Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity.

BACKGROUND: Overconsumption of dietary sugars, fructose in particular, is linked to cardiovascular risk factors such as type 2 diabetes, obesity, dyslipidemia and nonalcoholic fatty liver disease. However, clinical studies have to date not clarified whether these adverse cardiometabolic effects are induced directly by dietary sugars, or whether they are secondary to weight gain. OBJECTIVES: To assess the effects of fructose (75 g day-1 ), served with their habitual diet over 12 weeks, on liver fat content and other cardiometabolic risk factors in a large cohort (n = 71) of abdominally obese men. METHODS: We analysed changes in body composition, dietary intake, an extensive panel of cardiometabolic risk markers, hepatic de novo lipogenesis (DNL), liver fat content and postprandial lipid responses after a standardized oral fat tolerance test (OFTT). RESULTS: Fructose consumption had modest adverse effects on cardiometabolic risk factors. However, fructose consumption significantly increased liver fat content and hepatic DNL and decreased ß-hydroxybutyrate (a measure of ß-oxidation). The individual changes in liver fat were highly variable in subjects matched for the same level of weight change. The increase in liver fat content was significantly more pronounced than the weight gain. The increase in DNL correlated positively with triglyceride area under the curve responses after an OFTT. CONCLUSION: Our data demonstrated adverse effects of moderate fructose consumption for 12 weeks on multiple cardiometabolic risk factors in particular on liver fat content despite only relative low increases in weight and waist circumference. Our study also indicates that there are remarkable individual differences in susceptibility to visceral adiposity/liver fat after real-world daily consumption of fructose-sweetened beverages over 12 weeks.

Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men.

BACKGROUND AND AIMS: Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. METHODS AND RESULTS: As many as 66 obese (BMI 26-40 kg/m2) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). CONCLUSION: In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge.

Grey:white matter ratio at diagnosis and the risk of 10-year multiple sclerosis progression.

BACKGROUND AND PURPOSE: Grey matter (GM) and white matter (WM) are both affected in multiple sclerosis (MS). WM is predominantly involved in inflammatory demyelination of relapsing-remitting MS (RRMS), whereas GM is predominantly involved in neurodegenerative processes of secondary progressive MS. Thus, we investigated the ratio between GM and WM volumes in predicting MS evolution. METHODS: The present 10-year retrospective cohort study included 149 patients with newly-diagnosed RRMS, undergoing magnetic resonance imaging for segmentation and brain volumetry. The ratio between GM and normal-appearing WM (NAWM) volumes was calculated for each subject. Outcome measures of interest were Expanded Disability Status Scale (EDSS) progression, reaching EDSS 4.0 and conversion to secondary progressive (SP) MS. RESULTS: During a period of 10.6 ± 2.4 years, a median 1.5 EDSS progression was observed (range 0-5.5), 54 subjects (36.2%) reached EDSS 4.0 and 30 subjects (20.1%) converted to SP. With ordinal logistic regression models, EDSS progression was associated with GM:NAWM ratio (coefficient, -2.918; 95% CI, -4.739-1.097). With Cox regression models, subjects with higher GM:NAWM ratio at diagnosis had a 90% lower rate of reaching EDSS 4.0 (hazard ratio, 0.111; 95% CI, 0.020-0.609) and of converting to secondary progressive MS (hazard ratio, 0.017; 95% CI, 0.001-0.203) compared with subjects with lower GM:NAWM ratio. CONCLUSIONS: The GM:NAWM ratio is a predictor of disability progression and of SP conversion in subjects with newly diagnosed RRMS, suggesting that GM and NAWM are variably affected in relation to disease evolution from the early phases of MS.

Is avolition in schizophrenia associated with a deficit of dorsal caudate activity? A functional magnetic resonance imaging study during reward anticipation and feedback.

BACKGROUND: The neurobiological underpinnings of avolition in schizophrenia remain unclear. Most brain imaging research has focused on reward prediction deficit and on ventral striatum dysfunction, but findings are not consistent. In the light of accumulating evidence that both ventral striatum and dorsal caudate play a key role in motivation, we investigated ventral striatum and dorsal caudate activation during processing of reward or loss in patients with schizophrenia. METHOD: We used functional magnetic resonance imaging to study brain activation during a Monetary Incentive Delay task in patients with schizophrenia, treated with second-generation antipsychotics only, and in healthy controls (HC). We also assessed the relationships of ventral striatum and dorsal caudate activation with measures of hedonic experience and motivation. RESULTS: The whole patient group had lower motivation but comparable hedonic experience and striatal activation than HC. Patients with high avolition scores showed lower dorsal caudate activation than both HC and patients with low avolition scores. A lower dorsal caudate activation was also observed in patients with deficit schizophrenia compared to HC and patients with non-deficit schizophrenia. Dorsal caudate activity during reward anticipation was significantly associated with avolition, but not with anhedonia in the patient group. CONCLUSIONS: These findings suggest that avolition in schizophrenia is linked to dorsal caudate hypoactivation.

