Parkinsonian Symptoms Research Articles

Role of proinflammatory biomarkers in Parkinson's disease with non-motor symptoms: A systematic review and meta-analysis

Background and objectives. Neuroinflammation, characterized by microglial activation and elevated proinflammatory cytokines, plays a crucial role in Parkinson's disease (PD) pathogenesis and is linked to neurodegeneration and non-motor symptoms. This review aims to identify specific biomarkers associated with these non-motor symptoms, highlighting their roles and implications in PD management and therapy. Materials and methods. This systematic review followed PRISMA guidelines to assess proinflammatory biomarkers in PD patients with non-motor symptoms. We included 10 studies identified through comprehensive searches in PubMed/Medline, Wiley Online Library, Science Direct, Google Scholar, and Neurona. Bias was assessed using the ROBINS-I tool, and study quality was evaluated with GradePro. Meta-analysis was conducted using the Ordmeta test. Results. Proinflammatory biomarkers such as IL-6, TNF-α, CRP, and hs-CRP are notably associated with non-motor symptoms in PD. TNF-α shows a moderate correlation with depressive disorders in 194 patients (p=0.007±0.011), while IL-17A correlates similarly with anxiety, and IL-2 with mood disorders. Furthermore, TNF-α has a low yet meaningful correlation with sleep disorders. Ordmeta results reveal significant elevations of TNF-α in 52 PD patients with cognitive impairment (p=0.0003) and of IL-6 in 361 PD patients (p=0.023±0.008), underlining their roles in PD pathology. Conclusions. This study confirms that proinflammatory biomarkers such as CRP, hs-CRP, IL-6, IL-2, IL-17A, and TNF-α are significantly linked to non-motor symptoms in PD. TNF-α is notably elevated in patients with cognitive impairments and depressive disorders, while IL-6 is also significantly increased in those with cognitive issues.

Increased mean diffusivity of the caudal motor SNc identifies patients with REM sleep behaviour disorder and Parkinson’s disease

Idiopathic rapid eye movement sleep behaviour disorder (iRBD)—a Parkinson’s disease (PD) prodrome—might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1—the earliest-degenerating dopaminergic neurons in PD—and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson’s Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (padj < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.

A Comprehensive Approach to Parkinson's Disease: Addressing Its Molecular, Clinical, and Therapeutic Aspects.

Parkinson's disease (PD) is a gradually worsening neurodegenerative disorder affecting the nervous system, marked by a slow progression and varied symptoms. It is the second most common neurodegenerative disease, affecting over six million people in the world. Its multifactorial etiology includes environmental, genomic, and epigenetic factors. Clinical symptoms consist of non-motor and motor symptoms, with motor symptoms being the classic presentation. Therapeutic approaches encompass pharmacological, non-pharmacological, and surgical interventions. Traditional pharmacological treatment consists of administering drugs (MAOIs, DA, and levodopa), while emerging evidence explores the potential of antidiabetic agents for neuroprotection and gene therapy for attenuating parkinsonian symptoms. Non-pharmacological treatments, such as exercise, a calcium-rich diet, and adequate vitamin D supplementation, aim to slow disease progression and prevent complications. For those patients who have medically induced side effects and/or refractory symptoms, surgery is a therapeutic option. Deep brain stimulation is the primary surgical option, associated with motor symptom improvement. Levodopa/carbidopa intestinal gel infusion through percutaneous endoscopic gastrojejunostomy and a portable infusion pump succeeded in reducing "off" time, where non-motor and motor symptoms occur, and increasing "on" time. This article aims to address the general aspects of PD and to provide a comparative comprehensive review of the conventional and the latest therapeutic advancements and emerging treatments for PD. Nevertheless, further studies are required to optimize treatment and provide suitable alternatives.

Effects of Chronic Exposure to Low Doses of Rotenone on Dopaminergic and Cholinergic Neurons in the CNS of Hemigrapsus sanguineus.

