Parkinson's Disease Research Articles

Identification of Novel Genetic Loci Affecting Age at Onset of Parkinson's Disease: A Genome-wide Association Study.

The age at onset (AAO) of Parkinson's disease (PD) varies widely among individuals and significantly influences disease progression and prognosis. However, few genome-wide association studies (GWASs) have investigated genetic variants determining AAO, particularly in East Asian populations. To identify single-nucleotide polymorphisms (SNPs) affecting AAO of PD in Korean patients. We conducted a GWAS on AAO of PD in 1048 Korean patients using sex-adjusted linear regression models. Additionally, we conducted downstream analyses of our primary GWAS results. rs2134545 demonstrated genome-wide significance (β = -2.459; standard error [SE] = 0.851; P = 1.898 × 10-8) and is an intergenic SNP near the ALCAM gene associated with an average AAO reduction of 3.47 years. Additionally, rs4366309 (LYST; MIR1537) demonstrated suggestive significance (β = 2.949; SE = 1.072; P = 8.68 × 10-8) and was associated with an average delay of 3.05 years. The polygenic risk score based on known PD risk loci also affected the AAO for European and Korean PD risk loci, respectively (β = -0.149; P < 0.001 and β = -0.096; P = 0.002). However, the proportion of variance was small (r2 = 0.022 and 0.009, respectively). We identified a novel SNP associated with the AAO of PD near the ALCAM gene, distinct from previously reported PD risk loci. These findings need further functional validation; however, they suggest unique genetic pathways influencing the AAO of PD and highlight the need for further research in diverse populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The R1441C-Lrrk2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner in mice

Age is the greatest risk factor for many neurodegenerative diseases, yet immune system aging, a contributor to neurodegeneration, is understudied. Genetic variation in the LRRK2 gene affects risk for both familial and sporadic Parkinson’s disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein is implicated in peripheral immune cell signaling, but the effects of an aging immune system on LRRK2 function remain unclear. We analyzed peritoneal macrophages from R1441C-Lrrk2 knock-in mice and observed a biphasic, age-dependent effect of the R1441C-Lrrk2 mutation on peritoneal macrophage function. We report increases in antigen presentation, anti-inflammatory cytokine production, lysosomal activity, and pathogen uptake in peritoneal macrophages from young (2- to 3-month-old) female R1441C-Lrrk2 mice. Conversely, macrophages from aged (18- to 21-month-old) female R1441C-Lrrk2 mice exhibited decreased antigen presentation after inflammatory insult, decreased lysosomal function, and pathogen uptake, with a concomitant increase in DNA fragmentation in the presence of pathogens. This immune cell exhaustion phenotype was not observed in male R1441C-Lrrk2 mice and was driven by increased LRRK2 protein kinase activity. This phenotype was also observed in human peripheral myeloid cells, with monocyte-derived macrophages from patients with PD who had either the R1441C- or Y1699C-LRRK2 mutation exhibiting decreased pathogen uptake and increased PDL1 expression, consistent with immune cell exhaustion. Our findings that LRRK2 mutations conferred an immunological advantage at a young age but could predispose the carrier to age-acquired immune cell exhaustion have implications for the therapeutic development of LRRK2 inhibitors.

Exploring the Impact of Physiological C-Terminal Truncation on α-Synuclein Conformations to Unveil Mechanisms Regulating Pathological Aggregation.

Emerging evidence suggests that physiological C-terminal truncation of α-synuclein (αS) plays a critical role in regulating liquid-liquid phase separation and promoting amyloid aggregation, processes implicated in neurodegenerative diseases such as Parkinson's disease (PD). However, the molecular mechanisms through which C-terminal truncation influences αS conformation and modulates its aggregation remain poorly understood. In this study, we investigated the impact of C-terminal truncation on αS conformational dynamics by comparing full-length αS1-140 with truncated αS1-103 monomers using atomistic discrete molecular dynamics simulations. Our findings revealed that both αS1-140 and αS1-103 primarily adopted helical conformations around residues 7-32, while residues 36-95, located in the second half of the N-terminal and NAC domains, predominantly formed a dynamic β-sheet core. The C-terminus of αS1-140 was largely unstructured and dynamically wrapped around the β-sheet core. While residues 1-95 exhibited similar secondary structure propensities in both αS1-140 and αS1-103, the dynamic capping by the C-terminus in αS1-140 slightly enhanced β-sheet formation around residues 36-95. In contrast, key aggregation-driving regions (residues 2-9, 36-42, 45-57, and 68-78) were dynamically shielded by the C-terminus in αS1-140, reducing their exposure and potentially preventing interpeptide interactions that drive aggregation. C-terminal truncation, on the other hand, increased the exposed surface area of these aggregation-prone regions, thereby enhancing interpeptide interactions, phase separation, and amyloid aggregation. Overall, our simulations provide valuable insights into the conformational effects of C-terminal truncation on αS and its role in promoting pathological aggregation.

