Longitudinal cognitive decline in mild cognitive impairment subjects with early amyloid-ß neocortical deposition.

PURPOSE: The rate of clinical progression of cognitive impairment in subjects with early amyloid deposition is unknown. The primary aim of the study was to follow the rate of cognitive decline over 1 year in patients with amnestic mild cognitive impairment (aMCI) by determining amyloid retention levels in terms of standardized uptake value ratios (SUVr) that ranged from 0.85 to 1.57. The secondary objective was to compare the rate of cognitive decline between subjects with and without early amyloid positivity. METHODS: Of 66 aMCI subjects evaluated with [18F]florbetaben PET imaging and neuropsychological tests at baseline, 41 completed the 1-year follow-up. Amyloid status was determined with SUVr cut-off values generated from baseline images by visual assessment by three independent certified readers. Repeated-measures ANOVA with amyloid load and neuropsychological scores as the main effects was use to test group, time and group-by-time interactions. The Tukey post-hoc test was used to analyse all significant interactions. RESULTS: Of the 41 aMCI subjects, 38 completed the assessment according to the study protocol. Amyloid-positive (Aß+ ) subjects (N = 18, age 75.6 ± 5.8 years, six men, 12 women) showed greater clinical deterioration according to the Mattis Dementia Rating Scale (MDRS) score (p = 0.006). Amyloid-negative (Aß-) subjects (N = 20, age 72.4 ± 5.8 years, 11 men, 6 women) showed no significant changes in MDRS score over 1 year. MDRS score significantly decreased (MDRS+) in 37% of the aMCI subjects, and remained stable (MDRS-) in the remaining 63%. Among subjects with cognitive deterioration, 86% were Aß+ and 14% were Aß-, while 25% of the MDRS- subjects were Aß+ and 75% were Aß- (χ2 = 13, P = 0.0003). SUVr above 1.21 identified individuals who would show significant progression over 1 year, with a sensitivity of 67% and a specificity of 90%, as compared to Aß- subjects. The positive predictive value, negative predictive value, and likelihood ratio were 86% (95% CI 70-94%), 75% (95% CI 58-87%), 7 (95% CI 5-10). CONCLUSION: This study demonstrated that early amyloid deposition predicts cognitive decline in subjects with aMCI, with a higher rate of decline in those with SUVr above a threshold of 1.21. Detection of early amyloid positivity may help in selecting the target population for preventive therapeutic interventions and in designing treatment trials (Trial number, EudraCT 2015-001184-39).

Performance of the new SLICC classification criteria in childhood systemic lupus erythematosus: a multicentre study.

OBJECTIVES: The Systemic Lupus International Collaborating Clinics (SLICC) group has recently proposed a new set of criteria for the classification of systemic lupus erythematosus (SLE). We aimed to compare the sensitivity and specificity of the new SLICC criteria with those of the American College of Rheumatology (ACR) criteria in our childhood-onset SLE patients. METHODS: Three main paediatric lupus centres from Europe participated in this study. Of these centres, one was predominantly a paediatric nephrology centre (Great Ormond Street Hospital, London, UK), one was predominantly a paediatric rheumatology centre (Istituto Giannina Gaslini, Genoa, Italy), and one was a combined centre taking care of both group of patients (Hacettepe University, Ankara, Turkey). The features present at disease onset in patients with childhood-onset SLE, younger than 18 years of age, seen between January 2000 and December 2012 were retrospectively reviewed. For the evaluation of specificity, patients admitted to each centre between May and December 2012 for conditions other than SLE, in whom ANA was deemed necessary within the diagnostic work-up were included as controls. PASW 18.0 for Windows was used for statistical analyses. RESULTS: Both sets of classification criteria were analysed in 154 childhood SLE patients with a mean age at disease onset of 12.7 years and in 123 controls with a mean age of 8.9 years. The sensitivity and specificity of the ACR criteria were 76.6% and 93.4%, respectively, whereas those of the SLICC criteria were 98.7% and 85.3%, respectively. Four patients out of 5 with haemolytic uraemic syndrome (HUS) and 4 patients out of 8 with juvenile dermatomyositis (JDM) met four of the SLICC criteria, whereas 22 lupus nephritis patients failed to meet four of the ACR criteria. CONCLUSIONS: In our paediatric series, the SLICC criteria showed better sensitivity (p<0.001) and led to fewer misclassifications, but were less specific (p<0.001) than the ACR criteria.

