Amador Velázquez De Castro-Bono

Post-acute Neurological Sequelae of SARS-CoV-2 infection (Neuro-PASC) contribute substantially to Long COVID-related disability, with cognitive impairment, chronic fatigue, dysautonomia, and neuropsychiatric symptoms among its most debilitating manifestations. Although its pathogenesis remains incompletely understood, evidence implicates persistent immune activation, intestinal barrier dysfunction, microbiota dysbiosis, microbiome-derived metabolic alterations, mitochondrial dysfunction, and neuroimmune interactions in sustaining neuroinflammation and neurological impairment. This narrative review examines precision nutrition as a potential pathway-oriented strategy for Neuro-PASC. We synthesise evidence linking the gut microbiota, intestinal permeability, immunometabolic pathways, mitochondrial function, and neurological outcomes, while evaluating nutritional interventions targeting these mechanisms. We focus on candidate biomarkers, including serum zonulin, fatty acid-binding protein 2 (FABP2), faecal short-chain fatty acids (SCFAs), and the kynurenine-to-tryptophan ratio, which may support patient stratification and personalised nutritional strategies. We also propose a stepwise framework involving dietary stabilisation, functional foods, targeted supplementation, and microbiome-based interventions, alongside practical considerations for post-exertional symptom exacerbation, dysautonomia, and mast cell-related symptoms. Finally, we identify priorities for future research, including multi-omics integration, artificial intelligence, digital health, and biomarker-stratified randomised controlled trials. Because current evidence remains predominantly observational and mechanistic, precision nutrition should be considered a complementary strategy requiring rigorous clinical validation.

Alzheimer’s disease (AD) has been conceptualised as a proteinopathy driven by amyloid-β plaques and hyperphosphorylated tau neurofibrillary tangles. AD should not be understood as exclusively a proteinopathy or a metabolic/redox disorder, but as a network of interacting processes in which metabolic dysfunction, mitochondrial impairment, redox dysregulation, amyloid-β, tau, neuroinflammation, metal dyshomeostasis, and regulated cell death reinforce one another. This review examines AD through a redox-metabolic framework integrating cerebral glucose metabolism, insulin signalling, mitochondrial bioenergetics, metal homeostasis, and regulated cell death. We discuss how glucose hypometabolism, impaired oxidative phosphorylation, and weakened antioxidant defences may promote reactive oxygen species production and self-reinforcing oxidative and metabolic dysfunction. We examine interactions with amyloid-β and tau pathology, glial immunometabolism, gut–brain signalling, neuroinflammation, and metal-mediated toxicity. Advances in multi-omics, blood-based metabolomic and lipidomic biomarkers, and imaging may enable earlier biological stratification. Therapeutic strategies targeting mitochondria, NRF2 signalling, metabolic dysfunction, metal dyshomeostasis, and regulated oxidative cell death are evaluated based on current evidence and their potential complementarity with amyloid-directed therapies. Although temporal relationships remain unresolved, redox-metabolic dysfunction may represent an early determinant and amplifier of neuronal vulnerability. Evidence for lecanemab and donanemab supports an integrative rather than replacement model of AD treatment. This framework may facilitate earlier diagnosis, patient stratification, and complementary disease-modifying interventions.

Alzheimer’s disease (AD) is undergoing a profound paradigm shift, transitioning from a localized, monolithic proteinopathy into a complex, multisystem disorder. This critical review synthesizes recent mechanistic, translational, and clinical insights to dismantle the traditional linear amyloid cascade hypothesis. We explore the synergistic interplay between amyloid-β (Aβ) and tau propagation, positioning chronic neuroinflammation, endolysosomal failure, and metabolic starvation—often framed as “Type 3 Diabetes”—as fundamental disease drivers. Crucially, we highlight the emerging biological bridge of CNS-PNS crosstalk, where central neurodegeneration and peripheral neuropathies are linked by systemic immune activation and microbiota–gut–brain axis dysbiosis. The recent validation of disease-modifying therapies (DMTs) confirms Aβ clearance as a viable pharmacological target; however, the marginal clinical gains and severe radiological risks, such as Amyloid-Related Imaging Abnormalities (ARIA), expose the profound limitations of monotherapy. Ultimately, we argue that isolated amyloid clearance is merely an induction phase. The future of AD therapeutics mandates a sequential combination approach—pairing early plaque debulking with lifelong metabolic and neuroimmune maintenance. Supported by scalable fluid biomarkers (e.g., plasma p-tau217) and the expanded ATN(I) framework, the field must embrace proactive precision medicine and inclusive clinical trial designs to successfully transform AD into a manageable chronic condition.

Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO₄³⁻ and ionized calcium (Ca²⁺). It is a crucial process in the development of bones and teeth. However, pathological calcification can occur in almost any soft tissue of the organism. The better studied is vascular calcification, where calcium salts can accumulate in the intima or medial layer or in aortic valves, and it is associated with higher mortality and cardiovascular events, including myocardial infarction, stroke, aortic and peripheral artery disease (PAD), and diabetes or chronic kidney disease (CKD), among others. The process involves an intricate interplay of different cellular components, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and pericytes, concurrent with the activation of several signaling pathways, calcium, Wnt, BMP/Smad, and Notch, and the regulation by different molecular mediators, growth factors (GFs), osteogenic factors and matrix vesicles (MVs). In the present review, we aim to explore the cellular players, molecular pathways, biomarkers, and clinical treatment strategies associated with vascular calcification to provide a current and comprehensive overview of the topic.