Continuous Subcutaneous Foslevodopa-Foscarbidopa in Parkinson's Disease: A Mini-Review of Current Scope and Future Outlook.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, primarily because of the impairment of dopaminergic neurons. Long-term use of levodopa, the standard PD treatment, often results in fluctuating therapeutic effects and dyskinesia, necessitating alternative therapies. OBJECTIVES: This review aims to synthesize current insights and clinical experiences with foslevodopa-foscarbidopa, focusing on its pharmacokinetics, efficacy, and safety profile, to evaluate its potential in transforming PD therapy. METHODS: A systematic literature search was conducted up to November 2023 using databases PubMed, Web of Science, and Cochrane Library. The search yielded eight eligible articles, including pharmacological studies, case reports, observational studies, and controlled trials. No language restrictions were applied. RESULTS: Foslevodopa and foscarbidopa, as prodrugs of levodopa and carbidopa, exhibited excellent chemical stability and solubility, facilitating continuous subcutaneous infusion. Clinical trials demonstrated that these prodrugs maintain stable levodopa levels, thereby addressing the limitations of oral levodopa therapy. Phase 1 and 3 studies indicated significant improvements in motor function and quality of life in advanced PD patients. However, a higher incidence of treatment-emergent adverse events, mainly infusion site reactions, was observed compared to oral therapies. CONCLUSIONS: Foslevodopa-foscarbidopa emerges as a promising alternative for advanced PD treatment, offering sustained symptom control. Its efficacy in managing motor fluctuations and dyskinesia makes it a viable option in the PD therapeutic spectrum. Future research should focus on long-term safety, economic impact, and broader accessibility. Foslevodopa-foscarbidopa is now commercially distributed in many countries in Europe and in Japan.

Differential Components of Bradykinesia in Parkinson Disease Revealed by Deep Brain Stimulation.

Bradykinesia is a term describing several manifestations of movement disruption caused by Parkinson's disease (PD), including movement slowing, amplitude reduction, and gradual decrease of speed and amplitude over multiple repetitions of the same movement. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves bradykinesia in patients with PD. We examined the effect of DBS on specific components of bradykinesia when applied at two locations within the STN, using signal processing techniques to identify the time course of amplitude and frequency of repeated hand pronation-supination movements performed by participants with and without PD. Stimulation at either location increased movement amplitude, increased frequency, and decreased variability, though not to the range observed in the control group. Amplitude and frequency showed decrement within trials, which was similar in PD and control groups and did not change with DBS. Decrement across trials, by contrast, differed between PD and control groups, and was reduced by stimulation. We conclude that DBS improves specific aspects of movement that are disrupted by PD, whereas it does not affect short-term decrement that could reflect muscular fatigue.

Staged magnetic resonance-guided focused ultrasound thalamotomy for the treatment of bilateral essential tremor and Parkinson's disease related tremor: a systematic review and critical appraisal of current knowledge.

Introduction: Essential tremor (ET) and Parkinson's Disease (PD) are debilitating neurodegenerative disorders characterized by tremor as a predominant symptom, significantly impacting patients' quality of life. Magnetic Resonance-guided Focused Ultrasound (MRgFUS) Thalamotomy is an innovative therapeutic option for the treatment of unilateral medically refractory tremor with fewer adverse effects compared to traditional surgical interventions. A recent CE approval allows appropriate patients to have their second side treated. Objective: The objective of this systematic review was to analyze available current knowledge about the use of MRgFUS for the treatment of bilateral ET and PD related tremor, to identify the effectiveness and the risks associated with bilateral treatment. Methods: Eligible studies were identified by searching published studies in PubMed and Scopus databases from May 2014 to January 2024 and by identifying ongoing studies registered on the clinicaltrials.gov website. Data were summarized by considering the following information topics: the number of patients involved, the selected lesion target, the assessment tool used to evaluate clinical changes, the observed improvement, the reported side effects, and the time interval between the two treatments. The study was registered in PROSPERO (ID: CRD42024513178). Results: Nine studies were eligible for this review, 7 for ET and 2 for PD. The involved population included a variable number of patients, ranging from 1 to 11 subjects for ET and from 10 to 15 subjects for PD. The main lesional targets were the ventral intermediate nucleus of the thalamus, the pallidothalamic tract and the cerebellothalamic tract bilaterally. All studies investigated the tremor relief through the Clinical Rating Scale for Tremor (CRST) in patients with ET, and through the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD. A variable degree of improvement was observed, with all patients expressing overall satisfaction with the bilateral treatment. Adverse events were mild and transient, primarily involving gait disturbances, dysarthria, and ataxia. A standardized protocol for administering the two consecutive treatments was not identifiable; typically, the timing of the second treatment was delayed by at least 6 months. Conclusion: Available evidence supports the effectiveness and safety of staged bilateral MRgFUS treatments for ET and PD-related tremor.