The contribution of environmental pollutants to the risk of autism and other neurodevelopmental disorders: A systematic review of case-control studies.

Exposure to environmental pollutants, such as metals, pesticides, and air pollutants during early life, is a risk factor for neurodevelopmental disorders (NDDs), including Autism Spectrum Disorder (ASD). Our systematic review aimed to select and summarize more recent case-control studies that examined the association between prenatal and early postnatal exposure to environmental pollutants and NDDs. We searched five databases (Web of Science, PubMed, Embase, Scopus, Ovid), screened 2261 records, and included 24 eligible case-control studies. Meta-analyses were conducted on subgroups of at least three studies that shared both the outcome and the exposure. A noteworthy discovery from this literature review is the existence of non-linear or non-monotonic dose-response relationships between the exposure to certain metals and the risk of ASD. The meta-analysis revealed a significant association between exposure to particular matter (PM)10 during the first year of life and the risk of ASD. Overall, studies included in our systematic review indicate that exposure to several pollutants within the first three years of life was significantly associated with the risk of NDDs.

A snapshot of gut microbiota data from murine models of Autism Spectrum Disorder: Still a blurred picture.

Autism Spectrum Disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by deficits in social communication and interaction and repetitive/stereotyped behaviors. In recent years, the role of microbiota-gut-brain axis in ASD pathogenesis received growing attention, appearing as an attractive therapeutic target. We provide a comprehensive overview of changes in microbiota composition in ASD murine models so far identified, and summarize the therapeutic approaches targeting the microbiota on ASD-like neurobehavioral profile. Although alterations in microbiota composition have been observed in both genetic and environmental murine models of ASD, a clear microbiota profile shared by different ASD murine models has not been identified. We documented substantial discrepancies among studies (often within the same model), likely due to several confounding factors (from sex and age of animals to housing conditions). Despite these limitations, ASD animal models (under standardized conditions) remain a useful tool to evaluate (i) the beneficial effects of manipulations of gut microbiota on behavioral abnormalities; (ii) underlying neurobiological mechanisms related to gut-brain axis; and (iii) to identify optimal time windows for therapeutic interventions.

Maternal suboptimal selenium intake and low-level lead exposure affect offspring's microglial immune profile and its reactivity to a subsequent inflammatory hit.

Micronutrients such as selenium (Se) are essentials since prenatal life to support brain and cognitive development. Se deficiency, which affects up to 1 billion people worldwide, can interact with common adverse environmental challenges including (Pb), exacerbating their toxic effects. Exploiting our recently validated rat model of maternal Se restriction and developmental low Pb exposure, our aims were to investigate: (i) the early consequences of suboptimal Se intake and low-Pb exposure on neuroinflammation in neonates' whole brains; (ii) the potential priming effect of suboptimal Se and low-Pb exposure on offspring's glial reactivity to a further inflammatory hit. To these aims female rats were fed with suboptimal (0.04 mg/kg; Subopt) and optimal (0.15 mg/kg; Opt) Se dietary levels throughout pregnancy and lactation and exposed or not to environmentally relevant Pb dose in drinking water (12.5 µg/mL) since 4 weeks pre-mating. We found an overall higher basal expression of inflammatory markers in neonatal brains, as well as in purified microglia and organotypic hippocampal slice cultures, from the Subopt Se offspring. Subopt/Pb cultures were highly activated than Subopt cultures and showed a higher susceptibility to the inflammatory challenge lipopolysaccharide than cultures from the Opt groups. We demonstrate that even a mild Se deficiency and low-Pb exposure during brain development can influence the neuroinflammatory tone of microglia, exacerbate the toxic effects of Pb and prime microglial reactivity to subsequent inflammatory stimuli. These neuroinflammatory changes may be responsible, at least in part, for adverse neurodevelopmental outcomes.

