Injectable Thermogelling Nanostructured Ink as Simultaneous Optical and Magnetic Resonance Imaging Contrast Agent for Image-Guided Surgery.

The development of efficient and biocompatible contrast agents is particularly urgent for modern clinical surgery. Nanostructured materials raised great interest as contrast agents for different imaging techniques, for which essential features are high contrasts, and in the case of precise clinical surgery, minimization of the signal spatial dispersion when embedded in biological tissues. This study deals with the development of a multimodal contrast agent based on an injectable hydrogel nanocomposite containing a lanthanide-activated layered double hydroxide coupled to a biocompatible dye (indocyanine green), emitting in the first biological window. This novel nanostructured thermogelling hydrogel behaves as an efficient tissue marker for optical and magnetic resonance imaging because the particular formulation strongly limits its spatial diffusion in biological tissue by exploiting a simple injection. The synergistic combination of these properties permits to employ the hydrogel ink simultaneously for both optical and magnetic resonance imaging, easy monitoring of the biological target, and, at the same time, increasing the spatial resolution during a clinical surgery. The biocompatibility and excellent performance as contrast agents are very promising for possible use in image-guided surgery, which is currently one of the most challenging topics in clinical research.

Resting-state functional magnetic resonance imaging reveals functional connectivity alteration in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune degenerative disease targeting white matter in the central nervous system. The most common animal model that mimics MS is experimental autoimmune encephalomyelitis (EAE) and it plays a crucial role in pharmacological research, from the identification of a therapeutic target to the in vivo validation of efficacy. Magnetic resonance imaging (MRI) is largely used to detect MS lesions, and resting-state functional MRI (rsfMRI) to investigate alterations in the brain functional connectivity (FC). MRI was mainly used in EAE studies to detect lesions in the spinal cord and brain. The current longitudinal MRI study aims to validate rsfMRI as a biomarker of the disease progression in the myelin oligodendrocyte glycoprotein 35-55 induced EAE animal model of MS. MR images were acquired 14, 25, and 50 days postimmunization. Seed-based analysis was used to investigate the whole-brain FC with some predefined areas, such as the thalamic regions, cerebellum, motor and somatosensory cortex. When compared with the control group, the EAE group exhibited a slightly altered FC and a decreasing trend in the total number of activated voxels along the disease progression. The most interesting result regards the whole-brain FC with the cerebellum. A hyperconnectivity behavior was found at an early phase and a significant reduced connectivity at a late phase. Moreover, we found a negative correlation between the total number of activated voxels during the late phase and the cumulative disease index. The results obtained provide a clinically relevant experimental platform that may be pivotal for the elucidation of the key mechanisms of accumulation of irreversible disability, as well as the development of innovative therapies for MS. Moreover, the negative correlation between the disease severity and the size of the activated area suggests a possible research pathway to follow for the resolution of the clinico-radiological paradox.

Non-lesional white matter in relapsing-remitting multiple sclerosis assessed by multicomponent T2 relaxation.

INTRODUCTION: The purpose of the study is to investigate, by T2 relaxation, non-lesional white matter (WM) in relapsing-remitting (RR) multiple sclerosis (MS). METHODS: Twenty stable RR MS patients underwent 1.5T Magnetic Resonance Imaging (MRI) with 3D Fluid-Attenuated Inversion-Recovery (FLAIR), 3D-T1-weighted, and T2-relaxation multi-echo sequences. The Lesion Segmentation Tool processed FLAIR images to identify focal lesions (FLs), whereas T1 images were segmented to identify WM and FL sub-volumes with T1 hypo-intensity. Non-lesional WM was obtained as the segmented WM, excluding FL volumes. The multi-echo sequence allowed decomposition into myelin water, intra-extracellular water, and free water (Fw), which were evaluated on the segmented non-lesional WM. Correlation analysis was performed between the non-lesional WM relaxation parameters and Expanded Disability Status Scale (EDSS), disease duration, patient age, and T1 hypo-intense FL volumes. RESULTS: The T1 hypo-intense FL volumes correlated with EDSS. On the non-lesional WM, the median Fw correlated with EDSS, disease duration, age, and T1 hypo-intense FL volumes. Bivariate EDSS correlation of FL volumes and WM T2-relaxation parameters did not improve significance. CONCLUSION: T2 relaxation allowed identifying subtle WM alterations, which significantly correlated with EDSS, disease duration, and age but do not seem to be EDSS-predictors independent from FL sub-volumes in stable RR patients. Particularly, the increase in the Fw component is suggestive of an uninvestigated prodromal phenomenon in brain degeneration.