The Skin and Lewy Body Disease.

This manuscript reviews the significant skin manifestations of Lewy body disease, including Parkinson's disease and dementia with Lewy bodies, and the diagnostic utility of skin biopsy. Besides classic motor and cognitive symptoms, non-motor manifestations, particularly dermatologic disorders, can play a crucial role in disease presentation and diagnosis. This review explores the intricate relationship between the skin and Lewy body disease. Seborrheic dermatitis, autoimmune blistering diseases (bullous pemphigoid and pemphigus), rosacea, and melanoma are scrutinized for their unique associations with Parkinson's disease, revealing potential links through shared pathophysiological mechanisms. Advances in diagnostic techniques allow the identification of promising biomarkers such as α-synuclein in samples obtained by skin punch biopsy. Understanding the dermatologic aspects of Lewy body disease not only contributes to its holistic characterization but also holds implications for innovative diagnostic approaches.

Precision targeting in the globus pallidus interna: insights from the multicenter, prospective, blinded VA/NINDS CSP 468 study.

OBJECTIVE: Deep brain stimulation (DBS) targeting the globus pallidus interna (GPi) has been shown to significantly improve motor symptoms for the treatment of medication-refractory Parkinson's disease. Yet, heterogeneity in clinical outcomes persists, possibly due to suboptimal target identification within the GPi. By leveraging robust sampling of the GPi and 6-month postsurgical outcomes, this study aims to determine optimal symptom-specific GPi DBS targets. METHODS: In this study, the authors analyzed the anatomical lead location and 6-month postsurgical, double-blinded outcome measures of 86 patients who underwent bilateral GPi DBS. These patients were selected from the multicenter Veterans Affairs (VA)/National Institutes of Neurological Disorders and Stroke (NINDS) Cooperative Studies Program (CSP) 468 study to identify the optimal target zones ("sweet spots") for the control of overall motor (United Parkinson's Disease Rating Scale [UPDRS]-III), axial, tremor, rigidity, and bradykinesia symptoms. Lead coordinates were normalized to Montreal Neurological Institute space and the optimal target zones were identified and validated using a leave-one-patient-out approach. RESULTS: The authors' findings revealed statistically significant optimal target zones for UPDRS-III (R = 0.37, p < 0.001), axial (R = 0.22, p = 0.042), rigidity (R = 0.20, p = 0.021), and bradykinesia (R = 0.23, p = 0.004) symptoms. These zones were localized within the primary motor and premotor subdivisions of the GPi. Interestingly, these zones extended beyond the GPi lateral border into the GPi-globus pallidus externa (GPe) lamina and into the GPe, but they did not reach the GPi ventral border, challenging traditional surgical approaches based on pallidotomies. CONCLUSIONS: Drawing upon a robust dataset, this research effectively delineates specific optimal target zones for not only overall motor improvement but also symptom subscores. These insights hold the potential to enhance the precision of targeting in subsequent bilateral GPi DBS surgical procedures.

Guideline "Parkinson's disease" of the German Society of Neurology (Deutsche Gesellschaft für Neurologie): concepts of care.