Causal association between Parkinson’s disease and cancer: a bidirectional Mendelian randomization study

BackgroundPrevious observational research has indicated a correlation between Parkinson’s disease (PD) and multiple cancers; but the causality remains unclear. Thus, we utilized Mendelian randomization (MR) analysis to explore the potential causal link between PD and various cancers.MethodsWe conducted a bidirectional two-sample Mendelian randomization (TSMR) of genetic variants associated with PD and 14 types of cancers. Summary statistics on PD and 14 types of cancers were obtained from the International Parkinson’s Disease Genomics Consortium and the study by Sakaue et al. The primary method employed was inverse variance weighted (IVW), complemented by multiple sensitivity analyses to evaluate heterogeneity and pleiotropy. The false discovery rate (FDR) was employed to control the false positive rate of multiple hypothesis testing.ResultsFollowing rigorous sensitivity analyses and corrections, our findings revealed suggestive associations between PD and certain cancers. We observed that PD decreases the risk of gastric cancer and colorectal cancer (OR = 0.936, 95% CI = 0.881–0.995, p = 0.034, P FDR = 0.239; OR = 0.955, 95% CI = 0.912–0.999, p = 0.046, P FDR = 0.215), while increasing the risk of breast cancer (OR = 1.043, 95% CI = 1.004–1.084, p = 0.029, P FDR = 0.402). Notably, we found no evidence supporting a reverse causal relationship. Additionally, in the reverse pathway, skin cancer demonstrated a suggestive causal relationship with PD (OR = 0.913, 95% CI = 0.857–0.973, p = 0.005, P FDR = 0.066).ConclusionOur MR analysis provides evidence supporting unidirectional suggestive causal relationships between PD and certain cancers. These findings enrich our comprehension of the intricate interplay between PD and cancer, warranting further investigation into the underlying biological mechanisms.

Respiratory Dysfunction and Abnormal Hypoxic Ventilatory Response in Mild to Moderate Parkinson's Disease.

Respiratory dysfunction is an important contributor to morbidity and mortality in advanced Parkinson's disease (PD), but it is unclear what parameters are sensitive to diagnose and monitor respiratory dysfunction across disease phases. We aimed to characterize respiratory dysfunction in mild to moderate PD. In 20 individuals without cardiopulmonary comorbidity, pulmonary and inspiratory muscle function testing were performed ON-medication. Subsequently, the acute ventilatory response to hypoxia (HVR) was assessed by gradually decreasing FIO2 from 0.209 (room air) to 0.127, which was compared to eight age- and sex-matched healthy controls under arterial blood gas monitoring. Lastly, on different days, the same 20 individuals with PD underwent six blinded exposures to 45-min normobaric hypoxia at FiO2 0.163 and 0.127 or placebo OFF-medication to assess breathing responses. At rest, individuals with greatest PD severity had a lower tidal volume (pairwise comparisons: 0.59 vs. 0.74, P = 0.038-0.050) and tended to have a higher breathing frequency (17.7 vs. 14.4, P = 0.076), despite normal pulmonary function. A 45-min exposure to hypoxia induced a significantly lower acute HVR in individuals with PD compared to controls (-0.0489 vs. 0.133 L.min/%, P = 0.0038). Acute HVR was reduced regardless of disease severity. Subacute HVR in individuals with milder disease tended to be higher compared to those with more advanced disease (P = 0.079). Respiratory dysfunction is present in individuals with PD, including those with relatively mild disease severity, and is characterized by altered breathing patterns at rest, as well as a lower HVR, despite normal pulmonary and inspiratory muscle function testing.

