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The human brain is characterized by highly dynamic patterns of functional connectivity. However, it is unknown whether this time-variant ‘connectome’ is related to the individual differences in the behavioural and cognitive traits described in the five-factor model of personality. To answer this question, inter-network time-variant connectivity was computed in n = 818 healthy people via a dynamical conditional correlation model. Next, network dynamicity was quantified throughout an ad-hoc measure (T-index) and the generalizability of the multi-variate associations between personality traits and network dynamicity was assessed using a train/test split approach. Conscientiousness, reflecting enhanced cognitive and emotional control, was the sole trait linked to stationary connectivity across several circuits such as the default mode and prefronto-parietal network. The stationarity in the ‘communication’ across large-scale networks offers a mechanistic description of the capacity of conscientious people to ‘protect’ non-immediate goals against interference over-time. This study informs future research aiming at developing more realistic models of the brain dynamics mediating personality differences.

International audience; The traditional approach to biomarker discovery for any pathology has been through hypothesis-based research one candidate at a time. The objective of this study was to develop an agnostic approach for the simultaneous screening of plasma for consistent molecular differences between a group of individuals exhibiting a pathology and a group of healthy individuals. To achieve this, we focused on developing a predictive tool based on plasma for the amount of brain amyloid-β deposition as observed in PET scans. The accumulation of brain amyloid-β (Aβ) plaques is a key risk factor for the development of Alzheimer's disease. A contrast was established between cognitively normal individuals above the age of 70 that differed for the amount of brain amyloid-β observed in PET scans (INSIGHT study group). Positive selection was performed against a pool of plasma from individuals with high brain amyloid and negative selection against a pool of plasma from individuals with low brain amyloid This enriched, selected library was then applied to plasma samples from 11 individuals with high levels of brain amyloid and 11 individuals with low levels of brain Aβ accumulation. Each of these individually selected libraries was then characterized by next generation sequencing, and the relative frequency of 10,000 aptamer sequences that were observed in each selection was screened for ability to explain variation in brain amyloid using sparse partial least squares discriminant analysis. From this analysis a subset of 44 aptamers was defined, and the individual aptamers were synthesized. This subset was applied to plasma samples from 70 cognitively normal individuals all above the age of 70 that differed for brain amyloid deposition. 54 individuals were used as a training set, and 15 as a test set. Three of the 15 individuals in the test set were mis-classified resulting in an overall accuracy of 80% with 86% sensitivity and 75% specificity. The aptamers included in the subset serve directly as biomarkers, thus we have named them Aptamarkers. There are two potential applications of these results: extending the predictive capacity of these aptamers across a broader range of individuals, and/or using the individual aptamers to identify targets through covariance analysis and reverse omics approaches. We are currently expanding applications of the Aptamarker platform to other diseases and target matrices.

Background Plasma neurofilament light (NFL) and total Tau (t-Tau) proteins are candidate biomarkers for early stages of Alzheimer’s disease (AD). The impact of biological factors on their plasma concentrations in individuals with subjective memory complaints (SMC) has been poorly explored. We longitudinally investigate the effect of sex, age, APOE ε4 allele, comorbidities, brain amyloid-β (Aβ) burden, and cognitive scores on plasma NFL and t-Tau concentrations in cognitively healthy individuals with SMC, a condition associated with AD development. Methods Three hundred sixteen and 79 individuals, respectively, have baseline and three-time point assessments (at baseline, 1-year, and 3-year follow-up) of the two biomarkers. Plasma biomarkers were measured with an ultrasensitive assay in a mono-center cohort (INSIGHT-preAD study). Results We show an effect of age on plasma NFL, with women having a higher increase of plasma t-Tau concentrations compared to men, over time. The APOE ε4 allele does not affect the biomarker concentrations while plasma vitamin B12 deficiency is associated with higher plasma t-Tau concentrations. Both biomarkers are correlated and increase over time. Baseline NFL is related to the rate of Aβ deposition at 2-year follow-up in the left-posterior cingulate and the inferior parietal gyri. Baseline plasma NFL and the rate of change of plasma t-Tau are inversely associated with cognitive score. Conclusion We find that plasma NFL and t-Tau longitudinal trajectories are affected by age and female sex, respectively, in SMC individuals. Exploring the influence of biological variables on AD biomarkers is crucial for their clinical validation in blood.

