Plain language summaryLooking Past the Stomach to the Small Intestine to Explain Unreliable Parkinson's Medication AbsorptionPeople with Parkinson's Disease (PD) rely on the medication levodopa to move well, but over time it often works unpredictably. Doctors usually blame the stomach, which can empty too slowly in Parkinson's, a condition called gastroparesis. However, levodopa is absorbed not in the stomach but one step further along, in the small intestine. In this letter we argue that slow movement through the small intestine, which standard stomach tests cannot detect, may be the real cause. One author had a normal stomach test but a very slow small intestine. The small intestine deserves far more attention when medication fails.

Patients with Parkinson's disease now live for decades after deep brain stimulation, and many develop recurrent symptoms while the stimulator still functions. A continuous infusion is sometimes added, but the circumstances justifying it are undefined, and the two modalities are still viewed as competing rather than complementary. This review examines the addition of the four infusion therapies after stimulation. A search of three databases identified fifteen reports, almost all small and retrospective. They report 118 patients and 119 infusion courses: 68 with intestinal levodopa gel, 23 with apomorphine, 28 with foslevodopa/foscarbidopa, and none with entacapone. Off time fell in every study that measured it, though fewer than half did. The on-state motor examination improved significantly only in the largest series to test it. In a post hoc trial subgroup, off time improved similarly with and without previous stimulation, while activities of daily living and speech improved significantly less in those with prior stimulation. Severe adverse events were more frequent after prior stimulation. The combination is uncommon: 1% to 2% of patients in larger cohorts, under 0.1% in a national apomorphine cohort. Stimulation parameters are reported or unchanged in only 10 of the 118 patients, and primary failure cannot be separated from secondary failure in 29. We propose a structured assessment separating correctable device problems, recurrent dopaminergic symptoms, stimulation-induced effects and levodopa-resistant progression. Infusion therapy may help recurrent levodopa-responsive complications after stimulation has been re-evaluated and optimized. Its use in late axial or cognitive decline is untested rather than disproven.

Nuclear medicine neuroimaging is becoming increasingly important for the diagnosis and differential diagnosis of Parkinson's disease, atypical parkinsonian syndromes and more rare neurological (movement) disorders. We report on a 46-year-old woman presented with frequent falls, a gradually progressive bipyramidal syndrome with gait ataxia, dysphagia, urinary urgency and -incontinence, low mood with disturbed emotional regulation and a mild asymmetric hypokinetic rigid syndrome. Additionally, she had a blurry vision, asymmetrical ptosis and abnormal vertical saccades. [[18]F]FDG PET/CT of the brain showed unspecific pattern of regional cortical hypometabolism and, more pronounced, striatal hypometabolism. [[123]I]FP-CIT SPECT showed a complete absence of on-target binding. Subsequent genetic testing revealed two variants in SPG7. The patient showed a modest favourable response on levodopa. This case illustrates profound neurodegeneration of the presynaptic dopaminergic nigrostriatal neurons in SPG7.

Diffusion-based tractography has been used to predict deep brain stimulation (DBS) outcomes in Parkinson's disease (PD), but the predictive value of fractional anisotropy (FA) maps, which can be generated with far less computation, remains underexplored. We retrospectively analyzed preoperative diffusion MRI from 143 patients with PD who underwent DBS between 2013 and 2023. Whole-brain and tract-specific FA measures were extracted and evaluated against the pre-to-postoperative change in levodopa equivalent daily dose (ΔLEDD). Nested regression models compared clinical predictors alone with models that added whole-brain FA or stability-selected tract-specific FA. Tract-specific FA explained an additional 2.3-3.4% of ΔLEDD variance (p = 0.038), whereas whole-brain FA did not (p = 0.497); effects were in the same direction, though smaller and no longer significant, after adjustment for gold-standard motor response to dopaminergic medications. The uncinate fasciculus and cingulum of the cingulate gyrus were most consistently selected. Preoperative tract-specific FA may complement established clinical predictors of DBS outcome in PD.