Understanding Parkinson disease in Spain: Genetic and clinical insights.

Parkinson disease (PD) is a complex and heterogeneous neurodegenerative disorder with a broad spectrum of clinical manifestations, determined by a complex interplay of environmental and genetic factors. This study aimed to investigate genetic variants associated with PD and assess their impact on the disease phenotype through genotype-phenotype correlations. We employed a targeted resequencing panel to analyze 27 genes linked to PD in a cohort of 1185 PD patients from southern Spain. Variants were categorized based on the American College of Medical Genetics and Genomics pathogenicity criteria. Demographic and clinical data were also collected. Among the patients analyzed, 13.5% carried potential disease-causing pathogenic or likely pathogenic variants in 12 different genes, indicating significant genetic heterogeneity. The most frequently affected genes were LRRK2, PRKN, and GBA1 (accounting for 72.1% of positive cases). Sex-specific differences were observed, with a higher proportion of female patients carrying LRRK2 variants. Differences in age at onset and clinical features were also observed among the different mutated genes. Notably, variants in genes associated with atypical parkinsonism presented distinct clinical presentations, highlighting the importance of genetic factors in the differential diagnosis. Our study provides valuable information on the genetic landscape of PD and its clinical manifestations. The observed genotype-phenotype correlations, along with sex-specific differences, emphasize the complexity of PD pathogenesis, underlining the importance of personalized approaches to PD diagnosis and treatment. Further investigations into genetic interactions and population-specific effects are warranted to enhance our understanding of PD etiology and improve patient care.

Insulin Resistance Is a Modifying Factor for Parkinson's Disease.

Parkinson's disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non-genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance. We aimed to investigate insulin resistance and its role in GBA1mutation-associated PD pathogenesis and phenotype severity. Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1-N370S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue. The insulin signaling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA-PD. Additionally, our findings suggest a promising therapeutic potential of the anti-diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA-PD. Local insulin signaling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopamine Cell-Based Replacement Therapies.

Parkinson's disease (PD) is a common disorder that has, as part of its core pathology, the loss of the nigral dopaminergic nerve cells that project to the striatum. Replacing this loss with dopaminergic drugs has been the mainstay of therapy in PD for more than 50 years and while offering significant clinical benefit, especially in early-stage disease, leads to side effects over time. A conceptually more effective way to treat this aspect of the PD pathology would be to replace the missing dopaminergic system with grafts of new dopamine cells. This approach has been investigated for nearly 40 years using a variety of different dopamine cell sources. To date, a proof-of-principle has been shown using human fetal dopamine cells in patients with PD, but the more widespread adoption of this approach has been hampered by logistical reasons around tissue supply, the ethics of the cell source, and, most importantly, by the inconsistent results shown across trials, which in some cases have reported worrying side effects. Reasons for all this have been discussed extensively in the literature and one solution may lie in the development of new human stem cell-derived dopamine cells, which are now just entering first in human clinical trials.

Non-invasive, continuous oral delivery of solid levodopa-carbidopa for management of Parkinson's disease.

When short plasma half-life drugs act only briefly, they require frequent or continuous administration. We report the engineering of a non-invasive oral drug delivery system for long-term, continuous administration of these drugs. Their non-invasive, long-term, continuous administration at daily doses exceeding 100 mg has, for many years, been considered an insurmountable challenge. We show that over 1200 mg/day of 4:1 levodopa-carbidopa (LD-CD) can be non-invasively and continuously extruded when formulated as a semisolid paste, loaded with 63%w/w of the solid drugs. The drug delivery system comprises a reusable orthodontic retainer with a co-molded pocket into which the patient inserts after each meal a new 1 mL propellant-driven, prefilled, disposable, drug delivery extruder. The paste is delivered to the lingual side of the teeth where it is mixed with saliva and swallowed. As reported elsewhere, a 15-day, 16 patient open label clinical trial of the drug delivery system continuously extruding LD-CD paste significantly reduces the variability of the plasma LD concentration and alleviates symptoms of advanced Parkinson's disease (PD) as compared to LD-CD tablets.