Background The development of bone metastasis from breast cancer results from a functional interaction between tumor cells and osteoclasts or osteoblasts. The main aim of this study was therefore to test the hypothesis that the appearance of breast osteoblast-like cells (BOLCs) in primary mammary lesions is a precursor (and hence an early predictor) of the formation of breast cancer metastases to bone. Patients and Methods In this study, we collected 64 breast infiltrating carcinomas, 50 breast benignant lesions, and 10 biopsies of bone metastasis selected from patients with infiltrated carcinoma. Immunohistochemical, western blot, and ultrastructural analysis allowed us to investigate the presence of BOLCs in breast cancer lesions and metastatic sites. Results We established the presence of a high amount of breast cancer cells that underwent mesenchymal transformation in infiltrating carcinomas. In addition, our results demonstrated that the microenvironment of breast cancer is very similar to the microenvironment of bone. We noted a significantly higher expression of BMP-2/4 and PTX3 in breast-infiltrating carcinomas compared with benign lesions. Moreover, we also identified numerous BOLCs positive to RANKL and Vitamin D receptor. Thanks to ultrastructural analysis, we also revealed the presence of BOLCs at the metastatic site. Conclusions The identification of breast cancer cells with high affinity for a bone environment opens new perspectives on prevention and therapy of bone metastases from breast.

Introduction The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E e4 (APOE e4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion For the first time, we demonstrated that the pleiotropic biological effect of the APOE e4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.

The five-factor model (FFM) is a widely used taxonomy of human personality; yet its neuro anatomical basis remains unclear. This is partly because past associations between gray-matter volume and FFM were driven by different surface-based morphometry (SBM) indices (i.e. cortical thickness, surface area, cortical folding or any combination of them). To overcome this limitation, we used Free-Surfer to study how variability in SBM measures was related to the FFM in n = 507 participants from the Human Connectome Project. Neuroticism was associated with thicker cortex and smaller area and folding in prefrontal–temporal regions. Extraversion was linked to thicker pre-cuneus and smaller superior temporal cortex area. Openness was linked to thinner cortex and greater area and folding in prefrontal–parietal regions. Agreeableness was correlated to thinner prefrontal cortex and smaller fusiform gyrus area. Conscientiousness was associated with thicker cortex and smaller area and folding in prefrontal regions. These findings demonstrate that anatomical variability in prefrontal cortices is linked to individual differences in the socio-cognitive dispositions described by the FFM. Cortical thickness and surface area/folding were inversely related each others as a function of different FFM traits (neuroticism, extraversion and consciousness vs openness), which may reflect brain maturational effects that predispose or protect against psychiatric disorders.

Introduction: Successful development of effective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE epsilon 4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-beta (A beta) deposition, using positron emission tomography global standard uptake value ratios. Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline A beta-positron emission tomography global standard uptake value ratios. Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain A beta production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

