Parkinson's Disease Research Articles

Tribuli Fructus alleviates 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease by suppressing neuroinflammation via JNK signaling.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons. In particular, neuroinflammation associated with phosphorylation of c-Jun N-terminal kinase (JNK) is likely to cause the death of dopaminergic neurons. Therefore, protecting dopaminergic neurons through anti-neuroinflammation is a promising therapeutic strategy for PD. This study investigated whether Tribuli Fructus (TF) could alleviate PD by inhibiting neuroinflammation. Mouse primary mixed glial culture cells from the mouse cortex were treated with lipopolysaccharide (LPS) to induce neuroinflammation, and 1h later, cells were treated with TF. 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) was injected into C57BL/6J mice for 5 days, and TF was co and post-administered for 12 days. Our study showed that TF attenuated pro-inflammatory mediators and cytokines in LPS-stimulated primary mixed glial cultures. In the brains of MPTP-induced PD mouse model, TF inhibited the activation of microglia and astrocytes, protected dopaminergic neurons, and increased dopamine levels. TF alleviated MPTP-induced bradykinesia, a representative behavioral disorder in PD. In addition, the results in vitro and in vivo revealed that TF regulates the phosphorylation of JNK. Collectively, our data suggest that TF may be a new therapeutic candidate for PD by regulating JNK signaling.

Parkinson's disease subtypes and their association with probable rapid eye movement sleep behavior disorder severity: a brainstem tractography and machine learning investigation.

Rapid Eye Movement (REM) sleep behavior disorder (RBD) affects nearly half of Parkinson's disease (PD) patients. However, the structural heterogeneity within the brainstem, which regulates REM sleep, remains largely unexplored in PD. Our objective was to identify distinct PD subtypes based on microstructural characteristics in the brainstem and examine their associations with the severity of RBD. Data, including diffusion tensor imaging and REM sleep behavior disorder screening questionnaire (RBDSQ) responses, were obtained from 124 PD patients and 61 healthy controls through the Parkinson's Progression Marker Initiative database. Mean Quantitative Anisotropy (QA) values, representing axonal density, were extracted from 14 brainstem tracts and input into the semi-supervised machine learning algorithm, Heterogeneity through Discriminative Analysis (HYDRA), to cluster subtypes. Applying HYDRA, we identified two distinct PD subtypes (Subtype 1: n = 66, Subtype 2: n = 58). Subtype 2 exhibited reduced QA across assessed brainstem tracts and significantly higher RBDSQ scores than Subtype 1 and healthy controls (p < 0.001). Conversely, Subtype 1, characterized by lower RBDSQ scores, exhibited increased QA, notably in the right medial longitudinal fasciculus, when compared to Subtype 2 and controls (p < 0.001). These findings suggest that heterogeneous axonal damage in brainstem circuits correlates with variations in RBD severity, providing insights into the neurobiological underpinnings of early PD.

The Utility of Long-Read Sequencing in Diagnosing Early Onset Parkinson's Disease.

Variants in PRKN and PINK1 are the leading cause of early-onset autosomal recessive Parkinson's disease, yet many cases remain genetically unresolved. We previously identified a 7 megabases complex structural variant in a pair of monozygotic twins using Oxford Nanopore Technologies (ONT) long-read sequencing. This study aims to determine if ONT long-read sequencing can detect a second variant in other unresolved early-onset Parkinson's disease (EOPD) cases with 1 heterozygous PRKN or PINK1 variant. ONT long-read sequencing was performed on EOPD patients with 1 reported PRKN/PINK1 pathogenic variant, with onset age under 50. Positive controls included EOPD patients with 2 known PRKN pathogenic variants. Initial testing involved short-read targeted panel sequencing for single nucleotide variants and multiplex ligation-dependent probe amplification for copy number variants. A total of 47 patients were studied (PRKN "one-variant," n = 23; PINK1 "one-variant," n = 12; PRKN "two-variants," n = 12). ONT long-read sequencing identified a second pathogenic variant in 26% of PRKN "one-variant" patients (6/23), but none in PINK1 "one-variant" patients (0/12). Detected variants included 1 complex inversion, 2 structural variant overlaps, and 3 duplications. In the PRKN "two-variants" group, both variants were identified in all patients (100%, 12/12). ONT long-read sequencing effectively identifies pathogenic structural variants in the PRKN locus missed by conventional methods. It should be considered for unresolved EOPD cases when a second variant is not detected through conventional approaches. ANN NEUROL 2024.

Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.

The Parkinson's disease (PD)-linked protein Leucine-Rich Repeat Kinase 2 (LRRK2) consists of seven domains, including a kinase and a Roc G domain. Despite the availability of several high-resolution structures, the dynamic regulation of its unique intramolecular domain stack is nevertheless still not well understood. By in-depth biochemical analysis, assessing the Michaelis-Menten kinetics of the Roc G domain, we have confirmed that LRRK2 has, similar to other Roco protein family members, a KM value of LRRK2 that lies within the range of the physiological GTP concentrations within the cell. Furthermore, the R1441G PD variant located within a mutational hotspot in the Roc domain showed an increased catalytic efficiency. In contrast, the most common PD variant G2019S, located in the kinase domain, showed an increased KM and reduced catalytic efficiency, suggesting a negative feedback mechanism from the kinase domain to the G domain. Autophosphorylation of the G1+2 residue (T1343) in the Roc P-loop motif is critical for this phosphoregulation of both the KM and the kcat values of the Roc-catalyzed GTP hydrolysis, most likely by changing the monomer-dimer equilibrium. The LRRK2 T1343A variant has a similar increased kinase activity in cells compared to G2019S and the double mutant T1343A/G2019S has no further increased activity, suggesting that T1343 is crucial for the negative feedback in the LRRK2 signaling cascade. Together, our data reveal a novel intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism. Interestingly, PD mutants differently change the kinetics of the GTPase cycle, which might in part explain the difference in penetrance of these mutations in PD patients.

Emerging role of Nrf2 in Parkinson's disease therapy: a critical reassessment.

Parkinson's disease (PD) is the neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons, leading to the range of motor and non-motor symptoms. There is mounting evidence suggesting that oxidative stress, neuroinflammation and mitochondrial dysfunction play pivotal roles in the pathogenesis of PD. Current therapies only alleviate perturbed motor symptoms. Therefore, it is essential to find out new therapies that allow us to improve not only motor symptoms, but non-motor symptoms like cognitive impairment and modulate disease progression. Nuclear factor erythroid 2-related factor 2 (Nrf2) is transcription factor that regulates the expression of numerous anti-oxidants and cytoprotective genes can counteract oxidative stress, neuroinflammation and mitochondrial dysfunction, thereby potentially ameliorating PD-associated pathology. The current review discusses about the Nrf2 structure and function with special emphasis on various molecular signalling pathways involved in positive and negative modulation of Nrf2, namely Glycogen synthase kinase-3β, Phosphoinositide-3-kinase, AMP-activated protein kinase, Mitogen activated protein kinase, nuclear factor-κB and P62. Furthermore, this review highlights the various Nrf2 activators as promising therapeutic agents for slowing down the progression of PD.

MicroRNA signatures in neuroplasticity, neuroinflammation and neurotransmission in association with depression.

Depression is a multifactorial disorder that occurs mainly on account of the dysregulation of neuroplasticity, neurotransmission and neuroinflammation in the brain. In addition to environmental /lifestyle factors, the pathogenesis of disease has been associated with genetic and epigenetic factors that affect the reprogramming of normal brain function. MicroRNA (miRNAs), a type of non-coding RNAs, are emerging as significant players that play a vital role in the regulation of gene expression and have been extensively explored in neurodegenerative disorders. Recent studies have also shown the role of gut microbiota that forms a complex bidirectional network with gut brain axis, impacting neuroinflammation in case of Parkinson's disease and depression. Translating targeted miRNA-based therapies for the treatment of neurological disorders including depression, into clinical practice remains challenging due to the ineffective delivery of the therapeutic molecules and off-target effects of the specific miRNAs. This review provides significant insights into how miRNAs are emerging as vital players in the development of depression, especially the ones involved in three important processes including neuroplasticity, neurotransmission and neuroinflammation. In this review, the current status of miRNAs as biomarkers for therapeutic interventions in the case of depression has been discussed along with an overview of future perspectives, like use of nanotechnology and gene editing, keeping in view other multifactorial disorders where such interventions by mimics and inhibitors have already reached clinical trials. The challenges for targeting the specific miRNAs for therapeutic outcomes have also been highlighted.