Rotenone, as a common pesticide and insecticide frequently found in environmental samples, may be present in aquatic habitats worldwide. Exposure to low concentrations of this compound may cause alterations in the nervous system, thus contributing to Parkinsonian motor symptoms in both vertebrates and invertebrates. However, the effects of chronic exposure to low doses of rotenone on the activity of neurotransmitters that govern motor functions and on the specific molecular mechanisms leading to movement morbidity remain largely unknown for many aquatic invertebrates. In this study, we analyzed the effects that rotenone poisoning exerts on the activity of dopamine (DA) and acetylcholine (ACh) synthesis enzymes in the central nervous system (CNS) of Asian shore crab, Hemigrapsus sanguineus (de Haan, 1835), and elucidated the association of its locomotor behavior with Parkinson's-like symptoms. An immunocytochemistry analysis showed a reduction in tyrosine hydroxylase (TH) in the median brain and the ventral nerve cord (VNC), which correlated with the subsequent decrease in the locomotor activity of shore crabs. We also observed a variation in cholinergic neurons' activity, mostly in the ventral regions of the VNC. Moreover, the rotenone-treated crabs showed signs of damage to ChAT-lir neurons in the VNC. These data suggest that chronic treatment with low doses of rotenone decreases the DA level in the VNC and the ACh level in the brain and leads to progressive and irreversible reductions in the crab's locomotor activity, life span, and changes in behavior.

Intranasal delivery of liposome encapsulated flavonoids ameliorates l-DOPA induced dyskinesia in hemiparkinsonian mice

In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l-DOPA induced dyskinesia (LID), which is the debilitating side effect of l-DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l-DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals.

Study protocol for the MIND-PD study: a randomized controlled trial to investigate clinical and biological effects of mindfulness-based cognitive therapy in people with Parkinson’s disease

BackgroundPeople with Parkinson’s disease (PD) are very sensitive to the effects of stress. The prevalence of stress-related neuropsychiatric symptoms is high, and acute stress worsens motor symptoms. Animal studies suggest that chronic stress may accelerate disease progression, but evidence for this in humans is lacking. Mindfulness-based interventions (MBIs) train participants to focus on the present moment, on purpose and without judgement. Previous studies suggest that MBIs may alleviate stress and reduce depression and anxiety in PD. We aim to demonstrate the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) as a non-pharmacologic treatment strategy for neuropsychiatric (and motor) symptoms in PD, and to identify the mechanisms underlying stress and stress reduction in PD.MethodsIn a prospective randomized controlled trial (RCT), we investigate whether 8 weeks of MBCT, as compared to care as usual, can reduce symptoms of anxiety and depression in people with PD. We aim to include 124 PD patients, who experience mild-moderate symptoms of anxiety and depression, are eligible for magnetic resonance imaging (MRI) and naïve to mindfulness, and who have a disease duration ≤ 10 years. Every participant is followed for 12 months. Clinical and biochemical assessments take place at baseline (T0), after 2 months (T1), and after 12 months (T2); MRI assessments take place at T0 and T2. Our primary outcome is the total score on the Hospital Anxiety and Depression Scale (HADS) at T1, while correcting for the HADS score at T0, age, and gender. Beyond testing the effects of MBCT on symptoms of anxiety and depression in PD, we explore whether MBCT: (1) has an effect on motor symptom severity, (2) influences cerebral and biochemical markers of stress, and (3) leads to a change in biomarkers of PD progression.DiscussionMIND-PD is one of the first RCTs with a 1-year follow-up to investigate the effects of MBCT on symptoms of anxiety and depression in PD, and to explore possible mechanisms underlying stress and stress reduction in PD. Insight into these mechanisms can pave the way to new treatment methods in the future.Trial registrationClinicalTrials.gov, NCT05779137. Registered on 12 January 2023.

Peripheral mast cells derive the effects of acupuncture in Parkinson's disease.

