Maternal anxiety-driven modulation of fetal limbic connectivity designs a backbone linking neonatal brain functional topology to socio-emotional development in early childhood.

A link between maternal anxiety during pregnancy and adverse socio-emotional outcomes in childhood has been consistently sustained on the very early neurodevelopmental alteration of structural pathways between fetal limbic and cortical brain regions. In this study, we provide follow-up evidence for a feed-forward model linking (i) maternal anxiety, (ii) fetal functional neurodevelopment, (iii) neonatal functional network organization with (iv) socio-emotional neurobehavioral development in early childhood. Namely, we investigate a sample of 16 mother-fetus dyads and show how a maternal state-trait anxiety profile with pregnancy-specific worries can significantly influence functional synchronization patterns between regions of the fetal limbic system (i.e., hippocampus and amygdala) and the neocortex, as assessed through resting-state functional magnetic resonance imaging. Generalization of the findings was supported by leave-one-out cross-validation. We further show how this maternal-fetal cross-talk propagates to functional network topology in the neonate, specifically targeting connector hubs, and further maps onto socio-emotional profiles, assessed through Bayley-III socio-emotional scale in early childhood (i.e., in the 12-24 months range). Based on this evidence, we put forward the hypothesis of a "Maternal-Fetal-Neonatal Anxiety Backbone", through which neurobiological changes driven by maternal anxiety could trigger a divergence in the establishment of a cognitive-emotional development blueprint, in terms of the nascent functional homeostasis between bottom-up limbic and top-down higher-order neuronal circuitry.

Insulin resistance disrupts white matter microstructure and amplitude of functional spontaneous activity in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is linked to several structural and functional brain alterations. In addition, BD patients have a three-fold increased risk of developing insulin resistance, which is associated with neural changes and poorer BD outcomes. Therefore, we investigated the effects of insulin and two derived measures (insulin resistance and sensitivity) on white matter (WM) microstructure, resting-state (rs) functional connectivity (FC), and fractional amplitude of low-frequency fluctuation (fALFF). METHODS: BD patients (n = 92) underwent DTI acquisition, and a subsample (n = 22) underwent rs-fMRI. Blood samples were collected to determine insulin and glucose levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were computed. DTI data were analyzed via tract-based spatial statistics and threshold-free cluster enhancement. From rs-fMRI data, both ROI-to-ROI FC matrices and fALFF maps were extracted. RESULTS: Insulin showed a widespread negative association with fractional anisotropy (FA) and a positive effect on radial diffusivity (RD) and mean diffusivity (MD). HOMA-IR exerted a significant effect on RD in the right superior longitudinal fasciculus, whereas QUICKI was positively associated with FA and negatively with RD and MD in the left superior longitudinal fasciculus, left anterior corona radiata, and forceps minor. fALFF was negatively modulated by insulin and HOMA-IR and positively associated with QUICKI in the precuneus. No significant results were found in the ROI-to-ROI analysis. CONCLUSION: Our findings suggest that WM microstructure and functional alterations might underlie the effect of IR on BD pathophysiology, even if the causal mechanisms need to be further investigated.

Hemodynamic nature of black-blood enhancement in long-term coiled cerebral aneurysms.

PURPOSE: Vessel wall imaging (VWI) with black-blood (BB) technique can demonstrate aneurysmal enhancement preluding to growth/rupture in treatment-naive cerebral aneurysms. Interestingly, recent works showed that BB enhancement may also occur in endovascularly treated aneurysms, though its meaning is controversial. Hypothesizing a flow-related mechanism of BB enhancement, we explored its relationship with incomplete occlusion status and coil packing density at DSA. METHODS: We analyzed the subjects undergoing 3T MRI between January 2017 and October 2020 for a previous aneurysmal coiling. All the MRI studies included pre- and post-contrast 3D BB sequences. The presence of intra-aneurysmal pre-contrast BB signal was assessed. BB enhancement (when present) was classified as follows: (1) enhancement at the neck, (2) intrasaccular/intra-coil enhancement, and (3) peripheral enhancement. Coil packing density and aneurysmal occlusion status (according to the modified Raymond-Roy classification, MRRC) were determined on post-treatment DSA and compared with BB findings using generalized linear mixed-effect model and ANOVA. Significant p values were <0.05. RESULTS: Forty-eight aneurysms from 44 patients were eligible for analysis. Pre-contrast BB signal was observed in 50% of the aneurysms and showed a relationship with baseline aneurysmal size. BB enhancement was detectable in 31 aneurysms (65%), being significantly associated with incomplete aneurysmal occlusion and reduced coil packing density at DSA. CONCLUSION: BB enhancement of coiled aneurysms is related with increasing degrees of post-coiling aneurysmal remnants and with loose coil packing density at DSA. This supports a hemodynamic interpretation of BB enhancement in long-term coiled aneurysms.