A new cynodont from the Upper Triassic Los Colorados Formation (Argentina, South America) reveals a novel paleobiogeographic context for mammalian ancestors.

Probainognathia is a derived lineage of cynodonts which encompass Mammalia as their crown-group. The rich record of probainognathians from the Carnian of Argentina contrasts with their Norian representation, with only one named species. Here we describe a new probainognathian, Tessellatia bonapartei gen. et sp. nov., from the Norian Los Colorados Formation of the Ischigualasto-Villa Unión Basin of Argentina. The new taxon, represented by a partial cranium with associated lower jaws, was analyzed through neutron and X-rays micro-tomography (µCT). The high-resolution neutron µCT data allowed the identification of a unique character combination, including features inaccessible through traditional techniques. We constructed the largest phylogenetic data matrix of non-mammalian cynodonts. The new species and its sister taxon, the Brazilian Therioherpeton cargnini, are recovered as probainognathians, closely related to Mammaliamorpha. We conducted the first quantitative paleobiogeographic analysis of non-mammalian cynodonts, focusing in probainognathians. The results indicate that Probainognathia and Mammaliamorpha originated in southwestern Gondwana (in the Brazilian Paraná Basin), which was an important center of diversification during the Triassic. Finally, the Chinese Lufeng Basin is identified as the ancestral area of Mammaliaformes. These new findings, besides adding to the knowledge of the poorly represented Norian cynodonts from the Los Colorados Formation, are significant to improve our understanding of probainognathian diversity, evolution, and paleobiogeographic history.

Altered responsiveness to pups in virgin female mice of the BTBR strain: Insights from pattern of c-Fos expression in brain regions involved in maternal behavior.

BTBR is an inbred mouse strain that displays several behavioral alterations resembling the core symptoms of Autism Spectrum Disorder, including deficit in sociability. In the present study, we investigated whether the pup-induced maternal behavior in virgin female mice, a naturally rewarding behavior, is impaired in this strain similarly to social interaction with adult conspecifics. We firstly assessed the maternal responsiveness towards newly born pups expressed by either virgin female mice of the BTBR strain or of the normo-social B6 strain. Next, we examined in both strains the expression of c-Fos as a marker of neuronal activity in selected brain areas involved in the regulation of maternal behavior in rodents including the olfactory bulb, the medial preoptic area and the paraventricular nucleus (PVN). We also examined the effects of pup presentation on oxytocinergic neurons of the PVN, the major brain site of synthesis of oxytocin, which has a pivotal role in facilitation of maternal response and social responsiveness in general. As a final step, we assessed the c-Fos expression pattern comparing the effect of exposure to pups with that induced by exposure to another social stimulus, focusing on other areas implicated in maternal responsiveness as well as in the affective component of social behavior such as pyriform cortex and central and basolateral amygdala. Our data showed that BTBR virgin females are less responsive to presentation of pups in comparison to B6, in parallel with lower activation of brain areas implicated in the maternal and social responsiveness.

New perspectives for neutron imaging through advanced event-mode data acquisition.

Imaging using scintillators is a widespread and cost-effective approach in radiography. While different types of scintillator and sensor configurations exist, it can be stated that the detection efficiency and resolution of a scintillator-based system strongly depend on the scintillator material and its thickness. Recently developed event-driven detectors are capable of registering spots of light emitted by the scintillator after a particle interaction, allowing to reconstruct the Center-of-Mass of the interaction within the scintillator. This results in a more precise location of the event and therefore provides a pathway to overcome the scintillator thickness limitation and increase the effective spatial resolution of the system. Utilizing this principle, we present a detector capable of Time-of-Flight imaging with an adjustable field-of-view, ad-hoc binning and re-binning of data based on the requirements of the experiment including the possibility of particle discrimination via the analysis of the event shape in space and time. It is considered that this novel concept might replace regular cameras in neutron imaging detectors as it provides superior detection capabilities with the most recent results providing an increase by a factor 3 in image resolution and an increase by up to a factor of 7.5 in signal-to-noise for thermal neutron imaging.

