Role of fronto-limbic circuit in neuropsychiatric symptoms of dementia: clinical evidence from an exploratory study.

Background: Neuropsychiatric symptoms (NPSs) are a distressful aspect of dementia and the knowledge of structural correlates of NPSs is limited. We aimed to identify associations of fronto-limbic circuit with specific NPSs in patients with various types of cognitive impairment. Methods: Of 84 participants, 27 were diagnosed with mild cognitive impairment (MCI), 41 with Alzheimer's disease (AD) dementia and 16 with non-AD dementia. In all patients we assessed regional brain morphometry using a region of interest (ROI)-based analysis. The mean cortical thickness (CT) of 20 cortical regions and the volume (V) of 4 subcortical areas of the fronto-limbic system were extracted. NPSs were rated with the Neuropsychiatric Inventory (NPI). We used multiple linear regression models adjusted for age and disease duration to identify significant associations between scores of NPI sub-domains and MRI measures of brain morphometry. Results: All significant associations found were negative, except those between irritability and the fronto-opercular regions in MCI patients (corresponding to a 40-50% increase in CT) and between delusions and hippocampus and anterior cingulate gyrus (with a 40-60% increase). Apathy showed predominant involvement of the inferior frontal regions in AD group (a 30% decrease in CT) and of the cingulate cortex in non-AD group (a 50-60% decrease in CT). Anxiety correlated in MCI patients with the cingulate gyrus and caudate, with a CT and V decrease of about 40%, while hallucinations were associated with left enthorinal gyrus and right amygdala and temporal pole. Agitation showed associations in the AD group with the frontal regions and the temporal pole, corresponding to a 30-40% decrease in CT. Euphoria, disinhibition and eating abnormalities were associated in the MCI group with the entorhinal, para-hippocampal and fusiform gyri, the temporal pole and the amygdala (with a 40-70% decrease in CT and V). Finally, aberrant motor behavior reported a significant association with frontal and cingulate regions with a 50% decrease in CT. Conclusion: Our findings indicate that specific NPSs are associated with the structural involvement of the fronto-limbic circuit across different types of neurocognitive disorders. Factors, such as age and disease duration, can partly account for the variability of the associations observed.

Fate of melatonin orally administered in preterm newborns: Antioxidant performance and basis for neuroprotection.

Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading to an excess of lipid peroxidation with malondialdehyde (MDA) production, capable of contributing to brain damage. Melatonin (ME), an endogenous brain hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have an impaired antioxidant system, resulting in the inability to produce and release ME. This prospective, multicenter, parallel groups, randomized, double-blind, placebo-controlled trial aimed to assess: (i) the endogenous production of ME in very preterm infants (gestational age ≤ 29 + 6 WE, 28 infants in the ME and 26 in the placebo group); (ii) the exogenous hormone availability and its metabolization to the main metabolite, 6-OH-ME after 15 days of ME oral treatment; (iii) difference of MDA plasma concentration, as peroxidation marker, after treatment. Blood was collected before the first administration (T1) and after 15 days of administration (T2). ME and 6-OH-ME were detected by liquid chromatography tandem mass spectrometry, MDA was measured by liquid chromatograph with fluorescence detection. ME and 6-OH-ME were not detectable in the placebo group at any study time-point. ME was absent in the active group at T1. In contrast, after oral administration, ME and 6-OH-ME resulted highly detectable and the difference between concentrations T2 versus T1 was statistically significant, as well as the difference between treated and placebo groups at T2. MDA levels seemed stable during the 15 days of treatment in both groups. Nevertheless, a trend in the percentage of neonates with reduced MDA concentration at T2/T1 was 48.1% in the ME group versus 38.5% in the placebo group. We demonstrated that very preterm infants are not able to produce endogenous detectable plasma levels of ME during their first days of life. Still, following ME oral administration, appreciable amounts of ME and 6-OH-ME were available. The trend of MDA reduction in the active group requires further clinical trials to fix the dosage, the length of ME therapy and to identify more appropriate indexes to demonstrate, at biological and clinical levels, the antioxidant activity and consequent neuroprotectant potential of ME in very preterm newborns.

Virtual brain simulations reveal network-specific parameters in neurodegenerative dementias.

Introduction: Neural circuit alterations lay at the core of brain physiopathology, and yet are hard to unveil in living subjects. The Virtual Brain (TVB) modeling, by exploiting structural and functional magnetic resonance imaging (MRI), yields mesoscopic parameters of connectivity and synaptic transmission. Methods: We used TVB to simulate brain networks, which are key for human brain function, in Alzheimer's disease (AD) and frontotemporal dementia (FTD) patients, whose connectivity and synaptic parameters remain largely unknown; we then compared them to healthy controls, to reveal novel in vivo pathological hallmarks. Results: The pattern of simulated parameter differed between AD and FTD, shedding light on disease-specific alterations in brain networks. Individual subjects displayed subtle differences in network parameter patterns that significantly correlated with their individual neuropsychological, clinical, and pharmacological profiles. Discussion: These TVB simulations, by informing about a new personalized set of networks parameters, open new perspectives for understanding dementias mechanisms and design personalized therapeutic approaches.