Combining semi-quantitative rating and automated brain volumetry in MRI evaluation of patients with probable behavioural variant of fronto-temporal dementia: an added value for clinical practise?

PURPOSE: To evaluate the diagnostic value of combined semiquantitative and quantitative assessment of brain atrophy in the diagnostic workup of the behavioural-variant of frontotemporal dementia (bvFTD). METHODS: Three neuroradiologists defined brain atrophy grading and identified atrophy pattern suggestive of bvFTD on 3D-T1 brain MRI of 112 subjects using a semiquantitative rating scale (Kipps'). A quantitative atrophy assessment was performed using two different automated software (Quantib® ND and Icometrix®). A combined semiquantitative and quantitative assessment of brain atrophy was made to evaluate the improvement in brain atrophy grading to identify probable bvFTD patients. RESULTS: Observers' performances in the diagnosis of bvFTD were very good for Observer 1 (k value = 0.881) and 2 (k value = 0.867), substantial for Observer 3 (k value = 0.741). Semiquantitative atrophy grading of all the observers showed a moderate and a poor correlation with the volume values calculated by Icometrix® and by Quantib® ND, respectively. For the definition of neuroradiological signs presumptive of bvFTD, the use of Icometrix® software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.971 (p-value < 0.001). The use of Quantib® ND software improved the diagnostic accuracy for Observer 1 resulting in an AUC of 0.974, and for Observer 3 resulting in a AUC of 0.977 (p-value < 0.001). No improvement was observed for Observer 2. CONCLUSION: Combining semiquantitative and quantitative brain imaging evaluation allows to reduce discrepancies in the neuroradiological diagnostic workup of bvFTD by different readers.

In vivo detection of damage in multiple sclerosis cortex and cortical lesions using NODDI.

OBJECTIVE: To characterise in vivo the microstructural abnormalities of multiple sclerosis (MS) normal-appearing (NA) cortex and cortical lesions (CLs) and their relations with clinical phenotypes and disability using neurite orientation dispersion and density imaging (NODDI). METHODS: One hundred and seventy-two patients with MS (101 relapsing-remitting multiple sclerosis (RRMS), 71 progressive multiple sclerosis (PMS)) and 62 healthy controls (HCs) underwent a brain 3T MRI. Brain cortex and CLs were segmented from three-dimensional T1-weighted and double inversion recovery sequences. Using NODDI on diffusion-weighted sequence, intracellular volume fraction (ICV_f) and Orientation Dispersion Index (ODI) were assessed in NA cortex and CLs with default or optimised parallel diffusivity for the cortex (D//=1.7 or 1.2 µm2/ms, respectively). RESULTS: The NA cortex of patients with MS had significantly lower ICV_f versus HCs' cortex with both D// values (false discovery rate (FDR)-p <0.001). CLs showed significantly decreased ICV_f and ODI versus NA cortex of both HCs and patients with MS with both D// values (FDR-p ≤0.008). Patients with PMS versus RRMS had significantly decreased NA cortex ICV_f and ODI (FDR-p=0.050 and FDR-p=0.032) with only D//=1.7 µm2/ms. No CL microstructural differences were found between MS clinical phenotypes. MS NA cortex ICV_f and ODI were significantly correlated with disease duration, clinical disability, lesion burden and global and regional brain atrophy (r from -0.51 to 0.71, FDR-p from <0.001 to 0.045). CONCLUSIONS: A significant neurite loss occurs in MS NA cortex. CLs show a further neurite density reduction and a reduced ODI suggesting a simplification of neurite complexity. NODDI is relevant to investigate in vivo the heterogeneous pathology affecting the MS cortex.