INTRODUCTION: In 2023, the German Society of Neurology published a new guideline on Parkinson's disease. An important section dealt with PD care concepts, which represent a particularly dynamic field of PD research, including their implementation in clinical practice. Parkinson's disease is the second most common age-associated neurodegenerative disease. Current estimates of the number of cases in the population describe a significant increase in prevalence in Germany by 2030 with higher proportions in rural areas, which also have a lack of sufficient PD care resources. RECOMMENDATIONS: In comparison with other international guidelines, which have so far mentioned palliative care and Parkinson's nurses in particular, the German S2k guideline expands the recommended concepts of PD care to include PD day clinics, inpatient complex treatment, and PD networks. CONCLUSION: Concepts of PD care guidelines are necessary because of the complex and rapidly evolving field of PD care provision. If applied appropriately, the potential for optimized care can be exploited and both the patient burden and the economic burden can be reduced. Given that modern care concepts have so far only been applied in a few regions, it is often impossible to generate broad evidence-based data, so that the evaluation of PD care concepts is partly dependent on expert opinion.

Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precision level. Using parallel single-nucleus (sn)RNA-seq and snATAC-seq analyses we simultaneously profiled the transcriptomic and chromatin accessibility landscapes in temporal cortex tissues from 12 PD compared to 12 control subjects at a granular single cell resolution. An integrative bioinformatic pipeline was developed and applied for the analyses of these snMulti-omics datasets. The results identified a subpopulation of cortical glutamatergic excitatory neurons with remarkably altered gene expression in PD, including differentially-expressed genes within PD risk loci identified in genome-wide association studies (GWAS). This was the only neuronal subtype showing significant and robust overexpression of SNCA. Further characterization of this neuronal-subpopulation showed upregulation of specific pathways related to axon guidance, neurite outgrowth and post-synaptic structure, and downregulated pathways involved in presynaptic organization and calcium response. Additionally, we characterized the roles of three molecular mechanisms in governing PD-associated cell subtype-specific dysregulation of gene expression: (1) changes in cis-regulatory element accessibility to transcriptional machinery; (2) changes in the abundance of master transcriptional regulators, including YY1, SP3, and KLF16; (3) candidate regulatory variants in high linkage disequilibrium with PD-GWAS genomic variants impacting transcription factor binding affinities. To our knowledge, this study is the first and the most comprehensive interrogation of the multi-omics landscape of PD at a cell-subtype resolution. Our findings provide new insights into a precise glutamatergic neuronal cell subtype, causal genes, and non-coding regulatory variants underlying the neuropathological progression of PD, paving the way for the development of cell- and gene-targeted therapeutics to halt disease progression as well as genetic biomarkers for early preclinical diagnosis.

The protective effects of repetitive transcranial magnetic stimulation with different high frequencies on motor functions in MPTP/probenecid induced Parkinsonism mouse models.

BACKGROUND: High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS. OBJECTIVE: The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model. METHODS: Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored. RESULTS: We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1ß in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest. CONCLUSIONS: Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.

Neuroprotective Effects of Zinc Oxide Nanoparticles in a Rotenone-Induced Mouse Model of Parkinson's Disease.

Goals of the investigation: This work aimed to evaluate the neuroprotective effects of zinc oxide (ZnO) nanoparticles in an experimental mouse model of rotenone-induced PD and investigate the therapeutic effects of ZnO, cobalt ferrite nanoparticles, and their combination. Methods: The levels of dopamine, norepinephrine, epinephrine, and serotonin were assessed using ELISA in the control and experimental model of PD mice. The dopa-decarboxylase expression level was assayed by real-time PCR. The expression level of tyrosine hydroxylase (TH) was assessed by western blot analysis. Results: Our data showed that levels of dopamine decreased in PD mice compared to normal. ZnO NP increased dopamine levels in normal and PD mice (37.5% and 29.5%; respectively, compared to untreated mice). However, ZnO NP did not cause any change in norepinephrine and epinephrine levels either in normal or in PD mice. Levels of serotonin decreased by 64.0%, and 51.1% in PD mice treated with cobalt ferrite and dual ZnO- cobalt ferrite NPs; respectively, when compared to PD untreated mice. The mRNA levels of dopa-decarboxylase increased in both normal and PD mice treated with ZnO NP. Its level decreased when using cobalt ferrite NP and the dual ZnO-cobalt ferrite NP when compared to untreated PD mice. A significant decrease in TH expression by 0.25, 0.68, and 0.62 folds was observed in normal mice treated with ZnO, cobalt ferrite, and the dual ZnO-cobalt ferrite NP as compared to normal untreated mice. In PD mice, ZnO administration caused a non-significant 0.15-fold decrease in TH levels while both cobalt ferrite and the dual ZnO-cobalt ferrite NP administration caused a significant 0.3 and 0.4-fold decrease respectively when compared to untreated PD mice. Principal conclusion: This study reveals that ZnO NPs may be utilized as a potential intervention to elevate dopamine levels to aid in PD treatment.

