Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma.

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

Auditory cortical plasticity after cochlear implantation in asymmetric hearing loss is related to spatial hearing: a PET H215O study.

In asymmetric hearing loss (AHL), the normal pattern of contralateral hemispheric dominance for monaural stimulation is modified, with a shift towards the hemisphere ipsilateral to the better ear. The extent of this shift has been shown to relate to sound localization deficits. In this study, we examined whether cochlear implantation to treat postlingual AHL can restore the normal functional pattern of auditory cortical activity and whether this relates to improved sound localization. The auditory cortical activity was found to be lower in the AHL cochlear implanted (AHL-CI) participants. A cortical asymmetry index was calculated and showed that a normal contralateral dominance was restored in the AHL-CI patients for the nonimplanted ear, but not for the ear with the cochlear implant. It was found that the contralateral dominance for the nonimplanted ear strongly correlated with sound localization performance (rho = 0.8, P < 0.05). We conclude that the reorganization of binaural mechanisms in AHL-CI subjects reverses the abnormal lateralization pattern induced by the deafness, and that this leads to improved spatial hearing. Our results suggest that cochlear implantation enables the reconstruction of the cortical mechanisms of spatial selectivity needed for sound localization.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Alzheimer's disease genetic pathways impact cerebrospinal fluid biomarkers and imaging endophenotypes in non-demented individuals.

INTRODUCTION: Unraveling how Alzheimer's disease (AD) genetic risk is related to neuropathological heterogeneity, and whether this occurs through specific biological pathways, is a key step toward precision medicine. METHODS: We computed pathway-specific genetic risk scores (GRSs) in non-demented individuals and investigated how AD risk variants predict cerebrospinal fluid (CSF) and imaging biomarkers reflecting AD pathology, cardiovascular, white matter integrity, and brain connectivity. RESULTS: CSF amyloidbeta and phosphorylated tau were related to most GRSs. Inflammatory pathways were associated with cerebrovascular disease, whereas quantitative measures of white matter lesion and microstructure integrity were predicted by clearance and migration pathways. Functional connectivity alterations were related to genetic variants involved in signal transduction and synaptic communication. DISCUSSION: This study reveals distinct genetic risk profiles in association with specific pathophysiological aspects in predementia stages of AD, unraveling the biological substrates of the heterogeneity of AD-associated endophenotypes and promoting a step forward in disease understanding and development of personalized therapies. HIGHLIGHTS: Polygenic risk for Alzheimer's disease encompasses six biological pathways that can be quantified with pathway-specific genetic risk scores, and differentially relate to cerebrospinal fluid and imaging biomarkers. Inflammatory pathways are mostly related to cerebrovascular burden. White matter health is associated with pathways of clearance and membrane integrity, whereas functional connectivity measures are related to signal transduction and synaptic communication pathways.

Neuroinflammation PET imaging of the translocator protein (TSPO) in Alzheimer's disease: An update.

Neuroinflammation is a significant contributor to Alzheimer's disease (AD). Until now, PET imaging of the translocator protein (TSPO) has been widely used to depict the neuroimmune endophenotype of AD. The aim of this review was to provide an update to the results from 2018 and to advance the characterization of the biological basis of TSPO imaging in AD by re-examining TSPO function and expression and the methodological aspects of interest. Although the biological basis of the TSPO PET signal is obviously related to microglia and astrocytes in AD, the observed process remains uncertain and might not be directly related to neuroinflammation. Further studies are required to re-examine the cellular significance underlying a variation in the PET signal in AD.

Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study.

INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results.

PPAR Gamma and Viral Infections of the Brain.

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.

Modular slowing of resting-state dynamic functional connectivity as a marker of cognitive dysfunction induced by sleep deprivation.

Dynamic Functional Connectivity (dFC) in the resting state (rs) is considered as a correlate of cognitive processing. Describing dFC as a flow across morphing connectivity configurations, our notion of dFC speed quantifies the rate at which FC networks evolve in time. Here we probe the hypothesis that variations of rs dFC speed and cognitive performance are selectively interrelated within specific functional subnetworks. In particular, we focus on Sleep Deprivation (SD) as a reversible model of cognitive dysfunction. We found that whole-brain level (global) dFC speed significantly slows down after 24h of SD. However, the reduction in global dFC speed does not correlate with variations of cognitive performance in individual tasks, which are subtle and highly heterogeneous. On the contrary, we found strong correlations between performance variations in individual tasks -including Rapid Visual Processing (RVP, assessing sustained visual attention)- and dFC speed quantified at the level of functional sub-networks of interest. Providing a compromise between classic static FC (no time) and global dFC (no space), modular dFC speed analyses allow quantifying a different speed of dFC reconfiguration independently for sub-networks overseeing different tasks. Importantly, we found that RVP performance robustly correlates with the modular dFC speed of a characteristic frontoparietal module.

Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.

BACKGROUND: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults. METHODS: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. RESULTS: Significant MRI site and vendor effects (p â€‹< â€‹.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p â€‹< â€‹1.39E-36). In particular, volumes larger than 200 â€‹mm3 (for amygdalar nuclei) and 300 â€‹mm3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε â€‹< â€‹5% and DICE â€‹> â€‹0.80). CONCLUSION: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

PURPOSE/BACKGROUND: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers. METHODS/PROCEDURE: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task. FINDINGS/RESULTS: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459). IMPLICATIONS/CONCLUSIONS: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.

Quantitative amyloid PET in Alzheimer's disease: the AMYPAD prognostic and natural history study.

INTRODUCTION: The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) Prognostic and Natural History Study (PNHS) aims at understanding the role of amyloid imaging in the earliest stages of Alzheimer's disease (AD). AMYPAD PNHS adds (semi-)quantitative amyloid PET imaging to several European parent cohorts (PCs) to predict AD-related progression as well as address methodological challenges in amyloid PET. METHODS: AMYPAD PNHS is an open-label, prospective, multi-center, cohort study recruiting from multiple PCs. Around 2000 participants will undergo baseline amyloid positron emission tomography (PET), half of whom will be invited for a follow-up PET 12 at least 12 months later. RESULTS: Primary include several amyloid PET measurements (Centiloid, SUVr, BPND , R1 ), and secondary are their changes from baseline, relationship to other amyloid markers (cerebrospinal fluid and visual assessment), and predictive value of AD-related decline. EXPECTED IMPACT: Determining the role of amyloid PET for the understanding of this complex disease and potentially improving secondary prevention trials.

Enlarged perivascular spaces and florbetapir uptake in patients with intracerebral hemorrhage.

PURPOSE: Enlarged perivascular spaces in the centrum semiovale (CSO-EPVS) have been linked to cerebral amyloid angiopathy (CAA). To get insight into the underlying mechanisms of this association, we investigated the relationship between amyloid-ß deposition assessed by 18F-florbetapir PET and CSO-EPVS in patients with acute intracerebral hemorrhage (ICH). METHODS: We prospectively enrolled 18 patients with lobar ICH (suggesting CAA) and 20 with deep ICH (suggesting hypertensive angiopathy), who underwent brain MRI and 18F-florbetapir PET. EPVS were assessed on MRI using a validated 4-point visual rating scale in the centrum semiovale and the basal ganglia (BG-EPVS). PET images were visually assessed, blind to clinical and MRI data. We evaluated the association between florbetapir PET positivity and high degree (score> 2) of CSO-EPVS and BG-EPVS. RESULTS: High CSO-EPVS degree was more common in patients with lobar ICH than deep ICH (55.6% vs. 20.0%; p = 0.02). Eight (57.1%) patients with high CSO-EPVS degree had a positive florbetapir PET compared with 4 (16.7%) with low CSO-EPVS degree (p = 0.01). In contrast, prevalence of florbetapir PET positivity was similar between patients with high vs. low BG-EPVS. In multivariable analysis adjusted for age, hypertension, and MRI markers of CAA, florbetapir PET positivity (odds ratio (OR) 6.44, 95% confidence interval (CI) 1.32-38.93; p = 0.03) was independently associated with high CSO-EPVS degree. CONCLUSIONS: Among patients with spontaneous ICH, high degree of CSO-EPVS but not BG-EPVS is associated with amyloid PET positivity. The findings provide further evidence that CSO-EPVS are markers of vascular amyloid burden that may be useful in diagnosing CAA.

Dopaminergic denervation using [123I]-FPCIT and pain in Parkinson's disease: a correlation study.