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Of the 1955 molecules predicted by participants in Round 1 of the challenge, 73 were found to bind to LRRK2 in an SPR assay with a KD lower than 150 μM. These 73 molecules were advanced to the Round 2 hit expansion phase, where computational teams each selected up to 50 analogs. Binding was observed in two orthogonal assays for seven chemically diverse series, with affinities ranging from 18 to 140 μM. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants adopted strikingly diverging screening strategies. Machine learning-accelerated methods achieved similar results to brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha synuclein.

Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson's disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human α-synuclein (Snca+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby α-synuclein and inflammation interact to promote neurodegeneration in PD.

The emerging role of disease-associated microglia in Parkinson’s disease

Disease-associated microglia (DAM) are a subset of microglia that appear at various stages of central nervous system neurodegenerative diseases. DAM were identified using single-cell RNA sequencing within Alzheimer’s Disease (AD) where they were characterized by their unique localization near amyloid-β plaques and their phagocytic and lipid-metabolizing features. Unfortunately, activation and etiology of DAM are only understood within the context of AD where Triggering Receptor Expressed On Myeloid Cells 2 (TREM2), a receptor for amyloid-β, appears to be the key regulator in microglial transition to a DAM state. Despite this reliance on TREM2 in AD, DAM appear across other neurodegenerative diseases in which TREM2 may not be a critical player. This begs the question of if DAM are truly the same across all neurodegenerative diseases or if there exists a heterogeneity to DAM across neurodegenerative pathologies. Investigation into this critical gap in the field regarding DAM etiology and activation, as well as DAM function, could be delineated utilizing models of Parkinson’s disease (PD) to complement studies in models of AD. Though highly underexplored regarding DAM, PD with its pattern of protein aggregation-associated pathology like AD could serve as the spatiotemporal comparison against AD findings to ascertain the nature of DAM. The experimental vehicle that could guide the future of such investigation is the multi-omics model. With a compound approach focusing on exploring triggers for DAM at the chromatin or mRNA level and related protein output, it becomes possible to strongly characterize and firmly answer the question of what is a DAM.

Motor signs and incident dementia with Lewy bodies in older adults with mild cognitive impairment.

Motor signs may herald incident dementia and allow the earlier detection of high-risk individuals and the timely implementation of preventive interventions. The current study was performed to investigate the prognostic properties of motor signs with respect to incident dementia with Lewy bodies (DLB) in older adults with mild cognitive impairment (MCI). Emphasis was placed on sex differences. The specificity of these associations was explored. We analyzed data from the National Alzheimer's Coordinating Center Uniform Data Set. Participants 55 + years old with a diagnosis of MCI were included in the analysis. Those with Parkinson's disease (PD) or other parkinsonian disorders at baseline and those with PD dementia at follow-up were excluded. UPDRS III was used to assess the presence or absence of motor signs in nine domains: hypophonia; masked facies; resting tremor; action/postural tremor; rigidity; bradykinesia; impaired chair rise; impaired posture/gait; postural instability. Αdjusted Cox proportional hazards models featuring sex by motor sign interactions were estimated. Throughout the average follow-up of 3.7 ± 3.1 years, among 4623 individuals with MCI, 2211 progressed to dementia (66 of whom converted to DLB). Masked facies [HR = 4.21 (1.74-10.18)], resting tremor [HR = 4.71 (1.44-15.40)], and bradykinesia [HR = 3.43 (1.82-6.45)] exclusively increased the risk of DLB. The HR of DLB was approximately 15 times greater in women compared to men with masked facies. Impaired posture-gait (approximately 10 times) and resting tremor (approximately 8.5 times) exhibited a similar trend (prominent risk-conferring properties in women compared to men) but failed to achieve statistical significance. Rigidity and hypophonia elevated the risk of other dementia entities, as well. The remaining motor features were not related to incident dementia of any type. Specific motor signs may herald DLB among individuals with MCI. Different associations may exist between masked facies, impaired posture-gait, resting tremor, and incident DLB in men versus women.

Application of computational algorithms for single-cell RNA-seq and ATAC-seq in neurodegenerative diseases.