An increasing number of studies have aimed to compare diffusion tensor imaging (DTI)-related parameters [e.g., mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD)] to complementary new indexes [e.g., mean kurtosis (MK)/radial kurtosis (RK)/axial kurtosis (AK)] derived through diffusion kurtosis imaging (DKI) in terms of their discriminative potential about tissue disease-related microstructural alterations. Given that the DTI and DKI models provide conceptually and quantitatively different estimates of the diffusion tensor, which can also depend on fitting routine, the aim of this study was to investigate model- and algorithm-dependent differences in MD/FA/RD/AD and anisotropy mode (MO) estimates in diffusion-weighted imaging of human brain white matter.The authors employed (a) data collected from 33 healthy subjects (20-59 yr, F: 15, M: 18) within the Human Connectome Project (HCP) on a customized 3 T scanner, and (b) data from 34 healthy subjects (26-61 yr, F: 5, M: 29) acquired on a clinical 3 T scanner. The DTI model was fitted to b-value =0 and b-value =1000 s/mm(2) data while the DKI model was fitted to data comprising b-value =0, 1000 and 3000/2500 s/mm(2) [for dataset (a)/(b), respectively] through nonlinear and weighted linear least squares algorithms. In addition to MK/RK/AK maps, MD/FA/MO/RD/AD maps were estimated from both models and both algorithms. Using tract-based spatial statistics, the authors tested the null hypothesis of zero difference between the two MD/FA/MO/RD/AD estimates in brain white matter for both datasets and both algorithms.DKI-derived MD/FA/RD/AD and MO estimates were significantly higher and lower, respectively, than corresponding DTI-derived estimates. All voxelwise differences extended over most of the white matter skeleton. Fractional differences between the two estimates [(DKI - DTI)/DTI] of most invariants were seen to vary with the invariant value itself as well as with MK/RK/AK values, indicating substantial anatomical variability of these discrepancies. In the HCP dataset, the median voxelwise percentage differences across the whole white matter skeleton were (nonlinear least squares algorithm) 14.5% (8.2%-23.1%) for MD, 4.3% (1.4%-17.3%) for FA, -5.2% (-48.7% to -0.8%) for MO, 12.5% (6.4%-21.2%) for RD, and 16.1% (9.9%-25.6%) for AD (all ranges computed as 0.01 and 0.99 quantiles). All differences/trends were consistent between the discovery (HCP) and replication (local) datasets and between estimation algorithms. However, the relationships between such trends, estimated diffusion tensor invariants, and kurtosis estimates were impacted by the choice of fitting routine.Model-dependent differences in the estimation of conventional indexes of MD/FA/MO/RD/AD can be well beyond commonly seen disease-related alterations. While estimating diffusion tensor-derived indexes using the DKI model may be advantageous in terms of mitigating b-value dependence of diffusivity estimates, such estimates should not be referred to as conventional DTI-derived indexes in order to avoid confusion in interpretation as well as multicenter comparisons. In order to assess the potential and advantages of DKI with respect to DTI as well as to standardize diffusion-weighted imaging methods between centers, both conventional DTI-derived indexes and diffusion tensor invariants derived by fitting the non-Gaussian DKI model should be separately estimated and analyzed using the same combination of fitting routines.

Diffusion tensor imaging (DTI) is highly sensitive to noise and improvement of radiofrequency coil technology represents a straightforward way for augmenting signal-to-noise ratio (SNR) performance in magnetic resonance imaging (MRI) scanners. The aim of this study was to characterize the dependence of DTI measurements of fractional anisotropy (FA) and mean diffusivity (MD) on the choice of head coil, comparing two head coils with different functional designs and sensitivities.Fourteen healthy subjects underwent DTI acquisitions at 1.5 T. Every subject was scanned twice, using a standard quadrature birdcage head coil (coil-A) and an eight-channel array head coil (coil-B). FA and MD maps, estimated using both the linear least squares (LLS) and nonlinear least squares (NLLS) methods, were nonlinearly normalized into a standard space. Then, volumetric regions of interest encompassing typical white and gray matter structures [splenium of the corpus callosum (SCC), internal capsule (IC), cerebral peduncles (CP), middle cerebellar peduncles (MCP), globus pallidus (GP), thalamus (TH), caudate (CA), and putamen (PU)] were analyzed. Significant differences and trends of variation in DTI measurements were assessed by the Wilcoxon test for paired samples with and without Bonferroni correction for multiple comparisons, respectively.The overall SNR of coil-B was 30% higher than that of coil-A. When comparing DTI measurements (coil-B versus coil-A), mean FA values (SCC, IC, and TH), mean MD values (IC, CP, GP, and TH), FA standard deviation (CP, MCP, GP, and CA), and MD standard deviation (IC, CP, TH, and PU) resulted decreased (significant difference, p(cor)0.05, or trend of variation, P(uncor)0.05) in several gray and white matter regions of the human brain. With the exception of CP, the results in terms of revealed significant difference or trend of variation were independent of the method (LLS and NLLS) used for estimating the diffusion tensor.In various gray and white matter structures, the eight-channel array head coil yielded more precise and accurate measurements of DTI derived indices compared to the standard quadrature birdcage head coil.

