Advanced Stages Of Parkinson's Disease Research Articles

Association analysis of dopaminergic degeneration and the neutrophil-to-lymphocyte ratio in Parkinson's disease.

Peripheral inflammatory responses are suggested to play a major role in the pathophysiology of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a new recognized biomarker, can reflect peripheral inflammation in PD. However, the association between the NLR and dopaminergic degeneration in PD remains unclear. In this retrospective study, 101 enrolled PD patients were categorized into early-stage and advanced-stage PD based on the Hoehn and Yahr (HY) scale. We evaluated the clinical characteristics, peripheral immune profile, and 11C-CFT striatal dopamine transporter (DAT) binding levels. Linear regression analyses were employed to assess the associations between NLR and striatal DAT levels at different stages in PD patients. Covariate-controlled regression analysis revealed that higher NLR was significantly associated with lower DAT levels in the caudate (β = -0.27, p = 0.003) and the putamen (β = -0.27, p = 0.011). Moreover, in the early-stage PD subgroup, a similar association was observed (caudate: β = -0.37, p = 0.013; putamen: β = -0.45, p = 0.005). The lymphocytes count was correlated positively with the striatal DAT levels in the Spearman correlation analysis whether in total patients (caudate: ρ = 0.25, p = 0.013; putamen: ρ = 0.22, p = 0.026) or in the early-stage subgroup (caudate: ρ = 0.31, p = 0.023, putamen: ρ = 0.34, p = 0.011). Dopaminergic degeneration is associated with peripheral inflammation in PD. The NLR, a widely used inflammatory marker, may have the potential to reflect the degree of dopaminergic degeneration in individuals with early-stage PD.

Therapeutic singing-induced swallowing exercise for dysphagia in advanced-stage Parkinson's disease.

With longer life spans and medical advancements, the rising number of patients with advanced-stage Parkinson's disease (PD) warrants attention. Current literature predominantly addresses dementia and fall management in these patients. However, exploring the impact of swallowing function on patients with advanced PD is crucial. Previous research has demonstrated notable enhancements in the quality of life related to voice for participants following a group singing-intervention program. To further elucidate the effect of individual singing-induced swallowing exercises, our study aimed to investigate the quantitative and qualitative effects of therapeutic singing on swallowing function in patients with advanced PD in comparison to a matched usual care control group. The hypothesis of this study is that therapeutic singing-induced swallowing exercises can assist to maintain swallowing function in patients with advanced PD. This prospective matched control study compared the effects of a 6-week therapeutic singing-based swallowing intervention on swallowing function and quality of life in patients with advanced PD. The intervention group received individual sessions with a music therapist and conventional individual physical therapy. The control group received the same standard physical therapy for 6 weeks without music intervention. The primary outcome measure was Video Fluoroscopic Dysphagia Scale (VDS). The study revealed that the intervention group maintained swallowing function, whereas the control group experienced deterioration, indicating significant time-dependent changes in Penetration-Aspiration Scale (PAS), National Institutes of Health-Swallowing Safety Scale (NIH-SSS), and VDS. Analysis of PAS and NIH-SSS liquid food scores in both groups showed significant time effects. However, the intervention group exhibited no significant differences between the pre- and post-tests, indicating preservation of the swallowing function. VDS of liquid food indicated an interaction effect between time and group in the pharyngeal phase and total scores. The Swallowing-Quality of Life showed significant time-effect improvement in the intervention group. Therapeutic singing exercises may help maintain swallowing function in advanced PD patients, potentially enhancing quality of life related to swallowing in those with advanced-stage diseases. https://cris.nih.go.kr/cris/search/listDetail.do, identifier KCT0008644.