Tractography passes the test: Results from the diffusion-simulated connectivity (disco) challenge.

Estimating structural connectivity from diffusion-weighted magnetic resonance imaging is a challenging task, partly due to the presence of false-positive connections and the misestimation of connection weights. Building on previous efforts, the MICCAI-CDMRI Diffusion-Simulated Connectivity (DiSCo) challenge was carried out to evaluate state-of-the-art connectivity methods using novel large-scale numerical phantoms. The diffusion signal for the phantoms was obtained from Monte Carlo simulations. The results of the challenge suggest that methods selected by the 14 teams participating in the challenge can provide high correlations between estimated and ground-truth connectivity weights, in complex numerical environments. Additionally, the methods used by the participating teams were able to accurately identify the binary connectivity of the numerical dataset. However, specific false positive and false negative connections were consistently estimated across all methods. Although the challenge dataset doesn't capture the complexity of a real brain, it provided unique data with known macrostructure and microstructure ground-truth properties to facilitate the development of connectivity estimation methods.

Age-Related In Vivo Structural Changes in the Male Mouse Olfactory Bulb and Their Correlation with Olfactory-Driven Behavior.

Olfactory areas in mammalian brains are linked to centers that modulate behavior. During aging, sensitivity to odors decreases and structural changes are described in olfactory areas. We explored, in two groups of male mice (young and elderly, 6 and 19 months old, respectively), the link between the changes in olfactory bulb structure, detected with magnetic resonance imaging, and behavioral changes in a battery of tests on motor, olfactory, cognitive performance, and emotional reactivity. The behavioral pattern of elderly mice appears less anxious, being less scared by new situations. Additionally, the olfactory bulb of young and elderly mice differed in two variables derived from magnetic resonance imaging (fractional anisotropy and T2 maps). A random forest approach allowed to select the variables most predictive of the differences between young and elderly mice, and correlations were found between three behavioral variables indicative of anxious behavior and the two magnetic resonance variables mentioned above. These data suggest that in the living mouse, it is possible to describe co-occurring age-related behavioral and structural changes in the olfactory bulb. These data serve as a basis for studies on normal and pathological aging in the mouse, but also open new opportunities for in vivo human aging studies.

A New Method to Easily Assess Bacteriostatic and Bactericidal Activity of Ultraviolet Radiation Using Quantitative Image Analysis.

Ultraviolet (UV) radiation can elicit both bactericidal and bacteriostatic activity depending on light parameters and targeted bacteria. Current methods based on bacterial growth on solid medium allow measurement of only bactericidal but not bacteriostatic activity, while liquid cultures exhibit low light penetration. Here, we propose a method to quantify both bactericidal and bacteriostatic activity of radiation based on (a) bacterial cultures on solid medium, (b) acquisition and quantitative analysis of photographic images of plates containing bacterial colonies, (c) application of two mathematical equations to evaluate bactericidal and bacteriostatic activity. The proposed method considers the differences in growth on test and control (unexposed) plates. The measurements performed on the plates image are the independent variables of the mathematical equations returning the values of bactericidal and bacteriostatic activity. Experimentally, a test was performed using Escherichia coli grown on a solid medium and exposed to UVA (365 nm) radiation. The standard method allowed quantifying bactericidal activity and evaluating only qualitatively bacteriostatic activity of the radiation. Differently, the new method here proposed allowed quantification of both activities. The proposed method proved to be simple, enabling deep assessment of the antibacterial effects of UV radiation directly on the solid medium through image acquisition and analysis.

