Global transcriptomic changes occur in uterine fluid-derived extracellular vesicles during the endometrial window for embryo implantation.

STUDY QUESTION: Are uterine fluid-derived extracellular vesicles (UF-EVs) a 'liquid biopsy' reservoir of biomarkers for real-time monitoring of endometrial status? SUMMARY ANSWER: The transcriptomic cargo of UF-EVs reflects the RNA profile of the endometrial tissue as well as changes between the non-receptive and the receptive phase, possibly supporting its use for a novel endometrial receptivity test. WHAT IS KNOWN ALREADY: EVs have been previously isolated from uterine fluid, where they likely contribute to the embryo-endometrium crosstalk during implantation. Based on a meta-analysis of studies on endometrial tissue implantation-associated genes and the human exosomes database, 28 of the 57 transcripts considered as receptivity markers refer to proteins present in human exosomes. However, the specific transcriptomic content of receptive phase UF-EVs has yet to be defined. STUDY DESIGN, SIZE, DURATION: Two experimental series were set up. First, we simultaneously sequenced RNA species derived from paired UF-EVs and endometrial tissue samples collected from physiologically cycling women. Second, we analyzed RNA species of UF-EVs collected during the non-receptive (LH + 2) and receptive (LH + 7) phase of proven fertile women and from the receptive (LH + 7) phase of a population of women undergoing ART and transfer of euploid blastocysts. PARTICIPANTS/MATERIALS, SETTING, METHODS: For paired UF-endometrial tissue sampling, endometrial tissue biopsies were obtained with the use of a Pipelle immediately after UF collection performed by lavage of the endometrial cavity. Overall, n = 87 UF samples were collected and fresh-processed for EV isolation and total RNA extraction, while western blotting was used to confirm the expression of EV protein markers of the isolated vesicles. Physical characterization of UF-EVs was performed by Nanoparticle Tracking Analysis. To define the transcriptomic cargo of UF-EV samples, RNA-seq libraries were successfully prepared from n = 83 UF-EVs samples and analyzed by RNA-seq analysis. Differential gene expression (DGE) analysis was used to compare RNA-seq results between different groups of samples. Functional enrichment analysis was performed by gene set enrichment analysis with g:Profiler. Pre-ranked gene set enrichment analysis (GSEA) with WebGestalt was used to compare RNA-seq results with the gene-set evaluated in a commercially available endometrial receptivity array. MAIN RESULTS AND THE ROLE OF CHANCE: A highly significant correlation was found between transcriptional profiles of endometrial biopsies and pairwise UF-EV samples (Pearson's r = 0.70 P < 0.0001; Spearman's ρ = 0.65 P < 0.0001). In UF-EVs from fertile controls, 942 gene transcripts were more abundant and 1305 transcripts less abundant in the LH + 7 receptive versus the LH + 2 non-receptive phase. GSEA performed to evaluate concordance in transcriptional profile between the n = 238 genes included in the commercially available endometrial receptivity array and the LH + 7 versus LH + 2 UF-EV comparison demonstrated an extremely significant and consistent enrichment, with a normalized enrichment score (NES)=9.38 (P < 0.001) for transcripts up-regulated in LH + 7 in the commercial array and enriched in LH + 7 UF-EVs, and a NES = -5.40 (P < 0.001) for transcripts down-regulated in LH + 7 in the commercial array and depleted in LH + 7 UF-EVs. When analyzing LH + 7 UF-EVs of patients with successful versus failed implantation after transfer of one euploid blastocyst in the following cycle, we found 97 genes whose transcript levels were increased and 64 genes whose transcript levels were decreased in the group of women who achieved a pregnancy. GSEA performed to evaluate concordance in transcriptional profile between the commercially available endometrial receptivity array genes and the comparison of LH + 7 UF-EVs of women with successful versus failed implantation, demonstrated a significant enrichment with a NES = 2.14 (P = 0.001) for transcripts up-regulated in the commercial array in the receptive phase and enriched in UF-EVs of women who conceived, and a not significant NES = -1.18 (P = 0.3) for transcripts down-regulated in the commercial array and depleted in UF-EVs. In terms of physical features, UF-EVs showed a homogeneity among the different groups analyzed except for a slight but significant difference in EV size, being smaller in women with a successful implantation compared to patients who failed to conceive after euploid blastocyst transfer (mean diameter ± SD 205.5± 22.97 nm vs 221.5 ± 20.57 nm, respectively, P = 0.014). LARGE SCALE DATA: Transcriptomic data were deposited in NCBI Gene Expression Omnibus (GEO) and can be retrieved using GEO series accession number: GSE158958. LIMITATIONS, REASONS FOR CAUTION: Separation of RNA species associated with EV membranes might have been incomplete, and membrane-bound RNA species-rather than the internal RNA content of EVs-might have contributed to our RNA-seq results. Also, we cannot definitely distinguish the relative contribution of exosomes, microvesicles and apoptotic bodies to our findings. When considering patients undergoing ART, we did not collect UFs in the same cycle of the euploid embryo transfer but in the one immediately preceding. We considered this approach as the most appropriate in relation to the novel, explorative nature of our study. Based on our results, a validation of UF-EV RNA-seq analyses in the same cycle in which embryo transfer is performed could be hypothesized. WIDER IMPLICATIONS OF THE FINDINGS: On the largest sample size of human EVs ever analyzed with RNA-seq, this study establishes a gene signature to use for less-invasive endometrial receptivity tests. This report is indeed the first to show that the transcriptome of UF-EVs correlates with the endometrial tissue transcriptome, that RNA signatures in UF-EVs change with endometrial status, and that UF-EVs could serve as a reservoir for potential less-invasive collection of receptivity markers. This article thus represents a step forward in the design of less-invasive approaches for real-time monitoring of endometrial status, necessary for advancing the field of reproductive medicine. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by a competitive grant from European Society of Human Reproduction and Embryology (ESHRE Research Grant 2016-1). The authors have no financial or non-financial competing interests to disclose. TRIAL REGISTRATION NUMBER: NA.