Patient With Parkinson Disease and Care Partner Perceptions of Key Domains Affecting Health-Related Quality of Life: Systematic Review

To effectively customize Parkinson disease (PD) programs, it is important to incorporate the "individual's voice" and have a thorough understanding of the symptom priorities of people with PD (PwP) and care partners (CP). In this convergent integrated mixed-method systematic review, we aimed to analyze qualitative and quantitative evidence of PD motor and nonmotor symptoms affecting health-related quality of life (HRQOL) in PwP and CP, comparing priorities across different levels of disease severity. We searched MEDLINE, PsycINFO, Web of Science, Embase, and Scopus; ProQuest Dissertations and Theses Global; and the Michael J. Fox Foundation Data Resources for studies published up to June 29, 2022. We included qualitative, quantitative, and mixed-method studies investigating PD symptom priorities among PwP and CP. We critically appraised eligible studies for methodological quality using the Mixed-Methods Appraisal Tool. Derived terms were mapped and coded according to thematic attribution. Independent syntheses of qualitative and quantitative evidence and transformation of quantitative data into qualitative formats were performed. Of the 7,716 identified studies, we included 70 that provided qualitative (n = 13), quantitative (n = 53), and mixed (n = 4) evidence. We included 604 mapped terms representing 11 PwP-identified and CP-identified motor and nonmotor symptom categories. Across all PD stages, both PwP and CP considered 5 domains more affecting their HRQOL, namely: "motor functionality," "mood," "cognition," "gait, balance, posture, and falls," and "nighttime sleep disorders." In early disease, PwP and CP considered "mood" the domain that most affected their HRQOL. In advanced PD, PwP considered "pain" the domain that most affects their HRQOL, while CP considered "psychiatric symptoms." The domain "gait, balance, posture, and falls" was equally considered by both PwP and CP as the second domain that most affects their HRQOL in the advanced stage of PD. The ranking of the priority of symptoms is largely shared by PwP and CP, and motor symptom priorities dominate the full disease spectrum. However, the nonmotor symptom priorities shift according to the disease severity stage. Tailored care and research require that providers consider these shifting priorities and incorporate the "individual's voice" into treatment decisions.

Motor and process skills of people with parkinson's disease compared to healthy older adults. A cross-sectional study.

Both Parkinson's disease (PD) and the process of ageing are associated with functional limitations. The aim of this study was to determine the differences in motor and process skills between individuals with PD and healthy older adults, as well as to observe how disease progression affects motor and process skills performance in PD patients. A cross-sectional study was conducted. The Assessment of Motor and Process Skills (AMPS) measure was employed in order to analyze the differences in the motor and process skills of daily tasks in people with PD and healthy older adults age- and sex-matched. Part III of the Unified Parkinson Disease Rating Scale (UPDRS), the Hoehn and Yahr (HY) scale and the Schwab & England scale was administered to determine the severity of the disease. Seventy participants (49 patients with PD and 21 healthy older adults) were recruited for this study. Our results showed that even at moderate stages of the disease, both motor and process skills were found deteriorated in PD patients more than older healthy older adults (p < 0.001). As PD progresses, motor and process skills present significantly deterioration. PD leads to a greater deterioration in motor and process skills compared to healthy older adults. As disease stages advance according to the HY scale, performance in motor and process skills deteriorates significantly between moderate and advanced PD stages. According to the AMPS scale, PD patients show no impairment of processing skills up to HY IV, but motor impairment at HY stages II, III and IV.

Spatiotemporal patterns of brain iron-oxygen metabolism in patients with Parkinson's disease.

Iron deposition and mitochondrial dysfunction are closely associated with the genesis and progression of Parkinson's disease (PD). This study aims to extract susceptibility and oxygen extraction fraction (OEF) values of deep grey matter (DGM) to explore spatiotemporal progression patterns of brain iron-oxygen metabolism in PD. Ninety-five PD patients and forty healthy controls (HCs) were included. Quantitative susceptibility mapping (QSM) and OEF maps were computed from MRI multi-echo gradient echo data. Analysis of covariance (ANCOVA) was used to compare mean susceptibility and OEF values in DGM between early-stage PD (ESP), advanced-stage PD (ASP) patients and HCs. Then Granger causality analysis on the pseudo-time-series of MRI data was applied to assess the causal effect of early altered nuclei on iron content and oxygen extraction in other DGM nuclei. The susceptibility values in substantia nigra (SN), red nucleus, and globus pallidus (GP) significantly increased in PD patients compared with HCs, while the iron content in GP did not elevate obviously until the late stage. The mean OEF values for the caudate nucleus, putamen, and dentate nucleus were higher in ESP patients than in ASP patients or/and HCs. We also found that iron accumulation progressively expands from the midbrain to the striatum. These alterations were correlated with clinical features and improved AUC for early PD diagnosis to 0.824. Abnormal cerebral iron deposition and tissue oxygen utilization in PD measured by QSM and OEF maps could reflect pathological alterations in neurodegenerative processes and provide valuable indicators for disease identification and management. Noninvasive assessment of cerebral iron-oxygen metabolism may serve as clinical evidence of pathological changes in PD and improve the validity of diagnosis and disease monitoring. • Quantitative susceptibility mapping and oxygen extraction fraction maps indicated the cerebral pathology of abnormal iron accumulation and oxygen metabolism in Parkinson's disease. • Iron deposition is mainly in the midbrain, while altered oxygen metabolism is concentrated in the striatum and cerebellum. • The susceptibility and oxygen extraction fraction values in subcortical nuclei were associated with clinical severity.