Quantitative magnetic resonance characterization of the effect of physical training on skeletal muscle of the Ts65Dn mice, a model of Down syndrome.

Down syndrome (DS) is characterized by muscle hypotonia and low muscle strength associated with motor dysfunction. Elucidation of the determinants of muscle weakness in DS would be relevant for therapeutic approaches aimed at treating/mitigating a physical disability with a strong impact on the quality of life in persons with DS. The Ts65Dn mice is a recognized mouse model of DS, with trisomic mice presenting gross motor and muscle phenotypes. The aim of this work was to assess the effect of physical exercise, a well-known tool to improve skeletal muscle condition, in the hindlimbs of trisomic and euploid male mice using quantitative magnetic resonance imaging (MRI). Magnetic resonance spectroscopy (MRS) metabolomics and histological fiber typing were used to further characterize the post-exercise muscle. Quantitative MRI showed not significantly different amounts of skeletal muscle in proximal hindlimbs in trisomic and euploid mice both at baseline and after physical exercise (P>0.05). Similar results were obtained for hindlimbs subfascia adipose tissue, and subcutaneous adipose tissue (P>0.05). MRS showed lower amounts of exercise-related metabolites (valine, isoleucine, leucine) in euploid vs. trisomic mice after exercise (P≤0.05). The percentage of slow-twitch fibers was similar in the two genotypes (P>0.05). We conclude that in DS adapted physical exercise (one month of training) does not induce quantitative changes in skeletal muscle or fiber type composition therein; however, the metabolic response of skeletal muscle to exercise may be affected by trisomy. These findings prompt further research investigating the role of physical exercise as a cue to clarify the mechanisms of the muscular deficit found in DS.

Tractostorm 2: Optimizing tractography dissection reproducibility with segmentation protocol dissemination.

The segmentation of brain structures is a key component of many neuroimaging studies. Consistent anatomical definitions are crucial to ensure consensus on the position and shape of brain structures, but segmentations are prone to variation in their interpretation and execution. White-matter (WM) pathways are global structures of the brain defined by local landmarks, which leads to anatomical definitions being difficult to convey, learn, or teach. Moreover, the complex shape of WM pathways and their representation using tractography (streamlines) make the design and evaluation of dissection protocols difficult and time-consuming. The first iteration of Tractostorm quantified the variability of a pyramidal tract dissection protocol and compared results between experts in neuroanatomy and nonexperts. Despite virtual dissection being used for decades, in-depth investigations of how learning or practicing such protocols impact dissection results are nonexistent. To begin to fill the gap, we evaluate an online educational tractography course and investigate the impact learning and practicing a dissection protocol has on interrater (groupwise) reproducibility. To generate the required data to quantify reproducibility across raters and time, 20 independent raters performed dissections of three bundles of interest on five Human Connectome Project subjects, each with four timepoints. Our investigation shows that the dissection protocol in conjunction with an online course achieves a high level of reproducibility (between 0.85 and 0.90 for the voxel-based Dice score) for the three bundles of interest and remains stable over time (repetition of the protocol). Suggesting that once raters are familiar with the software and tasks at hand, their interpretation and execution at the group level do not drastically vary. When compared to previous work that used a different method of communication for the protocol, our results show that incorporating a virtual educational session increased reproducibility. Insights from this work may be used to improve the future design of WM pathway dissection protocols and to further inform neuroanatomical definitions.

Multicomponent T2 relaxometry reveals early myelin white matter changes induced by proton radiation treatment.