This research investigates the peripheral mechanisms of acupuncture in treating Parkinson's disease (PD), a progressive neurodegenerative disorder marked by motor impairments. While the central mechanisms of acupuncture have been extensively studied, our focus lies in the peripheral mechanisms at the acupoints, the sites of acupuncture signal initiation. Employing a PD model, we analyzed the local responses to acupuncture stimulation at these points. Our key finding was a significant elevation in both the number and activity of mast cells (MCs) in the peripheral tissues following acupuncture. Intriguingly, pre-treatment with an MC stabilizer diminished the acupuncture's therapeutic effects on PD symptoms. Similarly, local anesthesia with lidocaine at the acupoints attenuated the symptom improvement typically observed with acupuncture. Meanwhile, the augmentation of MC activity induced by acupuncture was significantly impeded by cromolyn, an MC stabilizer, but remained unaffected by lidocaine. This finding suggests that MC activity is a more upstream regulator of acupuncture effects compared to nerve conduction. This study provides groundbreaking insights into the initiation and transmission of acupuncture signals, highlighting the significant role of peripheral MC modulation in PD treatment.

Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of pain and anxiety symptoms in Parkinson's disease mice model.

Pain and anxiety are two common and undertreated non-motor symptoms in Parkinson's disease (PD), which affect the life quality of PD patients, and the underlying mechanisms remain unclear. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical long-term potentiation (LTP) and injury induced synaptic potentiation in the cortical areas including anterior cingulate cortex (ACC) and insular cortex (IC). Genetic deletion of AC1 or pharmacological inhibition of AC1 improved chronic pain and anxiety in different animal models. In this study, we proved the motor deficit, pain and anxiety symptoms of PD in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model. As a lead candidate AC1 inhibitor, oral administration (1 dose and seven doses) of NB001 (20 and 40mg/kg) showed significant analgesic effect in MPTP-treated mice, and the anxiety behavior was also reduced (40mg/kg). By using genetic knockout mice, we found that AC1 knockout mice showed reduced pain and anxiety symptoms after MPTP administration, but not AC8 knockout mice. In summary, genetic deletion of AC1 or pharmacological inhibition of AC1 improved pain and anxiety symptoms in PD model mice, but didn't affect motor function. These results suggest that NB001 is a potential drug for the treatment of pain and anxiety symptoms in PD patients by inhibiting AC1 target.

Advancing Parkinson's disease treatment: cell replacement therapy with neurons derived from pluripotent stem cells.

The motor symptoms of Parkinson's disease (PD) are caused by the progressive loss of dopamine neurons from the substantia nigra. There are currently no treatments that can slow or reverse the neurodegeneration. To restore the lost neurons, international groups have initiated clinical trials using human embryonic or induced pluripotent stem cells (PSCs) to derive dopamine neuron precursors that are used as transplants to replace the lost neurons. Proof-of-principle experiments in the 1980s and 1990s showed that grafts of fetal ventral mesencephalon, which contains the precursors of the substantial nigra, could, under rare circumstances, reverse symptoms of the disease. Improvements in PSC technology and genomics have inspired researchers to design clinical trials using PSC-derived dopamine neuron precursors as cell replacement therapy for PD. We focus here on 4 such first-in-human clinical trials that have begun in the US, Europe, and Japan. We provide an overview of the sources of PSCs and the methods used to generate cells for transplantation. We discuss pros and cons of strategies for allogeneic, immune-matched, and autologous approaches and novel methods for overcoming rejection by the immune system. We consider challenges for safety and efficacy of the cells for durable engraftment, focusing on the genomics-based quality control methods to assure that the cells will not become cancerous. Finally, since clinical trials like these have never been undertaken before, we comment on the value of cooperation among rivals to contribute to advancements that will finally provide relief for the millions suffering from the symptoms of PD.

