retinol deficiency is not involved in taurine-deficiency retinopathy. Moreover, taurine is required for linear growth of juvenile cats and for the maintenance of hepatic and renal pools of certain amino acids.

Penicillamine treatment in rheumatoid arthritis. A retrospective study.

Out of 64 patients with rheumatoid arthritis (RA), 42 were treated with D-penicillamine (D-Pa) for more than 6 months and 22 for less than 6 months. The latter patients were excluded from the evaluation of the effect. The former patients were treated with doses of 600-1 250 mg daily for 6-41 months (mean 16.8). The clinical effect was retrospectively assessed as favourable in 24 patients, 12 did not respond and the effect could not be assessed in 6. The clinical assessment was supported by significant reductions of ESR and orosomucoid. Adverse reactions, although rarely serious, led to withdrawal of the drug in 25 (39%) of the 64 patients. It is concluded that D-Pa is a valuable drug in the treatment of severe RA.