Natalizumab vs interferon beta 1a in relapsing-remitting multiple sclerosis: a head-to-head retrospective study.

BACKGROUND: No head-to-head study has been performed yet to assess whether natalizumab is more effective than classical immunomodulators in multiple sclerosis (MS). AIM: To retrospectively compare the efficacy of natalizumab vs IFN beta 1a SC (44 µg; Rebif(®) ) on clinical and radiological findings in two matched cohorts of patients with MS. PATIENTS AND METHODS: We retrospectively enrolled two cohorts of 42 patients (F/M: 35/7) with relapsing-remitting multiple sclerosis treated with natalizumab or IFN beta 1a for at least 12 consecutive months. Outcome measures were annualized relapse rate (ARR), changes in expanded disability status scale (EDSS) score, and number of contrast-enhancing lesions (CELs) at magnetic resonance imaging (MRI). RESULTS: In both groups, the ARR in the 12 months of treatment was lower than in the 12 months before therapy (0.24 vs 1.50 in natalizumab-treated group, P < 0.0000; 0.55 vs 1.10 in IFN beta 1a-treated group, P = 0.0006), being the effect of natalizumab significantly stronger (P = 0.0125). EDSS reduction was significantly different between the two groups in favor of natalizumab (P = 0.0018). The frequency and number of CELs per patient were decreased in both groups. In the second year, the treatment affected ARR and EDSS progression in the two groups of patients similarly to the first year, whereas number of CELs decreased more significantly in natalizumab group (P = 0.008). CONCLUSIONS: After 12 and 24 months of therapy, natalizumab was more effective than IFN beta 1a SC on both disease activity and disability progression. Prospective head-to-head studies would be helpful to further evaluate the differences observed in the MRI outcomes.

Insulin-like growth factor (IGF)-I and IGF-binding protein-3 serum levels in relapsing-remitting and secondary progressive multiple sclerosis patients.

BACKGROUND: Insulin-like growth factor (IGF)-I has a role in remyelination, and insulin-like growth factor-binding protein-3 (IGFBP-3) might reduce its bioavailability. A role of IGFBP-3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. OBJECTIVE: To evaluate serum levels of IGF-I and IGFBP-3 in patients with relapsing-remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. METHODS: Sixty-three (41 RR and 22 SP) 'naive' MS patients and 60 age-matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF-I and IGFBP-3 were measured by ELISA. RESULTS: Levels of IGF-I and IGFBP-3 were similar in the two MS groups. IGFBP-3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF-I/BP3 ratio (P < 0.001). Patients showing IGFBP-3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF-I or IGFBP-3 serum levels. CONCLUSIONS: Our patients showed high IGFBP-3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF-I. MSSS score was not related to IGFBP-3 levels, suggesting that IGFBP-3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease.

Predictive factors of neutralizing antibodies development in relapsing-remitting multiple sclerosis patients on interferon Beta-1b therapy.

The identification of predictive factors of NAbs development might have a relevant impact on clinical practice. Our objective is to look after predictive factors of NAbs development in MS IFN Beta-1b-treated patients. Database was screened for patients on IFN Beta-1b treatment with an Expanded Disability Status Scale (EDSS) at a baseline between 1 and 3.5, disease duration shorter than 15 years, and NAbs analysis performed every 6 months. The NAbs positive status was analysed in relation to baseline clinical, neuropsychological and brain imaging measures. Forty-nine patients were included. Sixteen patients had become NAbs positive at some point on IFN therapy (35%). NAbs producers differed from not producers for higher incidence of cognitive deficit and higher lesion load (OR = 5.0 and 5.6, respectively). Our study suggests that NAbs development might be a marker of a more aggressive disease and that worse outcome in NAbs producers might be biased by baseline condition.

A voxel-based morphometry study of disease severity correlates in relapsing-- remitting multiple sclerosis.

