Theranostic gold-magnetite hybrid nanoparticles for MRI-guided radiosensitization.

The main limitation of drug-enhanced radiotherapy concerns the difficulty to evaluate the effectiveness of cancer targeting after drug administration hindering the standardization of therapies based on current radiosensitizing compounds. The challenge regards the development of systems able to combine imaging and radiotherapy enhancement in order to perform highly reliable cancer theragnosis. For these reasons, gold-magnetite hybrid nanoparticles (H-NPs) are proposed as innovative theranostic nanotools for imaging-guided radiosensitization in cancer treatment. In this work we propose a novel method for the synthesis of hydrophilic and superparamagnetic Tween20-stabilized gold-magnetite H-NPs. Morphology and chemical composition of nanoparticles were assessed by transmission electron microscopy, x-ray diffraction analysis and ion-coupled plasma optical emission spectroscopy. Colloidal stability and magnetic properties of nanoparticles were determined by dynamic light scattering and magnetometry. The potentialities of H-NPs for magnetic resonance imaging were studied using a human 4T-MRI scanner. Nanoparticles were proven to induce concentration-dependent contrast enhancement in T2*-weighted MR-images. The cytotoxicity, the cellular uptake and the radiosensitization activity of H-NPs were investigated in human osteosarcoma MG63 cell cultures and murine 3T3 fibroblasts, using specific bioassays and laser scanning confocal microscopy. H-NPs did not exhibit significant toxicity and were demonstrated to be internalized by cells. A significant x-ray enhancement at specific H-NPs exposure concentrations was evidenced on MG63 cell line.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Resting-state functional connectivity abnormalities in subjective cognitive decline: A 7T MRI study.

Resting-state functional connectivity (FC) MRI is sensitive to brain changes in Alzheimer's disease in preclinical stages, however studies in persons with subjective cognitive decline (SCD) have reported conflicting findings, and no study is available at 7T MRI. In this study, we investigated FC alterations in sixty-six participants recruited at the Geneva Memory Center (24 controls, 14 SCD, 28 cognitively impaired [CI]). Participants were classified as SCD if they reported cognitive complaints without objective cognitive deficits, and underwent 7T fMRI to assess FC in canonical brain networks and their association with cognitive/clinical features. SCD showed normal cognition, a trend for higher depressive symptoms, and normal AD biomarkers. Compared to the other two groups, SCD showed higher FC in frontal default mode network (DMN) and insular and superior temporal nodes of ventral attention network (VAN). Higher FC in the DMN and VAN was associated with worse cognition but not depression, suggesting that hyper-connectivity in these networks may be a signature of age-related cognitive decline in SCD at low risk of developing AD.

MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients.

BACKGROUND/OBJECTIVES: A previous fMRI study demonstrated increased brain activation during working memory tasks in patients with HIV with mild dementia. The current study aims to determine whether patients who are HIV-1 positive and have normal cognitive function also show increased brain activation on fMRI. METHODS: Blood oxygenation level-dependent (BOLD) fMRI was performed in 10 patients with HIV (CD <500) and 10 age-, sex-, education-, and handedness-matched seronegative subjects. Each subject performed a battery of neuropsychological tests and fMRI with three tasks (0-back, 1-back, and 2-back) that required different levels of attention for working memory. RESULTS: Compared with control subjects, patients with HIV showed greater magnitude of brain activation (BOLD signal intensity changes, p

Neural correlates of attention and working memory deficits in HIV patients.

OBJECTIVES: To evaluate the neural correlates of attention and working memory deficits in patients with HIV-1. METHOD: fMRI was used to evaluate brain activity in 11 patients with HIV and 11 age-, sex-, education-, and handedness-matched seronegative subjects, while performing a battery of tasks that required different levels of attention for working memory. RESULTS: Patients with HIV showed greater brain activation (blood oxygenation level dependent signal changes) in some regions compared with control subjects while performing the same tasks. For the simpler tasks, patients with HIV showed greater activation in the parietal regions. However, with more difficult tasks, patients with HIV showed greater activation additionally in the frontal lobes. Reaction times during these tasks were slower but accuracy was similar in the patients with HIV compared with control subjects. CONCLUSION: Injury to the neural substrate caused by HIV infection may necessitate greater attentional modulation of the neural circuits, hence a greater use of the brain reserve; additional activation of the frontal lobes is required to perform the more complex tasks. The task-dependent increased frontal activation in patients with HIV suggests that the neural correlate of attentional deficits may be excessive attentional modulation as a result of frontostriatal brain injury.

GRASE imaging at 3 Tesla with template interactive phase-encoding.

A new method for ordering the phase-encoding gradient is proposed, and an application for short effective TE gradient- and spin-echo (GRASE) imaging is demonstrated. The proposed method calculates the phase-encoding order from the signal decay of a template scan (hence "template interactive phase-encoding" or TIPE). Computer simulations are used to compare the point spread functions of different phase-encoding orders giving short effective echo times (kb centric GRASE, centric GRASE, centric TIPE). The conventional centric phase-encoding order is also considered for GRASE. The conventional centric method is sensitive to both amplitude and phase modulation of the signal in k-space. The centric TIPE method gives the least amplitude modulation artifacts but is vulnerable to phase artifacts. The TIPE experiment was implemented on a 3 Tesla system. To the best of our knowledge, we present the first in vivo GRASE images at this field strength.

Functional MRI of the human brain with GRASE-based BOLD contrast.

The application of T2*-weighted gradient and spin-echo (GRASE) imaging was investigated as a method for blood oxygenation level-dependent (BOLD)-based functional magnetic resonance imaging (fMRI). The displaced-echo method was implemented to produce single-shot T2*-weighted GRASE images. This technique removes the requirement that the Carr-Purcell Meiboom-Gill (CPMG) condition be fulfilled. T2*-weighted GRASE images that are free from interference artifacts can thus be obtained, hence allowing the possibility of using single-shot GRASE for BOLD-based functional imaging. The method was demonstrated at 3 T and gave robust and reproducible activation-induced signal changes.

Brain areas specific for attentional load in a motion-tracking task.

Although visual attention is known to modulate brain activity in the posterior parietal, prefrontal, and visual sensory areas, the unique roles of these areas in the control of attentional resources have remained unclear. Here, we report a dissociation in the response profiles of these areas. In a parametric functional magnetic resonance imaging (fMRI) study, subjects performed a covert motion-tracking task, in which we manipulated "attentional load" by varying the number of tracked balls. While strong effects of attention--independent of attentional load--were widespread, robust linear increases of brain activity with number of balls tracked were seen primarily in the posterior parietal areas, including the intraparietal sulcus (IPS) and superior parietal lobule (SPL). Thus, variations in attentional load revealed different response profiles in sensory areas as compared to control areas. Our results suggest a general role for posterior parietal areas in the deployment of visual of attentional resources.