PURPOSE: To investigate MRI myelin water imaging (MWI) by multicomponent T2 relaxometry as a quantitative imaging biomarker for brain radiation-induced changes and to compare it with DTI. METHODS: Sixteen patients underwent fractionated proton therapy (PT) receiving dose to the healthy tissue because of direct or indirect (base skull tumors) irradiation. MWI was performed by a multi-echo sequence with 32 equally spaced echoes (10-320 ms). Decay data were processed to identify 3 T2 compartments: myelin water (Mw) below 40 ms, intra-extracellular water (IEw) between 40 and 250 ms, and free water (CSFw) above 250 ms. Both MWI and DTI scans were acquired pre (pre)-treatment and immediately at the end (end) of PT. After image registration, voxel-wise difference maps, obtained by subtracting MWI and DTI pre from those acquired at the end of PT, were compared with the corresponding biological equivalent dose (BED). RESULTS: Mw difference showed a positive correlation and IEw difference showed a negative correlation with BED considering end-pre changes (P < .01). The changes in CSFw were not significantly correlated with the delivered BED. The changes in DTI data, considering end-pre acquisitions, showed a positive correlation between fractional anisotropy and the delivered BED. CONCLUSION: MWI might detect early white matter radiation-induced alterations, providing additional information to DTI, which might improve the understanding of the pathogenesis of the radiation damage.

MRI characterization of rat brain aging at structural and functional level: Clues for translational applications.

Magnetic resonance imaging (MRI) paradigms, using non-invasive approaches, can provide relevant findings about brain aging. The attention has been primarily focused on neurodegenerative diseases, while little or nothing has been done to differentiate physiology from pathology. The present study aimed to test diffusion tensor imaging (DTI) and functional MRI (fMRI) metrics to analyze physiological age-related changes in rats at myelin structure and activation level; findings were validated by ex vivo histology. The purpose is to find comparable biomarkers in rodents and humans to allow a reliable translation from pre-clinical to clinical settings. Data evidenced: i) a significantly higher cerebrospinal fluid volume in middle-aged and aged vs. young rats; ii) a progressive alteration of white matter; iii) a significant reduction of evoked activity in aged animals. These results partially mirror the age-related changes in humans and may represent a preliminary step to find reliable tools for a lifelong monitoring with a value for the clinical practice (e.g., to provide support to the early diagnosis of dementia in asymptomatic subjects).

Quantitative Multicomponent T2 Relaxation Showed Greater Sensitivity Than Flair Imaging to Detect Subtle Alterations at the Periphery of Lower Grade Gliomas.

PURPOSE: To demonstrate that quantitative multicomponent T2 relaxation can be more sensitive than conventional FLAIR imaging for detecting cerebral tissue abnormalities. METHODS: Six patients affected by lower-grade non-enhancing gliomas underwent T2 relaxation and FLAIR imaging before a radiation treatment by proton therapy (PT) and were examined at follow-up. The T2 decay signal obtained by a thirty-two-echo sequence was decomposed into three main components, attributing to each component a different T2 range: water trapped in the lipid bilayer membrane of myelin, intra/extracellular water and cerebrospinal fluid. The T2 quantitative map of the intra/extracellular water was compared with FLAIR images. RESULTS: Before PT, in five patients a mismatch was observed between the intra/extracellular water T2 map and FLAIR images, with peri-tumoral areas of high T2 that typically extended outside the area of abnormal FLAIR hyper-intensity. Such mismatch regions evolved into two different types of patterns. The first type, observed in three patients, was a reduced extension of the abnormal regions on T2 map with respect to FLAIR images (T2 decrease pattern). The second type, observed in two patients, was the appearance of new areas of abnormal hyper-intensity on FLAIR images matching the anomalous T2 map extension (FLAIR increase pattern), that was considered as asymptomatic radiation induced damage. CONCLUSION: Our preliminarily results suggest that quantitative T2 mapping of the intra/extracellular water component was more sensitive than conventional FLAIR imaging to subtle cerebral tissue abnormalities, deserving to be further investigated in future clinical studies.

A smaller olfactory bulb in a mouse model of Down syndrome.

