Santa Barbara City College

Autism spectrum disorder (ASD) risk reflects genetic susceptibility and modifiable environmental exposures acting during fetal and early postnatal critical periods. Building on our prior two-path model, in which folate receptor autoantibody-driven cerebral folate deficiency and oxidative stress/neuroinflammation converge on disrupted neurodevelopment, this review provides the first full mechanistic treatment of environmental pollutants within that framework. We synthesize evidence across seven exposure categories: micro/nanoplastics, plastic-associated endocrine-disrupting chemicals, ambient/indoor air pollution, tire wear particles and 6PPD-quinone, heavy metals and pesticides, industrial chemicals and persistent organic pollutants, and ultra-processed food intake as a parallel, non-pollutant contributor to the same inflammatory pathway. Human biomonitoring of micro/nanoplastics has progressed beyond detection in the placenta, brain and breast milk to direct evidence of placental genotoxicity and fetal endocrine disruption, complementing rodent data linking early-life exposure to impaired corticogenesis, disrupted microglial synaptic pruning, and ASD-relevant behavioral deficits. Across categories, oxidative stress, barrier disruption, neuroinflammation, endocrine disruption, and epigenetic modification recur as convergent mechanisms acting on trimester- and age-specific windows of vulnerability. Genetic variation in folate pathway and mitochondrial genes, as well as folate/vitamin B sufficiency, are proposed as candidate effect modifiers rather than established protective factors to modify susceptibility to this pollutant burden. Most evidence is associational or mechanistic rather than trial-based; we grade evidence strength and translate findings into biomarker-guided clinical and population-level policy guidance.

Cannabinoids, compounds acting on the endocannabinoid system (ECS) and the broader endocannabinoidome, have demonstrated promising neuroprotective effects in retinal neurodegenerative diseases including glaucoma and age-related macular degeneration (AMD). This review evaluates the evidence for cannabinoid receptor expression and function in the retina, the capacity of cannabinoids to reduce oxidative stress and neuroinflammation, and outcomes in preclinical disease models. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) act through cannabinoid receptors 1 and 2 (CB1 and CB2) receptors, as well as non-canonical pathways including transient receptor potential cation channel subfamily V member 1 (TRPV1), G-protein coupled receptor 3 (GPR3), peroxisome proliferator-activated receptor gamma (PPARγ), to confer neuroprotective benefits. However, emerging evidence documents a critical divergence between these two principal phytocannabinoids: while CBD exerts anti-inflammatory, antioxidant, and cardioprotective effects, THC at high concentrations, and especially when uncounteracted by similar levels of CBD, induces neurotoxicity, cardiovascular injury, and arrhythmia, exemplified by a doubling of cardiovascular mortality, largely due to THC-mediated mechanisms. Critically, previously identified neuroprotective effects of cannabis may be substantially masked or reversed by the dramatically rising THC:CBD ratio in commercial strains, which has increased from approximately 10:1 in 2000 to 100:1 in many contemporary products. This shift means that modern cannabis is biochemically distinct from the preparations used in foundational neuroprotection studies. CBD-dominant formulations, or preparations maintaining lower THC:CBD ratios, represent a valid therapeutic direction for acute retinal neuroprotection, while the proven safety and efficacy of vitamins such as Age-Related Eye Disease Study 2 (AREDS2) therapy provide a reliable chronic neuroprotective strategy. While the biological plausibility and animal evidence for CBD/THC protection is good, human trials are needed to validate any use in retinal diseases.

Objectives Movement disorders (MDs), including Parkinson's disease (PD) and essential tremor, are growing causes of disability globally. Yet, data on MDs in low- and middle-income countries (LMICs), including Cabo Verde, remain scarce. This study aimed to estimate MD prevalence and incidence, identify at-risk groups, and evaluate access to care.Methods A multi-site, country-level cross-sectional study was conducted from July to December 2024, including 110 adults with confirmed MDs. Data were obtained via clinical record reviews, interviews, and a structured questionnaire. Analyses included descriptive statistics, multivariable logistic regression, and thematic analysis of open-text responses.Results The age-standardized MD prevalence was 17 per 100,000 population (95% CI: 13-20), with higher rates in men [19 (14-25)] and in those over 60 [117 (89-145)]. PD accounted for 79% of cases. While 78% used pharmacotherapy, 70% faced moderate or severe difficulties accessing medication, and 35% of those who sought therapy reported facing barriers. Fifty-one percent experienced a significant life impact.Conclusion Findings reveal significant access challenges and rising MD burden, underscoring the need for early diagnosis, decentralized services, and public health system strengthening in LMICs.

