Parkinson’s disease involves widespread neurodegeneration that extends far beyond the basal ganglia, giving rise to a diverse range of non-motor symptoms that frequently emerge before motor onset. These include autonomic dysfunction, cognitive decline, neuropsychiatric disturbances, sleep-related disorders, and sensory deficits. Here, we synthesize current evidence on the anatomical, neurochemical, and network-level mechanisms that drive these symptoms, and we examine how they shape disease progression and clinical heterogeneity. We highlight the limitations of dopamine-centric models and advocate for a framework that treats non-motor symptoms as the disorder’s primary, mechanistically distinct features. We also discuss how emerging technologies—such as multi-omic profiling, artificial intelligence, and network neuroscience—enable earlier identification, stratification of non-motor phenotypes, and the development of precision-based therapeutic strategies. Recognizing non-motor symptoms as central to Parkinson’s disease redefines how the disorder should be diagnosed, studied, and treated.

Parkinson’s disease encompasses a spectrum of motor and non-motor manifestations, with the latter often preceding motor symptoms and influencing disease trajectory. Sensory dysfunction, sleep-related disorders, autonomic impairment, neuropsychiatric symptoms, and cognitive decline reflect widespread neurodegeneration involving the brainstem, limbic system, and peripheral nervous system. Hyposmia and visual dysfunction are emerging as early biomarkers, while chronic pain and paraesthesias indicate central and peripheral nociceptive dysregulation. Sleep-related disorders, particularly REM sleep behaviour disorder and insomnia, frequently arise in the prodromal phase, highlighting disruptions in circadian regulation and neuroanatomical integrity. Neuropsychiatric symptoms—including depression, anxiety, apathy, and hallucinations—result from complex dysregulation of dopaminergic, serotonergic, and noradrenergic pathways, compounding disease burden and impairing quality of life. Autonomic dysfunction, affecting cardiovascular, gastrointestinal, thermoregulatory, and genitourinary systems, underscores the systemic nature of the disease. Despite growing recognition of these non-motor features, treatment strategies remain limited, constrained by a dopamine-centric therapeutic framework that does not fully address broader neurobiological dysfunction. The lack of reliable biomarkers hampers early diagnosis and precision medicine approaches, while the conventional dichotomy between motor and non-motor symptoms has hindered the development of integrative treatment paradigms. While previous reviews have examined individual non-motor manifestations in detail, this article provides a comprehensive synthesis, offering a clinically relevant perspective for medical students, primary care physicians, and non-specialists. Recognizing non-motor symptoms as core disease manifestations rather than secondary sequelae is essential to refine diagnostic criteria and develop targeted therapies. Parkinson’s disease is a complex, multisystem neurodegenerative disorder that necessitates a paradigm shift in research priorities and clinical management. A broader, integrative perspective is required to redefine how the disease is understood, taught, and treated, ensuring that motor and non-motor symptoms are addressed to improve patient outcomes.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which blood–brain barrier (BBB) dysfunction may arise early. We performed an age-stratified, cross-sectional analysis of pericyte- and endothelial-associated markers and junctional proteins (claudin-1, -3, -5, occludin, and VE-cadherin) in cerebral capillary-enriched fractions from male Non-Tg and 3xTg-AD mice at asymptomatic, early, and advanced stages (3, 6, 12, and 16 months of age). Protein abundance was assessed by Western blot, and BBB permeability to 3–5 kDa FITC-dextran was evaluated at 3 months in an independent cohort. At 3 months, the pSRC/SRC ratio and an MMP-9-immunoreactive band were also evaluated in a separate cohort as candidate signaling markers related to occludin dysregulation. We detected no significant age or genotype effects for the pericyte- and endothelial-associated markers or for most junctional protein outcomes. Occludin was the only protein outcome with a significant overall genotype effect, with the largest mean reductions observed at 3 (~80%) and 6 months (~68%). A small exploratory cohort showed a higher hemisphere-derived permeability index in 3xTg-AD mice at 3 months. Neither pSRC/SRC nor the abundance of the MMP-9-immunoreactive band differed significantly between genotypes. These findings identify lower occludin abundance as the principal BBB-associated protein alteration in the 3xTg-AD model and provide exploratory evidence of increased BBB permeability at 3 months. These independent observations warrant longitudinal and translational evaluation to determine whether occludin abundance and BBB permeability could serve as indicators of early neurovascular dysfunction in AD.

Background: Alzheimer’s disease is a progressive neurodegenerative disorder. Immunotherapy targeting Aβ and Tau proteins is a promising strategy, and accurate detection of anti-Aβ or anti-Tau antibodies is key to evaluating vaccine efficacy. Indirect ELISA is a sensitive method requiring high-quality coating antigens. Methodology: A recombinant Tau antigen fused to glutathione S-transferase (GST) was designed as an ELISA coating antigen. The Tau gene was cloned into the pGEX-6p-1 vector and expressed in Escherichia coli BL21 cells. Protein expression was induced with 1 mmol/L isopropyl-β-D-thiogalactoside (IPTG), and the GST-Tau fusion protein was identified by Western blot using anti-Tau and anti-GST antibodies. The protein was solubilized with 3 mol/L urea and purified via glutathione affinity chromatography. Purity was confirmed by densitometry and the optimal coating concentration for ELISA was determined to be 2 μg/mL. Results: A protocol was established to produce GST-Tau with adequate purity and yield for ELISA applications. The recombinant antigen retained immunogenic epitopes, recognized by anti-Tau antibodies. The standardized ELISA enabled sensitive detection of anti-Tau antibodies. Conclusions: A robust method was developed to produce and optimize GST-Tau as a coating antigen for indirect ELISA. This approach facilitates reliable quantification of anti-Tau antibodies to evaluate Alzheimer’s vaccine candidates.

Blood-brain barrier (BBB) dysfunction is increasingly recognized as an early pathological event in sporadic Alzheimer’s disease (AD), which represents over 95% of cases. Vascular risk factors and cerebral insulin resistance are considered potential contributors to its initiation. This review synthesizes evidence available through March 2026 on the temporal progression of morphological, functional, and molecular BBB alterations in AD patients and experimental models. This review emphasizes the proposed role of BBB disruption in perpetuating neurodegeneration through feedback loops involving pericyte damage, hypoxia, perivascular inflammation, and dysregulation of amyloid-β transport systems. By integrating data from neuroimaging, fluid biomarkers, and post-mortem studies, available evidence suggests that BBB alterations can be detected from preclinical stages, most consistently in the hippocampus, and may exhibit sex-specific differences. The review compares findings from familial transgenic models with the more limited characterization available in sporadic AD models (notably the intracerebroventricular streptozotocin model), and highlights key knowledge gaps regarding temporal dynamics. This synthesis supports further exploration of strategies to preserve BBB integrity. An integrated vascular approach may usefully complement current amyloid- and tau-centered therapies, particularly in sporadic AD.