The neurophysiological brain-fingerprint of Parkinson’s disease

Research in healthy young adults shows that characteristic patterns of brain activity define individual "brain-fingerprints" that are unique to each person. However, variability in these brain-fingerprints increases in individuals with neurological conditions, challenging the clinical relevance and potential impact of the approach. Our study shows that brain-fingerprints derived from neurophysiological brain activity are associated with pathophysiological and clinical traits of individual patients with Parkinson's disease (PD). We created brain-fingerprints from task-free brain activity recorded through magnetoencephalography in 79 PD patients and compared them with those from two independent samples of age-matched healthy controls (N=424 total). We decomposed brain activity into arrhythmic and rhythmic components, defining distinct brain-fingerprints for each type from recording durations of up to 4min and as short as 30s. The arrhythmic spectral components of cortical activity in patients with Parkinson's disease are more variable over short periods, challenging the definition of a reliable brain-fingerprint. However, by isolating the rhythmic components of cortical activity, we derived brain-fingerprints that distinguished between patients and healthy controls with about 90% accuracy. The most prominent cortical features of the resulting Parkinson's brain-fingerprint are mapped to polyrhythmic activity in unimodal sensorimotor regions. Leveraging these features, we also demonstrate that Parkinson's symptom laterality can be decoded directly from cortical neurophysiological activity. Furthermore, our study reveals that the cortical topography of the Parkinson's brain-fingerprint aligns with that of neurotransmitter systems affected by the disease's pathophysiology. The increased moment-to-moment variability of arrhythmic brain-fingerprints challenges patient differentiation and explains previously published results. We outline patient-specific rhythmic brain signaling features that provide insights into both the neurophysiological signature and symptom laterality of Parkinson's disease. Thus, the proposed definition of a rhythmic brain-fingerprint of Parkinson's disease may contribute to novel, refined approaches to patient stratification. Symmetrically, we discuss how rhythmic brain-fingerprints may contribute to the improved identification and testing of therapeutic neurostimulation targets. Data collection and sharing for this project was provided by the Quebec Parkinson Network (QPN), the Pre-symptomatic Evaluation of Novel or Experimental Treatments for Alzheimer's Disease (PREVENT-AD; release 6.0) program, the Cambridge Centre for Aging Neuroscience (Cam-CAN), and the Open MEG Archives (OMEGA). The QPN is funded by a grant from Fonds de Recherche du Québec - Santé (FRQS). PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the FRQS, an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. The Brainstorm project is supported by funding to SB from the NIH (R01-EB026299-05). Further funding to SB for this study included a Discovery grant from the Natural Sciences and Engineering Research Council of Canada of Canada (436355-13), and the CIHR Canada research Chair in Neural Dynamics of Brain Systems (CRC-2017-00311).

A Computational Model of Deep Brain Stimulation for Parkinson's Disease Tremor and Bradykinesia.

Parkinson's disease (PD) is a progressive neurological disorder that is typically characterized by a range of motor dysfunctions, and its impact extends beyond physical abnormalities into emotional well-being and cognitive symptoms. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) leads to an array of dysfunctions in the functioning of the basal ganglia (BG) circuitry that manifests into PD. While active research is being carried out to find the root cause of SNc cell death, various therapeutic techniques are used to manage the symptoms of PD. The most common approach in managing the symptoms is replenishing the lost dopamine in the form of taking dopaminergic medications such as levodopa, despite its long-term complications. Another commonly used intervention for PD is deep brain stimulation (DBS). DBS is most commonly used when levodopa medication efficacy is reduced, and, in combination with levodopa medication, it helps reduce the required dosage of medication, prolonging the therapeutic effect. DBS is also a first choice option when motor complications such as dyskinesia emerge as a side effect of medication. Several studies have also reported that though DBS is found to be effective in suppressing severe motor symptoms such as tremors and rigidity, it has an adverse effect on cognitive capabilities. Henceforth, it is important to understand the exact mechanism of DBS in alleviating motor symptoms. A computational model of DBS stimulation for motor symptoms will offer great insights into understanding the mechanisms underlying DBS, and, along this line, in our current study, we modeled a cortico-basal ganglia circuitry of arm reaching, where we simulated healthy control (HC) and PD symptoms as well as the DBS effect on PD tremor and bradykinesia. Our modeling results reveal that PD tremors are more correlated with the theta band, while bradykinesia is more correlated with the beta band of the frequency spectrum of the local field potential (LFP) of the subthalamic nucleus (STN) neurons. With a DBS current of 220 pA, 130 Hz, and a 100 microsecond pulse-width, we could found the maximum therapeutic effect for the pathological dynamics simulated using our model using a set of parameter values. However, the exact DBS characteristics vary from patient to patient, and this can be further studied by exploring the model parameter space. This model can be extended to study different DBS targets and accommodate cognitive dynamics in the future to study the impact of DBS on cognitive symptoms and thereby optimize the parameters to produce optimal performance effects across modalities. Combining DBS with rehabilitation is another frontier where DBS can reduce symptoms such as tremors and rigidity, enabling patients to participate in their therapy. With DBS providing instant relief to patients, a combination of DBS and rehabilitation can enhance neural plasticity. One of the key motivations behind combining DBS with rehabilitation is to expect comparable results in motor performance even with milder DBS currents.