Hybrid Machine Learning Framework for Multistage Parkinson's Disease Classification Using Acoustic Features of Sustained Korean Vowels.

Recent research has achieved a great classification rate for separating healthy people from those with Parkinson's disease (PD) using speech and the voice. However, these studies have primarily treated early and advanced stages of PD as equal entities, neglecting the distinctive speech impairments and other symptoms that vary across the different stages of the disease. To address this limitation, and improve diagnostic precision, this study assesses the selected acoustic features of dysphonia, as they relate to PD and the Hoehn and Yahr stages, by combining various preprocessing techniques and multiple classification algorithms, to create a comprehensive and robust solution for classification tasks. The dysphonia features extracted from the three sustained Korean vowels /아/(a), /이/(i), and /우/(u) exhibit diversity and strong correlations. To address this issue, the analysis of variance F-Value feature selection classifier from scikit-learn was employed, to identify the topmost relevant features. Additionally, to overcome the class imbalance problem, the synthetic minority over-sampling technique was utilized. To ensure fair comparisons, and mitigate the influence of individual classifiers, four commonly used machine learning classifiers, namely random forest (RF), support vector machine (SVM), k-nearest neighbor (kNN), and multi-layer perceptron (MLP), were employed. This approach enables a comprehensive evaluation of the feature extraction methods, and minimizes the variance in the final classification models. The proposed hybrid machine learning pipeline using the acoustic features of sustained vowels efficiently detects the early and mid-advanced stages of PD with a detection accuracy of 95.48%, and with a detection accuracy of 86.62% for the 4-stage, and a detection accuracy of 89.48% for the 3-stage classification of PD. This study successfully demonstrates the significance of utilizing the diverse acoustic features of dysphonia in the classification of PD and its stages.

Irritable bowel syndrome based on Rome IV diagnostic criteria associates with non-motor symptoms of Parkinson's disease

BackgroundRecent concepts suggest that the neuropathological hallmark of Parkinson's disease (PD) may in part originate from the enteric nervous system. We evaluated the frequency of functional gastrointestinal disorders in PD patients using Rome IV criteria and correlated the clinical severity of PD. MethodsPD patients and matched controls were recruited between January 2020 and December 2021. Rome IV criteria were used to diagnose constipation and irritable bowel syndrome (IBS). Severity of PD motor symptoms was evaluated using UPDRS part III scores and non-motor symptoms using Non-motor Symptoms Scale (NMSS). ResultsA total of 99 PD patients and 64 controls were enrolled. The prevalence of constipation (65.7% vs. 34.3%, P < 0.001) and IBS (18.1% vs 5%, P = 0.02) were significantly higher in PD patients than controls. The prevalence of IBS was higher in early-stage PD than advanced-stage PD (14.43% vs. 8.25%, P = 0.02), whereas constipation was more common in advanced stages (71.43% vs. 18.56%, P < 0.001). PD patients with IBS had higher NMSS total scores (P < 0.01) than those without IBS. The severity of IBS correlated with NMSS scores (r = 0.71, P < 0.001), especially subscores in domain 3 assessing mood disorders (r = 0.83, P < 0.001), but not UPDRS part III scores (r = 0.06, P = 0.45). The severity of constipation correlated with the UPDRS part III scores (r = 0.59, P < 0.001) but not the domain 3 mood subscores (r = 0.15, P = 0.07). ConclusionThe prevalence of IBS and constipation was higher in PD patients than controls and phenotypic correlation supported the occurrence of IBS with higher non-motor symptom burden, especially mood symptoms, in PD patients.