How the harm of drugs and their availability affect brain reactions to drug cues: a meta-analysis of 64 neuroimaging activation studies.

Visual drug cues are powerful triggers of craving in drug abusers contributing to enduring addiction. According to previous qualitative reviews, the response of the orbitofrontal cortex to such cues is sensitive to whether subjects are seeking treatment. Here we re-evaluate this proposal and assessed whether the nature of the drug matters. To this end, we performed a quantitative meta-analysis of 64 neuroimaging studies on drug-cue reactivity across legal (nicotine, alcohol) or illegal substances (cocaine, heroin). We used the ALE algorithm and a hierarchical clustering analysis followed by a cluster composition statistical analysis to assess the association of brain clusters with the nature of the substance, treatment status, and their interaction. Visual drug cues activate the mesocorticolimbic system and more so in abusers of illegal substances, suggesting that the illegal substances considered induce a deeper sensitization of the reward circuitry. Treatment status had a different modulatory role for legal and illegal substance abusers in anterior cingulate and orbitofrontal areas involved in inter-temporal decision making. The class of the substance and the treatment status are crucial and interacting factors that modulate the neural reactivity to drug cues. The orbitofrontal cortex is not sensitive to the treatment status per se, rather to the interaction of these factors. We discuss that these varying effects might be mediated by internal predispositions such as the intention to quit from drugs and external contingencies such as the daily life environmental availability of the drugs, the ease of getting them and the time frame of potential reward through drug consumption.

Acute uncomplicated diverticulitis: key points for early management. A single-centre retrospective study.