Persons with trisomy 21 (Down syndrome) present different phenotypes, including early neurodegeneration, which is prominent in the brain olfactory areas, and olfactory deficit. The use of in vivo techniques in animal models allows to characterize and follow up these slowly developing phenomena. We explored by means of magnetic resonance imaging the olfactory bulb of the Ts65Dn mouse, an established model of Down syndrome, searching for possible syndrome­related changes. In vivo imaging provided a first glimpse of the trisomic olfactory bulb as compared to euploid one. The olfactory bulb volume was smaller in trisomic mice, suggesting that changes in olfactory bulb may be apparent already in the young adult (2­ to 8­month­old) mice, which are amenable to follow­up in vivo. These findings lead the way to future work aimed at characterizing the Down syndrome­related development of morphological alterations in the olfactory bulb and relating them to changes in olfactory performance, which were detected in this mouse model.

Default mode network activity in bipolar disorder.

Since its discovery in 1997, the default mode network (DMN) and its components have been extensively studied in both healthy individuals and psychiatric patients. Several studies have investigated possible DMN alterations in specific mental conditions such as bipolar disorder (BD). In this review, we describe current evidence from resting-state functional magnetic resonance imaging studies with the aim to understand possible changes in the functioning of the DMN in BD. Overall, several types of analyses including seed-based and independent component have been conducted on heterogeneous groups of patients highlighting different results. Despite the differences, findings seem to indicate that BD is associated with alterations in both frontal and posterior DMN structures, mainly in the prefrontal, posterior cingulate and inferior parietal cortices. We conclude this review by suggesting possible future research directions.

Slow versus fast rewarming after hypothermic circulatory arrest: effects on neuroinflammation and cerebral oedema.

OBJECTIVES: Among the factors that could determine neurological outcome after hypothermic circulatory arrest (HCA) rewarming is rarely considered. The optimal rewarming rate is still unknown. The goal of this study was to investigate the effects of 2 different protocols for rewarming after HCA on neurological outcome in an experimental animal model. METHODS: Forty-four Sprague Dawley rats were cooled to 19 ± 1°C body core temperature by cardiopulmonary bypass (CPB). HCA was maintained for 60 min. Animals were randomized to receive slow (90 min) or fast (45 min) assisted rewarming with CPB to a target temperature of 35°C. After a total of 90 min of reperfusion in both groups, brain samples were collected and analysed immunohistochemically and with immunofluorescence. In 10 rats, magnetic resonance imaging was performed after 2 and after 24 h to investigate cerebral perfusion and cerebral oedema. RESULTS: Interleukin 6, chemokine (C-C motif) ligand 5, intercellular adhesion molecule 1 and tumour necrosis factor α in the hippocampus are significantly less expressed in the slow rewarming group, and microglia cells are significantly less activated in the slow rewarming group. Magnetic resonance imaging analysis demonstrated better cerebral perfusion and less water content in brains that underwent slow rewarming at 2 and 24 h. CONCLUSIONS: Slow rewarming after HCA might be superior to fast rewarming in neurological outcome. The present experimental study demonstrated reduction in the inflammatory response, reduction of inflammatory cell activation in the brain, enhancement of cerebral blood flow and reduction of cerebral oedema when slow rewarming was applied.

ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motoneurons. To date, there is no effective treatment available. Exosomes are extracellular vesicles that play important roles in intercellular communication, recapitulating the effect of origin cells. In this study, we tested the potential neuroprotective effect of exosomes isolated from adipose-derived stem cells (ASC-exosomes) on the in vivo model most widely used to study ALS, the human SOD1 gene with a G93A mutation (SOD1(G93A)) mouse. Moreover, we compared the effect of two different routes of exosomes administration, intravenous and intranasal. The effect of exosomes administration on disease progression was monitored by motor tests and analysis of lumbar motoneurons and glial cells, neuromuscular junction, and muscle. Our results demonstrated that repeated administration of ASC-exosomes improved the motor performance; protected lumbar motoneurons, the neuromuscular junction, and muscle; and decreased the glial cells activation in treated SOD1(G93A) mice. Moreover, exosomes have the ability to home to lesioned ALS regions of the animal brain. These data contribute by providing additional knowledge for the promising use of ASC-exosomes as a therapy in human ALS.