Attenuated afferent inhibition correlated with impaired gait performance in Parkinson’s disease patients with freezing of gait

BackgroundThe neural mechanisms underlying freezing of gait (FOG) in Parkinson’s disease (PD) have not been completely comprehended. Sensory-motor integration dysfunction was proposed as one of the contributing factors. Here, we investigated short-latency afferent inhibition (SAI) and long-latency afferent inhibition (LAI), and analyzed their association with gait performance in FOG PD patients, to further validate the role of sensorimotor integration in the occurrence of FOG in PD.MethodsTwenty-five levodopa responsive-FOG PD patients (LR-FOG), fifteen levodopa unresponsive-FOG PD patients (LUR-FOG), twenty-eight PD patients without FOG (NO-FOG PD) and twenty-two healthy controls (HC) were included in the study. Clinical features such as PD motor symptoms, FOG severity and cognitive abilities were evaluated using clinical scales in subjects with PD. All participants underwent paired associative stimulation (PAS) to evaluate SAI and LAI in addition to regular input-output curve by transcranial magnetic stimulation. The performances of gait were assessed using a portable gait analyzing system in 10-meter timed Up and Go task. The correlations between the gait spatiotemporal parameters or the scores of FOG scale and the magnitudes of SAI or LAI were analyzed.ResultsCompared to HC and NO-FOG PD patients, SAI was decreased in FOG PD subgroups. LAI was also reduced in both LR-FOG PD and LUR-FOG PD in relative to HC; however, only LUR-FOG PD showed significant reduction of LAI in comparison to NO-FOG PD group. FOG PD patients showed poorer gait performance compared to HC and NO-FOG PD group. The reduction of SAI and LAI were correlated with the impaired gait spatiotemporal parameters or scores of FOG scale in PD with FOG.ConclusionThe SAI and LAI were attenuated in PD patients with FOG, and the reduction of SAI or LAI were correlated to disturbed gait performance, indicating that sensory-motor integration dysfunction played a role in the development of FOG in PD.

Lead Phytomolecules for Treating Parkinson's Disease.

One percent of persons over 65 years of age suffer from Parkinson's disease, a neurological ailment marked by dopaminergic neurons in the nigrostriatal pathway gradually dying and being depleted in the striatum. Parkin and PINK1 gene mutations, which are essential for mitophagy and impair mitochondrial function, are the cause of it. Parkinson's disease is linked to a number of motor and impairment disorders, including bradykinesia, rigid muscles, tremor at rest, and imbalance. Numerous signaling pathways, including α-synuclein aggregation, lead to age-related decline in proteolytic defense systems. Parkinson's disease etiology involves oxidative stress, ferroptosis, mitochondrial failure, and neuroinflammation. Parkinson's disease is significantly influenced by neuroinflammation, which is a result of both innate and adaptive immune responses. The purpose of studying mechanisms and phytomolecules is to assist researchers in creating therapies for Parkinson's disease. Phytomolecules, like curcumin, β- amyrin, berberine, capsaicin, and gentisic acid, exert neuroprotective properties by reducing ROS levels, lessening α-synuclein-induced toxicity, and shielding the cells from apoptosis. In conclusion, the studies presented here provide valuable insights into the potential of various medications for Parkinson's disease treatment. By understanding the mechanisms behind these treatments, researchers can develop more effective treatments for PD.