OBJECTIVE: Acute uncomplicated diverticulitis is an important clinical condition usually managed in clinical practice with antibiotic therapies and hospitalization in ward. In this setting, recent papers and guidelines suggest to limit the use of antibiotics in selected cases and encourage an early discharge in low-risk patients. The purpose of this retrospective study is to identify serological inflammatory markers and CT findings of acute uncomplicated diverticulitis (AUD) at the onset of the disease and the correlation with the need for in-patient or out-patient management. PATIENTS AND METHODS: It was used a database drawn from the collection of the patients admitted to our Emergency Room from January 2016 to 2019 and undergoing urgent abdominal CT-scan for suspicious of acute diverticulitis. For each patient we considered biochemical and radiological parameters at the onset of the disease and if patients were managed as in-patients (hospitalization in ward) or as out-patient (early discharged or after observation in Short Stay Unit). RESULTS: Among patients with early diagnosis of AUD, 108 (65%) were hospitalized in ward with mean time of in-stay of 6.94 days, while only 58 (35%) patients with same diagnosis were managed as out-patient and early discharged from emergency room or after observation in short stay unit with a mean time of in-stay significantly shorter (3.39 days, p-value 0.0007). Higher levels of C reactive protein and the length of colon involved considered as percentage (%) in comparison with the entire colon were significantly related to the need for hospitalization (p-value 0.03). CONCLUSIONS: Biochemical parameters and a more advanced radiological evaluation, as the length (%) of colon involved, could allow a stratification of patients with diagnosis of AUD at the admission and help physicians in the early management.

Ferrous iron- and ammonium-rich diffuse vents support habitat-specific communities in a shallow hydrothermal field off the Basiluzzo Islet (Aeolian Volcanic Archipelago).

Ammonium- and Fe(II)-rich fluid flows, known from deep-sea hydrothermal systems, have been extensively studied in the last decades and are considered as sites with high microbial diversity and activity. Their shallow-submarine counterparts, despite their easier accessibility, have so far been under-investigated, and as a consequence, much less is known about microbial communities inhabiting these ecosystems. A field of shallow expulsion of hydrothermal fluids has been discovered at depths of 170-400 meters off the base of the Basiluzzo Islet (Aeolian Volcanic Archipelago, Southern Tyrrhenian Sea). This area consists predominantly of both actively diffusing and inactive 1-3 meters-high structures in the form of vertical pinnacles, steeples and mounds covered by a thick orange to brown crust deposits hosting rich benthic fauna. Integrated morphological, mineralogical, and geochemical analyses revealed that, above all, these crusts are formed by ferrihydrite-type Fe3+ oxyhydroxides. Two cruises in 2013 allowed us to monitor and sampled this novel ecosystem, certainly interesting in terms of shallow-water iron-rich site. The main objective of this work was to characterize the composition of extant communities of iron microbial mats in relation to the environmental setting and the observed patterns of macrofaunal colonization. We demonstrated that iron-rich deposits contain complex and stratified microbial communities with a high proportion of prokaryotes akin to ammonium- and iron-oxidizing chemoautotrophs, belonging to Thaumarchaeota, Nitrospira, and Zetaproteobacteria. Colonizers of iron-rich mounds, while composed of the common macrobenthic grazers, predators, filter-feeders, and tube-dwellers with no representatives of vent endemic fauna, differed from the surrounding populations. Thus, it is very likely that reduced electron donors (Fe2+ and NH4+ ) are important energy sources in supporting primary production in microbial mats, which form a habitat-specific trophic base of the whole Basiluzzo hydrothermal ecosystem, including macrobenthic fauna.

Emotional reactivity in chronic schizophrenia: structural and functional brain correlates and the influence of adverse childhood experiences.