Resting state networks activity in euthymic bipolar disorder.

OBJECTIVES: Bipolar disorder (BD) is a psychiatric condition causing shifts in mood, energy and activity levels severely altering the quality of life of the patients even in the euthymic phase. Although widely accepted, the neurobiological bases of the disorder in the euthymic phase remain elusive. This study aims at characterizing resting state functional activity of the BD euthymic phase in order to better understand the pathogenesis of the disease and build future neurobiological models. METHODS: Fifteen euthymic BD patients (10 females; mean age 40.2; standard deviation 13.5; range 20-61) and 27 healthy controls (HC) (21 females; mean age 37; standard deviation 10.6; range 22-60) underwent a 3T functional MRI scan at rest. Resting state activity was extracted through independent component analysis (ICA) run with automatic dimensionality estimation. RESULTS: ICA identified 22 resting state networks (RSNs). Within-network analysis revealed decreased connectivity in the visual, temporal, motor and cerebellar RSNs of BD patients vs HC. Between-network analysis showed increased connectivity between motor area and the default mode network (DMN) partially overlapping with the fronto-parietal network (FPN) in BD patients. CONCLUSION: Within-network analysis confirmed existing evidence of altered cerebellar, temporal, motor and visual networks in BD. Increased connectivity between the DMN and the motor area network suggests the presence of alterations of the fronto-parietal regions, precuneus and cingulate cortex in the euthymic condition. These findings indicate that specific connectivity alterations might persist even in the euthymic state suggesting the importance of examining both within and between-network connectivity to achieve a global understanding of the BD euthymic condition.

Heterogeneous Enhancement Pattern in DCE-MRI Reveals the Morphology of Normal Lymph Nodes: An Experimental Study.

Purpose: To investigate the heterogeneous enhancement pattern in normal lymph nodes of healthy mice by different albumin-binding contrast agents. Methods: The enhancement of normal lymph nodes was assessed in mice by dynamic contrast-enhanced MRI (DCE-MRI) after the administration of two contrast agents characterized by different albumin-binding properties: gadopentetate dimeglumine (Gd-DTPA) and gadobenate dimeglumine (Gd-BOPTA). To take into account potential heterogeneities of the contrast uptake in the lymph nodes, k-means cluster analysis was performed on DCE-MRI data. Cluster spatial distribution was visually assessed. Statistical comparison among clusters and contrast agents was performed on semiquantitative parameters (AUC, wash-in rate, and wash-out rate) and on the relative size of the segmented clusters. Results: Cluster analysis of DCE-MRI data revealed at least two main clusters, localized in the outer portion and in the inner portion of each lymph node. With both contrast agents, AUC (p < 0.01) and wash-in (p < 0.05) rates were greater in the inner cluster, which also showed a steeper wash-out rate than the outer cluster (Gd-BOPTA, p < 0.01; Gd-DTPA, p=0.056). The size of the outer cluster was greater than that of the inner cluster by Gd-DTPA (p < 0.05) and Gd-BOPTA (p < 0.01). The enhancement pattern of Gd-DTPA was not significantly different from the enhancement pattern of Gd-BOPTA. Conclusion: DCE-MRI in normal lymph nodes shows a characteristic heterogeneous pattern, discriminating the periphery and the central portion of the lymph nodes. Such a pattern deserves to be investigated as a diagnostic marker for lymph node staging.

The motor cortex of the sheep: laminar organization, projections and diffusion tensor imaging of the intracranial pyramidal and extrapyramidal tracts.