Hearing loss is not associated with risk of Parkinson's disease: A Mendelian randomization study.

Purpose: A few observational studies have indicated that Parkinson's disease (PD) risk may be higher in those with hearing loss, but the two's causal relationship is yet unknown. Using Mendelian randomization (MR) methods, this study sought to explore the causal link between hearing loss and the risk of PD. Methods: We identified single nucleotide polymorphisms (SNPs) linked to hearing loss (P-value<5E-08) in a genome-wide association study (GWAS) included 323,978 people from the UK Biobank. The summary data for PD in the discovery group came from a GWAS meta-analysis of 33,647 cases and 449,056 healthy participants of European descent. Using summary data from the aforementioned GWAS of PD (N = 33,647) and hearing loss (N = 323,978), we carried out a two-sample MR study. As validation groups, two separate PD GWAS studies were used. Inverse variance weighting (IVW) was utilized in the principal MR analysis. For our findings to be reliable, further analyses were carried out with the Cochran's Q test, MR-Egger intercept, and leave-one-out analysis. In addition, we assessed the causal link between various forms of hearing loss and PD using the IVW approach. Results: Twenty-two SNPs with genome-wide significance linked to hearing loss were used as instrumental factors. In the discovery dataset, we failed to detect a causal relationship between hearing loss and PD (OR = 1.297; 95 % CI = 0.420-4.007; P-value = 0.651). The findings of other methods agreed with the IVW method. The results were robust under sensitivity analyses. Furthermore, the above findings were confirmed in two validation PD datasets. Additionally, no causal correlation was found between genetic prediction of four different types of hearing loss and PD (conductive hearing loss, IVW: OR = 1.058, 95%CI = 0.988-1.133, P-value = 0.108; sudden idiopathic hearing loss, IVW: OR = 0.936, 95%CI = 0.863-1.016, P-value = 0.113; mixed conductive and sensorineural hearing loss, IVW: OR = 0.963, 95%CI = 0.878-1.058, P-value = 0.436; sensorineural hearing loss, IVW: OR = 1.050, 95%CI = 0.948-1.161, P-value = 0.354). Conclusion: In those of European heritage, our investigation revealed no causal link between hearing loss and PD risk.

The Effect of Gua Sha Therapy on Pain in Parkinson's Disease: a Randomized Controlled Trial.

Purpose: Pain is a common yet undertreated symptom of Parkinson's disease (PD). This study investigated the effect of Gua Sha therapy on pain in patients with PD. Patients and Methods: A total of 56 PD patients with pain were randomized into either the experimental group (n=28), receiving 12 sessions of Gua Sha therapy, or the control group (n=28) without additional treatment. Participants underwent assessment at baseline, after the twelfth invention, and at the 2-month follow-up timepoints. The primary outcome was KPPS and VAS. Secondary outcomes included UPDRS I-III, PDSS-2, HADS, PDQ-39, and blood biomarkers (5-HT, IL-8, IL-10). Results: The experimental group reported a significant improvement in pain severity, motor functions, affective disorder, and sleep quality (P < 0.05). Furthermore, increasing trends in both 5-HT and IL-10, as well as decreasing trends in IL-8 were observed. No serious adverse events occurred. Conclusion: The preliminary findings suggest that Gua Sha therapy may be effective and safe for alleviating pain and improving other disease-related symptoms in PD patients.

A bibliometric analysis of speech and language impairments in Parkinson's disease based on Web of Science.