Integrating bioinformatics and machine learning to uncover lncRNA LINC00269 as a key regulator in Parkinson's disease via pyroptosis pathways

BackgroundPyroptosis, a specific type of programmed cell death, which has become a significant factor to Parkinson's disease (PD). Concurrently, long non-coding RNAs (lncRNAs) have garnered attention for their regulatory roles in neurodegenerative disorders. This study was designed to ascertain the key lncRNAs in pyroptosis pathways of PD and elucidate their regulatory mechanisms.MethodsEmploying a combination of bioinformatics and machine learning, we analyzed PD data sets GSE133347 and GSE110716. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) recognized different lncRNAs. Through various algorithms such as Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest (RF), and Weighted Gene Co-expression Network Analysis (WGCNA), we recognized LINC01606 and LINC00269, which are key factors during the emergence and development of PD. Furthermore, experimental validation was conducted in PD mouse models to confirm these bioinformatics findings.ResultsThe analysis showed that there were a large number of apoptosis-related gene expression changes in Parkinson's syndrome, for example, CASP1 and GSDME were up-regulated, and CASP9 and AIM2 were down-regulated. Among the lncRNAs, LINC01606 and LINC00269 were identified as potential modulators of pyroptosis. Notably, LINC00269 was observed to be significantly downregulated in the brain tissues of a PD mouse model, supporting its involvement in PD. The study also highlighted potential interactions of these lncRNAs with genes like ONECUT2, PRLR, CTNNA3, and LRP2.ConclusionsThis study identifies LINC00269 as a potential contributor to pyroptosis pathways in PD. While further investigation is required to fully elucidate its role, these findings provide new insights into PD pathogenesis and suggest potential avenues for future research on diagnostic and therapeutic targets. The study underscores the importance of integrating bioinformatics with experimental validation in neurodegenerative disease research.

Association between the Amplification Parameters of the α-Synuclein Seed Amplification Assay and Clinical and Genetic Subtypes of Parkinson's Disease.

α-Synuclein seed amplification assay on cerebrospinal fluid (CSF-αSyn-SAA) has shown high accuracy for Parkinson's disease (PD) diagnosis. The analysis of CSF-αSyn-SAA parameters may provide useful insight to dissect the heterogeneity of synucleinopathies. To assess differences in CSF-αSyn-SAA amplification parameters in participants with PD stratified by rapid eye movement (REM) sleep behavior disorder (RBD), dysautonomia, GBA, and LRRK2 variants. Clinical and CSF-αSyn-SAA data from the Parkinson's Progression Marker Initiative dataset were used. CSF-αSyn-SAA parameters included maximum fluorescence (Fmax), time to reach 50% of Fmax (T50), time to threshold (TTT), slope, and area under the curve (AUC). Sporadic PD (n = 371) was stratified according to RBD and dysautonomia (DysA) symptoms. Genetic PD included carriers of pathogenic variants of GBA (GBA-PD, n = 52) and LRRK2 (LRRK2-PD, n = 124) gene. CSF-αSyn-SAA was positive in 77% of LRRK2-PD, 92.3% of GBA-PD, and 93.8% of sporadic PD. The LRRK2-PD cohort showed longer T50 and TTT, and smaller AUC than GBA-PD (P = 0.029, P = 0.029, P = 0.016, respectively) and sporadic PD (P = 0.034, P = 0.033, P = 0.014, respectively). In the sporadic cohort, CSF-αSyn-SAA parameters were similar between PD with (n = 157) and without (n = 190) RBD, whereas participants with DysA (n = 193) presented shorter T50 (P = 0.026) and larger AUC (P = 0.029) than those without (n = 150). CSF-αSyn-SAA parameters vary across genetic and non-genetic PD subtypes at the group level. These differences are mostly driven by the presence of LRRK2 variants and DysA. Significant overlaps in the amplification parameter values exist between groups and limit their use at the individual level. Further studies are necessary to understand the mechanisms of CSF-αSyn-SAA parameter differences. © 2024 International Parkinson and Movement Disorder Society.