BACKGROUND: Despite behavioural signs of flattened affect, patients affected by schizophrenia show enhanced sensitivity to negative stimuli. The current literature concerning neural circuitry for emotions supports dysregulations of cortico-limbic networks, but gives contrasting results. Adverse childhood experiences (ACEs) could persistently influence emotional regulation and neural correlates of response to emotional stimuli in healthy humans. This study evaluated the effect of ACEs and chronic undifferentiated schizophrenia on neural responses to emotional stimuli (negative facial expression). METHOD: Brain blood-oxygen-level-dependent functional magnetic resonance imaging neural responses to a face-matching paradigm, and regional grey matter (GM) volumes were studied at 3.0 T in the amygdala, hippocampus, anterior cingulated cortex (ACC) and prefrontal cortex (PFC). The severity of ACEs was assessed. Participants included 20 consecutively admitted in-patients affected by chronic undifferentiated schizophrenia, and 20 unrelated healthy volunteers from the general population. RESULTS: Patients reported higher ACEs than controls. Worse ACEs proportionally led to decreasing responses in the amygdala and hippocampus, and to increasing responses in the PFC and ACC in all participants. Patients showed higher activations in the amygdala and hippocampus, and lower activations in the PFC and ACC. Higher ACEs were associated with higher GM volumes in the PFC and ACC, and schizophrenia was associated with GM reduction in all studied regions. CONCLUSIONS: Structural and functional brain correlates of emotional reactivity are influenced by both current chronic undifferentiated schizophrenia and the severity of past ACEs.

Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-ß activity.

At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3-beta promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3-beta as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment.

Follow-up of coiled cerebral aneurysms at 3T: comparison of 3D time-of-flight MR angiography and contrast-enhanced MR angiography.

BACKGROUND AND PURPOSE: Our aim was to compare contrast-enhanced MR angiography (CE-MRA) and 3D time-of-flight (TOF) MRA at 3T for follow-up of coiled cerebral aneurysms. MATERIALS AND METHODS: Fifty-two patients treated with Guglielmi detachable coils for 54 cerebral aneurysms were evaluated at 3T MRA. 3D TOF MRA (TR/TE = 23/3.5; SENSE factor = 2.5) and CE-MRA by using a 3D ultrafast gradient-echo sequence (TR/TE = 5.9/1.8; SENSE factor = 3) enhanced with 0.1-mmol/kg gadobenate dimeglumine were performed in the same session. Source images, 3D maximum intensity projection, 3D shaded surface display, and/or 3D volume-rendered reconstructions were evaluated in terms of aneurysm occlusion/patency and artifact presence. RESULTS: In terms of clinical classification, the 2 MRA sequences were equivalent for 53 of the 54 treated aneurysms: 21 were considered fully occluded, whereas 16 were considered to have a residual neck and 16 were considered residually patent at follow-up MRA. The remaining aneurysm appeared fully occluded at TOF MRA but had a residual patent neck at CE-MRA. Visualization of residual aneurysm patency was significantly (P = .001) better with CE-MRA compared with TOF MRA for 10 (31.3%) of the 32 treated aneurysms considered residually patent with both sequences. Coil artifacts were present in 5 cases at TOF MRA but in none at CE-MRA. No relationship was apparent between the visualization of patency and either the size of the aneurysm or the interval between embolization and follow-up. CONCLUSION: At follow-up MRA at 3T, unenhanced TOF and CE-MRA sequences are similarly effective at classifying coiled aneurysms as occluded or residually patent. However, CE-MRA is superior to TOF MRA for visualization of residual patency and is associated with fewer artifacts.

Competing sigmatropic shift rearrangements in excited allyl radicals.

The competition between rearrangement of the excited allyl radical via a 1,3 sigmatropic shift versus sequential 1,2 shifts has been observed and characterized using isotopic substitution, laser excitation, and molecular beam techniques. Both rearrangements produce a 1-propenyl radical that subsequently dissociates to methyl plus acetylene. The 1,3 shift and 1,2 shift mechanisms are equally probable for CH(2)CHCH(2), whereas the 1,3 shift is favored by a factor of 1.6 in CH(2)CDCH(2). The translational energy distributions for the methyl and acetylene products of these two mechanisms are substantially different. Both of these allyl dissociation channels are minor pathways compared to hydrogen atom loss.

Voxel-wise analysis of diffusion tensor MRI improves the confidence of diagnosis of corticobasal degeneration non-invasively.