Alterations of brain structural MRI are associated with outcome of surgical treatment in trigeminal neuralgia.

BACKGROUND AND PURPOSE: To assess magnetic resonance imaging (MRI) alterations occurring in patients with trigeminal neuralgia (TN) and to explore the predictive ability of MRI for initial surgical outcome and long-term pain relief/recurrence after Gamma Knife radiosurgery (GKS). METHODS: Thirty patients with idiopathic or classic TN, who underwent GKS and were followed for at least 24 months, were retrospectively included. Pre-treatment structural MRI and pre- and serial, postoperative clinical features were investigated. Fifteen age- and sex-matched healthy controls were also enrolled. Cortical thickness and gray matter (GM) volumes were assessed in TN patients relative to controls, as well as between patient subgroups according to treatment outcomes (initial responders/non-responders, patients with pain recurrence/long-lasting pain relief at the last follow-up). Clinical and MRI predictors of treatment outcomes were explored. RESULTS: Cortical thinning of temporal, prefrontal, cingulate, somatosensory and occipital areas bilaterally was found in TN patients relative to controls. No cortical thickness and GM volume differences were observed when TN initial responders and non-responders were compared. Patients who experienced TN recurrence after initial pain relief were characterized by thicker parahippocampal and temporal cortices bilaterally and greater volume of right amygdala and hippocampus compared to patients with long-lasting pain relief. In TN patients, disease duration and baseline cortical thinning of right parahippocampal, left fusiform and middle temporal cortices were associated with poor outcome after GKS at the last follow-up (R2 =0.57, p<0.001). CONCLUSION: The study provides novel insights into structural brain alterations of TN patients, which might contribute to disease development and pain maintenance.

Multiple hypointense veins on susceptibility weighted imaging as a promising biomarker of impaired cerebral hemodynamics in chronic steno-occlusive disease: a multiparametric MRI study.

PURPOSE: Patients with steno-occlusive arterial disease may develop cerebral hypoperfusion with possible neurologic sequelae. The aim of the study is to verify the possible role of SWI, as a marker of cerebral hypoperfusion, in the identification of patient subgroups with significant chronic occlusions/stenoses at risk of critical cerebral hypoperfusion. METHODS: We retrospectively identified 37 asymptomatic patients with chronic intra-extracranial occlusion/stenosis of the anterior circulation from a prospective brain MRI register between 2016 and 2020. All patients underwent 3 Tesla MRI. The imaging protocol included the following: SWI, 3D-FLAIR, DWI sequences, and 3D-TOF MRA. SWI findings were graded for the presence of asymmetric intracranial cortical veins (grades 1 to 4). The presence of collateralization was assessed with concomitant multiphase-CTA. FLAIR was evaluated for the presence of distal hyperintense vessels (DHVs), a described marker of flow impairment, and possible collateralization. Cerebral blood flow and arterial transit artifacts (ATAs) were evaluated at pCASL in 29 patients. RESULTS: SWI showed multiple hypointense vessels (MHVs) in 22/37 patients in the cerebral hemisphere ipsilateral to vessel occlusion/stenosis. SWI-MHV grade 1 was found in 15 patients (40.5%), grade 2 in 18 patients (48.7%), and grade 3 in 3 patients (8.1%); in one patient, SWI was graded as 4 (2.7%). A significant relationship was found among MHV, DHV, collaterals, ATAs, and hypoperfused areas on pCASL and with patients' previous neurological symptoms. CONCLUSION: SWI-MVH correlates with chronic cerebral flow impairment and is related to hypoperfusion and collateralization. It may help identify a subgroup of patients benefitting from revascularization.

Morphometric study of the ventricular indexes in healthy ovine BRAIN using MRI.