Recent advancements in single-cell technologies, including single-cell RNA sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq), have greatly improved our insight into the epigenomic landscapes across various biological contexts and diseases. This paper reviews key computational tools and machine learning approaches that integrate scRNA-seq and scATAC-seq data to facilitate the alignment of transcriptomic data with chromatin accessibility profiles. Applying these integrated single-cell technologies in neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, reveals how changes in chromatin accessibility and gene expression can illuminate pathogenic mechanisms and identify potential therapeutic targets. Despite facing challenges like data sparsity and computational demands, ongoing enhancements in scATAC-seq and scRNA-seq technologies, along with better analytical methods, continue to expand their applications. These advancements promise to revolutionize our approach to medical research and clinical diagnostics, offering a comprehensive view of cellular function and disease pathology.

Comparative Proteomics Highlights that GenX Exposure Leads to Metabolic Defects and Inflammation in Astrocytes.

Exposure to PFAS such as GenX (HFPO dimer acid) has become increasingly common due to the replacement of older generation PFAS in manufacturing processes. While neurodegenerative and developmental effects of legacy PFAS exposure have been studied in depth, there is a limited understanding specific to the effects of GenX exposure. To investigate the effects of GenX exposure, we exposed Drosophila melanogaster to GenX and assessed the motor behavior and performed quantitative proteomics of fly brains to identify molecular changes in the brain. Additionally, metabolic network-based analysis using the iDrosophila1 model unveiled a potential link between GenX exposure and neurodegeneration. Since legacy PFAS exposure has been linked to Parkinson's disease (PD), we compared the proteome data sets between GenX-exposed flies and a fly model of PD expressing human α-synuclein. Considering the proteomic data- and network-based analyses that revealed GenX may be regulating GABA-associated pathways and the immune system, we next explored the effects of GenX on astrocytes, as astrocytes in the brain can regulate GABA. An array of assays demonstrated GenX exposure may lead to mitochondrial dysfunction and neuroinflammatory response in astrocytes, possibly linking non-cell autonomous neurodegeneration to the motor deficits associated with GenX exposure.

Transfer Learning with Hybrid Firefly Butterfly Optimization Feature Selection Model for Early Parkinson Disease Prediction

Transfer Learning with Hybrid Firefly Butterfly Optimization Feature Selection Model for Early Parkinson Disease Prediction

Pain beliefs and their relationship with pain, psychological distress and catastrophizing in individuals with Parkinson's disease.

In Parkinson's disease (PD), a large number of individuals are confronted with pain. This issue has been receiving increasing attention in literature in recent years, as the complexity of pain in this disease makes its evaluation and treatment challenging. However, psychological variables related to the pain experience have received limited attention, especially when it comes to the exploration of beliefs regarding pain which, to our knowledge, remains unexplored in PD. Pain beliefs are defined as a subset of a patient's belief system which represents a personal understanding of the pain experience. Four dimensions of pain beliefs have been isolated in literature: mystery, pain permanence, pain constancy and self-blame. Thus, the goal of this study was first to describe pain beliefs in individuals with PD and second, to explore the relationships between pain beliefs and clinical and psychological variables. One hundred and sixty-nine international individuals with PD completed an online survey with socio-demographic and medical data. Participants completed self-report instruments to assess their pain (King's Parkinson's Disease Pain Questionnaire, McGill Pain Questionnaire and Brief Pain Inventory), psychological distress (Beck Depression Inventory, short-form and Parkinson Anxiety Scale), pain catastrophizing (Pain Catastrophizing Scale) and pain beliefs catastrophizing (Pain Beliefs and Perception Inventory). The study's findings revealed that most participants' beliefs are marked by the dimension of permanence, suggesting that individuals with PD perceive the pain experience as chronic and enduring. Meanwhile, pain is minimally perceived as constant, mysterious, or a source of guilt. Our finding concerning the permanence dimension deserves specific attention: even though this belief is prevalent in our population, it is not, or only weakly, associated with an impact on mood or pain catastrophizing. These results bring forth several hypotheses for understanding, highlighting the role of acceptance, and offer new perspectives toward improving clinical practices in terms of assessing and managing pain in PD.