Parkinson's disease (PD) is characterised by progressive dopaminergic neurodegeneration and alpha-synuclein (α-syn) aggregation, with levodopa remaining the gold-standard symptomatic therapy despite its inability to halt disease progression or prevent levodopa-induced dyskinesia (LID). Caenorhabditis elegans has emerged as a highly tractable model for mechanistic PD research owing to its conserved dopaminergic pathways, optical transparency, rapid lifecycle, and suitability for high-throughput pharmacological screening. This review critically examines the pharmacological effects of levodopa in C. elegans PD models across locomotor behaviour, α-syn aggregation, lifespan, and dyskinesia-related phenotypes, while comparing these findings with phytochemicals evaluated in analogous experimental systems. Levodopa consistently restored dopamine-dependent locomotor deficits but failed to substantially reduce α-syn aggregation or extend lifespan, recapitulating the clinical dissociation between symptomatic motor rescue and persistent neurodegeneration. In contrast, phytochemicals, including Frondoside A, hydroxytyrosol/Hidrox®, Neurogrit Gold, Mucuna pruriens extract, quercetin, and quercetin nanoemulsions, demonstrated broader mechanistic profiles involving antioxidant responses, mitophagy, proteostasis, and dopaminergic neuroprotection. The available evidence suggests that phytochemicals are best regarded not as replacements for levodopa but as candidate adjuncts that, in preclinical worm models, appear to act on upstream pathological processes; whether this translates into genuine complementarity in vivo remains a hypothesis requiring direct testing. The central argument advanced here is methodological rather than pharmacological: C. elegans is currently the only PD model in which symptomatic motor rescue and α-synuclein pathology can be quantified simultaneously in the same living animal, and this dissociation provides a measurable framework for defining what an adjunctive compound would need to achieve. On this basis, levodopa is proposed as a mandatory positive control for future C. elegans phytochemical screening. Critical translational limitations-including the absence of a blood-brain barrier in C. elegans, phytochemical bioavailability constraints, and uncertainty regarding the relationship between aggregate reduction and true neuroprotection-are also discussed.

BackgroundImage-guided programming (IGP) enables optimization and personalization of deep brain stimulation (DBS) for patients with Parkinson's disease. Although its role in initial programming has been examined, evidence for its value in chronic stimulation remains limited. We aimed to evaluate the effectiveness of IGP in individuals with Parkinson's disease receiving chronic subthalamic nucleus (STN)-DBS with conventional programming (CP).MethodsWe reviewed optimal stimulation configurations using IGP with STIMVIEW™ XT in 30 patients with PD implanted with directional DB2202 electrodes. When discrepancies were identified between CP- and IGP-derived configurations, stimulation parameters were adjusted. Motor outcomes were assessed using the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Parts III and IV and levodopa equivalent daily dose (LEDD) at baseline and 1 month after switching to IGP.ResultsDiscrepancies between CP- and IGP-selected configurations were found in at least one electrode in 20 patients (66.7%), and 18 were included in the analysis. Of these, 11 (61.1%) showed improvement in MDS-UPDRS Part III and/or IV scores, 4 (22.2%) showed no change, and 3 (16.7%) worsened. Mean MDS-UPDRS Part III scores significantly decreased from 20.7 ± 16.5 to 16.9 ± 13.3 (p = 0.008), and LEDD from 655.2 ± 326.6 mg to 609.9 ± 311.1 mg (p = 0.046). Discrepancies occurred more often in stimulation direction than level, and IGP-based stimulation was applied bilaterally in most individuals.ConclusionIGP for STN-DBS can improve motor symptom control in patients with Parkinson's disease. It may benefit those with suboptimal outcomes under CP and represent a practical approach for individualized DBS management.

Background: Advanced Parkinson's disease (aPD) is characterized by motor fluctuations, unpredictable oral absorption, and severe dyskinesias. Levodopa-entacapone-carbidopa intestinal gel (LECIG) is designed to provide dopaminergic stimulation and optimize levodopa bioavailability. We evaluated 18-month clinical outcomes, motor stabilization, disease burden, and oral medication simplification in a real-world cohort transitioning to LECIG. Methods: This retrospective longitudinal study included 41 patients with medication-refractory aPD. Patients underwent nasojejunal titration (mean 5.58 ± 1.50 days), followed by percutaneous endoscopic gastrojejunostomy. Assessments were performed at baseline, initiation, and 6, 12, and 18 months. Primary endpoints were daily OFF time, dyskinesia duration, and non-linear fluctuations. Disease burden was analyzed using Linear Mixed-Effects Models and medication changes using McNemar tests and paired t-tests. Results: Patients (56.1% male; mean age 65.39 ± 8.32 years; disease duration 10.46 ± 4.23 years) demonstrated significant and sustained clinical improvements. For the 38 patients evaluable at 18 months, daily OFF time decreased from 4.67 ± 0.79 h to 1.34 ± 0.40 at initiation and 1.55 ± 0.69 at 18 months (p < 0.0001; 66.8% reduction). Severe peak-dose dyskinesia was absent after initiation (2.17 ± 1.00 to 0.00 h/day; p < 0.001), whereas early morning akinesia decreased from 78.0% to 36.6% and freezing of gait from 56.1% to 31.6%. Total Clinical Burden Score decreased from 9.33 to 3.49 (-62.6%). Dopamine agonist use decreased from 80.5% to 42.1% at 18 months (McNemar p < 0.0001), while adjunct medications decreased from 1.73 to 1.39/patient (p = 0.0284). Adverse events were predominantly mild-to-moderate. No patient discontinued therapy because of an adverse event or hardware failure; one patient discontinued LECIG by personal choice. Two additional patients died from sudden cardiac arrest during follow-up, both considered unrelated to LECIG therapy or pump hardware. At 18 months, 38 of 41 patients remained evaluable. Conclusions: In this observational cohort, LECIG initiation was followed by sustained reductions in motor complications, OFF time, and clinical burden over 18 months. Treatment was also associated with a reduction in dopamine agonist use and overall adjunctive medication burden. The favorable tolerability and low discontinuation rate observed support further evaluation of LECIG as an advanced treatment pathway. However, pre-switch LEDD calculations may support initial pump programming but should not be considered definitive predictors of individualized maintenance settings; inpatient clinical titration remains necessary.