BACKGROUND: Sheep (Ovis aries) have been largely used as animal models in a multitude of specialties in biomedical research. The similarity to human brain anatomy in terms of brain size, skull features, and gyrification index, gives to ovine as a large animal model a better translational value than small animal models in neuroscience. Despite this evidence and the availability of advanced imaging techniques, morphometric brain studies are lacking. We herein present the morphometric ovine brain indexes and anatomical measures developed by two observers in a double-blinded study and validated via an intra- and inter-observer analysis. RESULTS: For this retrospective study, T1-weighted Magnetic Resonance Imaging (MRI) scans were performed at 1.5 T on 15 sheep, under general anaesthesia. The animals were female Ovis aries, in the age of 18-24 months. Two observers assessed the scans, twice time each. The statistical analysis of intra-observer and inter-observer agreement was obtained via the Bland-Altman plot and Spearman rank correlation test. The results are as follows (mean ± Standard deviation): Indexes: Bifrontal 0,338 ± 0,032 cm; Bicaudate 0,080 ± 0,012 cm; Evans' 0,218 ± 0,035 cm; Ventricular 0,241 ± 0,039 cm; Huckman 1693 ± 0,174 cm; Cella Media 0,096 ± 0,037 cm; Third ventricle ratio 0,040 ± 0,007 cm. Anatomical measures: Fourth ventricle length 0,295 ± 0,073 cm; Fourth ventricle width 0,344 ± 0,074 cm; Left lateral ventricle 4175 ± 0,275 cm; Right lateral ventricle 4182 ± 0,269 cm; Frontal horn length 1795 ± 0,303 cm; Interventricular foramen left 1794 ± 0,301 cm; Interventricular foramen right 1,78 ± 0,317 cm. CONCLUSIONS: The present study provides baseline values of linear indexes of the ventricles in the ovine models. The acquisition of these data contributes to filling the knowledge void on important anatomical and morphological features of the sheep brain.

Cerebral hyperdensity on CT imaging (CTHD) post-reperfusion treatment in patients with acute cerebral stroke: understanding its clinical meaning.

OBJECTIVES: To investigate the clinical meaning of brain parenchymal computed-tomography hyperdensities (CTHD) in patients treated of anterior circulation acute stroke with reperfusion therapy. METHODS: Patients were retrospectively enrolled from three different hospitals. Brain CT scans were assessed at four time points: We recorded ASPECT scores of pre-treatment CTs, assessed ASPECT scores and the presence of CTHD on post-treatment CTs acquired within 24-30 h and 24-72 h, and examined a one-month CTs follow-up to determine the ischemic evolution of CTHD. We correlated the presence of CTHD with clinical and radiological data to define its predictive and prognostic factors. RESULTS: In total, 165 patients were evaluated. At post-treatment CTs acquired within 24-30 h, 68 (41%) patients showed the presence of CTHD. On post-treatment CTs acquired within 24-72 h, 43 (63%) of the CTHD showed hemorrhagic transformation. Sixty-five (95%) out of the 68 CTHD evolved in a final ischemic brain area. Multivariate statistical analysis identified puncture to recanalization time to be the only independent factors predicting the presence of CTHD (p = 0.045). The presence of CTHD at the first post-treatment CTs was an independent factor for clinical outcome determined with mRS scores at 3-month follow-up (p = 0.05). Outcomes were worse for hemorrhagic transformation at follow-up CTs compared to the ischemic evolution of the CTHD (p = 0.01). CONCLUSIONS: The presence of CTHD at CTs imaging acquired within 24-30 h after reperfusion therapy is an independent prognostic factor of a worse clinical outcome, regardless of its ASPECT score at baseline CTs and of its hemorrhagic evolution.

Insights into Infusion-Based Targeted Drug Delivery in the Brain: Perspectives, Challenges and Opportunities.

Targeted drug delivery in the brain is instrumental in the treatment of lethal brain diseases, such as glioblastoma multiforme, the most aggressive primary central nervous system tumour in adults. Infusion-based drug delivery techniques, which directly administer to the tissue for local treatment, as in convection-enhanced delivery (CED), provide an important opportunity; however, poor understanding of the pressure-driven drug transport mechanisms in the brain has hindered its ultimate success in clinical applications. In this review, we focus on the biomechanical and biochemical aspects of infusion-based targeted drug delivery in the brain and look into the underlying molecular level mechanisms. We discuss recent advances and challenges in the complementary field of medical robotics and its use in targeted drug delivery in the brain. A critical overview of current research in these areas and their clinical implications is provided. This review delivers new ideas and perspectives for further studies of targeted drug delivery in the brain.