Corticobasal degeneration (CBD) presents with symptoms that often overlap with other neurological conditions. In many cases, diagnosis, prognosis and consequent clinical management remain uncertain. Structural and functional asymmetric brain changes represent the most consistent imaging findings that may assist in CBD diagnosis. Diffusion Tensor MRI (DT-MRI) is a quantitative technique that allows microscopic tissue abnormalities to be non-invasively assessed in vivo. A single case of clinically suspected CBD with symmetric diffuse brain atrophy on conventional-MRI scans was studied using DT-MRI by voxel-wise comparison with eight healthy subjects. The lateralized distribution of DT-MRI abnormalities was consistent with clinical features providing a substantial support to the diagnosis.

The "mirror-neuron system" in MS: A 3 tesla fMRI study.

OBJECTIVE: The mirror neuron system (MNS) is an observation-execution matching system activated, in humans, during action observation, motor learning, and imitation of action. We used functional MRI (fMRI) to investigate the properties of the MNS in patients with multiple sclerosis (MS). METHODS: Using a 3 tesla scanner, we acquired fMRI in 16 right-handed patients with relapsing-remitting MS and 14 controls. Two motor tasks were studied. The first consisted of repetitive flexion-extension of the last four fingers of the right hand (simple task) alternated to epochs of rest; the second (MNS task) consisted of observation of a movie showing the hand of another subject while performing the same task. RESULTS: During the simple task, compared to controls, patients with MS had more significant activations of the contralateral primary sensorimotor cortex and supplementary motor area. During the MNS task, both groups showed the activation of several visual areas, the infraparietal sulcus, and the inferior frontal gyrus (IFG), bilaterally. The IFG and the visual areas were significantly more active in patients than controls. The between-group interaction analysis showed that in patients with MS, part of the regions of the MNS were more active also during the simple task. CONCLUSIONS: This study suggests increased activation of the mirror neuron system in patients with multiple sclerosis (MS) with a normal level of function and widespread CNS damage. The potentialities of this system in facilitating clinical recovery in patients with MS and other neurologic conditions should be investigated.

Clock genes beyond the clock: CLOCK genotype biases neural correlates of moral valence decision in depressed patients.

Gene polymorphisms in the mammalian biological clock system influence individual rhythms. A single nucleotide polymorphism (SNP) in the 3' flanking region of CLOCK (3111 T/C; rs1801260) influenced diurnal preference in healthy humans and caused sleep phase delay and insomnia in patients affected by bipolar disorder. Genes of the biological clock are expressed in many brain structures other than in the 'master clock' suprachiasmatic nuclei. These areas, such as cingulate cortex, are involved in the control of many human behaviors. Clock genes could then bias 'nonclock' functions such as information processing and decision making. Thirty inpatients affected by a major depressive episode underwent blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI). The cognitive activation paradigm was based on a go/no-go task. Morally connoted words were presented. Genotyping of CLOCK was performed for each patients. We measured activity levels through actimetry during the day before the fMRI study. CLOCK 3111 T/C SNP was associated with activity levels in the second part of the day, neuropsychological performance and BOLD fMRI correlates (interaction of genotype and moral valence of the stimuli). Our results support the hypothesis that individual clock genotype may influence several variables linked with human behaviors in normal and psychopathological conditions.

Altered functional and structural connectivities in patients with MS: a 3-T study.

OBJECTIVE: To determine the functional and structural substrates of motor network dysfunction in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Using a 3-T scanner, in 12 right-handed RRMS patients and 14 matched controls, we acquired diffusion tensor (DT) MRI and functional MRI during the performance of a simple motor task with the right (R) hand. Using DT MRI tractography, we calculated DT-derived metrics from several motor and nonmotor white matter (WM) fiber bundles. Functional connectivity analysis was performed using SPM2. RESULTS: Compared with control, MS patients had abnormal DT MRI metrics of all the WM bundles studied. Compared with controls, MS patients had more significant activations of the left (L) supplementary motor area (SMA), the L primary sensorimotor cortex (SMC), and the R cerebellum. They also had increased functional connectivity between the R primary SMC and the R cerebellum (p = 0.01) and the L SMA and the L primary SMC (p = 0.04). Coefficients of altered connectivity were correlated with structural MRI metrics of tissue damage of the corticospinal and the dentatorubrothalamic tract (r values ranging from -0.73 to 0.85). CONCLUSIONS: The correlations found between measures of functional connectivity and structural damage to some of the major brain motor white matter bundles suggest an adaptive role of functional connectivity changes in limiting the clinical consequences of structural damage in patients with relapsing-remitting multiple sclerosis. Combining measures of altered functional and structural connectivities of specific brain networks is a promising tool to elucidate the mechanisms responsible for clinical manifestations of CNS damage.