Controlled-Release Levodopa for the Treatment of Rapid Motor Fluctuations in Parkinson's Disease Subjects with Subthalamic Nucleus Deep Brain Stimulation.

Objectives We aimed to investigate the efficiency of controlled-release levodopa/benserazide (Madopar HBS) use during daytime in our pilot study on advanced-stage Parkinson's disease (PD) subjects with deep brain stimulation of the subthalamic nucleus (STN-DBS) therapy. Methods We have evaluated all PD subjects with STN-DBS who had admitted to our outpatient polyclinic between February 2022 and March 2022. Among these patients, those who were taking levodopa therapy at least five times throughout the day and the efficiency of levodopa lasted less than 3 hours were detected. The standard levodopa therapy was switched to Madopar HBS in all patients who accepted the therapy chance and the clinical evaluation of the patients on Madopar HBS therapy was performed in the second month of the therapy. Results Ultimately, the follow-up of all four patients in whom the levodopa therapy was changed to Madopar HBS yielded a significant reduction in the "off" periods and improvement in the PSQ-39 scores. Conclusion We suggest the use of Madopar HBS in PD patients with STN-DBS surgery suffering from motor fluctuations, particularly in the subgroup with milder dyskinesias. Future study results of a large number of PD subjects with STN-DBS therapy are warranted to confirm our observations. The results of these studies may provide critical applications in clinical practice.

The impact of dysphagia in Parkinson's disease patients treated with levodopa/carbidopa intestinal gel

BackgroundDysphagia is common in advanced phases of Parkinson disease (PD), and is a risk factor for aspiration pneumonia. Nonetheless, dysphagia has been poorly investigated in PD patients treated with levodopa-carbidopa intestinal gel (LCIG). We aimed to analyze the impact of dysphagia on mortality in LCIG treated patients and its relationship with other PD disability milestones. MethodsWe retrospectively evaluated 95 consecutive PD patients treated with LCIG. Kaplan-Meier and log-rank test were used to compare mortality in patients with dysphagia from others. Cox regression was used to estimate the impact of dysphagia, age, disease duration, and Hoehn and Yahr (H&Y) on mortality in the entire cohort. Finally, univariate and multivariate regression analyses were used to estimate the association between dysphagia and age, disease duration, H&Y, hallucinations, and dementia. ResultsA significantly higher mortality rate was observed in patients with dysphagia. In the Cox model, dysphagia was the only feature significantly associated with mortality (95%CI 2.780–20.609; p < 0.001). Univariate analyses showed a significant correlation between dysphagia and dementia (OR: 0.387; p:0.033), hallucinations (OR: 0.283; p:0.009), and H&Y score (OR: 2.680; p < 0.001); in the multivariate analysis, only the H&Y stage was associated with the presence of dysphagia (OR: 2.357; p:0.003). ConclusionDysphagia significantly increased the risk of death in our cohort of LCIG-treated patients, independently from other relevant features such as age, disease duration, dementia, and hallucinations. These findings support the management of this symptom as a priority in the advanced PD stages, even in people treated with LCIG.

Plasma Metabolic Analysis Reveals the Dysregulation of Short-Chain Fatty Acid Metabolism in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by high morbidity, high disability rate, and slow course of disease. The clinical diagnostic method of PD is complex and time-consuming, and there is no clear biomarker for clinical use. We aimed to investigate the plasma metabolites in PD and find out potential biomarkers with diagnostic ability. In the analysis of more than 40 metabolites including short-chain fatty acids, long-chain fatty acids, amino acids, and carbohydrates, the difference of short-chain fatty acids was observed. Acetic acid concentration was higher in PD than in healthy controls, and propanoic acid and 2,3,4-trihydroxybutyric acid were lower in PD. Compared with the early stage of PD, acetic acid increased significantly in the advanced stage of PD. Propanoic acid increased significantly in medicated PD compared with drug naïve PD. ROC analysis revealed acetic acid discriminated PD from healthy controls with 100% sensitivity, 88.9% specificity, and an area under the curve (AUC) of 0.981, and propanoic acid discriminated PD from healthy controls with an AUC of 0.981, 100% sensitivity, and 94.4% specificity. Acetic acid and propanoic acid may be a potential biomarker for differentiating PD from health, and the propanoic acid was evaluated as the most potential diagnostic marker because of its extremely high sensitivity and specificity.

