ABSTRACT
Introducción: La doble tarea es una intervención no farmacológica en personas con condiciones neurodegenerativas, utilizada en la enfermedad de Parkinson (EP), principalmente para favorecer el desempeño motor. El objetivo de esta revisión es reunir la evidencia actual sobre cómo el entrenamiento de doble tarea afecta a los procesos cognitivos en personas que presenten EP. Material y métodos. Se desarrolló una revisión sistemática, aplicando las directrices de PRISMA, incluyendo artículos obtenidos en las bases de datos de PubMed, Web of Science, Science Direct y Springer Link. La calidad metodológica se evaluó mediante PEDro y ROBINS-I. Resultados: Doce artículos cumplieron con los criterios de inclusión y exclusión: nueve de ellos corresponden a ensayos controlados aleatorizados y los tres restantes fueron estudios no aleatorizados. Se identificaron mejoras en la atención y las funciones ejecutivas, aunque la diversidad en enfoques y duración dificulta llegar a conclusiones definitivas. Conclusiones: Es crucial expandir la investigación, estandarizando los programas de intervención. Del mismo modo, es importante llevar a cabo estudios longitudinales y controlados aleatorizados en muestras representativas que permitan llegar a conclusiones aplicables a otros contextos.(AU)
Introduction: Dual-tasking is a non-pharmacological intervention in people with neurodegenerative conditions, and is used in Parkinsons disease (PD), primarily to enhance motor performance. The aim of this review is to compile the current evidence on how dual-task training affects cognitive processes in people with PD. Material and methods: A systematic review was undertaken, applying PRISMA guidelines, which included articles obtained from the PubMed, Web of Science, Science Direct and Springer Link databases. Methodological quality was assessed using PEDro and ROBINS-I. Results: Twelve articles met the inclusion and exclusion criteria: nine of them were randomized controlled trials, and the remaining three were non-randomized studies. Improvements in attention and executive functions were identified, although the diversity of approaches and duration means that reaching definitive conclusions is difficult. Conclusions: Increased research and standardized intervention programmes are essential. Longitudinal and randomized controlled studies in representative samples which provide conclusions that are applicable to other contexts are also important.(AU)
Subject(s)
Humans , Male , Female , Cognition , Parkinson Disease , Neurology , Nervous System DiseasesABSTRACT
Depression is a common non-motor symptom of Parkinson's disease. Previous studies demonstrated that hydroxysafflor yellow A had properties of improving motor symptoms of Parkinson's disease. The effect of hydroxysafflor yellow A on depression in Parkinson's disease mice is investigated in this study. To induce Parkinson's disease model, male Swiss mice were exposed to rotenone (30 mg/kg) for 6 weeks. The chronic unpredictable mild stress was employed to induce depression from week 3 to week 6. Sucrose preference, tail suspension, and forced swimming tests were conducted. Golgi and Nissl staining of hippocampus were carried out. The levels of dopamine, 5-hydroxytryptamine and the expression of postsynaptic density protein 95, brain-derived neurotrophic factor in hippocampus were assayed. It showed that HSYA improved the depression-like behaviors of Parkinson's disease mice. Hydroxysafflor yellow A attenuated the injury of nerve and elevated contents of dopamine, 5-hydroxytryptamine in hippocampus. Treatment with hydroxysafflor yellow A also augmented the expression of postsynaptic density protein 95 and brain-derived neurotrophic factor. These findings suggest that hydroxysafflor yellow A ameliorates depression-like behavior in Parkinson's disease mice through regulating the contents of postsynaptic density protein 95 and brain-derived neurotrophic factor, therefore protecting neurons and neuronal dendrites of the hippocampus.