A longitudinal conventional and magnetization transfer magnetic resonance imaging study of optic neuritis.

Eleven consecutive patients with a first episode of acute optic neuritis were evaluated, using conventional and magnetization transfer (MT) magnetic resonance imaging (MRI), in order to assess the temporal evolution of optic nerve (ON) damage and to investigate the correlation of ON damage with visual outcome and electrophysiological parameters. Patients underwent neuroophthalmological, neurological, electrophysiological, and MRI assessments at baseline and after three and 12 months. ON volumes were measured on coronal T1-weighted images using a local thresholding segmentation technique. MT ratio (MTR) from the ON was derived from gradient echo images. No significant volume difference was detected between affected and healthy ON, both at baseline and follow-up. At baseline, mean MTR values were significantly higher in affected ON than in healthy ON (P =0.001), whereas at months 3 and 12, the mean MTR values were significantly reduced in the affected ON (P =0.02 and 0.003, respectively). Mean MTR of the affected ON, corrected for healthy ON values, progressively decreased over time (P =0.04 at month 3 and P =0.0012 at month 12). On the contrary, MTR values of healthy ON remained stable. No correlations were found between MTR measures and clinical or electrophysiological data. This study shows the presence of subtle pathological changes, possibly due to residual demyelination and subsequent additional demyelination and impaired remyelination, in the ON of patients with a first episode of optic neuritis. In the early phase of optic neuritis, MT MRI is more sensitive than atrophy measurements in detecting disease-related changes.

The contribution of voxel-based morphometry in staging patients with mild cognitive impairment.

OBJECTIVE: To assess whether different patterns of regional gray matter loss in patients with mild cognitive impairment (MCI) are associated with different risks of conversion to Alzheimer disease (AD), using MRI and voxel-based morphometry (VBM). METHODS: The authors recruited 22 patients with MCI, 22 patients with probable AD, and 20 healthy subjects (HS). T1 volumes from each subject were postprocessed according to an optimized VBM protocol. All patients were clinically followed up (mean [SD] time = 28.7 [5.7] months), and patients with MCI were reclassified into two groups (converters and nonconverters to AD). RESULTS: When comparing patients with AD to HS, widespread areas of reduced gray matter density were found predominantly in temporal, frontal, and parietal lobes and in the insula. Comparing MCI converters and nonconverters with HS, the converters showed more widespread areas of reduced gray matter density than nonconverters, with a pattern of abnormalities similar to that seen in patients with AD. Conversely, when comparing the same groups with patients with AD, MCI nonconverters showed a pattern of gray matter density similar to that of HS. Areas of decreased gray matter density were also found in MCI converters compared with nonconverters. CONCLUSIONS: Different patterns of gray matter density distribution in patients with mild cognitive impairment may be associated to different rates of conversion to Alzheimer disease.

Angiographic follow-up of cerebral aneurysms treated with Guglielmi detachable coils: an analysis of 162 cases with 173 aneurysms.