Brucella abortus is an intracellular pathogen that must withstand oxidative stress and other hostile conditions encountered within host cells. Here, we investigated the contribution of BAB2_0534, a gene encoding a putative multicopper oxidase, to bacterial adaptation and persistence. Deletion of BAB2_0534 impaired pigment production in the presence of the melanin precursors L-DOPA and homogentisic acid, supporting a role for BAB2_0534 in phenolic substrate oxidation and melanin-like pigment biosynthesis. The mutant also exhibited increased susceptibility to oxidative stress and reduced survival with macrophages, indicating that BAB2_0534 contribute to intracellular adaptation. In vivo, mice infected with the ΔBAB2_0534 mutant showed significantly reduced splenic bacterial burdens compared with animals infected with the wild-type or complemented strains, demonstrating impaired persistence during infection. Consistently, Fontana-Masson-positive pigment was detected in tissues from wild-type-infected animals but was markedly reduced following infection with the mutant. Collectively, these findings support a model in which BAB2_0534-associated multicopper oxidase activity and pigment production contribute to oxidative stress resistance and intracellular persistence of B. abortus. This study characterizes BAB2_0534 as a previously unrecognized component of the adaptive mechanisms underlying Brucella persistence.

Background: The most effective pharmacological treatment for Parkinson's disease (PD) remains levodopa, whose responsiveness is distinguished into two temporally and mechanistically distinct components: the short-duration response (SDR), which lasts hours, closely paralleling drug plasma concentration, and the long-duration response (LDR), which derives from prolonged administration of levodopa and persists for days to weeks after drug discontinuation. The mechanisms underlying the LDR and, in particular, the behavior in early PD patients are incompletely understood. This review aims to gather current evidence on the pharmacodynamics, neurobiological substrate, natural history, and clinical implications of the LDR, with a specific focus on early PD patients. Methods: A narrative review was conducted based on a selection of original research articles, clinical studies, and reviews identified through PubMed/MEDLINE, covering the period from January 1995 to July 2026. Studies were selected for their methodological relevance to the characterization of LDR in drug-naive or early-stage PD patients, including pharmacodynamic studies, neuroimaging investigations, and neurophysiological assessments. Results: Evidence consistently demonstrates that the LDR is a pharmacodynamically distinct component of levodopa response, present from the earliest stages of dopaminergic therapy. In drug-naive patients, the LDR represents a quantitatively substantial fraction of total levodopa benefit, and it is linked to modifications in cortical excitability, dopaminergic neuroplasticity, and motor learning. Structural neuroimaging identifies predisposing gray matter features in motor cortex regions. Whether LDR magnitude declines with disease and treatment duration, and thereby underlies the emergence of motor fluctuations, remains disputed across studies. This discrepancy appears attributable, at least in part, to differences in how the LDR is measured (direct washout assessment versus inference against a projected untreated trajectory) rather than necessarily to divergent underlying biology. Conclusions: The LDR to levodopa represents a neurobiologically and clinically significant dimension of levodopa response. Its characterization in early PD patients may refine therapeutic strategies, inform the design of neuroprotection trials, and open new possibilities for precision medicine approaches.

Current Parkinson's disease (PD) therapies like Levodopa (L-DOPA) only provide symptomatic relief, highlighting the need for multi-target neuroprotective agents. This study investigates the mechanisms and preclinical effects of trans-vitisin B (tVB), an oligomeric stilbene, in PD models. In LPS-stimulated HMC3 and RAW 264.7 cells, tVB (0.1-10.0 µM) significantly suppressed reactive oxygen species (ROS), nitric oxide (NO), COX-2, and pro-inflammatory cytokines (IL-1β, TNF-α), while restoring HSP70 chaperone levels to normalize proteostasis. These findings were validated in vivo using C57BL/6 mice with rotenone-induced chronic PD. Administration of tVB attenuated motor deficits (Cylinder test) and reduced pathological freezing (Open Field) and working memory impairments (Y-maze) in this model, without inducing the dyskinesia-like side effects of L-DOPA treatment in rodents. Histologically, tVB mitigated the loss of dopaminergic neurons (TH[+]) in the substantia nigra, reduced microglial activation (IBA-1[+]) and neuronal NO synthase, and suppressed pathological phosphorylated Tau protein (p-TauSer202) accumulation. Unlike L-DOPA's direct dopaminergic stimulation, tVB's neuroprotective efficacy is mediated through multilevel regulation of key PD pathogenetic pathways, including neuroinflammation, oxidative stress, and impaired proteostasis.