Parkinson's Disease: Unravelling the Medicinal Perspectives and Recent Developments of Heterocyclic Monoamine Oxidase-B Inhibitors.

Parkinson's disease is a neurodegenerative condition characterized by slow movement (bradykinesia), tremors, and muscle stiffness. These symptoms occur due to the degeneration of dopamine- producing neurons in the substantia nigra region of the brain, leading to reduced dopamine levels. The development of Parkinson's Disease (PD) involves a combination of genetic and environmental factors. PD is associated with abnormal regulation of the monoamine oxidase (MAO) enzyme. Monoamine oxidase inhibitors (MAOIs) are an important class of drugs used to treat PD and other neurological disorders. In the early stages of PD, monotherapy with MAO-B inhibitors has been shown to be both safe and effective. These inhibitors are also commonly used as adjuncts in long-term disease management, as they can improve both motor and non-motor symptoms, reduce "OFF" periods, and potentially slow disease progression. However, current MAO-B inhibitors come with side effects like dizziness, nausea, vomiting, light-headedness, and fainting. Therefore, accelerating the development of new MAO-B inhibitors with fewer side effects is crucial. This review explores natural compounds that may inhibit monoamine oxidase B (MAO-B), focusing on key findings from the past seven years. It highlights the most effective heterocyclic compounds against MAO-B, including thiazolyl hydrazone, pyridoxine-resveratrol, pyridazine, isoxazole, oxadiazole, benzothiazole, benzoxazole, coumarin, caffeine, pyrazoline, piperazine, piperidine, pyrrolidine, and morpholine derivatives. The review covers in vitro, in silico, and in vivo data, along with the structure- activity relationship of these compounds. These findings offer valuable insights for the development of more effective MAO-B inhibitors and advancements in Parkinson's disease research.

Depressive symptoms in Brazilian Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation: A Cross-Sectional study.

Parkinson's disease (PD) is a neurological disorder that primarily affects movement and is often accompanied by depressive symptoms. Subthalamic nucleus (STN) deep brain stimulation (DBS) has emerged as a therapeutic intervention for PD, although its impact on depressive symptoms remains complex. This study investigates the relationship between PD, DBS, and depressive symptoms, focusing on how DBS influences cognitive function and mood among PD patients in Brazil. The study involved two cohorts: one in 2019 with 46 participants and another in 2022 with 31 patients. Distinct assessment instruments, including the Geriatric Depression Scale-15 and Beck Depression Inventory-II, were employed to evaluate depressive symptoms. The results revealed no significant correlation between participants' gender and the presence of DBS, but substantial differences were observed in age, disease duration, and Activities of Daily Living scores. Patients undergoing DBS showed notably poorer cognitive performance compared to those treated solely with medication. Furthermore, the use of DBS was associated with higher scores on depressive symptoms scales within one of the cohorts. These findings underscore the intricate interplay among PD, DBS treatment, and depressive symptoms, highlighting the necessity for tailored approaches to patient care.

Reliable change indices for the Italian version of the Montreal Cognitive Assessment (MoCA) in non-demented Parkinson’s disease patients

Background. The present study aimed at deriving regression-based reliable change indices (RCIs) for the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented Parkinson’s disease (PD) patients.MethodsN = 33 consecutive, non-demented PD patients were followed-up at a 5-to-8-month interval (M = 6.6; SD = 0.6) with the MoCA. Practice effects and test-retest reliability were assessed via dependent-sample t-tests and intra-class correlation (ICC) coefficients, respectively. RCIs were derived separately for raw and demographically adjusted MoCA scores according to a standardized regression-based approach by accounting for both baseline confounders (i.e., demographics, disease duration and Unified Parkinson’s Disease Rating Scale scores) and retest interval.ResultsNo practice effects were found (t(32) = 0.29; p = .778), with acceptable test-retest reliability being detected (ICC = 0.67). MoCA scores at T0 proved to be the only significant predictor of T1 MoCA performances within both the model addressing raw scores and that addressing adjusted scores (ps < 0.001).ConclusionsThe present study provides Italian practitioners and researchers with regression-based RCIs for the MoCA in non-demented PD patients, which can be reliably adopted for retest interval ≥ 5 and ≤ 8 months without encountering any practice effect.