Paracentrotus lividus sea urchin gonadal extract mitigates neurotoxicity and inflammatory signaling in a rat model of Parkinson's disease.

The present study investigates the neuroprotective effects of the sea urchin Paracentrotus lividus gonadal extract on rotenone-induced neurotoxicity in a Parkinson's disease (PD) rat model. Parkinson's disease, characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN), is exacerbated by oxidative stress and neuroinflammation. The study involved fifty Wistar rats divided into five groups: control, dimethyl sulfoxide (DMSO) control, Paracentrotus lividus gonadal extract-treated, rotenone-treated, and combined rotenone with Paracentrotus lividus gonadal extract-treated. Behavioral assessments included the rotarod and open field tests, while biochemical analyses measured oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH)), antioxidants (superoxide dismutase (SOD), catalase (CAT)), pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), and neurotransmitters (dopamine (DA), levodopa (L-Dopa)). Histological and immunohistochemical analyses evaluated the neuronal integrity and tyrosine hydroxylase (TH) and alpha-synuclein expression. The results showed that Paracentrotus lividus gonadal extract significantly mitigated rotenone-induced motor deficits and improved locomotor activity. Biochemically, the extract reduced oxidative stress and inflammation markers while enhancing antioxidant levels. Histologically, it restored neuronal integrity and reduced alpha-synuclein accumulation. Molecularly, it increased tyrosine hydroxylase and dopa decarboxylase gene expression, essential for dopamine synthesis. These findings suggest that Paracentrotus lividus gonadal extract exerts neuroprotective effects by modulating oxidative stress, neuroinflammation, and dopaminergic neuron integrity, highlighting its potential as a therapeutic agent for Parkinson's disease.

Neuroinflammation as an Integral Component of Neurodegeneration in Parkinson's Disease

Parkinson's disease (PD) is a progressively advancing neurodegenerative disorder, the pathogenetic mechanisms of which remain poorly understood. The disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. Given the improvement in the quality of medical care provided to the population, it is projected that the total number of patients diagnosed with PD worldwide will rise to 8.7 million by 2030. This review addresses the fundamental aspects of neuroinflammation in the context of PD pathogenesis. There is no doubt that pro-inflammatory immunological mechanisms play a critical role in the onset and progression of the disease. Neuronal-derived cells, such as microglia and astrocytes, act as inducers of neuroinflammation, affecting the permeability of the blood-brain barrier to peripheral immune-competent cells. Furthermore, cytokine patterns of the immune response in PD appear to exist. Potential therapeutic approaches for mitigating neuroinflammation in PD, which have been studied in experimental and in vitro models, are also discussed.

Cognitive aspects of motor control deteriorate while off treatment following subthalamic nucleus deep brain stimulation surgery in Parkinson’s disease

IntroductionThe long-term effects of surgery for subthalamic nucleus deep brain stimulation (STN-DBS) on cognitive aspects of motor control for people with Parkinson’s disease (PD) are largely unknown. We compared saccade latency and reach reaction time (RT) pre- and post-surgery while participants with PD were off-treatment.MethodsIn this preliminary study, we assessed people with PD approximately 1 month pre-surgery while OFF medication (OFF-MEDS) and about 8 months post-surgery while OFF medication and STN-DBS treatment (OFF-MEDS/OFF-DBS). We examined saccade latency and reach reaction time (RT) performance during a visually-guided reaching task requiring participants to look at and reach toward a visual target.ResultsWe found that both saccade latency and reach RT significantly increased post-surgery compared to pre-surgery. In addition, there was no significant change in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III score.DiscussionWe found detrimental post-surgical changes to saccade latency and reach RT. We discuss the potential contributions of long-term tissue changes and withdrawal from STN-DBS on this detrimental cognitive effect.

Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson’s disease and parkinsonism-dementia of Guam

Mitochondrial dysfunction is a central aspect of Parkinson’s disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism-Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscores the role of α-Syn’s mitochondrial localization in inducing TOM40 degradation. PDe-related etiological factors, such as 6-hydroxydopamine or ROS/metal ions stress, which promotes α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.