Frataxin deficiency, responsible for Friedreich’s ataxia (FRDA), is crucial for cell survival since it critically affects viability of neurons, pancreatic beta cells and cardiomyocytes. In FRDA, the heart is frequently affected with typical manifestation of hypertrophic cardiomyopathy, which can progress to heart failure and cause premature death. A microarray analysis performed on FRDA patient’s lymphoblastoid cells stably reconstituted with frataxin, indicated HS-1-associated protein X-1 (HAX-1) as the most significantly upregulated transcript (FC = +2, P

While associations between exposure to air pollutants and increased morbidity and mortality are well established, few rigorous studies on this issue are available. The aim of the current study is to implement a new approach to the spatial analysis of mortality and morbidity, based on testing for the presence of the same association in other areas of similar size. Additionally, we perform a case study in Val d’Agri (VA), an area of Basilicata Region, Southern Italy, where oil and natural gas extraction began in 1998. In order to examine the spatial distribution of morbidity and mortality in the region of interest, Hospital discharge (2001–2013) and mortality (2003–2014) rates for the main environment-related diseases were calculated. In addition, a comparison between the period 1980–1998 and the period 1999–2014 was performed for cardiovascular disease mortality. For the period under study, a neutral scenario emerged for cancer and respiratory diseases, where we found no differences in morbidity and mortality as compared to the national benchmark. In some cases significantly lower values (as compared to the nation-wide benchmark) were found. Conversely, a slight excess in morbidity and mortality (as compared to the nation-wide benchmark) emerged for cardiovascular diseases. Still, this excess was common to a number of municipalities in the surroundings of VA, and appeared to be already present in 1980. Higher rates of cardiovascular diseases, lower rates of neoplastic disorders no differences in mortality for respiratory causes (as compared to the nation-wide benchmark) were found in multiple areas of the region, and were therefore not specific to VA. In summary, our data do not support the hypothesis of a role of industrial activities related to oil extraction in VA in determining mortality and morbidity patterns and trends.