BACKGROUND AND PURPOSE: The endovascular approach, with the use of Guglielmi detachable coils (GDC), has been increasingly used to treat ruptured and unruptured cerebral aneurysms in recent years. Our objective was to assess the mid- to long-term radiologic outcome of cerebral aneurysms treated with GDC embolization. METHODS: One hundred and sixty-two patients with a total of 173 aneurysms embolized with GDCs underwent angiographic follow-up 1 to 54 months after the procedure and were reviewed retrospectively. Each angiogram was reviewed by 2 neuroradiologists and 1 neurosurgeon, each of whom made a comparison between the initial and follow-up angiograms. Morphologic outcomes were scored as follows: unchanged, progressive thrombosis, and reopening or regrowth. RESULTS: Of the 173 aneurysms with GDC embolization, 142 had total or nearly total occlusion, 23 subtotal occlusion, and 8 partial occlusion on the initial angiograms. The incidence of reopening was 17.1% (13/76) in less than 3 months and 6.2% (6/97) between 3 and 6 months after the procedure. Four aneurysms (2.3%) were found to be recurrent in the second follow-up angiography within 1 year after the procedure. The 1-year cumulative recurrent rate was 13.3%. Among 56 aneurysms with a third follow-up angiography in the period of 12 to 54 months after the procedure, 4 (7.1%) displayed a slight enlargement; the long-term cumulative recurrent rate was 20.4%. CONCLUSION: The direct and primary causes for aneurysmal recurrence are incomplete and loose packing. The first angiographic follow-up is recommended to be performed at 3 months or earlier for incompletely occluded aneurysms and at 6 months for totally or nearly totally occluded aneurysms. In case of total or nearly total occlusion that remains stable at follow-up, the interval for monitoring should be prolonged appropriately. Retreatment with balloon- or stent-assisted coil embolization is recommended for reopened aneurysms.

Diffusion tensor magnetic resonance imaging at 3.0 tesla shows subtle cerebral grey matter abnormalities in patients with migraine.

BACKGROUND AND OBJECTIVE: Diffusion tensor (DT) magnetic resonance imaging (MRI) has the potential to disclose subtle abnormalities in the brain of migraine patients. This ability may be increased by the use of high field magnets. A DT MRI on a 3.0 tesla scanner was used to measure the extent of tissue damage of the brain normal appearing white (NAWM) and grey matter in migraine patients with T2 visible abnormalities. METHODS: Dual echo, T1 weighted and DT MRI with diffusion gradients applied in 32 non-collinear directions were acquired from 16 patients with migraine and 15 sex and age matched controls. Lesion load on T2 weighted images was measured using a local thresholding segmentation technique, and brain atrophy assessed on T1 weighted images using SIENAx. Mean diffusivity and fractional anisotropy histograms of the NAWM and mean diffusivity histograms of the grey matter were also derived. RESULTS: Brain atrophy did not differ between controls and patients. Compared with healthy subjects, migraine patients had significantly reduced mean diffusivity histogram peak height of the grey matter (p=0.04). No diffusion changes were detected in patients' NAWM. In migraine patients, no correlation was found between T2 weighted lesion load and brain DT histogram derived metrics, whereas age was significantly correlated with grey matter mean diffusivity histogram peak height (p=0.05, r=-0.52). CONCLUSIONS: DT MRI at high field strength discloses subtle grey matter damage in migraine patients, which might be associated with cognitive changes in these patients.

A whole brain MR spectroscopy study from patients with Alzheimer's disease and mild cognitive impairment.

Brain damage in Alzheimer's disease (AD) and mild cognitive impairment (MCI) is widespread with involvement of large portions of the neocortex and the subcortical white matter. A quantitative measure of neuronal damage of the entire brain might be valuable in the context of large-scale, longitudinal studies of these patients. This study investigated the extent of neuroaxonal injury of patients with AD and MCI using a novel unlocalized proton magnetic resonance spectroscopy ((1)H-MRS) technique, which allows quantification of the concentration of N-acetylaspartate from the whole of the brain tissue (WBNAA). Conventional brain MRI and WBNAA were obtained from 28 AD patients, 27 MCI patients and 25 age-matched controls. Normalized brain volume (NBV) was also measured using an automated segmentation technique. WBNAA and NBV showed a significant heterogeneity between groups (P < 0.001). WBNAA concentration was different between controls and MCI patients (P = 0.003), but not between MCI and AD patients (P = 0.33). NBV differed both between controls and MCI patients (P = 0.02) and between MCI and AD patients (P = 0.03). A multivariate regression model retained WBNAA as the best MRI predictor of the Mini Mental State Examination score (P = 0.001). Significant neuronal damage, which is related to the extent of cognitive decline, can be quantified in the whole brain tissue of patients with AD, using a novel (1)H-MRS approach. The demonstration in patients with MCI of MR structural and metabolic findings, intermediate between those of healthy volunteers and those of AD patients, indicates that neuronal damage is already evident and widespread in individuals with MCI before they are clinically demented.