Can kynurenine pathway be considered as a next-generation therapeutic target for Parkinson's disease? An update information

By far, no revolutionary breakthrough in the treatment of Parkinson's disease (PD) was found. It is indeed a knotty problem to select a satisfactory strategy for treating some patients with advanced stage PD. Development of novel therapeutic targets against PD has been an urgent task faced by global PD researchers. Targets in the tryptophan-kynurenine pathway (KP) were then considered. Metabolites in the KP are liposoluble. Some neurotoxic metabolites, including 3-hydroxykynurenine and its downstream 3-hydroxyanthranilic acid and quinolinic acid, are mainly produced peripherally. They can easily cross the blood-brain barrier (BBB) and exert their neurotoxic effects in the central neuron system (CNS), which is considered as a potential pathophysiological mechanism of neurodegenerative diseases. Hence, agents against the targets in the KP have two characteristics: (1) being independent from the dopaminergic system and (2) being seldom affected by the BBB. Inspiringly, one agent, namely, the inhibitor of indoleamine 2,3-dioxygenase 1, has been currently reported to present satisfactory efficacy comparable to levodopa, implying that the KP might be a potential novel target for PD. This review collected and summarized the updated information regarding the association of the KP with PD, which is helpful for understanding the clinical value of the KP in the PD scenario.

Towards Symptom-Specific Intervention Recommendation Systems.

Mobile devices and their capabilities (e.g., device sensors and human-device interactions) are increasingly being considered for use in clinical assessments and disease monitoring due to their ability to provide objective, repeatable, and more accurate measures of neurocognitive performance. These mobile-based assessments also provide a foundation for the design of intervention recommendations. The purpose of this work was to assess the benefits of various physical intervention programs as they relate to Parkinson's disease (PD), its symptoms, and stages (Hoehn and Yahr (H&Y) Stages 1-5). Ninety-five participants (n = 70 PD; n = 25 control) completed 14 tablet-based neurocognitive functional tests (e.g., motor, memory, speech, executive, and multi-function) and standardized health questionnaires. 208 symptom-specific digital features were normalized to assess the benefits of various physical intervention programs (e.g., aerobic activity, non-contact boxing, functional strength, and yoga) for individuals with PD. While previous studies have shown that physical interventions improve both motor and non-motor PD symptoms, this paper expands on previous works by mapping symptom-specific neurocognitive functionalities to specific physical intervention programs across stages of PD. For early-stage PD (e.g., H&Y Stages 1 & 2), functional strength activities provided the largest overall significant delta improvement (Δ= 0.1883; p = 0.0265), whereas aerobic activity provided the largest overall significant delta improvement (Δ= 0.2700; p = 0.0364) for advanced stages of PD (e.g., H&Y Stages 3-5). As mobile-based digital health technology allows for the collection of larger, labeled, objective datasets, new ways to analyze and interpret patterns in this data emerge which can ultimately lead to new personalized medicine programs.

Sublingual apomorphine therapy as an alternative to complex continuous infusion pumps in advanced Parkinson's disease treatment: a district nurse-led intervention.

In the UK, Parkinson's disease (PD) is estimated to affect an annual incidence of 15-20 per 100 000 of the population over the age of 60. Service users living with advanced-stage PD require the use of apomorphine, which is generally used to control symptoms. The district nursing service plays a key role in monitoring and in the administration of apomorphine therapy. Although apomorphine is effective, skin problems such as nodules are commonly reported adverse events that can complicate efficiency of treatment. A sublingual delivery route to apomorphine has been known for years as a feasible alternative to subcutaneous route. Collaboration between the multidisciplinary team is essential to meet the complex needs of service users with advanced PD. However, due to the increase in demands of the district nurse service, this time crucial intervention can be unpredictable to meet. An alternative route can enable district nurses to become less task-orientated. However, an increased risk of oral cavity related adverse events should be taken into consideration with the sublingual administration of apomorphine.

Non-Oral Drug Delivery in Parkinson's Disease: Current Applications and Future.