Subject(s)
Behavior, Animal , Brain-Derived Neurotrophic Factor , Chalcone , Depression , Hippocampus , Quinones , Serotonin , Animals , Quinones/pharmacology , Quinones/therapeutic use , Chalcone/analogs & derivatives , Chalcone/pharmacology , Chalcone/therapeutic use , Male , Mice , Brain-Derived Neurotrophic Factor/metabolism , Depression/drug therapy , Depression/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Behavior, Animal/drug effects , Serotonin/metabolism , Dopamine/metabolism , Rotenone/pharmacology , Disease Models, Animal , Disks Large Homolog 4 Protein/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/psychologyABSTRACT
Background and purpose: The aim of this study was to assess the possible pharmacological interactions between safinamide and antidepressants, and in particular the appearance of serotonin syndrome with data from real life. Methods: We conducted a retrospective observational study of patients with Parkinson's disease from our Movement Disorders Unit, who were under treatment with any antidepressant drug and safinamide. Specifically, symptoms suggestive of serotonin syndrome were screened for. Also, we collected time of simultaneous use, doses of levodopa and other antiparkinsonian drugs. Results: Clinical records were reviewed for the study period of September 2018 to September 2019. Seventy-eight PD patients who were treated with safinamide of which 25 (32.05%) had a concomitant treatment with an antidepressant drug, being sertraline and escitalopram the most frequent. Mean age was 80 years ± 8.43 and H&Y stage was 3 [24]. Mean dose of levodopa used was 703.75 mg ± 233.15. Median duration of concomitant treatment with safinamide and antidepressant drug was 6 months (IQR 20.5), and over eighteen months in 5 cases. No case of serotonin syndrome was recorded, neither was any of its typical manifestations combined or in isolation. Conclusions: Our real clinical practice study suggests that concomitant use of safinamide with antidepressant drugs in PD patients seemed to be safe and well tolerated, even in the long term. However, caution is warranted, individualizing treatment regimens and monitoring the potential appearance of adverse effects.(AU)
Objetivos: El objetivo de este estudio ha sido evaluar las posibles interacciones farmacológicas entre safinamida y antidepresivos; en particular la aparición del síndrome serotoninérgico mediante datos obtenidos en la vida real. Material y métodos: Realizamos un estudio observacional retrospectivo de pacientes con enfermedad de Parkinson (EP) de nuestra unidad de trastornos del movimiento, que estaban en tratamiento con algún fármaco antidepresivo y safinamida. Específicamente, se examinaron los síntomas sugestivos de síndrome serotoninérgico. Además, se recogieron tiempos de uso simultáneo, dosis de levodopa y otros fármacos antiparkinsonianos concomitantes. Resultados: Se revisaron las historias clínicas correspondientes al período de estudio de septiembre de 2018 a septiembre de 2019. Setenta y ocho pacientes con EP se encontraban en tratamiento con safinamida, de los cuales 25 (32,05%) se encontraban recibiendo además un fármaco antidepresivo, siendo sertralina y escitalopram los más frecuentes. La edad media fue de 80 años ± 8,43 y el estadio H&Y fue de 3 [2-4]. La dosis media de levodopa utilizada fue de 703,75 mg ± 233,15. La mediana de duración del tratamiento concomitante con safinamida y un fármaco antidepresivo fue de 6 meses (IQR: 20,5), y más de 18 meses en 5 casos. No se registró ningún caso de síndrome serotoninérgico, ni tampoco ninguno de sus síntomas de forma aislada. Conclusión: Nuestro estudio de práctica clínica real sugiere que el uso concomitante de safinamida con fármacos antidepresivos en pacientes con EP parece ser seguro y bien tolerado, incluso a largo plazo. Sin embargo, es necesaria precaución, individualizando los regímenes de tratamiento, y controlando la posible aparición de efectos adversos.(AU)
Subject(s)
Humans , Male , Female , Parkinson Disease , Depression , Serotonin Agents , Movement Disorders , Antidepressive Agents , Neurology , Nervous System Diseases , Retrospective Studies , Medical Records/statistics & numerical dataABSTRACT
Introduction: Reliable assessment of individuals with Parkinson's disease (PD) is essential for providing adequate treatment. Clinical assessment is a complex and time-consuming task, especially for bradykinesia, since its evaluation can be influenced by the degree of experience of the examiner, patient collaboration and individual bias. Improvement of the clinical evaluation can be obtained by considering assessments from several professionals. However, this is only true when inter and intra-rater agreement are high. Recently, the Movement Disorder Society highlighted, during the COVID-19 pandemic, the need to develop and validate technologies for remote assessment of the motor status of people with PD. Thus, this study introduces an objective strategy for the remote evaluation of bradykinesia using multi-specialist analysis. Methods: Twelve volunteers with PD participated and these were asked to execute finger tapping, hand opening/closing and pronation/supination movements. Each task was recorded and rated by fourteen PD health experts for each patient. The scores were assessed on an individual basis. Intra and inter-rater agreement and correlation were estimated. Results: The results showed that agreements and correlations between experienced examiners were high with low variability. In addition, group analysis was noted as possessing the potential to solve individual inconsistency bias. Conclusion: Furthermore, this study demonstrated the need for a group with prior training and experience, along with indicating the importance for the development of a clinical protocol that can use telemedicine for the evaluation of individuals with PD, as well as the inclusion of a specialized mediating group. In Addition, this research helps to the development of a valid remote assessment of bradykinesia.(AU)