Diagnostic efficacy and safety of gadoteridol compared to gadobutrol and gadoteric acid in a large sample of CNS MRI studies at 1.5T.

PURPOSE: To evaluate safety and diagnostic accuracy of gadoteridol vs. other macrocyclic gadolinium-based contrast agents (GBCAs) in a large cohort of consecutive and non-selected patients referred for CE-MRI of the CNS. MATERIAL AND METHODS: Between November 2017 and March 2018, we prospectively enrolled a consecutive cohort of patients referred for neuroradiological CE-MRI (1.5T MRI). Image quality and adverse events were assessed. Diagnostic performance was determined for a subgroup of patients with truth standard findings available. Comparison was made between patients receiving gadoteridol and patients receiving other macrocyclic GBCAs. Inter-reader agreement (kappa) between two expert neuroradiologists was calculated for the diagnosis of malignancy. RESULTS: Overall, 460 patients (220M/240F; mean age 54±16 years) were enrolled of which 230 received gadoteridol (Group 1) and 230 either gadoteric acid or gadobutrol [n=83 (36.1%) and n=147 (63.9%), respectively; Group 2]. Image quality was rated as good or excellent in both groups. The sensitivity, specificity and diagnostic accuracy for determination of malignancy was 88.2%, 96.5% and 95.4%, respectively, for Group 1 and 93.7%, 97.4% and 96.9%, respectively, for Group 2, with no significant differences between groups (P>0.75) for any determination. Inter-reader agreement for the identification of malignancy was excellent [K=0.877 (95%CI: 0.758-0.995) and K=0.818 (95%CI: 0.663-0.972) for groups 1 and 2, respectively; P=0.0913]. Adverse events occurred in 5 of 460 (1.09%) patients overall, with no significant difference (P=0.972) between groups. CONCLUSION: Gadoteridol was safe and guaranteed good image quality without significant differences when compared to gadobutrol and gadoteric acid in a wide range of CNS pathologies.

MYD88 L265P mutation and interleukin-10 detection in cerebrospinal fluid are highly specific discriminating markers in patients with primary central nervous system lymphoma: results from a prospective study.

Reliable biomarkers are needed to avoid diagnostic delay and its devastating effects in patients with primary central nervous system (CNS) lymphoma (PCNSL). We analysed the discriminating sensitivity and specificity of myeloid differentiation primary response (88) (MYD88) L265P mutation (mut-MYD88) and interleukin-10 (IL-10) in cerebrospinal fluid (CSF) of both patients with newly diagnosed (n = 36) and relapsed (n = 27) PCNSL and 162 controls (118 CNS disorders and 44 extra-CNS lymphomas). The concordance of MYD88 mutational status between tumour tissue and CSF sample and the source of ILs in PCNSL tissues were also investigated. Mut-MYD88 was assessed by TaqMan-based polymerase chain reaction. IL-6 and IL-10 messenger RNA (mRNA) was assessed on PCNSL biopsies using RNAscope technology. IL levels in CSF were assessed by enzyme-linked immunosorbent assay. Mut-MYD88 was detected in 15/17 (88%) PCNSL biopsies, with an 82% concordance in paired tissue-CSF samples. IL-10 mRNA was detected in lymphomatous B cells in most PCNSL; expression of IL-6 transcripts was negligible. In CSF samples, mut-MYD88 and high IL-10 levels were detected, respectively, in 72% and 88% of patients with newly diagnosed PCNSL and in 1% of controls; conversely, IL-6 showed a low discriminating sensitivity and specificity. Combined analysis of MYD88 and IL-10 exhibits a sensitivity and specificity to distinguish PCNSL of 94% and 98% respectively. Similar figures were recorded in patients with relapsed PCNSL. In conclusion, high detection rates of mut-MYD88 and IL-10 in CSF reflect, respectively, the MYD88 mutational status and synthesis of this IL in PCNSL tissue. These biomarkers exhibit a very high sensitivity and specificity in detecting PCNSL both at initial diagnosis and relapse. Implications of these findings in patients with lesions unsuitable for biopsy deserve to be investigated.