Magnetic resonance advanced imaging analysis in adolescents: cortical thickness study to identify attenuated psychosis syndrome.

PURPOSE: Psychosis is a symptom common to several mental illnesses and a defining feature of schizophrenia spectrum disorders, whose onset typically occurs in adolescence. Neuroradiological studies have reported evidence of brain structural abnormalities in patients with overt psychosis. However, early identification of brain structural changes in young subjects at risk for developing psychosis (such as those with Attenuated Psychosis Syndrome -APS) is currently lacking. METHODS: Brain 3D T1-weighted and 64 directions diffusion-weighted images were acquired on 55 help-seeking adolescents (12-17 years old) with psychiatric disorders who referred to our Institute. Patients were divided into three groups: non-APS (n = 20), APS (n = 20), and Early-Onset Psychosis (n = 15). Cortical thickness was calculated from T1w images, and Tract-Based Spatial Statistics analysis was performed to study the distribution of white matter fractional anisotropy and all diffusivity metrics. A thorough neuropsychological test battery was adopted to investigate cognitive performance in several domains. RESULTS: In patients with Attenuated Psychotic Syndrome, the left superior frontal gyrus was significantly thinner compared to patients with non-APS (p = 0.048), and their right medial orbitofrontal cortex thickness was associated with lower working memory scores (p = 0.0025, r = -0.668 for the working memory index and p = 0.001, r = -0.738 for the digit span). Early-Onset Psychosis patients showed thinner left pars triangularis compared to non-APS individuals (p = 0.024), and their left pars orbitalis was associated with impaired performance at the symbol search test (p = 0.005, r = -0.726). No differences in diffusivity along main tracts were found between sub-groups (p > 0.05). CONCLUSION: This study showed specific associations between structural imaging features and cognitive performance in patients with APS. Characterizing this disorder using neuroimaging could reveal useful information that may aid in the development and evaluation of preventive strategies in these individuals.

CoreValve vs. Sapien 3 Transcatheter Aortic Valve Replacement: A Finite Element Analysis Study.

AIM: to investigate the factors implied in the development of postoperative complications in both self-expandable and balloon-expandable transcatheter heart valves by means of finite element analysis (FEA). MATERIALS AND METHODS: FEA was integrated into CT scans to investigate two cases of postoperative device failure for valve thrombosis after the successful implantation of a CoreValve and a Sapien 3 valve. Data were then compared with two patients who had undergone uncomplicated transcatheter heart valve replacement (TAVR) with the same types of valves. RESULTS: Computational biomechanical modeling showed calcifications persisting after device expansion, not visible on the CT scan. These calcifications determined geometrical distortion and elliptical deformation of the valve predisposing to hemodynamic disturbances and potential thrombosis. Increased regional stress was also identified in correspondence to the areas of distortion with the associated paravalvular leak. CONCLUSION: the use of FEA as an adjunct to preoperative imaging might assist patient selection and procedure planning as well as help in the detection and prevention of TAVR complications.

Bioengineering Case Study to Evaluate Complications of Adverse Anatomy of Aortic Root in Transcatheter Aortic Valve Replacement: Combining Biomechanical Modelling with CT imaging.

Gated computed tomography (CT) might not adequately predict occurrence of post-implantation transcatheter aortic valve replacement (TAVR) complications in hostile aortic root as it would require a more complex integration of morphological, functional and hemodynamical parameters. We used a computational framework based on finite element analysis (FEA) to simulate patient-specific implantation. Application of biomechanical modelling using FEA to gated-CT was able to demonstrate the relation of the device with voluminous calcification, its consequent misalignment and a significant stent deformation. Use of FEA and other advanced computed predictive modelling techniques as an adjunct to CT scan could improve our understanding of TAVR, potentially predict complications and fate of the devices after implantation and inform patient-specific treatment.

A Finite Element Analysis Study from 3D CT to Predict Transcatheter Heart Valve Thrombosis.