Introducción: La evaluación confiable de las personas con la enfermedad de Parkinson (EP) es esencial para lograr con un tratamiento adecuado. La evaluación clínica es una tarea compleja y que requiere mucho tiempo, especialmente para la bradicinesia, ya que su evaluación puede verse influenciada por el grado de experiencia del examinador, la colaboración del paciente y el sesgo individual. La mejora de la evaluación clínica se puede obtener considerando las evaluaciones de varios profesionales. Sin embargo, esto solo es más preciso cuando el convenio intra e inter evaluadores es alto. Recientemente, la Sociedad de Trastornos del Movimiento destacó, durante la pandemia COVID-19, la necesidad de desarrollar y validar tecnologías para la evaluación remota del estado motor de las personas con EP. Por lo tanto, este estudio presenta una estrategia objetiva para la evaluación remota de la bradicinesia mediante un análisis multi evaluadores. Métodos: Participaron 12 voluntarios con EP y se les pidió que ejecutaran movimientos de golpeteo de dedos de las manos, movimientos con las manos y pronación-supinación de las manos. Cada ejecución del movimiento fue registrado y calificado por 14 expertos en salud. Las puntuaciones se evaluaron de forma individual. Se estimó el convenio y la correlación intra e inter evaluadores. Resultados: Los resultados mostraron que los convenios y las correlaciones inter evaluadores experimentados son altos con baja variabilidad. Además, se observó que el análisis de grupo posee el potencial de resolver el sesgo de inconsistencia individual. Conclusiones: De esta forma, este estudio demostró la necesidad de un grupo con formación y experiencia previa, señalando la importancia para el desarrollo de un protocolo clínico que utiliza la telemedicina para la evaluación de personas con EP y como la inclusión de un grupo mediador especializado. En realidad, esta investigación propone una evaluación remota eficaz de la bradicinesia.(AU)
Subject(s)
Humans , Male , Female , Neurology , Parkinson Disease , Hypokinesia , Telemedicine , Mental Status and Dementia TestsABSTRACT
Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson's disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.
Subject(s)
Circadian Rhythm , Deep Brain Stimulation , Globus Pallidus , Levodopa , Parkinson Disease , Humans , Globus Pallidus/physiopathology , Parkinson Disease/physiopathology , Circadian Rhythm/physiology , Male , Female , Middle Aged , Retrospective Studies , Aged , Levodopa/therapeutic use , Subthalamic Nucleus/physiopathologyABSTRACT
Parkinson's disease is managed using levodopa; however, as Parkinson's disease progresses, patients require increased doses of levodopa, which can cause undesirable side effects. Additionally, the oral bioavailability of levodopa decreases in Parkinson's disease patients due to the increased metabolism of levodopa to dopamine by gut bacteria, Enterococcus faecalis, resulting in decreased neuronal uptake and dopamine formation. Parkinson's disease patients have varying levels of these bacteria. Thus, decreasing bacterial metabolism is a promising therapeutic approach to enhance the bioavailability of levodopa in the brain. In this work, we show that Mito-ortho-HNK, formed by modification of a naturally occurring molecule, honokiol, conjugated to a triphenylphosphonium moiety, mitigates the metabolism of levodopa-alone or combined with carbidopa-to dopamine. Mito-ortho-HNK suppresses the growth of E. faecalis, decreases dopamine levels in the gut, and increases dopamine levels in the brain. Mitigating the gut bacterial metabolism of levodopa as shown here could enhance its efficacy.
Subject(s)
Brain , Dopamine , Enterococcus faecalis , Gastrointestinal Microbiome , Levodopa , Parkinson Disease , Levodopa/metabolism , Levodopa/administration & dosage , Gastrointestinal Microbiome/drug effects , Dopamine/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/microbiology , Brain/metabolism , Brain/drug effects , Animals , Enterococcus faecalis/metabolism , Enterococcus faecalis/drug effects , Male , Antiparkinson Agents/metabolism , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/pharmacology , Carbidopa , Humans , Biphenyl Compounds/metabolism , Mice , Organophosphorus Compounds/metabolism , Mice, Inbred C57BLABSTRACT
Background: To date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson's disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk. Methods: By employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results. Results: Our MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility. Conclusion: In general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.