In patients with Parkinson's disease (PD), abnormal activations of nociceptive brain areas and lowered pain thresholds were reported, probably reflecting a central modification of pain processing. The aim of this study was to investigate the possible correlation between the striatal and extrastriatal dopaminergic system and pain threshold in PD patients. We included 25 PD patients with various intensities of central pain (visual analog scale). Subjective pain threshold (thermotest) and a motor examination (UPDRS III) were performed. Patients underwent SPECT imaging with [123I]-FP-CIT. We analyzed the correlation between [123I]-FP-CIT binding and subjective pain threshold, using a simple linear regression model for striatal uptake and a voxel-based approach for extrastriatal uptake. The covariables were age, sex, duration of PD, and UPDRS motor score. A pain matrix mask was also used to identify clusters in relation with pain matrix. Striatal analysis revealed that [123I]-FP-CIT binding was negatively correlated with age (p = 0.02), duration of PD (p = 0.0002) and UPDRS motor score (p = 0.006), but no correlation with pain threshold was observed. The extrastriatal analysis showed a positive correlation between [123I]-FP-CIT binding and subjective heat pain threshold for the left posterior cingulate cortex (PCC) (p < 0.001) and negative correlations for the right secondary visual cortex (p < 0.001) and left insula (p < 0.001). When applying the pain matrix mask, correlations remained significant only in the left PCC and the left insula. We suggest that pain perception abnormalities in PD are not directly related to striatal dopaminergic dysfunction. Painful sensations may be related to extrastriatal monoaminergic systems.

Functional connectivity of hypothalamus in chronic migraine with medication overuse.

OBJECTIVE: To investigate the functional connectivity of the hypothalamus in chronic migraine compared to interictal episodic migraine in order to improve our understanding of migraine chronification. METHODS: Using task-free fMRI and ROI-to-ROI analysis, we compared anterior hypothalamus intrinsic connectivity with the spinal trigeminal nucleus in patients with chronic migraine (n = 25) to age- and sex-matched patients with episodic migraine in the interictal phase (n = 22). We also conducted a seed-to-voxel analysis with anterior hypothalamus as a seed. RESULTS: All patients with chronic migraine had medication overuse. We found a significant connectivity (T = 2.08, p = 0.024) between anterior hypothalamus and spinal trigeminal nucleus in the chronic group, whereas these two regions were not connected in the episodic group. The strength of connectivity was not correlated with pain intensity (rho: 0.09, p = 0.655). In the seed-to-voxel analysis, three regions were more connected with the anterior hypothalamus in the chronic group: The spinal trigeminal nuclei (MNI coordinate x = 2, y = -44, z = -62), the right dorsal anterior insula (MNI coordinate x = 10, y = 10, z = 18), and the right caudate (MNI coordinate x = 12, y = 28, z = 6). However, these correlations were no longer significant after whole brain FWE correction. CONCLUSION: An increased functional connectivity between the anterior hypothalamus and the spinal trigeminal nucleus, as previously reported in preictal episodic migraine, was demonstrated in chronic migraine with medication overuse. This finding confirms a major role of the anterior hypothalamus in migraine and suggests that chronic migraineurs are locked in the preictal phase.

The use of labelled leucocyte scintigraphy to evaluate chronic periprosthetic joint infections: a retrospective multicentre study on 168 patients.

Labelled leucocyte scintigraphy (LS) is regarded as helpful when exploring bone and joint infections. The aim of this study was to evaluate the utility of LS for the diagnosis of chronic periprosthetic joint infections (PJIs) in patients exhibiting arthroplastic loosening. One hundred sixty-eight patients were referred to centres for treatment of complex PJI. One hundred fifty underwent LS using 99mTc-HMPAO (LLS); 18 also underwent anti-granulocyte scintigraphy (AGS) and 13 additional SPECT with tomodensitometry imaging (SPECT-CT). The LS results were compared with bone scan data. For all, the final diagnoses were determined microbiologically; perioperative samples were cultured. LS values were examined, as well as sensitivity by microorganism, anatomical sites, and injected activity. LS results were also evaluated according to the current use of antibiotics or not. The sensitivity, specificity, and positive predictive value of LLS were 72%, 60%, and 80%, respectively. LLS performed better than did AGS. SPECT-CT revealed the accurate locations of infections. The sensitivity of LS was not significantly affected by the causative pathogen or the injected activity. No correlation was evident between the current antibiotic treatment and the LS value. The test was more sensitive for knee (84%) than hip arthroplasty (57%) but was less specific for knee (52% vs. 75%). Sensitivity and specificity of LLS varied by the location of infection bone scan provide no additional value in PJI diagnosis. Current antibiotic treatment seems to have no influence on LS sensitivity as well as labelling leukocyte activity or pathogens responsible for chronic PJI.

Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status.

INTRODUCTION: The Multidomain Alzheimer Preventive Trial (MAPT) assessed the efficacy of omega-3 fatty acid supplementation, a multidomain intervention (MI), or a combination of both on cognition. Impact according to cerebral amyloid status was evaluated by PET scan. METHODS: Participants were nondemented and had memory complaints, limitation in one instrumental activity of daily living, or slow gait. The primary outcome was a change from baseline in 36 months measured with a cognitive composite Z score. RESULTS: No effect was observed on cognition in the negative amyloid group (n = 167). In the positive amyloid group (n = 102), we observed a difference of 0.708 and 0.471 in the cognitive composite score between the MI plus omega-3 fatty acid group, the MI alone group, and the placebo group, respectively. DISCUSSION: MI alone or in combination with omega-3 fatty acids was associated with improved primary cognitive outcome in subjects with positive amyloid status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01513252.