Regenerative medicine in Huntington's disease: Strengths and weaknesses of preclinical studies.

Huntington's disease (HD) is an inherited neurodegenerative disorder, characterized by impairment in motor, cognitive and psychiatric domains. Currently, there is no specific therapy to act on the onset or progression of HD. The marked neuronal death observed in HD is a main argument in favour of stem cells (SCs) transplantation as a promising therapeutic perspective to replace the population of lost neurons and restore the functionality of the damaged circuitry. The availability of rodent models of HD encourages the investigation of the restorative potential of SCs transplantation longitudinally. However, the results of preclinical studies on SCs therapy in HD are so far largely inconsistent; this hampers the individuation of the more appropriate model and precludes the comparative analysis of transplant efficacy on behavioural end points. Thus, this review will describe the state of the art of in vivo research on SCs therapy in HD, analysing in a translational perspective the strengths and weaknesses of animal studies investigating the therapeutic potential of cell transplantation on HD progression.

Simple reaction-time changes in patients with unilateral brain damage.

Changes of simple visual reaction time were analysed in two groups of unilateral brain-damaged patients in order to evaluate to what extent properties of lesions, clinical parameters and experimental variables might influence speed of motor response. The results confirmed that brain damage, independent of its side, produces a retardation of speed. However, the two hemispheric groups differed in so far as volume of damage had a different bearing depending on side of lesion. In spite of such a difference the presence of a general interaction between size of damage and rate of progression of lesion was noted in both the hemispheres, reminiscent of Jackson's concept of 'lesion momentum'. Aphasia was related to a significant retardation of speed in left-hemisphere-diseased patients, although a specific effect of the disturbance of language could not be demonstrated. Experimental variables such as warned vs unwarned stimulation did not affect significantly the performance of brain-damaged patients.

Further evidence for asymmetry of point localization in normals and unilateral brain damaged patients.

The properties of errors made by normals and unilateral brain damaged patients in localizing points in each half of a plane have been further investigated. A lesion of either hemisphere affects specifically the performance in the left half of the plane, where controls attain the highest degree of constancy. Consideration of the orientation of pathologic vectors may contribute to differentiation between damage of the two hemispheres.

Reaction time to square-wave gratings as a function of spatial frequency, complexity and contrast.

Visuomotor reaction time (RT) of normal human subjects to briefly presented square-wave bar patterns were measured. The pattern varied with respect to magnitude and number of spatial frequencies (one cycle/degree of visual angle, 3 cycles/degree, and both combined) with each spatial frequency stimulus presented at 3 levels of contrast. Space-average luminance was held constant. RT increased with the higher spatial frequency and was intermediate in value for the combination stimulus at each level of contrast. RT increased with decreasing contrast levels for each spatial frequency stimulus. There was no interaction between the two parameters. The findings indicate that a behavioral response measure can be employed to study the multiple channel hypothesis of human vision. The results were compared with those of other investigators employing sine-wave gratings, perceptual response measures and the evoked potentials technique.

Further evidence for focal effect of right hemisphere damage on simple reaction time.

Changes of simple visual reaction time were analyzed in two groups of unilateral brain damaged patients in order to evaluate to what extent intrahemispheric localization of lesions affects performance. Possible interactions with size were avoided by selecting a localization criterion, i.e. the median section of lesion, uncorrelated with size of damage. By preliminarly establishing that the distribution of lesions in our hemispheric groups did not differ, we were enabled to confirm that intrahemispheric localization of damage has a different bearing on performance depending on side of lesion. In the right hemisphere group slower performances were generally associated with frontal damage whereas in the left hemisphere group localization did not influence the performance. The use of independent indexes for size and locus of lesion proved the existence of an interaction between these parameters in the right hemisphere group.

Functional vascular volume and blood-brain barrier permeability images by angio-CT in the diagnosis of cerebral lesions.