Fumaria vaillantii extract protects PC12 cells against neurotoxicity induced by 6-OHDA.

Parkinson's disease is a neurological disorder caused by the loss of dopaminergic neurons in the midbrain. Various mechanisms are involved in the incidence of the disease including oxidative stress. Several herbs and natural products may interfere with the oxidative-stress pathway due to their antioxidant effects. Herein, we aimed to investigate the neuroprotective role of F. vaillantii extract on Parkinson's in vitro and in vivo model owing to the presence of the bioactive agents with antioxidant properties. In vitro experments showed that 6-hydroxydopamine could induce toxicity in PC12 cells. The impact of F. vaillantii extract on cell viability was measured by using MTT assay. Nuclear morphological changes were qualitatively evaluated employing Hoechst staining. The antioxidant activity of the extract was determined by ROS and lipid peroxidation assays. Tyrosine hydroxylase protein expression was measured by western blotting in PC12 cells. For in vivo study, movement parameters were evaluated. The results indicated that 75 µΜ of 6-OHDA induced 50% toxicity in PC12 cells for 24h. Following post-treatment with F. vaillantii extract (0.1mg/ml) for 72h, we observed that the extract effectively prevented cell toxicity induced by 6-OHDA and reduced the apoptotic cell population. Furthermore, the extract attenuated the ROS level, lipid peroxidation and increased protein expression of TH after 72h of treatment. In addition, oral administration of 300mg/kg of F. vaillantii extract for 14 days improved locomotor activity, catalepsy, bradykinesia, motor coordination and reduced the apomorphine-caused rotation in 6-OHDA- induced Parkinson's disease-like symptoms in male rats. The present study suggests a protective role for the extract of F. vaillantii against oxidative stress-induced cell damage in the PC12 cells exposed to neurotoxin 6-OHDA which was verified in in vivo model by reducing the motor defects induced by 6-OHDA. This extract could be a promising therapeutic agent for the prevention of PD progression.

Research of upper limb tremor reduction with a vibrational medical device for Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disease that manifests as a various movement disorders: tremor, rigidity and postural instability. These dysfunctions can significantly impact the individual’s quality of life, leading to a decline in overall well-being. However, recent innovations in medical devices field promise additional methods to alleviate PD symptoms. The VILIM Ball is a local hand-arm stimulation device that generates mechanical vibrations within the frequency range of 8–18 Hz. It was shown in this study that Parkinson’s disease patients (PD) may experience enhanced upper limb functionality and reduction in tremor power through physiotherapy in conjunction to therapy with VILIM Ball device. A total of 24 participants were recruited and divided into two groups: the control group (N= 12) underwent physiotherapy alone, while the experimental group (N= 12) received physiotherapy in combination with the VILIM Ball. Hand coordination, tremor power, and the right-hand grip strength before and after interventions were assessed to quantify the effects of the interventions. The right-hand tremor power decreased by an average of 7.38% for the control group and by an average of 48.11% for the experimental group. The left-hand tremor power increased by 3.89% for the control group and decreased by the 30.23% for the experimental group. There were no significant changes in the right-hand grip strength after the interventions. These findings indicate that the local hand-arm vibration provided by the VILIM Ball in conjunction to physiotherapy can benefit patients more than the physiotherapy alone.