Subject(s)
Autoimmune Diseases , Genetic Predisposition to Disease , Genome-Wide Association Study , Mendelian Randomization Analysis , Parkinson Disease , Humans , Parkinson Disease/genetics , Parkinson Disease/epidemiology , Autoimmune Diseases/genetics , Autoimmune Diseases/epidemiology , Polymorphism, Single NucleotideABSTRACT
Parkinson's disease (PD) is a common and incurable neurodegenerative disorder that arises from the loss of dopaminergic neurons in the substantia nigra and is mainly characterized by progressive loss of motor function. Monogenic familial PD is associated with highly penetrant variants in specific genes, notably the PRKN gene, where homozygous or compound heterozygous loss-of-function variants predominate. PRKN encodes Parkin, an E3 ubiquitin-protein ligase important for protein ubiquitination and mitophagy of damaged mitochondria. Accordingly, Parkin plays a central role in mitochondrial quality control but is itself also subject to a strict protein quality control system that rapidly eliminates certain disease-linked Parkin variants. Here, we summarize the cellular and molecular functions of Parkin, highlighting the various mechanisms by which PRKN gene variants result in loss-of-function. We emphasize the importance of high-throughput assays and computational tools for the clinical classification of PRKN gene variants and how detailed insights into the pathogenic mechanisms of PRKN gene variants may impact the development of personalized therapeutics.
Subject(s)
Parkinson Disease , Ubiquitin-Protein Ligases , Humans , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Parkinson Disease/genetics , Parkinson Disease/pathology , Parkinson Disease/metabolism , Mitochondria/metabolism , Mitochondria/genetics , Mitochondria/pathology , Ubiquitination/genetics , Mitophagy/genetics , AnimalsABSTRACT
BACKGROUND: Deep brain stimulation (DBS) reliably ameliorates cardinal motor symptoms in Parkinson's disease (PD) and essential tremor (ET). However, the effects of DBS on speech, voice and language have been inconsistent and have not been examined comprehensively in a single study. OBJECTIVE: We conducted a systematic analysis of literature by reviewing studies that examined the effects of DBS on speech, voice and language in PD and ET. METHODS: A total of 675 publications were retrieved from PubMed, Embase, CINHAL, Web of Science, Cochrane Library and Scopus databases. Based on our selection criteria, 90 papers were included in our analysis. The selected publications were categorized into four subcategories: Fluency, Word production, Articulation and phonology and Voice quality. RESULTS: The results suggested a long-term decline in verbal fluency, with more studies reporting deficits in phonemic fluency than semantic fluency following DBS. Additionally, high frequency stimulation, left-sided and bilateral DBS were associated with worse verbal fluency outcomes. Naming improved in the short-term following DBS-ON compared to DBS-OFF, with no long-term differences between the two conditions. Bilateral and low-frequency DBS demonstrated a relative improvement for phonation and articulation. Nonetheless, long-term DBS exacerbated phonation and articulation deficits. The effect of DBS on voice was highly variable, with both improvements and deterioration in different measures of voice. CONCLUSION: This was the first study that aimed to combine the outcome of speech, voice, and language following DBS in a single systematic review. The findings revealed a heterogeneous pattern of results for speech, voice, and language across DBS studies, and provided directions for future studies.
Subject(s)
Deep Brain Stimulation , Language , Parkinson Disease , Speech , Voice , Deep Brain Stimulation/methods , Humans , Parkinson Disease/therapy , Parkinson Disease/physiopathology , Speech/physiology , Voice/physiology , Essential Tremor/therapy , Essential Tremor/physiopathologyABSTRACT
There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.