AMYPAD Diagnostic and Patient Management Study: Rationale and design.

INTRODUCTION: Reimbursement of amyloid-positron emission tomography (PET) is lagging due to the lack of definitive evidence on its clinical utility and cost-effectiveness. The Amyloid Imaging to Prevent Alzheimer's Disease-Diagnostic and Patient Management Study (AMYPAD-DPMS) is designed to fill this gap. METHODS: AMYPAD-DPMS is a phase 4, multicenter, prospective, randomized controlled study. Nine hundred patients with subjective cognitive decline plus, mild cognitive impairment, and dementia possibly due to Alzheimer's disease will be randomized to ARM1, amyloid-PET performed early in the diagnostic workup; ARM2, amyloid-PET performed after 8 months; and ARM3, amyloid-PET performed whenever the physician chooses to do so. ENDPOINTS: The primary endpoint is the difference between ARM1 and ARM2 in the proportion of patients receiving a very-high-confidence etiologic diagnosis after 3 months. Secondary endpoints address diagnosis and diagnostic confidence, diagnostic/therapeutic management, health economics and patient-related outcomes, and methods for image quantitation. EXPECTED IMPACTS: AMYPAD-DPMS will supply physicians and health care payers with real-world data to plan management decisions.

MRI supervised and unsupervised classification of Parkinson's disease and multiple system atrophy.

BACKGROUND: Multimodal MRI approach is based on a combination of MRI parameters sensitive to different tissue characteristics (eg, volume atrophy, iron deposition, and microstructural damage). The main objective of the present study was to use a multimodal MRI approach to identify brain differences that could discriminate between matched groups of patients with multiple system atrophy, Parkinson's disease, and healthy controls. We assessed the 2 different MSA variants, namely, MSA-P, with predominant parkinsonism, and MSA-C, with more prominent cerebellar symptoms. METHODS: Twenty-six PD patients, 29 MSA patients (16 MSA-P, 13 MSA-C), and 26 controls underwent 3-T MRI comprising T2*-weighted, T1-weighted, and diffusion tensor imaging scans. Using whole-brain voxel-based MRI, we combined gray-matter density, T2* relaxation rates, and diffusion tensor imaging scalars to compare and discriminate PD, MSA-P, MSA-C, and healthy controls. RESULTS: Our main results showed that this approach reveals multiparametric modifications within the cerebellum and putamen in both MSA-C and MSA-P patients, compared with PD patients. Furthermore, our findings revealed that specific single multimodal MRI markers were sufficient to discriminate MSA-P and MSA-C patients from PD patients. Moreover, the unsupervised analysis based on multimodal MRI data could regroup individuals according to their clinical diagnosis, in most cases. CONCLUSIONS: This study demonstrates that multimodal MRI is able to discriminate patients with PD from those with MSA with high accuracy. The combination of different MR biomarkers could be a great tool in early stage of disease to help diagnosis. © 2018 International Parkinson and Movement Disorder Society.

Molecular PET imaging in adaptive radiotherapy: brain.

INTRODUCTION: Owing to their heterogeneity and radioresistance, the prognosis of primitive brain tumors, which are mainly glial tumors, remains poor. Dose escalation in radioresistant areas is a potential issue for improving local control and overall survival. This review focuses on advances in biological and metabolic imaging of brain tumors that are proving to be essential for defining tumor target volumes in radiation therapy (RT) and for increasing the use of DPRT (dose painting RT) and ART (adaptative RT), to optimize dose in radio-resistant areas. EVIDENCE ACQUISITION: Various biological imaging modalities such as PET (hypoxia, glucidic metabolism, protidic metabolism, cellular proliferation, inflammation, cellular membrane synthesis) and MRI (spectroscopy) may be used to identify these areas of radioresistance. The integration of these biological imaging modalities improves the diagnosis, prognosis and treatment of brain tumors. EVIDENCE SYNTHESIS: Technological improvements (PET and MRI), the development of research, and intensive cooperation between different departments are necessary before using daily metabolic imaging (PET and MRI) to treat patients with brain tumors. CONCLUSIONS: The adaptation of treatment volumes during RT (ART) seems promising, but its development requires improvements in several areas and an interdisciplinary approach involving radiology, nuclear medicine and radiotherapy. We review the literature on biological imaging to outline the perspectives for using DPRT and ART in brain tumors.

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation.

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.