The laminar organization of the motor cortex of the sheep and other large domestic herbivores received scarce attention and is generally considered homologous to that of rodents and primates. Thickness of the cortex, subdivision into layers and organization are scarcely known. In the present study, we applied different modern morphological, mathematical and image-analyses techniques to the study of the motor area that controls movements of the forelimb in the sheep. The thickness of the cortex resulted comparable to that of other terrestrial Cetartiodactyls (but thicker than in marine Cetartiodactyls of similar body mass). The laminar organization showed marked development of layer 1, virtual absence of layer 4, and image analysis suggested prevalence of large irregular neural cells in the deeper layers. Diffusion tensor imaging revealed robust projections from the motor cortex to the pyramids in the brainstem, and well evident tracts descending to the tegmentum of the mesencephalon and dorsal pons. Our data contrast the general representation of the motor system of this species, considered to be predominantly based on extra-pyramidal tracts that originate from central pattern generators in the brainstem.

Easy formulation of liposomal doxorubicin modified with a bombesin peptide analogue for selective targeting of GRP receptors overexpressed by cancer cells.

The article concerns the obtainment of liposomal doxorubicin (Dox) in which liposomes are externally modified with a targeting peptide able to drive the formulation in a selective way on membrane receptors overexpressed in tumors. We developed a kit composed by three different vials: (A) a vial containing a sterile, translucent, red dispersion of the liposomal doxorubicin drug (Doxil®), (B) a vial filled with a lyophilized powder of a modified phospholipid with a reactive function (DSPE-Peg-maleimide), and (C) a vial containing a 1-9 bombesin peptide analogue (Cys-BN-AA1) chemically modified to react in stoichiometric ratio respect to DSPE-Peg-maleimide. The chosen peptide is a stable analogue antagonist of the wild-type 1-9 bombesin peptide; it is very stable in serum; maintains high specificity, with nanomolar affinity, towards gastrin release peptide receptors (GRPRs indicated also as BB2); and is overexpressed in some cancer cells. Results on animal studies clearly indicate that in mice treated with the kit product (i.e., pegylated liposomal Dox modified with the bombesin analogue, Doxil-BN-AA1), tumor growth is reduced, with an improved efficacy respect to mice treated with non-modified pegylated liposomal Dox or with saline solution.

Central nervous system microbleeds in the acute phase are associated with structural integrity by DTI one year after mild traumatic brain injury: A longitudinal study.

INTRODUCTION: Several imaging modalities are under investigation to unravel the pathophysiological mystery of delayed performance deficits in patients after mild traumatic brain injury (mTBI). Although both imaging and neuropsychological studies have been conducted, only few data on longitudinal correlations of diffusion tensor imaging (DTI), susceptibility weighted imaging (SWI) and extensive neuropsychological testing exist. METHODS: MRI with T1- and T2-weighted, SWI and DTI sequences at baseline and 12 months of 30 mTBI patients were compared with 20 healthy controls. Multiparametric assessment included neuropsychological testing of cognitive performance and post-concussion syndrome (PCS) at baseline, 3 and 12 months post-injury. Data analysis encompassed assessment of cerebral microbleeds (Mb) in SWI, tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM) of DTI (VBM-DTI). Imaging markers were correlated with neuropsychological testing to evaluate sensitivity to cognitive performance and post-concussive symptoms. RESULTS: Patients with Mb in SWI in the acute phase showed worse performance in several cognitive tests at baseline and in the follow-ups during the chronic phase and higher symptom severity in the post concussion symptom scale (PCSS) at twelve months post-injury. In the acute phase there was no statistical difference in structural integrity as measured with DTI between mTBI patients and healthy controls. At twelve months post-injury, loss of structural integrity in mTBI patients was found in nearly all DTI indices compared to healthy controls. CONCLUSIONS: Presence of Mb detected by SWI was associated with worse cognitive outcome and persistent PCS in mTBI patients, while DTI did not prove to predict neuropsychological outcome in the acute phase.