Anthocyanins: Dietary Sources, Bioavailability, Human Metabolic Pathways, and Potential Anti-Neuroinflammatory Activity

The objectives of this chapter are to summarize and discuss (i) the anthocyanins structure and content in foodstuffs and their dietary intake (ii) the anthocyanins bioavailability and human metabolic pathways and (iii) the in vitro and in vivo potent anti-neuroinflammatory effects of anthocyanins and their metabolites. Indeed, anthocyanins are polyphenolic compounds belonging to the group of flavonoids, and are one of the most commonly consumed polyphenols in a normal diet. They are responsible of red, blue and purple color of several fruits and vegetables and their intake has been related with several human health benefits. The anthocyanins structures diversities as well as their content in various fruits, vegetables and cereals is addressed. Moreover, despite the growing evidence for the protective effects of anthocyanins, it is important to highlight that the in vivo bioavailability of these compounds is relatively low in comparison to their more stable metabolites. Indeed, after consumption, these bioactives are subjected to substantial transformations in human body. Phase I and II metabolites generated by intestinal and hepatic enzymatic reactions, and phenolic acids produced by gut microbiota and their metabolized forms, are the most important metabolic anthocyanins forms. For this reason, the study of the biological properties of these circulating metabolites represents a more in vivo realistic situation. Although the anthocyanin bioavailability researches in humans are limited, they will be discussed together with a global metabolic pathway for the main anthocyanins. Moreover, several works have demonstrated that anthocyanins can cross the blood brain barrier, and accumulate in brain endothelial cells, brain parenchymal tissue, striatum, hippocampus, cerebellum and cortex. Consequently, the study of anthocyanins as potent therapeutic agents in neurodegenerative diseases has gained relevance and the principal and the most recent studies are also discussed in the book chapter.

Deep medullary veins are associated with widespread brain structural abnormalities

Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p < 0.05, adjusted for age and sex). Also, fewer DMVs were significantly related to a lower gray matter fraction and a hippocampal fraction (0.10 and 0.11 per DMV, respectively; SE, 0.03 for both; p < 0.001 for both). A significant correlation between DMVs’ reduction and cortical atrophy was observed in the bilateral occipital lobes, temporal lobes, hippocampus, and frontal lobes (p < 0.001, adjusted for age, sex, and total intracranial volume). Our results provided evidence that cerebral small venules disease play a role in brain parenchymal lesions and neurodegenerative processes.

Leptomeningeal disease and brain control after postoperative stereotactic radiosurgery with or without immunotherapy for resected brain metastases

PurposeImmunotherapy has shown activity in patients with brain metastases (BM) and leptomeningeal disease (LMD). We have evaluated LMD and intraparenchymal control rates for patients with resected BM receiving postoperative stereotactic radiosurgery (SRS) and immunotherapy or postoperative SRS alone. We hypothesize that postoperative SRS and immunotherapy will result in a lower rate of LMD with acceptable toxicity compared with postoperative SRS.Patients and methodsOne hundred and twenty-nine patients with non-small-cell lung cancer (NSCLC) and melanoma BM who received postoperative fractionated SRS (fSRS; 3×9 Gy) in combination with immunotherapy or postoperative fSRS alone for completely resected BM were retrospectively evaluated. The primary endpoint of the study was the rate of LMD after treatments. The secondary endpoints were local failure, distant brain parenchymal failure (DBF), overall survival (OS), and treatment-related toxicity.ResultsSixty-three patients received postoperative SRS and immunotherapy, either nivolumab or pembrolizumab, and 66 patients received postoperative SRS alone to the resection cavity. With a median follow-up of 15 months, LMD occurred in 19 patients: fSRS group, 14; fSRS and immunotherapy, 5. The 12-month LMD cumulative rates were 22% (95% CI 14% to 37%) in the fSRS group and 6% (95% CI 2% to 17%) in the combined treatment group (p=0.007). Resection cavity control was similar between the groups, whereas DBF and OS were significantly different; the 1-year DBF rates were 31% (95% CI 20% to 46%) in the fSRS and immunotherapy group and 52% (95% CI 39% to 68%) in the fSRS group; respective OS rates were 78% (95% CI 67% to 88%) and 58.7% (95% CI 47% to 70%). Twenty-two patients undergoing postoperative fSRS and immunotherapy and nine subjected to postoperative fSRS experienced treatment-related imaging changes suggestive of radiation-induced brain necrosis (p=0.02).ConclusionsPostoperative fSRS in combination with immunotherapy decreases the incidence of LMD and DBF in patients with resected BM from NSCLC and melanoma as compared with fSRS alone, reducing the rate of neurological death and prolonging survival.