Brain tissue damage in dementia with Lewy bodies: an in vivo diffusion tensor MRI study.

The aim of the present study was to apply diffusion tensor MRI (DT-MRI), a quantitative MRI measure which reflects tissue organization, to dementia with Lewy bodies (DLB). DT-MRI scans were obtained from 15 patients with probable DLB and 10 sex- and age-matched healthy controls. Abnormalities were found in the corpus callosum, pericallosal areas and the frontal, parietal, occipital and, less prominently, temporal white matter of patients compared with controls. Abnormalities were also found in the caudate nucleus and the putamen. The average grey matter volume was lower in patients than in controls. These findings of concomitant grey matter atrophy and white matter abnormalities (as detected by DT-MRI) in regions with a high prevalence of long connecting fibre tracts might suggest the presence of neurodegeneration involving associative cortices. The modest involvement of the temporal lobe fits with the relative preservation of global neuropsychological measures and memory tasks in the early stage of DLB. The selective involvement of parietal, frontal and occipital lobes might explain some of the clinical and neuropsychological features of DLB, providing a possible distinctive marker for this disease. The abnormalities found in the subcortical grey matter may indicate that DLB and Parkinson's disease share a similar nigrostriatal involvement caused by common pathophysiological mechanisms.

A Deconvolution Approach Based on Multi-Tensor Model to Solve Fiber Crossing in Diffusion-MRI.

A deconvolution approach, based on a multi-tensor model, is presented to solve fiber crossing in diffusion MRI. In order to provide a direct physical interpretation of the signal generation process, we re-wrote the classical multi-tensor model, identifying a significant scalar parameter alpha to characterize the deconvolution process. Simulations show that, in presence of noise, the method is able to correctly separate fiber crossing. Application on in-vivo data highlights the ability of our approach to distinguish more than two fibers within the same voxel, suggesting its application in fiber tracking or connectivity studies even of complex brain structures.

A functional MRI study of movement-associated cortical changes in patients with Devic's neuromyelitis optica.

Movement-associated cortical changes have been shown in several neurological conditions and were found to be associated to the extent of brain and cord damage. Devic's neuromyelitis optica (DNO) is characterized by a severe involvement of the cord and optic nerve, with sparing of the brain. To assess the actual role of cord pathology on the pattern of movement-associated cortical recruitment, we obtained functional magnetic resonance imaging (fMRI) from patients with DNO and investigated whether the extent of brain activation is correlated with the extent of cervical cord damage. We studied 10 right-handed DNO patients and 15 sex- and age-matched healthy controls. The MRI assessment consisted of the following: (a) fMRI during repetitive flexion extension of the last four fingers of the right and left hand, (b) brain and cervical cord conventional MRI, and (c) cervical cord magnetization transfer (MT) MRI. Compared to controls and for both tasks, DNO patients had an increased recruitment of several regions of the sensorimotor network (primary sensorimotor cortex, postcentral gyrus, middle frontal gyrus, rolandic operculum, secondary sensorimotor cortex, precuneus, and cerebellum) and of several other regions mainly in the temporal and occipital lobes, such as MT/V5, the fusiform gyrus, the cuneus, and the parahippocampal gyrus. For both tasks, strong correlations (r values ranging from -0.76 to -0.85) were found between relative activations of cortical sensorimotor areas and the severity of cervical cord damage. This study shows an abnormal pattern of movement-associated cortical activations in patients with DNO, which extends beyond the 'classical' sensorimotor network and also involves visual areas devoted to motion processing. The correlation found between fMRI changes and the extent of cord damage suggests that such functional cortical changes might have an adaptive role in limiting the clinical outcome of DNO structural pathology.