Differentiating IDH-mutant astrocytomas and 1p19q-codeleted oligodendrogliomas using DSC-PWI:high performance through cerebral blood volume and percentage of signal recovery percentiles

Objective: Presurgical differentiation between astrocytomas and oligodendrogliomas remains an unresolved challenge in neuro-oncology. This research aims to provide a comprehensive understanding of each tumor’s DSC-PWI signatures, evaluate the discriminative capacity of cerebral blood volume (CBV) and percentage of signal recovery (PSR) percentile values, and explore the synergy of CBV and PSR combination for pre-surgical differentiation. Methods: Patients diagnosed with grade 2 and 3 IDH-mutant astrocytomas and IDH-mutant 1p19q-codeleted oligodendrogliomas were retrospectively retrieved (2010–2022). 3D segmentations of each tumor were conducted, and voxel-level CBV and PSR were extracted to compute mean, minimum, maximum, and percentile values. Statistical comparisons were performed using the Mann-Whitney U test and the area under the receiver operating characteristic curve (AUC-ROC). Lastly, the five most discriminative variables were combined for classification with internal cross-validation. Results: The study enrolled 52 patients (mean age 45-year-old, 28 men): 28 astrocytomas and 24 oligodendrogliomas. Oligodendrogliomas exhibited higher CBV and lower PSR than astrocytomas across all metrics (e.g., mean CBV = 2.05 and 1.55, PSR = 0.68 and 0.81 respectively). The highest AUC-ROCs and the smallest p values originated from CBV and PSR percentiles (e.g., PSRp70 AUC-ROC = 0.84 and p value = 0.0005, CBVp75 AUC-ROC = 0.8 and p value = 0.0006). The mean, minimum, and maximum values yielded lower results. Combining the best five variables (PSRp65, CBVp70, PSRp60, CBVp75, and PSRp40) achieved a mean AUC-ROC of 0.87 for differentiation. Conclusions: Oligodendrogliomas exhibit higher CBV and lower PSR than astrocytomas, traits that are emphasized when considering percentiles rather than mean or extreme values. The combination of CBV and PSR percentiles results in promising classification outcomes. Clinical relevance statement: The combination of histogram-derived percentile values of cerebral blood volume and percentage of signal recovery from DSC-PWI enhances the presurgical differentiation between astrocytomas and oligodendrogliomas, suggesting that incorporating these metrics into clinical practice could be beneficial. Key Points: • The unsupervised selection of percentile values for cerebral blood volume and percentage of signal recovery enhances presurgical differentiation of astrocytomas and oligodendrogliomas. • Oligodendrogliomas exhibit higher cerebral blood volume and lower percentage of signal recovery than astrocytomas. • Cerebral blood volume and percentage of signal recovery combined provide a broader perspective on tumor vasculature and yield promising results for this preoperative classification.</p

Sirtuin-2, NAD-Dependent Deacetylase, is a new potential therapeutic target for HIV-1 infection and HIV-related neurological dysfunction

The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction

Emotion regulation and excess weight: impaired affective processing characterized by dysfunctional insula activation and connectivity

Emotion-regulation strategies are understood to influence food intake. This study examined the neurophysiological underpinnings of negative emotion processing and emotion regulation in individuals with excess weight compared to normal-weight controls. Fifteen participants with excess-weight (body mass index >25) and sixteen normal-weight controls (body mass index 18-25) performed an emotion-regulation task during functional magnetic resonance imaging. Participants were exposed to 24 negative affective or neutral pictures that they were instructed to Observe (neutral pictures), Maintain (sustain the emotion elicited by negative pictures) or Regulate (down-regulate the emotion provoked by negative pictures through previously trained reappraisal techniques). When instructed to regulate negative emotions by means of cognitive reappraisal, participants with excess weight displayed persistently heightened activation in the right anterior insula. Decreased responsivity was also found in right anterior insula, the orbitofrontal cortex and cerebellum during negative emotion experience in participants with excess weight. Psycho-physiological interaction analyses showed that excess-weight participants had decreased negative functional coupling between the right anterior insula and the right dlPFC, and the bilateral dmPFC during cognitive reappraisal. Our findings support contentions that excess weight is linked to an abnormal pattern of neural activation and connectivity during the experience and regulation of negative emotions, with the insula playing a key role in these alterations. We posit that ineffective regulation of emotional states contributes to the acquisition and preservation of excess weight

Human ventromedial prefrontal cortex and the positive affective processing of safety signals

Human functional magnetic resonance imaging (fMRI) studies suggest that the ventromedial prefrontal cortex (vmPFC) contributes to the learned discrimination of threat and safety signals, although its precise contribution to these processes remains unclear. One hypothesis is that the vmPFC supports the positive affective processing of safety signals linked to their implicit stress-relieving properties. We set out to test this hypothesis and to examine the specificity of vmPFC responses to safety signal processing versus its high level of 'default mode' activity. Sixty participants completed an fMRI conditioning task that involved the generation of a conditioned threat (CS+) and safety (CS-) signal following the completion of a pre-conditioning baseline. Confirming past findings, activation of the vmPFC and other midline cortical and parietal areas - broadly resembling the default mode network - robustly discriminated between the CS- and CS+. However, when adjusting for this network's characteristic 'baseline' activity, only a subset of regions, including the vmPFC, was activated by the CS-. Regional selectivity for safety signal processing was confirmed by demonstrating a significant correlation between the magnitude of vmPFC responses and self-rated positive affect evoked by the CS-. Taken together, our current findings confirm a link between human vmPFC activity and the positive affective processing of safety signals. We discuss these findings with regards a broader model of human vmPFC function and its suggested higher-order contribution to emotionally adaptive behavior.publisher: Elsevier articletitle: Human ventromedial prefrontal cortex and the positive affective processing of safety signals journaltitle: NeuroImage articlelink: http://dx.doi.org/10.1016/j.neuroimage.2017.02.080 content_type: article copyright: © 2017 Elsevier Inc. All rights reserved.status: publishe