Along-tract statistics of neurite orientation dispersion and density imaging diffusion metrics to enhance MR tractography quantitative analysis in healthy controls and in patients with brain tumors.

Along-tract statistics analysis enables the extraction of quantitative diffusion metrics along specific white matter fiber tracts. Besides quantitative metrics derived from classical diffusion tensor imaging (DTI), such as fractional anisotropy and diffusivities, new parameters reflecting the relative contribution of different diffusion compartments in the tissue can be estimated through advanced diffusion MRI methods as neurite orientation dispersion and density imaging (NODDI), leading to a more specific microstructural characterization. In this study, we extracted both DTI- and NODDI-derived quantitative microstructural diffusion metrics along the most eloquent fiber tracts in 15 healthy subjects and in 22 patients with brain tumors. We obtained a robust intraprotocol reference database of normative along-tract microstructural metrics, and their corresponding plots, from healthy fiber tracts. Each diffusion metric of individual patient's fiber tract was then plotted and statistically compared to the normative profile of the corresponding metric from the healthy fiber tracts. NODDI-derived metrics appeared to account for the pathological microstructural changes of the peritumoral tissue more accurately than DTI-derived ones. This approach may be useful for future studies that may compare healthy subjects to patients diagnosed with other pathological conditions.

Changes in functional and structural brain connectome along the Alzheimer's disease continuum.

The aim of this study was two-fold: (i) to investigate structural and functional brain network architecture in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI), stratified in converters (c-aMCI) and non-converters (nc-aMCI) to AD; and to assess the relationship between healthy brain network functional connectivity and the topography of brain atrophy in patients along the AD continuum. Ninety-four AD patients, 47 aMCI patients (25 c-aMCI within 36 months) and 53 age- and sex-matched healthy controls were studied. Graph analysis and connectomics assessed global and local, structural and functional topological network properties and regional connectivity. Healthy topological features of brain regions were assessed based on their connectivity with the point of maximal atrophy (epicenter) in AD and aMCI patients. Brain network graph analysis properties were severely altered in AD patients. Structural brain network was already altered in c-aMCI patients relative to healthy controls in particular in the temporal and parietal brain regions, while functional connectivity did not change. Structural connectivity alterations distinguished c-aMCI from nc-aMCI cases. In both AD and c-aMCI, the point of maximal atrophy was located in left hippocampus (disease-epicenter). Brain regions most strongly connected with the disease-epicenter in the healthy functional connectome were also the most atrophic in both AD and c-aMCI patients. Progressive degeneration in the AD continuum is associated with an early breakdown of anatomical brain connections and follows the strongest connections with the disease-epicenter. These findings support the hypothesis that the topography of brain connectional architecture can modulate the spread of AD through the brain.

White matter deficits correlate with visual motion perception impairments in dyslexic carriers of the DCDC2 genetic risk variant.

Motion perception deficits in dyslexia show a large intersubjective variability, partly reflecting genetic factors influencing brain architecture development. In previous work, we have demonstrated that dyslexic carriers of a mutation of the DCDC2 gene have a very strong impairment in motion perception. In the present study, we investigated structural white matter alterations associated with the poor motion perception in a cohort of twenty dyslexics with a subgroup carrying the DCDC2 gene deletion (DCDC2d+) and a subgroup without the risk variant (DCDC2d-). We observed significant deficits in motion contrast sensitivity and in motion direction discrimination accuracy at high contrast, stronger in the DCDC2d+ group. Both motion perception impairments correlated significantly with the fractional anisotropy in posterior ventral and dorsal tracts, including early visual pathways both along the optic radiation and in proximity of occipital cortex, MT and VWFA. However, the DCDC2d+ group showed stronger correlations between FA and motion perception impairments than the DCDC2d- group in early visual white matter bundles, including the optic radiations, and in ventral pathways located in the left inferior temporal cortex. Our results suggest that the DCDC2d+ group experiences higher vulnerability in visual motion processing even at early stages of visual analysis, which might represent a specific feature associated with the genotype and provide further neurobiological support to the visual-motion deficit account of dyslexia in a specific subpopulation.

The effects of the functional interplay between the Default Mode and Executive Control Resting State Networks on cognitive outcome in preterm born infants at 6 months of age.