BACKGROUND AND PURPOSE: The ability of DTI to track the progression of microstructural damage in patients with inherited ataxias has not been explored so far. We performed a longitudinal DTI study in patients with spinocerebellar ataxia type 2. MATERIALS AND METHODS: Ten patients with spinocerebellar ataxia type 2 and 16 healthy age-matched controls were examined twice with DTI (mean time between scans, 3.6 years [patients] and 3.3 years [controls]) on the same 1.5T MR scanner. Using tract-based spatial statistics, we analyzed changes in DTI-derived indices: mean diffusivity, axial diffusivity, radial diffusivity, fractional anisotropy, and mode of anisotropy. RESULTS: At baseline, the patients with spinocerebellar ataxia type 2, as compared with controls, showed numerous WM tracts with significantly increased mean diffusivity, axial diffusivity, and radial diffusivity and decreased fractional anisotropy and mode of anisotropy in the brain stem, cerebellar peduncles, cerebellum, cerebral hemisphere WM, corpus callosum, and thalami. Longitudinal analysis revealed changes in axial diffusivity and mode of anisotropy in patients with spinocerebellar ataxia type 2 that were significantly different than those in the controls. In patients with spinocerebellar ataxia type 2, axial diffusivity was increased in WM tracts of the right cerebral hemisphere and the corpus callosum, and the mode of anisotropy was extensively decreased in hemispheric cerebral WM, corpus callosum, internal capsules, cerebral peduncles, pons and left cerebellar peduncles, and WM of the left paramedian vermis. There was no correlation between the progression of changes in DTI-derived indices and clinical deterioration. CONCLUSIONS: DTI can reveal the progression of microstructural damage of WM fibers in the brains of patients with spinocerebellar ataxia type 2, and mode of anisotropy seems particularly sensitive to such changes. These results support the potential of DTI-derived indices as biomarkers of disease progression.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, including cognitive deficits. Several magnetic resonance imaging approaches have been applied to investigate brain atrophy in PD. The aim of this study was to detect early structural cortical and subcortical changes in de novo PD whilst distinguishing cognitive status, clinical phenotype and motor laterality. METHODS: Eighteen de novo PD with mild cognitive impairment (PD-MCI), 18 de novo PD without MCI (PD-NC) and 18 healthy control subjects were evaluated. In the PD-MCI group, nine were tremor dominant and nine were postural instability gait disorder (PIGD) phenotype; 11 had right-sided symptom dominance and seven had left-sided symptom dominance. FreeSurfer was used to measure cortical thickness/folding, subcortical structures and to study group differences as well as the association with clinical and neuropsychological data. RESULTS: Parkinson's disease with MCI showed regional thinning in the right frontal, right middle temporal areas and left insula compared to PD-NC. A reduction of the volume of the left and right thalamus and left hippocampus was found in PD-MCI compared to PD-NC. PD-MCI PIGD showed regional thinning in the right inferior parietal area compared to healthy controls. A decreased volume of the left thalamus was reported in PD-MCI with right-sided symptom dominance compared to PD-NC and PD-MCI with left-sided symptom dominance. CONCLUSIONS: When MCI was present, PD patients showed a fronto-temporo-parietal pattern of cortical thinning. This cortical pattern does not appear to be influenced by motor laterality, although one-sided symptom dominance may contribute to volumetric reduction of specific subcortical structures.

The term leuko‐araiosis (LA) describes a common chronic affection of the cerebral white matter (WM) in the elderly due to small vessel disease with variable clinical correlates. To explore whether severity of LA entails some adaptive reorganization in the cerebral cortex we evaluated with functional MRI (fMRI) the cortical activation pattern during a simple motor task in 60 subjects with mild cognitive impairment and moderate or severe (moderate‐to‐severe LA group, n = 46) and mild (mild LA group, n = 14) LA extension on visual rating. The microstructural damage associated with LA was measured on diffusion tensor data by computation of the mean diffusivity (MD) of the cerebral WM and by applying tract based spatial statistics (TBSS). Subjects were examined with fMRI during continuous tapping of the right dominant hand with task performance measurement. Moderate‐to‐severe LA group showed hyperactivation of left primary sensorimotor cortex (SM1) and right cerebellum. Regression analyses using the individual median of WM MD as explanatory variable revealed a posterior shift of activation within the left SM1 and hyperactivation of the left SMA and paracentral lobule and of the bilateral cerebellar crus. These data indicate that brain activation is modulated by increasing severity of LA with a local remapping within the SM1 and increased activity in ipsilateral nonprimary sensorimotor cortex and bilateral cerebellum. These potentially adaptive changes as well lack of contralateral cerebral hemisphere hyperactivation are in line with sparing of the U fibers and brainstem and cerebellar WM tracts and the emerging microstructual damage of the corpus callosum revealed by TBSS with increasing severity of LA. Hum Brain Mapp 35:819–830, 2014. © Wiley Periodicals, Inc.