Previous studies have shown a preferential loss of grey matter in fronto-temporal regions in patients with multiple sclerosis. Studies of correlates of disease severity are more controversial, because some studies have suggested an association between sensorimotor cortex atrophy and Expanded Disability Status Scale score, while others did not find such a correlation. The objective of this study was to assess the correlation of regional loss of grey matter and white matter with indexes of clinical and radiological severity in relapsing-remitting multiple sclerosis, including the Expanded Disability Status Scale and lesion load. Correlations between Expanded Disability Status Scale, lesion load and disease duration were assessed in 128 patients with relapsing-remitting multiple sclerosis (Expanded Disability Status Scale range 1.0-6.0) using optimized voxel-based morphometry. Bilateral loss of grey matter in sensorimotor cortices was correlated with Expanded Disability Status Scale, and tissue loss also involved adjacent white matter, extending along pyramidal tracts to the brainstem. Increasing lesion load was correlated with loss of deep grey matter and white matter. No specific region of grey matter or white matter showed a significant correlation with disease duration. These findings support the hypothesis that motor neuron involvement plays a major role in the progression of physical disability. Lesion load accrual affects mainly highly interconnected subcortical structures, while disease duration has a less significant impact on brain atrophy, probably owing to the inter-subject heterogeneity of the clinical course of the disease.

Brain atrophy evolution and lesion load accrual in multiple sclerosis: a 2-year follow-up study.

BACKGROUND: To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression. METHODS: Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points. RESULTS: The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression. CONCLUSIONS: In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.

Mapping the relative contribution of gray matter activity vs. volume in brain PET: a new approach.

Interpretation of brain positron emission tomography (PET) in terms of function vs. structure is ambiguous owing to the partial volume effect (PVE). Therefore, observed differences in tracer distribution could reflect differences in either activity or volume, a problem that applies principally to gray matter (GM) since white matter (WM) virtually always has uniform activity. To assess the contribution of GM volume vs. activity, we implemented a method to directly compare PET images with underlying structure, and applied it to resting-state (18)Fluoro-deoxy-glucose-PET (FDG) of healthy subjects. Methods. Average GM and WM PVE-corrected mean FDG uptake values were applied onto co-registered segmented magnetic resonance imaging data sets to generate a "virtual PET" in which activity is proportional to GM volume and resolution set to that of PET. The raw PET and virtual PET values were then compared across the sample of subjects, first voxel-wise to detect clusters with significant activity-volume mismatch, and second within regions-of-interest (ROI) to quantify mismatches between unsmoothed voxel values. Results. Relative to volume, there was significant hyperactivity of most GM structures of the dorsal brain-except the thalamus-and significant hypoactivity of the temporal lobe, hippocampal region, and cerebellum, consistent across the voxel- and ROI-based analyses. Conclusion. As applied to normals, our method documented the expected contribution of functional activity independently of local differences in GM volume in the normal pattern of FDG uptake, and disclosed marked heterogeneities in functional activity per unit GM volume among structures. This generic method should find applications in pathological states as well as for other PET and SPECT radiotracers.

Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study.

Global grey matter (GM) loss has been reported in multiple sclerosis (MS). We addressed the question of if and where GM loss is localized by means of optimized voxel-based morphometry, applied to MRI studies of 51 patients with clinically defined relapsing-remitting MS and 34 age-matched normal subjects, segmented into normal and abnormal brain tissues using a multiparametric approach. Segmented GM volumes were subsequently compared on a voxel-by-voxel basis to highlight regions of relative GM loss (P < 0.05, corrected for multiple comparisons at AnCova). Additionally, localized differences in brain asymmetry between the MS and the control groups were assessed by comparing on a voxel-by-voxel basis maps of GM differences between the two hemispheres (P < 0.05 corrected for multiple comparisons). In MS patients, GM volume was significantly decreased at the level of the left fronto-temporal cortex and precuneus, as well as of anterior cingulate gyrus and of caudate nuclei bilaterally. The only cortical region of significant GM loss in the right hemisphere was located in the postcentral area. Furthermore, GM loss regions were colocalized with increased GM asymmetries (Left < Right) in MS, confirming a preferential left-sided GM loss. Caudate atrophy correlated with lesion load, while no correlation between cortical regional GM loss and disease duration, clinical status or lesion load emerged. Our findings suggest that in RR-MS cortical GM reduction preferentially involves left fronto-temporal structures and deep GM, the latter correlating preferentially to global lesion load.

Brain atrophy and lesion load in a large population of patients with multiple sclerosis.

OBJECTIVE: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. METHODS: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). RESULTS: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. CONCLUSIONS: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.

Simultaneous measurement of DeltaR2 and DeltaR2* in cat brain during hypoxia and hypercapnia.

