Genetic testing is traditionally emphasized in early-onset or familial Parkinson's disease (PD), leaving its role in advanced disease uncertain. This mini-review explores, from the perspectives of patients, their family members, and clinical researchers, whether genetic investigation remains meaningful once patients reach advanced PD. In large prospective clinical-genetic screening cohorts, roughly one in seven PD patients has genetic PD. Established genotype-phenotype correlations, spanning cognitive trajectory, levodopa responsiveness, and deep brain stimulation outcomes, continue to inform clinical decision-making even at advanced stages. Thus, patients may gain psychological clarity, receive refined prognostic counseling, and become eligible for gene-specific trials or registries. In addition, patients express altruistic motivations, considering the merit of sharing their genetic testing results with their families and the research community. Unaffected relatives may benefit from more precise, penetrance-informed risk assessment, appropriately scaled surveillance, lifestyle counseling, and reproductive planning, particularly as potential environmental modifiers of penetrance and age at onset become better characterized. Researchers rely on genetically characterized advanced-stage cohorts to identify genotype-phenotype relations, modifiers of onset, progression and treatment response, validate biomarkers, and build the large, deep longitudinal datasets required for emerging gene- and pathway-targeted therapies. Collectively, these perspectives argue against a narrow early-disease "window of opportunity" for genetic testing in PD. Rather than becoming obsolete once the disease reaches a more advanced stage, genetic characterization continues to shape individualized care, family counseling, and translational research. Thus, in the future, the challenge should no longer be to justify genetic testing in advanced PD, but to embed it equitably and systematically within standard care and international research infrastructure across the entire disease course.

A novel simple, direct, selective and rapid fluorometric method is described for the determination of guanine. The method is based on a "turn-on" response by the enhancement of the fluorescence of levodopa (L-3,4-dihydroxyphenylalanine (L-DOPA), under optimized conditions. The reaction is subjected to detailed spectroscopic and thermodynamic investigation. Upon addition of guanine, to levodopa, a significant enhancement of the fluorescence intensity is observed, accompanied by a slight bathochromic shift of ~ 10 nm in the emission maximum. This fluorescence response is consistent with an interaction-dependent change in the local environment of L-DOPA. Spectroscopic and association analyses support non-covalent association under the investigated conditions, although the available data do not establish a unique molecular binding geometry or identify the specific functional groups involved. Among the tested nucleobases, guanine produced the most pronounced fluorescence enhancement, demonstrating a preferential analytical response under the optimized conditions. A linear relationship between fluorescence intensity and guanine concentration is obtained over the concentration range of 0-280 µM guanine, with a detection limit of 0.088 µM (0.0133 µg/ml). The proposed method is validated following the standards of ISO/IEC 17025, AOAC, USP, U.S.EPA, and U.S.FDA by measuring data trueness, accuracy, bias, precision, within-day repeatability, between-days reproducibility, standard deviations, robustness, sensitivity, range, durability, stability, and limit of detection. The results reveal good data quality, reliability, and consistency. The method is applied for the determination of guanine in human serum samples using the standard addition (spiking) technique. An average accuracy of (93.3-102.2%) with good precision (mean RSD = 0.67%, n = 3) are obtained. The method provides a simple, label-free, and low-complexity approach for guanine determination in aqueous media, offering a practical alternative to more elaborate sensing platform.

1. Parkinson's disease (PD) involves dopaminergic dysfunction, oxidative stress, and neuroinflammation. This study evaluated an optimised astaxanthin-loaded nanoemulsion (AXTNE) in paraquat-induced experimental Parkinsonism.2. Male Wistar rats were randomly assigned to nine groups (n = 6). Parkinsonian alterations were induced by paraquat (10 mg/kg, i.p.) twice weekly for 4 weeks. Aqueous astaxanthin (AXT; 30 mg/kg), AXTNE (15 and 30 mg/kg), levodopa + carbidopa (15 + 3.75 mg/kg), and AXTNE-levodopa combinations were administered orally for 28 days. Motor function was assessed using catalepsy, locomotor activity, grip strength, postural instability, and beam-walk tests. Pooled bilateral striatal tissue was analysed for oxidative stress, inflammatory cytokines, monoaminergic neurotransmitters, and dopaminergic protein markers.3. Paraquat induced motor deficits, oxidative imbalance, increased inflammatory cytokines, reduced dopamine and noradrenaline, and altered tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and α-synuclein levels. AXTNE attenuated these alterations and reduced MDA levels measured by TBARS. AXTNE-levodopa combinations produced additional improvements across several endpoints.4. AXTNE attenuated multiple paraquat-associated Parkinsonian alterations, with generally greater numerical improvements than aqueous AXT. Combination with levodopa showed potential complementary effects. Further histopathological, pharmacokinetic, biodistribution, and mechanistic studies are warranted.