Associations between gut microbiota characteristics and non-motor symptoms following pharmacological and surgical treatments in Parkinson's disease patients.

The gut microbiota has been implicated in Parkinson's disease (PD), with alterations observed in microbial composition and reduced microbial species richness, which may influence gastrointestinal symptoms in PD patients. It remains to be determined whether the severity of gastrointestinal symptoms correlates with microbiota variations in PD patients treated pharmacologically or with subthalamic nucleus deep brain stimulation (STN-DBS) therapy. This study aims to explore how these treatments affect gut microbiota and gastrointestinal symptoms in PD, identifying specific microbial differences associated with each treatment modality. A total of 42 individuals diagnosed with PD, along with 38 age-matched household control participants, contributed stool samples for microbiota characterization. Differences in the gut microbiota across various groups of PD patients and their households were identified through comprehensive sequencing of the 16S rRNA gene amplicon sequencing. Differences in microbial communities were observed between PD patients and controls, as well as between PD patients receiving pharmacological treatment and those with STN-DBS. Pharmacologically treated advanced PD patients have higher gastrointestinal dysfunctions. Gut microbiota profile linked to STN-DBS and reduced levodopa consumption, characterized by its anti-inflammatory properties, might play a role in diminishing gastrointestinal dysfunction relative to only pharmacological treatments. Advanced PD patients on medication exhibit more gastrointestinal issues, despite relatively stable microbial diversity, indicating a complex interaction between gut microbiota, PD progression, and treatment effects. An imbalanced gut-brain axis, particularly due to reduced butyrate production, may lead to constipation by affecting the enteric nervous system, which emphasizes the need to incorporate gut microbiome insights into treatment strategies.

Emergence of pathological beta oscillation and its uncertainty quantification in a time-delayed feedback Parkinsonian model

It has been experimentally found that transmission delays play an important role in the emergence of excessively synchronized beta oscillations (13–30 Hz) related to the onset of Parkinson’s symptoms. In order to clarify the dynamical mechanism underlying beta oscillations, we generalize a conventional resonance model based on the subthalamic nucleus (STN)-external segment of globus pallidus (GPe)-cortex circuit to a feedback Parkinsonian model by incorporating the transmission delay within the basal ganglia (STN-GPe circuit) and the transmission delay from the STN to the cortex. By combining the theory of center manifolds and normal forms with numerical simulations, it is revealed how the pathological beta oscillations occur as the transmission delays increase beyond critical values. Furthermore, by regarding the transmission delays and the connection weights as random variables, variance-based sensitivity analysis is performed based on polynomial chaos expansion. It is identified that the transmission delays and connection strength in the long STN-cortex circuit are more significant than those in the STN-GPe circuit for beta oscillations. Our results also suggest that the severity of the Parkinsonian symptoms could be alleviated if a clinical therapy, such as deep brain stimulation, can enlarge the transmission delays in the STN-GPe and STN-cortex circuits simultaneously.

Neuroprotective Potentials of Berberine in Rotenone-Induced Parkinson's Disease-like Motor Symptoms in Rats.