Parkinson's disease (PD) is a type of movement disorder that affects the ability to perform daily activities. It is considered that 1 million people in the U.S. and more than 10 million people worldwide live with PD. It is a chronic and progressive disease, so symptoms worsen over the time. Patients experience motor symptoms such as tremors, stiffness and slow motion, and non-motor symptoms such as sleep problems, constipation, anxiety, depression and fatigue. Dopaminergic drugs are critical for treating motor symptoms in PD. Levodopa (L-DOPA) is the "gold standard" medication for the control of motor symptoms. Because of the progression of the disease, the effectiveness of oral L-DOPA decreases over time and motor fluctuations such as "delayed ON", "no ON" and unpredictable "ON-OFF" periods appear. These motor fluctuations affect the quality of life of the patient at a high rate and the patient has problems in fulfilling his daily morning routines. Gastrointestinal (GI) problems, as the common non-motor symptom, are the most important cause of motor fluctuations that occur because of inadequate oral treatment with the progression of PD. When oral treatments are not sufficient, non-oral treatments that are not affected by GI problems are required. In this review, the treatment strategies, developed and approved non-oral drug delivery systems in the early and advanced stages of PD are emphasized.

Review of Active Extracorporeal Medical Devices to Counteract Freezing of Gait in Patients with Parkinson Disease.

Parkinson Disease (PD) primarily affects older adults. It is the second-most common neurodegenerative disease after Alzheimer’s disease. Currently, more than 10 million people suffer from PD, and this number is expected to grow, considering the increasing global longevity. Freezing of Gait (FoG) is a symptom present in approximately 80% of advanced-stage PD’s patients. FoG episodes alter the continuity of gait, and may be the cause of falls that can lead to injuries and even death. The recent advances in the development of hardware and software systems for the monitoring, stimulus, or rehabilitation of patients with FoG has been of great interest to researchers because detection and minimization of the duration of FoG events is an important factor in improving the quality of life. This article presents a review of the research on non-invasive medical devices for FoG, focusing on the acquisition, processing, and stimulation approaches used.

Motor Progression and Nigrostriatal Neurodegeneration in Parkinson Disease.

The motor severity in Parkinson disease (PD) is believed to parallel dopaminergic terminal degeneration in the striatum, although the terminal was reported to be virtually absent by 4 years postdiagnosis. Meanwhile, neuromelanin-laden dopamine neuron loss in the substantia nigra (SN) elucidated a variability at early stages and gradual loss with less variability 10 years postdiagnosis. Here, we aimed to clarify the correlation between motor impairments and striatal dopaminergic terminal degeneration and nigral neuromelanin-laden dopamine neuron loss at early to advanced stages of PD. Ninety-three PD patients were divided into early and advanced subgroups based on motor symptom duration and whether motor fluctuation was present. Striatal dopaminergic terminal degeneration was evaluated using a presynaptic dopamine transporter tracer, 123 I-ioflupane single photon emission computed tomography (SPECT). Nigral neuromelanin-laden dopamine neuron density was assessed by neuromelanin-sensitive magnetic resonance imaging (NM-MRI). In patients with early stage PD (motor symptoms for ≤8 or 10 years), motor dysfunction during the drug-off state was paralleled by a decline in 123 I-ioflupane uptake in the striatum despite the absence of a correlation with reductions in NM-MRI signals in SN. Meanwhile, in patients with advanced stage PD (motor symptoms for >8 or 10 years and with fluctuation), the degree of motor deficits during the drug-off state was not correlated with 123 I-ioflupane uptake in the striatum, despite its significant negative correlation with NM-MRI signals in SN. We propose striatal dopaminergic terminal loss measured using 123 I-ioflupane SPECT and nigral dopamine neuron loss assessed with NM-MRI as early stage and advanced stage motor impairment biomarkers, respectively. ANN NEUROL 2022;92:110-121.

Multi-omic landscaping of human midbrains identifies disease-relevant molecular targets and pathways in advanced-stage Parkinson's disease.

BackgroundParkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease‐mediated alterations, we investigated the molecular landscape of PD in human post‐mortem midbrains, a region that is highly affected during the disease process.MethodsTissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi‐omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole‐time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies.ResultsOur analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real‐time polymerase chain reaction/western blotting) several PD‐deregulated molecular candidates, including miR‐539‐3p, miR‐376a‐5p, miR‐218‐5p and miR‐369‐3p, the valid miRNA‐mRNA interacting pairs miR‐218‐5p/RAB6C and miR‐369‐3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi‐omic analyses allowed validating disease‐mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function.ConclusionsThis comprehensive assessment of PD‐affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD.