Many individuals with Parkinson's disease suffer from speech and language impairments that significantly impact their quality of life. Despite several studies on these disorders, there is a lack of relevant bibliometric analyses. This paper conducted a bibliometric analysis of 3,610 papers on speech and language impairments in Parkinson's disease patients from January 1961 to November 2023, based on the Web of Science Core Collection database. Using Citespace software, the analysis focused on annual publication volume, cooperation among countries and institutions, author collaborations, journals, co-citation references, and keywords, aiming to explore the current research status, hotspots, and frontiers in this field. The number of annual publications related to speech and language impairment in Parkinson's disease have been increasing over the years. The USA leads in the number of publications. Research hotspots include the mechanism underlying speech and language impairments, clinical symptoms, automated diagnosis and classification of patients with PD using linguistic makers, and rehabilitation interventions.

Motor improvement of remote programming in patients with Parkinson's disease after deep brain stimulation: a 1-year follow-up.

Background: Remote programming (RP) is an emerging technology that enables the adjustment of implantable pulse generators (IPGs) via the Internet for people with Parkinson's disease (PwPD) who have undergone deep brain stimulation (DBS). Previous studies have not comprehensively explored the effectiveness of RP in managing motor symptoms, often omitting assessments such as the rigidity and retropulsion tests during the follow-up. This study evaluates the comprehensive improvements in motor performance and the potential cost benefits of RP for PwPD with DBS. Methods: A retrospective analysis was conducted on two groups of patients-those who received RP and those who received standard programming (SP). Clinical outcomes including motor improvement, quality of life, and daily levodopa dosage were compared between the groups during a 12 (± 3)-month in-clinic follow-up. Results: A total of 44 patients were included in the study, with 18 in the RP group and 26 in the SP group. No significant differences were observed in the frequency of programming sessions or clinical outcomes between the groups (p > 0.05). However, the RP group experienced significantly lower costs per programming session than the SP group (p < 0.05), despite patients in the former group living further from our center (p < 0.05). Conclusions: Our findings suggest that RP could significantly reduce the costs of programming for PwPD with DBS, especially without compromising the effectiveness of treatment across all motor symptoms in the short term.

Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation.

Accumulation of aggregated α-synuclein (α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease (PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids (LPLs), particularly targeting lysophosphatidylcholine (LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

Multidisciplinary care use in neurodegenerative complex diseases: The example of progressive supranuclear palsy and advanced Parkinson's disease in real-life.

BACKGROUND: In spite of being considered the gold-standard of care, little is known about the real-life use of in-home and multidisciplinary care in atypical parkinsonism. OBJECTIVE: Primary: Examine real-life multidisciplinary care use for Progressive Supranuclear Palsy (PSP). Secondary: a) Compare PSP care to advanced Parkinson's disease (APD) care; (b) Explore demographic and clinical variables associated with care needs in both groups. METHODS: A cross-sectional multicenter observational study enrolled 129 PSP patients and 65 APD patients (Hoehn and Yahr ≥3), matched for sex and age. Univariate and multivariate regression analysis were performed. RESULTS: Over the previous year, 40 % of PSP patients did not encounter a physical therapist, while only one-third met a speech and language therapist and 5 % an occupational therapist. More than 20 % received in-home care and 32 % needed home structural changes. Compared to APD, PSP patients required more day-time, night-time and home structural changes. When considering both PSP and APD in multivariate analysis, reduced functional autonomy and living without a family caregiver were both related to day-time home assistance and to the need of at least one home care service. A PSP diagnosis compared to APD was a risk factor for having at least four multidisciplinary visits in a year. Finally, PSP diagnosis and being from the Northern Italy were significantly related with home structural changes. CONCLUSIONS: There's a significant gap in providing multidisciplinary care for PSP patients. Our findings emphasize the need for a shared, integrated care plan at a national level for patients with atypical parkinsonism.

Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology.