Subject(s)
Dopamine Agonists , Parkinson Disease , Tyrosine 3-Monooxygenase , Animals , Humans , Dopamine/metabolism , Dopamine Agonists/therapeutic use , Dopamine Agonists/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/metabolism , Drug Therapy, Combination , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/pharmacology , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Tyrosine 3-Monooxygenase/antagonists & inhibitors , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Background: Parkinson's disease (PD) and Essential tremor (ET) are the two most common tremor diseases with recognized genetic pathogenesis. The overlapping clinical features suggest they may share genetic predispositions. Our previous study systematically investigated the association between rare coding variants in ET-associated genes and early-onset PD (EOPD), and found the suggestive association between teneurin transmembrane protein 4 (TENM4) and EOPD. In the current research, we explored the potential genetic interplay between ET-associated genetic loci/genes and sporadic late-onset PD (LOPD). Methods: We performed whole-genome sequencing in the 1962 sporadic LOPD cases and 1279 controls from mainland China. We first used logistic regression analysis to test the top 16 SNPs identified by the ET genome-wide association study for the association between ET and LOPD. Then we applied the optimized sequence kernel association testing to explore the rare variant burden of 33 ET-associated genes in this cohort. Results: We did not observe a significant association between the included SNPs with LOPD. We also did not discover a significant burden of rare deleterious variants of ET-associated genes in association with LOPD risk. Conclusion: Our results do not support the role of ET-associated genetic loci and variants in LOPD. Highlights: 1962 cases and 1279 controls were recruited to study the potential genetic interplay between ET-associated genetic loci/variants and sporadic LOPD.No significant association between the ET-associated SNPs and LOPD were observed.No significant burden of rare deleterious variants of ET-associated gene in LOPD risk were found.
Subject(s)
Essential Tremor , Genetic Predisposition to Disease , Genome-Wide Association Study , Parkinson Disease , Polymorphism, Single Nucleotide , Humans , Essential Tremor/genetics , Parkinson Disease/genetics , Female , Male , Polymorphism, Single Nucleotide/genetics , Aged , Middle Aged , Genetic Predisposition to Disease/genetics , Age of Onset , China , Case-Control StudiesABSTRACT
Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.
Subject(s)
Language , Parkinson Disease , Speech , Subthalamic Nucleus , Humans , Parkinson Disease/physiopathology , Parkinson Disease/drug therapy , Subthalamic Nucleus/physiopathology , Subthalamic Nucleus/drug effects , Male , Speech/physiology , Speech/drug effects , Female , Middle Aged , Aged , Magnetic Resonance Imaging , Dopamine/metabolism , Nerve Net/drug effects , Nerve Net/physiopathology , Cognition/drug effects , Dopamine Agents/pharmacology , Dopamine Agents/therapeutic useABSTRACT
Aspiration pneumonia is the leading cause of death in patients with Parkinson's disease. The incidence of silent aspiration is high in such patients owing to decreased pharyngeal and laryngeal sensation; thus, interventions for this condition may help prevent pneumonia. In this single-arm, open-label study, we used a cervical percutaneous interferential current stimulation device to activate pharyngeal and laryngeal sensory nerves. We evaluated its effectiveness in patients with Hoehn-Yahr stages 2-4 Parkinson's disease. The primary endpoint was the proportion of patients with a normal cough reflex after consuming 1% citric acid at the end of the intervention compared with baseline measurements. In total, 25 patients received neck percutaneous interferential current stimulation for 20 min twice weekly for 8 weeks. Afterward, the proportion of patients with a normal cough reflex after 1% citric acid consumption increased significantly (p = 0.001), whereas other indicators, such as tongue pressure, peak expiratory flow, and penetration or aspiration during videofluoroscopic examination, remained unchanged. A longer duration of illness, higher Unified Parkinson's Disease Rating Scale total scores, and higher levodopa equivalent daily doses were significantly associated with improved cough test outcomes. Hence, cervical percutaneous interferential current stimulation significantly improved cough reflexes and may improve silent aspiration. Trial Registration: Japan Registry of Clinical Trials, jRCTs062220013, first registered 09/05/2022.
Subject(s)
Citric Acid , Cough , Parkinson Disease , Humans , Parkinson Disease/therapy , Parkinson Disease/physiopathology , Female , Male , Aged , Cough/drug therapy , Middle Aged , Pneumonia, Aspiration/etiology , Pneumonia, Aspiration/prevention & control , Electric Stimulation Therapy/methodsABSTRACT
Parkinson's disease (PD) is recognized as the second most prevalent primary chronic neurodegenerative disorder of the central nervous system. Clinically, PD is characterized as a movement disorder, exhibiting an incidence and mortality rate that is increasing faster than any other neurological condition. In recent years, there has been a growing interest concerning the role of the gut microbiota in the etiology and pathophysiology of PD. The establishment of a brain-gut microbiota axis is now real, with evidence denoting a bidirectional communication between the brain and the gut microbiota through metabolic, immune, neuronal, and endocrine mechanisms and pathways. Among these, the vagus nerve represents the most direct form of communication between the brain and the gut. Given the potential interactions between bacteria and drugs, it has been observed that the therapies for PD can have an impact on the composition of the microbiota. Therefore, in the scope of the present review, we will discuss the current understanding of gut microbiota on PD and whether this may be a new paradigm for treating this devastating disease.