Preterm birth can affect cognitive functions, such as attention or more generally executive control mechanisms, with severity in impairments proportional to prematurity. The functional cross-talk between the Default Mode (DMN) and Executive Control (ECN) networks mirrors the integrity of cognitive processing and is directly related to brain development. In this study, a cohort of 20 preterm-born infants was investigated using rs-fMRI. First, we addressed biological maturity of the DMN per se and its interplay with the ECN in terms of patterns of increased functional connectivity. Second, we assessed the impact of the degree of prematurity on the DMN-ECN functional interplay development in relation to cognitive outcome at six months. Our results highlighted the emergence of DMN in preterm neonates, with connectivity strength and synchronization between the anterior DMN hub and frontal areas increasing as a function of biological maturity. Further, cognitive scores at 6 months were predicted by mPFC-ECN connectivity strength with degree of prematurity impacting on mPFC-ECN connectivity and triggering differential patterns of functional maturation of the ECN for very early/early and moderate/late preterm neonates. Our findings suggest that the prematurity window allows to observe precursors of functional plasticity that may underlie different developmental trajectories in preterm children.

A hierarchical procedure to select intrauterine and extrauterine factors for methodological validation of preterm birth risk estimation.

BACKGROUND: Etiopathogenesis of preterm birth (PTB) is multifactorial, with a universe of risk factors interplaying between the mother and the environment. It is of utmost importance to identify the most informative factors in order to estimate the degree of PTB risk and trace an individualized profile. The aims of the present study were: 1) to identify all acknowledged risk factors for PTB and to select the most informative ones for defining an accurate model of risk prediction; 2) to verify predictive accuracy of the model and 3) to identify group profiles according to the degree of PTB risk based on the most informative factors. METHODS: The Maternal Frailty Inventory (MaFra) was created based on a systematic review of the literature including 174 identified intrauterine (IU) and extrauterine (EU) factors. A sample of 111 pregnant women previously categorized in low or high risk for PTB below 37 weeks, according to ACOG guidelines, underwent the MaFra Inventory. First, univariate logistic regression enabled p-value ordering and the Akaike Information Criterion (AIC) selected the model including the most informative MaFra factors. Second, random forest classifier verified the overall predictive accuracy of the model. Third, fuzzy c-means clustering assigned group membership based on the most informative MaFra factors. RESULTS: The most informative and parsimonious model selected through AIC included Placenta Previa, Pregnancy Induced Hypertension, Antibiotics, Cervix Length, Physical Exercise, Fetal Growth, Maternal Anxiety, Preeclampsia, Antihypertensives. The random forest classifier including only the most informative IU and EU factors achieved an overall accuracy of 81.08% and an AUC of 0.8122. The cluster analysis identified three groups of typical pregnant women, profiled on the basis of the most informative IU and EU risk factors from a lower to a higher degree of PTB risk, which paralleled time of birth delivery. CONCLUSIONS: This study establishes a generalized methodology for building-up an evidence-based holistic risk assessment for PTB to be used in clinical practice. Relevant and essential factors were selected and were able to provide an accurate estimation of degree of PTB risk based on the most informative constellation of IU and EU factors.

The role of CE-MRA of the supraortic vessels in the detection of associated intracranial pathology.

BACKGROUND: Contrast-enhanced magnetic resonance angiography (CE-MRA) has become a very popular imaging technique in the evaluation of the extracranial vessels pathology, while it is not commonly used to rule out intracranial vascular pathology. On the contrary, 3D time of flight MRA (TOF-MRA) has a solid role in the study of intracranial arterial vessels disease. MATERIALS AND METHODS: One hundred and eight patients were consecutively included in the study. All patients were submitted to a 3 Tesla 3D CE-MRA imaging to rule out extracranial vessels pathology. A comparison was made with a 3D-TOF sequence acquired at the same time in the assessment of intracranial vessels diseases such as steno-occlusion, dissection, and aneurysms. RESULTS: With regard to steno-occlusive disease, Spearman's rank correlation coefficient was of 0.56 for stenosis detection and of 0.57 for occlusive disease detection. The two techniques shared similar results in the evaluation of anterior circulation, while 3D-TOF found higher grades of stenosis for posterior circulation. With regard to dissection, Spearman's rank correlation coefficient was of 0.7. 3D-TOF depicted more intramural hematoma (Spearman's rank = 0.46), while CE-MRA showed more pseudo-aneurysms (Spearman's rank = 0.56). Both the technique equally evaluated the presence of intracranial aneurysms (Spearman's rank = 1). CONCLUSION: CE-MRA can be considered a reliable tool to rule out intracranial pathology associated to supraortic steno-occlusive disease, also allowing time reduction. In the suspicion of dissection a T1-weighted sequence has to be added to detect the presence of a subacute vessel wall hematoma.

Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis.

Glioblastoma (GBM) is the most malignant brain tumor of adults and is characterized by extensive cell dissemination within the brain parenchyma and enhanced angiogenesis. Effective preclinical modeling of these key features suffers from several shortcomings. Aim of this study was to determine whether modulating the expression of extracellular matrix (ECM) modifiers in proneural (PN) and mesenchymal (MES) cancer stem cells (CSCs) and in conventional glioma cell lines (GCLs) might improve tumor invasion and vascularization. To this end, we selected secreted, acidic and rich in cysteine-like 1 (SPARCL1) as a potential mediator of ECM remodeling in GBM. SPARCL1 transcript and protein expression was assessed in PN and MES CSCs as well as GCLs, in their xenografts and in patient-derived specimens by qPCR, WB and IHC. SPARCL1 expression was then enforced in both CSCs and GCLs by lentiviral-based transduction. The effect of SPARCL1 gain-of-function on microvascular proliferation, microglia activation and advanced imaging features was tested in intracranial xenografts by IHC and MRI and validated by chorioallantoic membrane (CAM) assays. SPARCL1 expression significantly enhanced the infiltrative and neoangiogenic features of PN and MES CSC/GCL-induced tumors, with the concomitant activation of inflammatory responses associated with the tumor microenvironment, thus resulting in experimental GBMs that reproduced both the parenchymal infiltration and the increased microvascular density, typical of GBM. Overall, these results indicate that SPARCL1 overexpression might be instrumental for the generation of CSC-derived preclinical models of GBM in which the main pathognomonic hallmarks of GBMs are retrievable, making them suitable for effective preclinical testing of therapeutics.

Randomized controlled trial on the efficacy of a multilevel non-pharmacologic intervention in older adults with subjective memory decline: design and baseline findings of the E.Mu.N.I. study.

BACKGROUND: Alzheimer's Disease (AD) is a multifactorial disorder driven by genetic and modifiable lifestyle risk factors. Lifestyle primary prevention initiatives may reduce the prevalence and incidence of dementia in older adults. OBJECTIVES: The E.Mu.N.I study is a randomized controlled trial investigating the effect of multilevel non-pharmacologic interventions on cognitive performances (primary outcome) and structural and vascular brain MRI markers (secondary outcome), as well as markers of brain functional connectivity change (exploratory outcome), in older adults with subjective memory decline (SMD). Here, we present the study design and the baseline features of the sample. METHODS: Cognitively intact older adults with SMD, enrolled between February 2016 and June 2017, were randomly assigned to one of the 3 interventions for 1 year: Active Control Intervention (ACI), i.e., educational lessons; Partial Intervention (PI), i.e., homotaurine administration (100 mg/die) and lessons on the Mediterranean diet; Multilevel Intervention (MI), i.e., PI plus computerized cognitive training and physical exercise training. RESULTS: One-hundred and twenty-eight eligible participants were enrolled (66% female; age: 68 ± 5 years). Eighty-two percent of the sample was composed of volunteers with SMD from the community. Participants were randomly allocated to the interventions as follows: ACI (N = 40), PI (N = 44), MI (N = 44). No significant differences among groups emerged on socio-demographic, clinical-neuropsychological variables and MRI markers at baseline. CONCLUSIONS: The outcomes obtained from the E.Mu.N.I. study will clarify the efficacy of multilevel non-pharmacologic interventions on cognitive and neuroimaging markers in SMD individuals. This is a crucial step forward for the development of cost-effective non-pharmacologic primary prevention initiatives for AD.