Parkinson's disease (PD) is a debilitating neurodegenerative disease affecting millions of individuals worldwide. Hallmark features of PD pathology are the formation of Lewy bodies in neuromelanin-containing dopaminergic neurons of the substantia nigra pars compacta (SNpc), and the subsequent irreversible death of these neurons. Although genetic risk factors have been identified, around 90% of PD cases are sporadic and likely caused by environmental exposures and gene-environment interaction. Mechanistic studies have identified a variety of chemical PD risk factors. PD neuropathology occurs throughout the brain and peripheral nervous system, but it is the loss of dopamine neurons in the SNpc that produce many of the cardinal motor symptoms. Toxicology studies have found specifically the dopaminergic neuron population of the SNpc exhibit heightened sensitivity to highly variable chemical insults (both in terms of chemical structure and mechanism of neurotoxic action). Thus, it has become clear that the inherent neurobiology of nigral dopamine neurons likely underlies much of this neurotoxic response to broad insults. This review focuses on inherent neurobiology of nigral dopaminergic neurons and how such neurobiology impacts the primary mechanism of neurotoxicity. While interactions with a variety of other cell types are important in disease pathogenesis, understanding how inherent dopaminergic biology contributes to selective sensitivity and primary mechanisms of neurotoxicity is critical to advancing the field. Specifically, key biological features of dopaminergic neurons that increase neurotoxicant susceptibility.

Exploring α-synuclein stability under the external electrostatic fields: Effect of repeat unit.

Parkinson's disease (PD) is a category of neurodegenerative disorders (ND) that currently lack comprehensive and definitive treatment strategies. The etiology of PD can be attributed to the presence and aggregation of a protein known as α-synuclein. Researchers have observed that the application of an external electrostatic field holds the potential to induce the separation of the fibrous structures into peptides. To comprehend this phenomenon, our investigation involved simulations conducted on the α-synuclein peptides through the application of Molecular Dynamics (MD) simulation techniques under the influence of a 0.1 V/nm electric field. The results obtained from the MD simulations revealed that in the presence of external electric field, the monomer and oligomeric forms of α-synuclein are experienced significant conformational changes which could prevent them from further aggregation. However, as the number of peptide units in the model system increases, forming trimers and tetramers, the stability against the electric field also increases. This enhanced stability in larger aggregates indicates a critical threshold in α-synuclein assembly where the electric field's effectiveness in disrupting the aggregation diminishes. Therefore, our findings suggest that early diagnosis and intervention could be crucial in preventing PD progression. When α-synuclein predominantly exists in its monomeric or dimeric form, applying even a lower electric field could effectively disrupt the initial aggregation process. Inhibition of α-synuclein fibril formation at early stages might serve as a viable solution to combat PD by halting the formation of more stable and pathogenic α-synuclein fibrils.

Mechanistic Insight into Intestinal α-Synuclein Aggregation in Parkinson's Disease Using a Laser-Printed Electrochemical Sensor.

Aggregated deposits of the protein α-synuclein and depleting levels of dopamine in the brain correlate with Parkinson's disease development. Treatments often focus on replenishing dopamine in the brain; however, the brain might not be the only site requiring attention. Aggregates of α-synuclein appear to accumulate in the gut years prior to the onset of any motor symptoms. Enteroendocrine cells (specialized gut epithelial cells) may be the source of intestinal α-synuclein, as they natively express this protein. Enteroendocrine cells are constantly exposed to gut bacteria and their metabolites because they border the gut lumen. These cells also express the dopamine metabolic pathway and form synapses with vagal neurons, which innervate the gut and brain. Through this connection, Parkinson's disease pathology may originate in the gut and spread to the brain over time. Effective therapeutics to prevent this disease progression are lacking due to a limited understanding of the mechanisms by which α-synuclein aggregation occurs in the gut. We previously proposed a gut bacterial metabolic pathway responsible for the initiation of α-synuclein aggregation that is dependent on the oxidation of dopamine. Here, we develop a new tool, a laser-induced graphene-based electrochemical sensor chip, to track α-synuclein aggregation and dopamine level over time. Using these sensor chips, we evaluated diet-derived catechols dihydrocaffeic acid and caffeic acid as potential inhibitors of α-synuclein aggregation. Our results suggest that these molecules inhibit dopamine oxidation. We also found that these dietary catechols inhibit α-synuclein aggregation in STC-1 enteroendocrine cells. These findings are critical next steps to reveal new avenues for targeted therapeutics to treat Parkinson's disease, specifically in the context of functional foods that may be used to reshape the gut environment.