We performed angio-CT following i.v. administration of an iodinated contrast medium and analyzed the pixel contrast time-density curves from 4 to 10 min postinjection to derive vascular and volume BBB permeability images. This was performed by applying multiple regression analysis of pixel contrast curves versus blood contrast and integrated blood contrast curves. The two regression coefficients, mapped pixel by pixel, correspond respectively to vascular volume and BBB unidirectional transport rate. Initial application in a small number of normal subjects and patients allowed us to characterize areas of steady-state contrast enhancement according to changes of vascular volume and BBB permeability.

[Cystic adenomatoid malformation of the lung at the fetal stage. Ultrasonographic diagnosis and counseling]. / Malformazione adenomatoide cistica del polmone in epoca fetale. Diagnosi ecografica e counseling.

BACKGROUND: The aim of this study was to report the series of cystic malformation of the lung (CAML) detected at the Center for Prenatal Diagnosis of the University of Naples Federico II and compare the data with the current literature. METHODS: In the period 1994-1997, ten cases of CAML have been detected at our unit. For each case, the following parameters were recorded: size of the cysts (according to the Stocker classification), side, presence of mediastinal shift, hydrops. For confirmation, necropsies and post natal files were sought. RESULTS: CAML was type I in 3 cases, type II in 3, and type III in 4 cases. mediastinal shift was present in 7 cases, hydrops in 2 and bilateral renal agenesis in 1. Seven cases underwent termination of pregnancy, 2 are currently alive and thriving after surgery and one pregnancy is ongoing at 36 weeks of gestation. The diagnosis was straightforward in all cases, and there were no problems of differential diagnosis. CONCLUSIONS: From an analysis of the data published in recent literature, it can be affirmed that hydrops but not mediastinal shift have negative prognostic significance. The abortion rate of 70% in our series, including 4 cases with a good prognosis, is somewhat frustrating. This figure underlines the need for a multidisciplinary counseling in which the pediatric surgeon, the psychologist and the sonographer may support the couple in overcoming the stress related to the acknowledgement of the lesion in order to reach the final decision about the outcome of the pregnancy.

[Congenital diaphragmatic hernia. Prenatal diagnosis and neonatal outcome]. / Ernia diaframmatica congenita. Diagnosi prenatale e outcome neonatale.

BACKGROUND: The objective of this study is to determine the management and the outcome of 17 cases of congenital diaphragmatic hernia observed, and to compare the results with the literature data. METHODS: The study was made between June 1994 and June 1998 in the Department of Obstetrics and Gynecology of the University of Naples Federico II and it collected 17 pregnant women with diagnosed or suspected congenital diaphragmatic hernia, referred to our diagnostic unit from other institutes: between 18 and 37 weeks' gestation, a detailed ultrasound examination and an echocardiography were performed to confirm the diagnosis, to establish the site and contents of the hernia exactly and to detect associated structural malformations. Fetal kariotyping was made in 7 cases. When the women decided to continue pregnancy, or the legal limit for termination of pregnancy was exceeded, the pregnancy was monitored with ultrasound examination, delivery took place in our department and the baby was transferred to an intensive care unit. RESULTS: Ultrasound examination led to the diagnosis of 14 postero-lateral left-sided diaphragmatic hernias (82.3%), 1 antero-lateral left-sided (5.9%), 1 bilateral postero-lateral sided (5.9%) and 1 diaphragmatic eventration (5.9%). Associated structural malformation were diagnosed in 4 fetuses (27%). In 1 case only (14.3% of examinated kariotyping) an abnormal result was found. Five pregnancies (29.4%) were terminated, 2 (11.7%) are still going on and 10 fetuses (58.9%) were born alive: 5 fetuses (50%) died in the first days of life before surgical intervention, 2 (40% of operated children and 20% of born alive) died after the operation and 3 (60% of operated children and 30% of born alive) are actually alive and in good health. The total postnatal mortality was 70% and 40% after operation. CONCLUSIONS: From the analysis of these data and from the international literature the conclusion is drawn that congenital diaphragmatic hernia is associated with a high postnatal mortality, although potentially it can be corrected with surgery: a better postnatal management and a better knowledge of evaluable in uterus prognostic factors are necessary to improve postnatal outcome.