Adenocarcinoma lung presenting with meningeal carcinomatosis

Meningeal infiltration by malignant metastasis process without brain parenchymal involvement is very unusual event in patients with bronchogenic carcinoma. This manuscript describes a case of adenocarcinoma right lung in a 48-year old male having persistent headache. The cerebrospinal fluid cytology revealed the presence of metastatic deposits of adenocarcinoma lung that confirmed the diagnosis of meningeal carcinomatosis.

EXTH-36. ELECTROCONVULSIVE SEIZURE-INDUCED CHANGES IN THE TUMOR MICROENVIRONMENT PROMOTE SURVIVAL IN GLIOMA-BEARING MICE

PURPOSE Growing evidence indicates that the neurotransmitters dysregulated in psychiatric disorders are similarly dysregulated in glioblastoma (GBM) biology. GBM cells are dependent on bountiful neuronal glutamate, utilize elevated dopamine receptor expression to augment progression, and catabolize serotonin to drive proliferation and inhibit anti-tumor immunity. The clinical induction of seizure, known as electroconvulsive therapy (ECT), has been used by psychiatrists since the 1930s to correct these dysregulations and can additionally improve medication blood-brain barrier (BBB) penetrance. We hypothesized that seizure-induced changes in the glioma microenvironment occur with ECT, slowing tumor progression, increasing BBB permeability, and prolonging overall survival in glioma-bearing mice. METHODS C57BL6 mice were orthotopically injected with CT-2A-Luc mouse glioma cells. Mice were randomized to receive ECT via ear-clip electrodes or sham treatment daily up to five times per week. Intracranial progression was monitored via bioluminescent signal from CT-2A-Luc xenografts. BBB permeability was assessed by subjecting mice to ECT or sham treatment immediately following intravenous injection of sodium fluorescein. RESULTS Intracranial progression was maximally reduced in ECT-treated mice relative to sham-treated mice after 17 ECT treatments (ECT radiance 2.6 x 109 photons/second versus sham 4.7 x 109 photons/second, p=0.013), which was further confirmed by both decreased tumor weight and tumor size on histologic evaluation. This translated into an improvement in overall survival from median 29 days in sham-treated mice to 38 days in ECT-treated mice (p=0.0018). Mean seizure duration was 41.8 seconds and positively correlated with overall survival (Pearson coefficient r=0.63, p=0.028). Brain parenchymal uptake of sodium fluorescein was significantly higher in ECT-treated mice (mean relative increase in ECS to sham radiance of 1.47, p&lt; 0.05). CONCLUSION Repeated ECT slows tumor progression and prolongs overall survival in C57BL6 mice bearing CT-2A-Luc xenografts. The BBB is compromised immediately following ECT. ECT merits further oncologic investigation as a potential therapeutic in GBM.

P.062 Does the intensity of brain parenchymal contrast staining on post-recanalization dual energy head CT (DECT) of stroke patients predict the fate of brain tissue?

Background: On DECT, the ratio of maximum iodine concentration within parenchyma compared to the superior sagittal sinus has been shown to predict hemorrhagic transformation. We aimed to determine if this ratio also predicts the development of an infarct. Methods: 53 patients with small infarct cores (ASPECTS≥7) and good endovascular recanalization (mTICI 2b/3) were enrolled. Maximum brain parenchymal iodine concentration as per DECT relative to the superior sagittal sinus (iodine ratio) was correlated with the development of an infarct on follow up CT. Results: All patients showed contrast staining, 52 developed infarcts in the area of staining. The extent of infarction (smaller, equal or larger than area of staining) did not correlate with the iodine ratio. Conclusions: Brain parenchyma with contrast staining on post-procedure head CT almost invariably goes on to infarct, however the extent of infarct development is not predicted by the intensity of contrast staining. n=53 patients with successful recanalization of anterior circulation LVO infarct (TICI2b,3) with post procedural parenchymal iodine staining There was no correlation between the degree of contrast staining on initial post procedural CT as expressed in iodine ratio and F/U infarct extent.