Autophagy and Protein Quality Control in Parkinson's Disease.

Autophagy is a vital cellular process responsible for the degradation of proteins, organelles, and other cellular components within lysosomes. In neurons, basal autophagy is indispensable for maintaining cellular homeostasis and protein quality control. Accordingly, lysosomal dysfunction has been proposed to be associated with neurodegeneration, and with Parkinson's disease (PD) in particular. Aging, dopamine metabolism, and PD-linked genetic mutations are thought to impair the autophagic-lysosomal pathway, disrupt cellular proteostasis, and contribute to PD pathogenesis. These alterations represent an opportunity to identify potential new therapeutic targets and disease biomarkers, thus laying the groundwork for the development of novel disease-modifying strategies for PD that are aimed at restoring cellular proteostasis and quality control systems.

How Women and Men with Parkinson's Disease Approach Decision-Making for Deep Brain Stimulation Surgery.

Women make up only 23% to 30% of recipients for deep brain stimulation (DBS) surgery for Parkinson's disease (PD), a discrepancy that is not accounted for by differences in disease incidence. One of the many factors that may contribute to this gap includes gender differences in decision-making. The aim was to explore how women and men approach the decision for DBS in terms of informational needs, weighing risks and benefits, and decision-making. Semistructured interviews were conducted with 33 participants with PD who had undergone DBS evaluation within the past 3 years. Data were analyzed using content analysis. Sixteen women and 17 men participated in interviews. We identified 4 key themes. First, information sources were similar between women and men, and they valued hearing personal experiences. Second, the motivations for DBS surgery were often very personal. Third, the decision-making process occurred over time, sometimes years. Fourth, although many expressed fear of brain surgery, trust in the surgeon helped many overcome this fear. Women overall had less support than men during decision-making and after surgery. Women also placed greater value on talking to other women who had undergone DBS, although they had a hard time finding these women. Men, on the contrary, were less often worried about support and valued numerical information when weighing risks and benefits. We found gender differences in information needs, support, motivating factors, and how patients weighed risks and benefits. These differences can be used to inform educational tools and counseling for DBS.

Pathophysiology of Motor Control Abnormalities in Parkinson's Disease.

Research in the last few decades has brought us closer to an understanding of the brain circuit abnormalities that underlie parkinsonian motor signs. This article summarizes the current knowledge in this rapidly emerging field. Traditional observations of activity changes of basal ganglia neurons that accompany akinesia and bradykinesia have been supplemented with new knowledge regarding specific pathophysiologic changes that are associated with other parkinsonian signs, such as tremor and gait impairments. New research also emphasizes the role of non-basal ganglia structures in parkinsonism, including the pedunculopontine nucleus, the cerebellum, and the cerebral cortex, and the role of structural and functional neuroplasticity. A more detailed understanding of the brain network abnormalities that result from Parkinson's disease is necessary to arrive at more effective and specific treatments for these symptoms in parkinsonian patients through circuit interventions reaching from deep brain stimulation to genetic and chemogenetic treatments.

Clinical utility of synuclein skin biopsy in the diagnosis and evaluation of synucleinopathies

IntroductionThe diagnosis of diseases known as synucleinopathies, Parkinson’s disease (PD), multiple system atrophy (MSA) and Lewy body dementia (DLB), is predominantly based on clinical criteria. However, diagnostic uncertainty may persist until late in the disease process leading to delays in diagnosis and medical mismanagement. Skin biopsy detection of phosphorylated alpha-synuclein (P-SYN) is a sensitive and specific technique that increases diagnostic sensitivity of synucleinopathies, although the clinical utility of this test has not been fully explored.MethodsTo determine the role of skin biopsy in the diagnosis of synucleinopathies we performed a retrospective chart review of patients who underwent skin biopsy for detection of P-SYN in the evaluation of neurodegenerative disease at a tertiary care academic institution to investigate the change in diagnosis and medical management based on the results of skin biopsy detection of P-SYN.ResultsWe included 97 patients suspected to have a synucleinopathy: 54 with PD, 19 with DLB and 24 with MSA. After skin biopsy testing for P-SYN, 78% of patients had a change in their clinical care with 66% having a change in their diagnosis and 55% having a change in their treatment. Changes in diagnosis were most common in patients with parkinsonism with prominent action tremor (93%), lower-extremity predominant parkinsonism (postural instability and gait dysfunction) (90%), and parkinsonism with predominant cognitive dysfunction (76%).DiscussionIn patients with suspected synucleinopathies, skin biopsy detection of P-SYN had a high level of clinical utility leading to changes in clinical diagnosis and treatment.