Subject(s)
Brain-Gut Axis , Brain , Gastrointestinal Microbiome , Parkinson Disease , Humans , Parkinson Disease/microbiology , Parkinson Disease/therapy , Brain/microbiology , Brain/pathology , Brain-Gut Axis/physiology , AnimalsABSTRACT
Parkinson's disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form of genetic variation, single nucleotide variants (SNVs), while other important forms of genetic variation, such as structural variants (SVs), are mostly ignored due to the complexity of detecting these variants with traditional sequencing methods. Yet, these forms of genetic variation play crucial roles in gene expression and regulation in the human brain and are causative of numerous neurological disorders, including forms of PD. This review aims to provide a comprehensive overview of our current understanding of the involvement of coding and noncoding SVs in the genetic architecture of PD.
Subject(s)
Genetic Predisposition to Disease , Parkinson Disease , Polymorphism, Single Nucleotide , Parkinson Disease/genetics , Humans , Genetic Variation , Genome-Wide Association StudyABSTRACT
While an association between Parkinson's disease (PD) and viral infections has been recognized, the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on PD progression remains unclear. Here, we demonstrate that SARS-CoV-2 infection heightens the risk of PD using human embryonic stem cell (hESC)-derived dopaminergic (DA) neurons and a human angiotensin-converting enzyme 2 (hACE2) transgenic (Tg) mouse model. Our findings reveal that SARS-CoV-2 infection exacerbates PD susceptibility and cellular toxicity in DA neurons pre-treated with human preformed fibrils (hPFFs). Additionally, nasally delivered SARS-CoV-2 infects DA neurons in hACE2 Tg mice, aggravating the damage initiated by hPFFs. Mice infected with SARS-CoV-2 display persisting neuroinflammation even after the virus is no longer detectable in the brain. A comprehensive analysis suggests that the inflammatory response mediated by astrocytes and microglia could contribute to increased PD susceptibility associated with SARS-CoV-2. These findings advance our understanding of the potential long-term effects of SARS-CoV-2 infection on the progression of PD.
Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Disease Models, Animal , Dopaminergic Neurons , Mice, Transgenic , Parkinson Disease , SARS-CoV-2 , Animals , Dopaminergic Neurons/pathology , Dopaminergic Neurons/metabolism , Dopaminergic Neurons/virology , Humans , COVID-19/pathology , COVID-19/virology , Parkinson Disease/pathology , Parkinson Disease/virology , Mice , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Microglia/pathology , Microglia/metabolism , Microglia/virology , Human Embryonic Stem Cells/metabolism , Astrocytes/pathology , Astrocytes/virology , Astrocytes/metabolism , Brain/pathology , Brain/virologyABSTRACT
Loss of ambulation is common and highly variable in Parkinson's disease (PD), and poorly understood from the perspectives of those with PD. Gaining insights to the anticipated perceived trajectories and their drivers, will facilitate patient-centered care. Latent class growth analysis, a person-centered mixture modelling approach, was applied to 16,863 people with PD stratified by early (N = 8612; < 3 years), mid (N = 6181; 3-10 years) and later (N = 2070; > 10 years) disease to discern clusters with similar longitudinal patterns of self-reported walking difficulty, measured by EuroQoL 5D-5L that is validated for use in PD. There were four clusters in early and mid-disease strata, with a fifth identified in later disease. Trajectories ranged from none to moderate walking difficulty, with small clusters with severe problems. The percentage of subjects with moderate (early = 17.5%, mid = 26.4%, later = 32.5%) and severe (early = 3.8%, mid = 7.4%, later = 15.4%) walking difficulty at baseline increased across disease duration groups. The trajectories tended to be stable with variability in moderate and severe groups. Across strata, clusters with moderate to severe problems were associated with more severe impairment, depression, anxiety, arthritis, higher BMI, lower income, and lower education, but no consistent race or gender differences. The findings reveal distinct longitudinal patterns in perceived difficulties in walking in PD.
Subject(s)
Parkinson Disease , Walking , Humans , Parkinson Disease/psychology , Parkinson Disease/physiopathology , Parkinson Disease/complications , Male , Female , Aged , Middle Aged , Longitudinal Studies , Quality of LifeABSTRACT
BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