Autism spectrum disorder (ASD) arises from converging genetic, immune, and metabolic perturbations, and current medical treatments for core symptoms remain both limited and largely postnatal. Folate receptor‑alpha autoantibodies (FRAA) and folate‑pathway polymorphisms create cerebral folate deficiency despite adequate systemic folate, and FRAA are enriched in ASD children and their mothers, defining a mechanistically coherent, testable risk subgroup. Randomized trials in ASD children demonstrate that folinic acid (leucovorin), a reduced and bioactive folate that bypasses FRAA‑blocked folate receptor alpha via alternative transporters, improves communication and global symptom scores, with greatest efficacy at younger ages, and it has a favorable safety profile. Translating this finding upstream, a pilot randomized trial in FRAA‑positive pregnancies found that perinatal leucovorin, compared with standard folic acid, was associated with markedly lower ASD incidence, lower ADOS‑2 scores, and higher Bayley‑4 cognitive indices in offspring, while a case series of two FRAA‑positive mothers with prior neurodivergent children reported neurotypical development to age three after preconception and gestational leucovorin. Additional case series in women with MTHFR polymorphisms and infertility suggest that replacing folic acid with reduced folates can restore fertility without increasing total folate dose, underscoring folate form as a modifiable determinant of reproductive and neurodevelopmental outcome. In parallel, preclinical and epidemiologic data raise concern that high‑dose synthetic folic acid remains unmetabolized and may perturb neurodevelopmental trajectories in susceptible subgroups. Together, these converging lines of evidence support a precision perinatal folate paradigm in which leucovorin replaces folic acid for FRAA‑positive and folate‑pathway impaired women, warranting systematic screening and multicenter trials to test leucovorin as a viable prenatal strategy for reducing ASD incidence.

Disruptions in folate (vitamin B9) and vitamin B12 metabolism, including nutritional deficiency, folate receptor alpha (FRα) autoantibodies, and MTHFR/DHFR polymorphisms, impair one-carbon metabolism and produce measurable retinal structural, microvascular, and functional changes, offering a non-invasive window into systemic and cerebral metabolic dysfunction, particularly cerebral folate deficiency (CFD). This review synthesizes peer-reviewed evidence on retinal alterations linked to folate/B12 deficiency, hyperhomocysteinemia, FRα autoantibody syndromes, and MTHFR/DHFR variants, alongside artificial intelligence (AI) and machine learning (ML) approaches applied to retinal imaging for metabolic, anemic, and nutritional optic neuropathy detection. Three convergent phenotypes emerge: structural changes (retinal nerve fiber layer and ganglion cell complex thinning, optic disc pallor, chorioretinal atrophy), microvascular abnormalities (reduced vessel density, foveal avascular zone enlargement, capillary dropout), and functional deficits (centrocecal scotoma, dyschromatopsia, reduced contrast sensitivity); they arise from homocysteine-mediated endothelial toxicity, mitochondrial impairment, and eNOS uncoupling. Existing AI/ML models for anemia and optic neuropathy establish technical feasibility but do not target folate-specific phenotypes. We propose a dedicated multimodal ML framework integrating structural, perfusion, functional, and biochemical/genetic data as a research agenda for automated, non-invasive CFD detection. Given the established folate–autism spectrum disorder (ASD) risk association reported in FRAA-positive cohorts, such a framework, once validated, could support prenatal and neonatal screening in FRAA-positive or genetically high-risk pregnancies, enabling earlier leucovorin treatment and reducing neurodevelopmental risk.