Spinocerebellar ataxia type 2 (SCA2) is the second most frequent autosomal dominant inherited ataxia worldwide. We investigated the capability of magnetic resonance imaging (MRI) to track in vivo progression of brain atrophy in SCA2 by examining twice 10 SCA2 patients (mean interval 3.6 years) and 16 age- and gender-matched healthy controls (mean interval 3.3 years) on the same 1.5 T MRI scanner. We used T1-weighted images and tensor-based morphometry (TBM) to investigate volume changes and the Inherited Ataxia Clinical Rating Scale to assess the clinical deficit. With respect to controls, SCA2 patients showed significant higher atrophy rates in the midbrain, including substantia nigra, basis pontis, middle cerebellar peduncles and posterior medulla corresponding to the gracilis and cuneatus tracts and nuclei, cerebellar white matter (WM) and cortical gray matter (GM) in the inferior portions of the cerebellar hemisphers. No differences in WM or GM volume loss were observed in the supratentorial compartment. TBM findings did not correlate with modifications of the neurological deficit. In conclusion, MRI volumetry using TBM is capable of demonstrating the progression of pontocerebellar atrophy in SCA2, supporting a possible role of MRI as biomarker in future trials.

Objective This study describes changes in heart rate (HR) and HR variability (HRV) related to clinical onset of seizures in nocturnal frontal lobe epilepsy (NFLE) in order to determine whether signs of autonomic activation precede onset of seizure motor manifestations, which was selected as seizure onset (SO). Further, to clarify the nature (epileptic or physiologic) of the changes in autonomic cardiac control presumed to precede SO, time-dependent variations in HR and HRV related to physiological cortical arousals associated with motor activity (phases of transitory activation, PAT) were also investigated. Methods HR and HRV spectral power, quantified by means of wavelet transform, were analyzed in relation to the onset of motor manifestations in 45 NFLE seizures and 45 PAT derived from whole night video-polysomnographic recordings of ten patients and of ten control subjects, respectively. Results Analysis of HRV showed a shift of sympathetic/parasympathetic cardiac control toward a sympathetic predominance in the 10 s immediately preceding SO, while changes in HR were evident only one second before SO. This sympathetic activation was not associated with a sleep-wake transition or changes in respiratory activity, both of which occurred concurrently with SO. Similar changes in HR and HRV were observed in the 10 s before the motor and electroencephalographic onset of PAT. Conclusions Our study demonstrates that a similar autonomic activation precedes the motor manifestations of NFLE seizures and physiological arousal. This autonomic activation could represent part of the arousal response, which could be implicated in the occurrence of both seizure and arousal motor manifestations.

Task- and stimulus-based neuroimaging studies have begun to unveil the central autonomic network which modulates autonomic nervous system activity. In the present study, we aimed to evaluate the central autonomic network without the bias constituted by the use of a task. Additionally, we assessed whether this circuitry presents signs of dysregulation in the early stages of Parkinson's disease (PD), a condition which may be associated with dysautonomia. We combined heart-rate-variability based methods for time-varying assessments of the autonomic nervous system outflow with resting-state fMRI in 14 healthy controls and 14 de novo PD patients, evaluating the correlations between fMRI time-series and the instantaneous high-frequency component of the heart-rate-variability power spectrum, a marker of parasympathetic outflow. In control subjects, the high-frequency component of the heart-rate-variability power spectrum was significantly anti-correlated with fMRI time-series in several cortical, subcortical and brainstem regions. This complex central network was not detectable in PD patients. In between-group analysis, we found that in healthy controls the brain activation related to the high-frequency component of the heart-rate-variability power spectrum was significantly less than in PD patients in the mid and anterior cingulum, sensorimotor cortex and supplementary motor area, insula and temporal lobe, prefrontal cortex, hippocampus and in a region encompassing posterior cingulum, precuneus and parieto-occipital cortex. Our results indicate that the complex central network which modulates parasympathetic outflow in the resting state is impaired in the early clinical stages of PD.