BACKGROUND: Transcatheter aortic valve replacement has proved its safety and effectiveness in intermediate- to high-risk and inoperable patients with severe aortic stenosis. However, despite current guideline recommendations, the use of transcatheter aortic valve replacement (TAVR) to treat severe aortic valve stenosis caused by degenerative leaflet thickening and calcification has not been widely adopted in low-risk patients. This reluctance among both cardiac surgeons and cardiologists could be due to concerns regarding clinical and subclinical valve thrombosis. Stent performance alongside increased aortic root and leaflet stresses in surgical bioprostheses has been correlated with complications such as thrombosis, migration and structural valve degeneration. MATERIALS AND METHODS: Self-expandable catheter-based aortic valve replacement (Medtronic, Minneapolis, MN, USA), which was received by patients who developed transcatheter heart valve thrombosis, was investigated using high-resolution biomodelling from computed tomography scanning. Calcific blocks were extracted from a 250 CT multi-slice image for precise three-dimensional geometry image reconstruction of the root and leaflets. RESULTS: Distortion of the stent was observed with incomplete cranial and caudal expansion of the device. The incomplete deployment of the stent was evident in the presence of uncrushed refractory bulky calcifications. This resulted in incomplete alignment of the device within the aortic root and potential dislodgment. CONCLUSION: A Finite Element Analysis (FEA) investigation can anticipate the presence of calcified refractory blocks, the deformation of the prosthetic stent and the development of paravalvular orifice, and it may prevent subclinical and clinical TAVR thrombosis. Here we clearly demonstrate that using exact geometry from high-resolution CT scans in association with FEA allows detection of persistent bulky calcifications that may contribute to thrombus formation after TAVR procedure.

Complementary Role of the Computed Biomodelling through Finite Element Analysis and Computed Tomography for Diagnosis of Transcatheter Heart Valve Thrombosis.

INTRODUCTION: The TAVR procedure is associated with a substantial risk of thrombosis. Current guidelines recommend catheter-based aortic valve implantation for prohibitive-high-risk patients with severe aortic valve stenosis but acknowledge that the aetiology and mechanism of thrombosis are unclear. METHODS: From 2015 to 2018, 607 patients with severe aortic valve stenosis underwent either self-expandable or balloon-expandable catheter-based aortic valve implantation at our institute. A complementary study was designed to support computed tomography as a predictor of complications using an advanced biomodelling process through finite element analysis (FEA). The primary evaluation of study was the thrombosis of the valve at 12 months. RESULTS: At 12 months, 546 patients had normal valvular function. 61 patients had THVT while 6 showed thrombosis and dislodgement with deterioration to NYHA Class IV requiring rehospitalization. The FEA biomodelling revealed a strong link between solid uncrushed calcifications, delayed dislodgement of TAVR and late thrombosis. We observed an interesting phenomenon of fibrosis/calcification originating at the level of the misplaced valve, which was the primary cause of coronary obstruction. CONCLUSION: The use of cardiac CT and predictive biomodelling should be integrated into routine practice for the selection of TAVR candidates and as a predictor of negative outcomes given the lack of accurate investigations available. This would assist in effective decision-making and diagnosis especially in a high-risk cohort of patients.

Transcatheter Technologies for Valvular Replacement: an Update.

This report provides a brief overview of the basic principles, recent advances, and recommendations for the treatment of severe aortic stenosis with transcatheter aortic valve replacement (TAVR) in adults. Approaches that avoid neurological, cardiac and peripheral vascular complications have been developed. In addition, TAVR can be performed in intermediate- and low-risk patients. However, these procedures require specialized training and may not allow for complete resolution of the underlying issue. Even if cardiologists learn to perform the procedure and despite advancements in device technology, TAVR is still susceptible to structural valve degeneration, thrombosis and late cerebral embolization. To date, TAVR has shown no consistent advantage over surgical aortic valve replacement (SAVR) in intermediate- and low-risk patients.

Aortic root 3D parametric morphological model from 2D-echo images.

The gold standard for the study of the macro-anatomy of the aortic root are multi-detector computed tomography (MDCT) and magnetic resonance (MR) imaging. Both technologies have major advantages and limitations. Although 4D echo is entering the study of the aortic root, 2D echo is the most commonly used diagnostic tool in daily practice. We designed and developed an algorithm for 3D modeling of the aortic root based on measures taken routinely at 2D echocardiography from 20 healthy individuals with normal aortic root. The tool was then translated in 12 patients who underwent both echo and MDCT. The results obtained with the 3D modeling program were quantitatively and qualitatively compared with 3D reconstruction from MDCT. Ad hoc ratios describing the morphology of the aortic root in MDCT and in the 3D model were used for comparison. In 12 patients with aortic root dilatation, the ratios obtained with our model are in good agreement with those from MDCT. Linear correlation for both long axis and short axis ratios was strong. The 3D modeling software can be easily adopted by cardiologists routinely involved in clinical evaluation of the pathology of the aortic root. The tool is easy to apply, does not require additional costs, and may be used to generate a set of data images for monitoring the evolution of the morphology and dimension of the aortic root, flanking the 3D MDCT and MR that remain the gold standard tools.