Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

Purple Corn Extract as Anti-allodynic Treatment for Trigeminal Pain: Role of Microglia.

Natural products have attracted interest in the search for new and effective analgesics and coadjuvant approaches to several types of pain. It is in fact well known that many of their active ingredients, such as anthocyanins (ACNs) and polyphenols, can exert potent anti-inflammatory actions. Nevertheless, their potential beneficial effects in orofacial painful syndromes have not been assessed yet. Here, we have evaluated the preventive effect of an ACN-enriched purple corn extract against the development of orofacial allodynia, in comparison with isogenic yellow corn extract containing only polyphenols. Orofacial allodynia developed following induction of temporomandibular joint (TMJ) inflammation in male rats, due to the injection of Complete Freund's Adjuvant (CFA), and was evaluated by von Frey filaments. Animals drank purple or yellow corn extracts or water starting from 11 days before induction of inflammation and up to the end of the experiment 3 days later. To highlight possible additive and/or synergic actions, some animals also received the anti-inflammatory drug acetyl salicylic acid (ASA). In parallel with the evaluation of allodynia, we have focused our attention on the activation of microglia cells in the central nervous system (CNS), as it is well-known that they significantly contribute to neuronal sensitization and pain. Our data demonstrate that purple corn extract is as effective as ASA in preventing the development of orofacial allodynia, and only partial additive effect is observed when the two agents are co-administered. Yellow corn exerted no effect. Multiple mechanisms are possibly involved in the action of purple corn, including reduction of trigeminal macrophage infiltration and the shift of microglia cell polarization to an anti-inflammatory phenotype. In fact, in rats receiving yellow corn or water microglia cells show thick, short cell processes typical of activated cells. Conversely, thinner and longer microglia cell processes are observed in the brainstem of animals drinking purple corn extract; shape changes are accompanied by a reduction in the expression of pro-inflammatory molecules and increased production of anti-inflammatory mediators. Administration of purple corn extracts therefore represents a possible low-cost and easy way to reduce trigeminal-associated pain in various pathological conditions also thanks to the modulation of microglia reactivity.

Tackling Chronic Pain and Inflammation through the Purinergic System.

The purinergic system is composed of purine and pyrimidine transmitters, the enzymes that modulate the interconversion of nucleotides and nucleosides, the membrane transporters that control their extracellular concentrations, and the many receptor subtypes that are responsible for their cellular responses. The components of this system are ubiquitously localized in all tissues and organs, and their involvement in several physiological conditions has been clearly demonstrated. Moreover, extracellular purine and pyrimidine concentrations rise several folds under pathological conditions like tissue damage, ischemia, and inflammation, which suggest that this signaling system might contribute both to disease outcome and, possibly, to its tentative resolution. The complexity of this system has greatly impaired the clear identification of the mediators and receptors that are actually involved in a given pathology, also due to the often opposite roles played by the various receptor subtypes. Nevertheless, this knowledge is fundamental for the possible exploitation of these molecular entities as targets for the development of new pharmacological approaches. In this review, we aim at highlighting what is currently known on the role of the purinergic system in various pain conditions and during inflammatory processes. Although some confusion may arise from conflicting results, literature data clearly show that targeting specific purinergic receptors may represent an innovative approach to various pain and inflammatory conditions, and that new purine-based drugs are now very close to reach the market with these indications.