Rotenone (RTN) induces neurotoxicity and motor dysfunction in rats, mirroring the pathophysiological traits of Parkinson's disease (PD), including striatal oxidative stress, mitochondrial dysfunction, and changes in neural structure. This makes RTN a valuable model for PD research. Berberine (BBR), an isoquinoline alkaloid recognized for its antioxidative, anti-inflammatory, and neuroprotective properties, was evaluated for its ability to counteract RTN-induced impairments. Rats received subcutaneous RTN at 0.5 mg/kg for 21 days, resulting in weight loss and significant motor deficits assessed through open-field, bar catalepsy, beam-crossing, rotarod, and grip strength tests. BBR, administered orally at 30 or 100 mg/kg doses, one hour prior to RTN exposure for the same duration, effectively mitigated many of the RTN-induced motor impairments. Furthermore, BBR treatment reduced RTN-induced nitric oxide (NO) and lipid peroxidation (LPO) levels, bolstered antioxidative capacity, enhanced mitochondrial enzyme activities (e.g., succinate dehydrogenase (SDH), ATPase, and the electron transport chain (ETC)), and diminished striatal neuroinflammation and apoptosis markers. Notably, the co-administration of trigonelline (TGN), an inhibitor of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway, significantly attenuated BBR's protective effects, indicating that BBR's neuroprotective actions are mediated via the Nrf2 pathway. These results underscore BBR's potential in ameliorating motor impairments akin to PD, suggesting its promise in potentially delaying or managing PD symptoms. Further research is warranted to translate these preclinical findings into clinical settings, enhancing our comprehension of BBR's therapeutic prospects in PD.

An Ethnographic Study of Patient Life Experience in Early-Stage Parkinson's Disease in the United States and Germany.

Existing qualitative research on early-stage Parkinson's disease draws on patients' reported disease experience, aiming to capture the symptoms and impacts most relevant to patients living with the disease. As a complement to this research, the present study investigated the patient experience of early-stage Parkinson's disease from a holistic, ethnographic perspective. We explored the attitudes, beliefs, and social structures that shape how people understand and adapt to life with early-stage Parkinson's disease. Researchers interviewed 30 people with early-stage Parkinson's disease, 10 relatives, and 10 neurologists and movement disorder specialists in the USA and Germany. Many of these interviews took place in-person, allowing researchers to spend time in participants' homes and witness their daily lives. A multidisciplinary team of social scientists, clinical researchers, and patient organization representatives led the mixed-methods study design and analysis. In-depth ethnographic interviews yielded qualitative insights, with a quantitative survey following to assess their prevalence in a larger sample of 150 patients. In addition to developing a patient life experience pathway of early-stage Parkinson's disease, we identified five key thematic findings that provide insight into how the clinical features of the disease become meaningful to patients on the context of their daily lives, family relations, and subjective well-being: (1) People with early-stage Parkinson's disease start coming to terms with their disease before receiving a medical diagnosis; (2) Acceptance is not a finalized achievement, but a cyclical process; (3) People with early-stage Parkinson's disease "live in the moment" to make the future more manageable; (4) Slowing disease progression is an important goal driving the actions of people with early-stage Parkinson's; and (5) People with early-stage Parkinson's disease value information that is grounded in lived experience and relevant to their stage of disease progression. This holistic, ethnographic approach to patient life experience provided five key thematic findings that complement insights from qualitative and quantitative datasets on early-stage Parkinson's disease. An enhanced understanding of how early-stage Parkinson's symptoms impact patients' health-related quality of life and their broader social lives can help us better understand how patients make decisions about their usage of healthcare services and therapies.

Exploring the experiences, priorities and preferences of people living with Parkinson's on exercise and physical activity promotion in the UK.