NeuroVoz: a Castillian Spanish corpus of parkinsonian speech

The screening of Parkinson’s Disease (PD) through speech is hindered by a notable lack of publicly available datasets in different languages. This fact limits the reproducibility and further exploration of existing research. To address this gap, this manuscript presents the NeuroVoz corpus consisting of 112 native Castilian-Spanish speakers, including 58 healthy controls and 54 individuals with PD, all recorded in ON state. The corpus showcases a diverse array of speech tasks: sustained vowels; diadochokinetic tests; 16 Listen-and-Repeat utterances; and spontaneous monologues. The dataset is also complemented with subjective assessments of voice quality performed by an expert according to the GRBAS scale (Grade/Roughness/Breathiness/Asthenia/Strain), as well as annotations with a thorough examination of phonation quality, intensity, speed, resonance, intelligibility, and prosody. The corpus offers a substantial resource for the exploration of the impact of PD on speech. This data set has already supported several studies, achieving a benchmark accuracy of 89% for the screening of PD. Despite these advances, the broader challenge of conducting a language-agnostic, cross-corpora analysis of Parkinsonian speech patterns remains open.

Feasibility of a Pharmabuddy Care Service for patients with Parkinson’s disease

BackgroundPharmaceutical care for patients with Parkinson’s disease (PD) is complex. Specialized pharmaceutical care provided by a dedicated pharmacy team member (pharmabuddy) for these patients may reduce medication-related problems. The feasibility of this service for PD patients is unknown.ObjectiveTo evaluate the feasibility of a Pharmabuddy Care Service (PCS) for PD patients in primary care pharmacies.MethodsPharmabuddies who offered PCS were invited to fill in a questionnaire to evaluate the feasibility of PCS. Patients received a patient questionnaire and were invited for an interview. Patient records provided information on medication-related problems and interventions. Feasibility was evaluated conform four domains of Bowen’s Framework. First, acceptability included patients’ satisfaction ratings and experiences, Pharmabuddy impression on start and continuation of the service. Second, demand included use by patients and provision by pharmabuddies. Third, implementation/practicality: implementation indicators and barriers and facilitators from patient- and pharmabuddy perspective and fourth limited efficacy: effect of the PCS on PD symptoms, medication related problems identified and interventions from patient records.ResultsTwenty-three (59%) patients completed the questionnaire, 9 were interviewed, 12 (67%) pharmabuddies responded. Acceptability was high among patients (mean 9.5 (SD 1.3) out of 10), 6 (50%) pharmacies (still) provided PCS. Demand: 56% of patients had 1–2 contact moments, 28% two or more. Ten pharmacies provided up to 14 patients per pharmacy with PCS, one up to 24. Implementation/practicality: important barriers were time constraints and perception of other healthcare professionals. Positive reactions from patients encouraged pharmabuddies to carry out their PCS-activities. Patients were positive about pharmabuddy’s listening competency while knowledge could be improved. Limited efficacy: from patient records, 89 interventions were made in response to 93 (median 3 per patient (range 1–16)) medication related problems or questions, with 20 (87%) patients reporting a positive effect from their interaction with a pharmabuddy.ConclusionThis study shows PCS is highly appreciated by responding patients and can be feasible for primary care pharmacies. Several implementation issues are still present. Future studies should focus on quantifiable effects of PCS services as well as resource and perception hurdles.