Abstract P201: Negative Regulation Of PVN Pre-sympathetic Neuronal Activity By Resident Microglia

Hypothalamic paraventricular nucleus (PVN) is a critical integrating region in controlling peripheral sympathetic tonicity. While the vast studies have unraveled the regulatory circuits affecting PVN pre-sympathetic neurons, local factors for maintaining the homeostasis of neuronal excitability are barely understood. In the present study we investigated the role of microglia, the primary resident immune cells of the CNS, in this context. By electrophysiological recording, we found that loss of resident microglia induced an increased firing frequency and attenuated outward potassium currents in the PVN pre-sympathetic neurons, tachycardia and impaired heart rate variability. Combining the transcriptomics analysis of the PVN microglia, we identified a releasable factor, which was dominantly expressed in microglia compared to other brain parenchymal cells. ICV infusion of the recombinant peptide restored potassium currents in the PVN pre-sympathetic neurons and autonomic function in microglia-depleted mice. In summary, our results provided a novel intrinsic regulatory mechanism by which microglia suppress neuronal over excitation in physiological condition.

COMPARISON OF POST-CONTRAST 3D-T1-SPACE, 3D-T2-FLAIR AND 3D-T1-MPRAGE MR SEQUENCES IN THE EVALUATION OF MENINGEAL AND BRAIN PARENCHYMAL PATHOLOGIES

Background and purpose: The purpose of this study was to assess the value added by contrast-enhanced threedimensional (3D) -T2 fluid-attenuated inversion recovery sequence (FLAIR) and 3D-T1 sampling perfection with application optimized contrast using different flip-angle evolutions(SPACE) sequences to conventional post-contrast 3D-T1 magnetisation prepared rapid gradient-echo (MPRAGE) images in the evaluation of meningeal and brain parenchymal diseases. Materials and methods:A total of 60 patients with magnetic resonance imaging (MRI) findings suggestive of infectious / inflammatory / metastatic parenchymal and/or meningeal abnormalities, were selected from patients who underwent MRI brain with intravenous (IV) contrast from March 2019 to Nov 2019.All the patients had their diagnosis confirmed by histopathological or microbiological studies, as deemed appropriate. Two radiologists independently assessed the presence of additional information on post-contrast (PC) 3D-T2-FLAIR and 3D-T1-SPACE images and compared them with PC 3D-T1-MPRAGE images. Results: Both reviewers found that post contrast 3 D-T1-SPACE provided more additional information than post contrast 3D-T1-MPRAGE in the evaluation of brain parenchymal and supratentorial meningeal abnormalities.PC 3D-T2-FLAIR is an excellent tool in the evaluation of intratentorial leptomeningeal abnormalities and identifying the scolex in patients with neurocysticercosis (NCC), presenting with ring enhancing lesions.

Monocyte gene expression distinguishes enhancing brain parenchymal cysticercal granulomas from tuberculomas

Background In patients with enhancing brain parenchymal lesions, parenchymal neurocysticercosis (pNCC) is often difficult to distinguish from tuberculoma, necessitating biopsy or empirical therapy. Materials and methods In a prospective study, peripheral blood monocytes were isolated from patients with definitive pNCC (n=39) and brain tuberculomas (n=20). Patients with tuberculomas were diagnosed by the presence of concurrent systemic tuberculosis (n=7), pathological or bacteriological confirmation (n=5), and resolution of typical brain lesions following a therapeutic trial of anti-tuberculous therapy (n=8). Expressions of 14 NCC associated monocyte genes were determined by qPCR and analyzed for diagnostic usefulness between the two groups. Results Expression of seven genes (TAX1BP1, RAP1A, PLCG2, TOR3A, GBP1P1, LRRFIP2 and FEZ2) was significantly higher in pNCC patients than in tuberculoma patients with TAX1BP1 and RAP1A expressions greater than 22- and 5-fold higher in pNCC patients. TAX1BP1 had the highest sensitivity of 66.7% at a specificity of 100% in discriminating pNCC from tuberculoma. A combination of TAX1BP1 and RAP1A increased the sensitivity to 84.6% and including GBP1P1 with TAX1BP1 and RAP1A further increased sensitivity to 87.2% while maintaining specificity of 100%. Conclusion Expression of a panel of genes in blood monocytes distinguishes pNCC from brain tuberculomas in patients with enhancing brain lesions.