Opicapone (OPC) is an effective add-on medication for motor fluctuations in Parkinson's disease (PD), with a favorable safety and tolerability profile. Elderly PD patients are a great proportion of the real-world PD population, often underrepresented in clinical trials. This multicenter, retrospective, longitudinal study aimed to assess the real-world safety and tolerability of OPC in PD patients aged ≥ 65 years. Clinical-demographic data were collected at OPC initiation (T0) and at the last follow-up visit (T1). OPC-related adverse events (AEs) and reasons for discontinuation were recorded. Patients were compared according to age and treatment continuation. Logistic regression analyses were used to evaluate association between baseline features and occurrence of AEs and discontinuation. One-hundred and one elderly PD patients were included and followed up for 20.6 ± 18.8 months after OPC initiation. Overall, 49 patients (48.5%) reported AEs, and OPC was discontinued in 29 (28.7%) within 9.4 ± 15.3 months, with neuropsychiatric and cardiovascular/autonomic AEs being the most common reasons. Patients aged ≥ 75 years reported greater disease severity and frequency of AEs compared to younger patients, but similar discontinuation rates at follow-up. At T1, OPC discontinuers exhibited greater motor impairment and a lower total levodopa equivalent dose. Univariate analyses showed that age, disease stage, and comorbidity burden were significantly associated with AEs occurrence. In the multivariable analysis, disease stage remained the only significant baseline feature associated with AEs. OPC was generally well tolerated in this cohort of real-world elderly PD patients. Larger, prospective studies are warranted.

Levodopa-induced dyskinesia is a prevalent and almost inevitable complication of long-term levodopa therapy in Parkinson's disease, significantly impairing patients' quality of life. Despite its clinical significance, levodopa-induced dyskinesia remains insufficiently understood, and effective therapeutic strategies are still limited. Wolfberry glycopeptides, bioactive components extracted from Lycium barbarum L. have recently been widely reported to possess neuroimmune activities. In this study, levodopa-induced dyskinesia was induced through chronic levodopa administration in multiple Parkinson's disease animal models, including synuclein alpha-overexpressing mice and glutathione peroxidase 4 conditional knockdown mice, and then treated with wolfberry glycopeptides. Behavioral assessment using abnormal involuntary movements scoring showed that wolfberry glycopeptides significantly alleviated levodopa-induced dyskinesia-like symptoms across these models. Mechanistically, wolfberry glycopeptides preserved nigral dopaminergic neurons by restoring membrane lipid oxidative homeostasis, thereby delaying neuronal loss, and modestly improving dopamine metabolic homeostasis in the brain. Collectively, these findings demonstrate that wolfberry glycopeptides effectively mitigate levodopa-induced dyskinesia through dopaminergic neuroprotection and support their use as an integrative strategy in combination with levodopa to reduce levodopa-induced dyskinesia development and improve Parkinson's disease symptom management.

Before the advent of levodopa therapy for Parkinson's disease, surgical lesioning of the motor thalamus or globus pallidus represented the primary therapeutic intervention for Parkinson's disease and essential tremor at a time when effective medical alternatives were severely limited. In this context, Irving S. Cooper directed one of the most prolific and controversial lesioning practices of the mid-20th century, performing thousands of procedures and documenting outcomes. Through chemopallidectomy, chemothalamectomy, and later cryosurgical techniques, Cooper investigated the relationship between basal ganglia targets and motor symptoms, establishing reproducible symptom-anatomy associations for tremor and rigidity. Cooper's work introduced a systematic approach to target selection that contrasted with earlier lesioning methods. His outcomes demonstrated alleviation of tremor and rigidity when lesions were accurately placed, while highlighting risks of bilateral procedures. Most notably, the cryogenic "test-freeze" method allowed reversible intraoperative physiological inhibition, enabling assessment of clinical benefit before permanent lesions. Although many techniques were later abandoned, principles derived from Cooper's work continue to shape contemporary practice. Modern neuromodulation strategies, including deep brain stimulation and MR-guided focused ultrasound, rely on symptom-based targeting paradigms established during the lesioning era. This vignette examines how Cooper's innovations informed modern targeting strategies and standards of safety in functional neurosurgery.

Parkinson's disease (PD) represents the second most common neurodegenerative disorder across the globe. Conventional levodopa treatment can only alleviate disease-related symptoms and fails to restrain the progressive deterioration of PD. Metabolic abnormalities that mainly include mitochondrial dysfunction, cerebral insulin resistance, and disrupted energy homeostasis have been proven to be core pathogenic factors of PD, which makes metabolic interventions a promising therapeutic strategy for disease management. The ketogenic diet (KD) is a high-fat, low-carbohydrate dietary regimen that can induce endogenous ketone synthesis, and it exerts multi-dimensional neuroprotective effects on PD. This review systematically elaborates the potential molecular mechanisms through which KD protects against PD, which covers the improvement of cerebral energy metabolism, antioxidant and anti-apoptotic activities, suppression of neuroinflammation, regulation of α-synuclein (α-syn) pathological aggregation, and modulation of gut-brain axis. We comprehensively synthesize preclinical research evidence from cell and animal models as well as clinical data across case reports, pilot studies and randomized controlled trials, and we summarize critical clinical application principles that include dietary protocols selection, patient screening criteria, safety monitoring indicators and diet-drug interactions. Although KD intervention appears to improve selected motor and non-motor symptoms of PD, the current evidence remains preliminary, with prominent limitations including inconsistent trial outcomes, high dropout rates, heterogeneous dietary schemes and insufficient exploration of multi-omics. The inconsistent clinical outcomes, high trial dropout rates, heterogeneous dietary protocols, limited biomarker validation, and insufficient long-term efficacy and safety data limit its widespread clinical application. Large-scale, well-controlled clinical trials with standardized ketosis monitoring, disease-progression biomarkers, and extended follow-up are therefore required to verify the translational application value of KD in PD management.