People with Parkinson's (PwP) want access to timely, relevant, and specific exercise and physical activity (PA) information to enable them to manage their symptoms and maintain wellbeing and quality of life. Research that promotes exercise in this population group is limited. Little is also known about the clinical practice around PA promotion in this population, especially around the time of diagnosis. To explore the experiences, preferences, and priorities of PwP around exercise and PA promotion and assess their knowledge on these topics. A cross-sectional online survey for PwP in the United Kingdom was conducted from July to December 2021. 430 participants started the survey and 405 completed it. Participants had a mean age of 65.1 (±9.2) and had been living with Parkinson's for a varying time (up to 2 years = 38%, up to 6 years = 39% and for 7 or more years = 23%). Most participants reported they had not received an education (68%; n = 276) or exercise intervention (54%; n = 217) as part of their routine management by the National Health Service (NHS) since diagnosis and had sought services privately. Knowledge of the overall benefits of exercise was good, however participants lacked specific knowledge on the impact of Parkinson's Disease (PD) on posture, falls and muscle strength. 90% of participants reported they would participate in an exercise and PA education interventions. PwP want exercise and PA education interventions that provide knowledge, skills and access to opportunities that enable participation. For the majority, these interventions have not been provided as part of their routine care pathway. To align with the priorities and preferences of PwP, interventions should be offered around the time of diagnosis, include content that is relevant and specific to how exercise and PA can mitigate symptoms of PD and should be delivered in person or online in a group setting.

Non-motor symptoms in PD evaluated during pharmacological ON state by a new tool: The NoMoS-ON scale. Is always the "ON" state beneficial?

ObjectivesTo evaluate non-motor symptoms (NMS) occurring during ON pharmacological state and validate a new questionnaire, the Non-motor symptoms-ON scale (NoMoS-ON), exploring ON NMS in Parkinson's disease (PD). Material and methodsPatients with PD were evaluated by a new questionnaire, the NoMoS-ON scale, evaluating 17 items related to the main symptoms experienced during the ON state. PD patients who experienced at least one symptom in ON were defined ON-NMS+. Internal consistency and test-retest reliability of NoMoS-ON scale were also assessed. ResultsOne-hundred and thirty-seven PD patients were consecutively enrolled (79 men and 58 women, age 69.4 ± 9.5 years (mean ± SD)). Seventy-seven patients were ON-NMS+ (56.6 %). PD patients with short disease duration (<7 years) showed the presence of unpleasant NMS: “sleepiness”, “light-headedness”, “nausea/vomiting”. PD patients with longer disease duration experienced pleasant non-motor features including “feel lot of energy”, “feel physical well-being”. ON-NMS+ were also associated with female gender (OR 2.81, 95%CI 1.37–5.77, p-value 0.005) and with motor fluctuations (OR 2.41, 95%CI 1.20–4.83, p-value 0.013). Cronbach's alpha was 0.61 and 5 items had adequate item-to-total correlations (r ≥ 0.40). Test–retest reliability was acceptable (intraclass correlation coefficient, ICC = 0.77). ConclusionsThe NoMoS-ON scale is a valid, reproducible and reliable questionnaire capturing the ON NMS in PD. PD patients with disease duration shorter than 7 years showed the presence of unpleasant NMS whereas those with longer disease duration experienced pleasant non-motor features. This could help the physician in the therapy management of PD patients in different phases of their disease.

A Comprehensive Study for Assessing the Demand and Supply Dynamics of Parkinson's Disease Medication in Roorkee, Uttarakhand

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. This depletion of dopamine, a neurotransmitter crucial for regulating movement, leads to the characteristic motor symptoms of PD, including tremors, rigidity, bradykinesia, and postural instability. In India, the prevalence of PD is increasing, necessitating greater attention to the availability and distribution of appropriate medication. This comprehensive study aims to assess the demand and supply dynamics of PD medication in Roorkee, Uttarakhand. After recording the sales per week of various drugs, brands, dosage forms, and strengths available in Roorkee, it was determined that SINEMET (Carbidopa + Levodopa) is widely accessible in the region, with STALEVO, MIRAPEX (Pramipexole), and ARTANE (Trihexyphenidyl) being the other prominent brands available in local medical stores. These medications are primarily in tablet form. Sales data from different stores indicated that SINEMET (Carbidopa + Levodopa 25/250 mg) is the most popular drug in the Roorkee area for treating PD. In terms of drug type analysis, levodopa-based decarboxylase inhibitors, particularly the combination of Levodopa and Carbidopa, currently hold a dominant position in the PD drug market in the region