Artificial intelligence applications and robotic systems in Parkinson's disease (Review).

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder following Alzheimer's disease. Advanced stages of PD, 4 or 5 of the Hoehn and Yahr Scale, are characterized by severe motor complications, limited mobility without assistance, risk of falling, and non-motor complications. The aim of this review was to provide a practical overview on specific artificial intelligence (AI) systems for the management of advanced stages of PD, as well as relevant technological limitations. The authors conducted a systematic search on PubMed and EMBASE with predefined keywords searching for studies published until December 2020. Full articles that satisfied the inclusion criteria were included in the systematic review. To minimize results bias, the reference list was manually searched for pertinent articles to identify any additional relevant missed publications. Exclusion criteria included the following: Other stages of PD than 4 and 5 of the Hoehn and Yahr Scale, case reports, reviews, practice guidelines, commentaries, opinions, letters, editorials, short surveys, articles in press, conference abstracts, conference papers, and abstracts published without a full article. The search identified 21 studies analyzing AI-based applications and robotic systems used for the management of advanced stages of PD, out of which 6 articles analyzed AI-based applications for autonomous management of pharmacologic therapy, 5 articles analyzed home-based telemedicine systems and 10 articles analysed robot-assisted gait training systems. The authors identified significant evidence demonstrating that current AI-based technologies are feasible for automatic management of patients with advanced stages of PD. Improving the quality of care and reducing the cost for patients and healthcare systems are the most important advantages.

Validation of cepstral peak prominence in assessing early voice changes of Parkinson's disease: Effect of speaking task and ambient noise.

Although the cepstral peak prominence (CPP) and its variant, the cepstral peak prominence smooth (CPPS), are considered to be robust acoustic measures for the evaluation of dysphonia, whether they are sensitive to capture early voice changes in Parkinson's disease (PD) has not yet been explored. This study aimed to investigate the voice changes via the CPP measures in the idiopathic rapid eye movement sleep behavior disorder (iRBD), a special case of prodromal neurodegeneration, and recently diagnosed and advanced-stage Parkinson's disease (AS-PD) patients using different speaking tasks across noise-free and noisy environments. The sustained vowel phonation, reading of passages, and monologues of 60 early stage untreated PD, 30 advanced-stage Parkinson's disease, 60 iRBD, and 60 healthy control (HC) participants were evaluated. Significant differences were found between the PD groups and controls in sustained phonation via the CPP (p < 0.05) and CPPS (p < 0.01) and the monologue via the CPP (p < 0.01), although neither the CPP nor CPPS measures were sufficiently sensitive to capture the possible prodromal dysphonia in the iRBD. The quality of the CPP and CPPS measures was influenced substantially by the addition of ambient noise. It was anticipated that the CPP measures might serve as a promising digital biomarker in assessing the dysphonia from the early stages of PD.

Serum levels of lipocalin-2 in patients with Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Evidence has shown that lipocalin-2 (LCN2) is involved in the pathological process of PD. We aimed to explore whether serum levels of LCN2 could be a biomarker of PD. We recruited consecutive PD patients and healthy controls (HC) in our hospital from June 2020 to July 2020. Serum LCN2 levels were detected using the LCN2 enzyme-linked immunosorbent assay (ELISA) kit. The motor section of the Unified Parkinson's Disease Rating Scale (UPDRS III) and the Hoehn and Yahr Staging Scale (H&Y) were assessed on admission to evaluate disease severity in patients with PD. Cognitive status was measured by the Montreal Cognitive Assessment (MoCA). We finally recruited 75 patients, including 40 PD patients and 35 HC. Serum LCN2 levels were not significantly increased in PD patients compared with HC (4.9 [- 0.7 to 18.6] vs 1.9 [- 1.5 to 16.9] ng/mL, P = 0.33). Besides, there was no significant difference in LCN2 levels between patients at early and advanced stage of PD (P = 0.75), as well as between cognitively impaired PD patients, PD patients with normal cognition, and HC (P = 0.30). Moreover, LCN2 had no correlation with disease duration (r = - 0.1, P = 0.37), UPDRS III score (r = 0.07, P = 0.65), and MoCA score (r = 0.221, P = 0.17). Overall, our study suggests that serum LCN2 levels may not be a biomarker for PD.