One of the most important issues in blood-oxygen-level-dependent (BOLD)-based brain functional magnetic resonance imaging is the understanding of the vascular structures that are responsible for the signal changes observed. The T2*-related signal changes observed during variations in susceptibility-induced magnetic field gradients are a function both of non-refocusable mechanisms, such as diffusion, and of refocusable effects such as field inhomogeneities. Conversely, T2-related signal changes are only a function of non-refocusable effects. It has been suggested that T2-weighted images could be less sensitive to blood susceptibility changes in a macrovascular environment than T2*-weighted images and could thus be more accurate in identifying the "activation" of the parenchyma rather than "draining vein" effects. In this study we use hypoxia and hypercapnia challenges in cats to provide a change in blood deoxyhemoglobin concentration (as a model for classic BOLD changes and not as a model for neuronal activation). A combined gradient echo and spin echo echo-planar-imaging (EPI) pulse sequence was used to map DeltaR2 (i.e., Delta(1/T2)) and DeltaR2* (i.e., Delta(1/T2*)) changes during the challenges. Our experiments demonstrate that: (i) the acquisition of T2-weighted EPI data does not in itself differentiate signal changes in the parenchyma from those occurring in regions around larger vessels, but that (ii) the simultaneous acquisition of T2- and T2*-weighted images could be useful in identifying microvascular regions in gray matter by analyzing the ratio DeltaR2/DeltaR2*. This value seems independent of the degree of deoxyhemoglobin concentration change, but is related to properties of the vascular environment. We suggest a possible application of the results to the study of brain function in humans.

Sentence reading: a functional MRI study at 4 tesla.

In this study, changes in blood oxygenation and volume were monitored while monolingual right-handed subjects read English sentences. Our results confirm the role of the left peri-sylvian cortex in language processing. Interestingly, individual subject analyses reveal a pattern of activation characterized by several small, limited patches rather than a few large, anatomically well-circumscribed centers. Between-subject analyses confirm a lateralized pattern of activation and reveal active classical language areas including Broca's area, Wernicke's area, and the angular gyms. In addition they point to areas only more recently considered as language-relevant including the anterior portion of the superior temporal sulcus. This area has not been reliably observed in imaging studies of isolated word processing. This raises the hypothesis that activation in this area is dependent on processes specific to sentence reading.

Functional MRI: primary motor cortex localization in patients with brain tumors.

PURPOSE: Our goal was (a) to test the ability of functional MRI (fMRI) to localize the hand primary motor cortex in patients with brain neoplasms using a conventional scanner and (b) to compare within the same subject the location and morphology of the activated motor areas in the affected hemisphere with the contralateral ones. METHOD: Seventeen right-handed patients with frontoparietal intra- and extraaxial tumors were studied. Hand motor performance ranged from normal to slight impairment of finger dexterity. The fMRI study was based on a series of FLASH images. Two or three contiguous slices parallel to the bicommissural plane were acquired through the level of frontoparietal cortex. Each patient was requested to perform with each hand a finger-tapping task or a simpler repetitive flexion-extension of the last four fingers. Pseudo-color activation maps were then calculated by a Z-score method and superimposed on high resolution images. RESULTS: Five patients were excluded because of gross motion artifacts. In all other patients, areas of significant signal increase were detected on the precentral gyrus. They had a spot-like appearance, and no substantial side-to-side differences in shape or extension could be observed. In the presence of severe compression of the gyri, a displacement of the activated areas in the affected hemisphere with respect to the contralateral ones was noticeable. CONCLUSION: fMRI localization of the primary motor area using a conventional scanner can be obtained also in patients with brain tumors, although with a lower success rate than in normal volunteer studies, mainly because of subject compliance problems. Areas of significantly increased signal are detectable even in cortex where normal anatomical patterns are lost.

An elastic computerized brain atlas for the analysis of clinical PET/SPET data.

An elastic computerized brain atlas was developed for the analysis of positron emission tomography/single-photon emission tomography (PET/SPET) data. It consists of a set of digital anatomical contours and a template of regions of interest, schematically describing the brain, derived from a currently used anatomical/functional brain atlas. A warping algorithm, matching equivalent contours, was implemented to elastically fit the atlas to individual brain images. The elastic computerized brain atlas was applied to representative magnetic resonance imaging (MRI)-PET/SPET studies, MRI providing the anatomical information used by the matching procedure. The atlas is suited for clinical use in a nuclear medicine environment.

A bioimaging integration system implemented for neurological applications.

A system aimed at the management and fusion of multimodal biomedical images, including X-ray computed tomography, magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, has been implemented for neurological applications. This bioimaging integration system (BIS) consists of a network for image transmission from acquisition machines to dedicated image processing workstations, a software library for image standardization, and an image registration technique to project multimodal volumetric images into a common reference space. The registration procedure was evaluated in MRI/PET correlation studies, in which misalignment errors of 2.6 mm in the xy transaxial plane and 3.4 mm along the z axis were found. BIS has been validated for the anatomical-functional correlation analysis of MRI and PET images in neurological research protocols and clinical studies.