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1.
Artículo en Inglés | MEDLINE | ID: mdl-39088860

RESUMEN

The increasing prevalence of Parkinson disease (PD) highlights the need to develop interventions aimed at slowing or halting its progression. As a result of sophisticated disease modeling in preclinical studies, and refinement of specific clinical/genetic/pathological profiles, our understanding of PD pathogenesis has grown over the years, leading to the identification of several targets for disease modification. This has translated to the development of targeted therapies, many of which have entered clinical trials. Nonetheless, up until now, none of these treatments have satisfactorily shown disease-modifying effects in PD. In this review, we present the most up-to-date disease-modifying pharmacological interventions in the clinical trial pipeline for PD. We focus on agents that have reached more advanced stages of clinical trials testing, highlighting both positive and negative results, and critically reflect on strengths, weaknesses, and challenges of current disease-modifying therapeutic avenues in PD.

2.
Neurobiol Dis ; 188: 106343, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37926171

RESUMEN

BACKGROUND: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. OBJECTIVES: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. METHODS: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. RESULTS: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. CONCLUSIONS: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.


Asunto(s)
Enfermedad de Gaucher , Enfermedad de Parkinson , Humanos , Estudios Transversales , Enfermedad de Parkinson/genética , Fenotipo , Penetrancia , Enfermedad de Gaucher/genética , Síntomas Prodrómicos
3.
Eur J Neurol ; 30(7): 1963-1972, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36971736

RESUMEN

OBJECTIVE: To evaluate correlations between speech and gait parameters in the long term and under different medication and subthalamic nucleus deep brain stimulation (STN-DBS) conditions in a cohort of advanced Parkinson's disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Axial symptoms were evaluated using a standardized clinical-instrumental approach. Speech and gait were assessed by perceptual and acoustic analyses and by the instrumented Timed Up and Go (iTUG) test, respectively. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. RESULTS: Twenty-five PD patients with a 5-year median follow-up after surgery (range 3-7 years) were included (18 males; disease duration at surgery: 10.44 [SD 4.62] years; age at surgery: 58.40 [SD 5.73] years). In the off-stimulation/off-medication and on-stimulation/on-medication conditions, patients who spoke louder had also the greater acceleration of the trunk during gait; whereas in the on-stimulation/on-medication condition only, patients with the poorer voice quality were also the worst to perform the sit to stand and gait phases of the iTUG. Conversely, patients with the higher speech rate performed well in the turning and walking phases of the iTUG. CONCLUSIONS: This study underlines the presence of different correlations between treatment effects of speech and gait parameters in PD patients treated with bilateral STN-DBS. This may allow us to better understand the common pathophysiological basis of these alterations and to develop a more specific and tailored rehabilitation approach for axial signs after surgery.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Masculino , Humanos , Persona de Mediana Edad , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/tratamiento farmacológico , Habla , Resultado del Tratamiento , Marcha
4.
Curr Neurol Neurosci Rep ; 23(4): 121-130, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36881256

RESUMEN

PURPOSE OF REVIEW: Genetic variants in GBA1 and LRRK2 genes are the commonest genetic risk factor for Parkinson disease (PD); however, the preclinical profile of GBA1 and LRRK2 variant carriers who will develop PD is unclear. This review aims to highlight the more sensitive markers that can stratify PD risk in non-manifesting GBA1 and LRRK2 variant carriers. RECENT FINDINGS: Several case-control and a few longitudinal studies evaluated clinical, biochemical, and neuroimaging markers within cohorts of non-manifesting carriers of GBA1 and LRRK2 variants. Despite similar levels of penetrance of PD in GBA1 and LRRK2 variant carriers (10-30%), these individuals have distinct preclinical profiles. GBA1 variant carriers at higher risk of PD can present with prodromal symptoms suggestive of PD (hyposmia), display increased α-synuclein levels in peripheral blood mononuclear cells, and show dopamine transporter abnormalities. LRRK2 variant carriers at higher risk of PD might show subtle motor abnormalities, but no prodromal symptoms, higher exposure to some environmental factors (non-steroid anti-inflammatory drugs), and peripheral inflammatory profile. This information will help clinicians tailor appropriate screening tests and counseling and facilitate researchers in the development of predictive markers, disease-modifying treatments, and selection of healthy individuals who might benefit from preventive interventions.


Asunto(s)
Enfermedad de Parkinson , Humanos , Glucosilceramidasa/genética , Heterocigoto , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Leucocitos Mononucleares , Estudios Longitudinales , Mutación , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Síntomas Prodrómicos
5.
Neurobiol Dis ; 166: 105663, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35183702

RESUMEN

Dysfunction of the endolysosomal system is implicated in the pathogenesis of both sporadic and familial Parkinson disease (PD). Variants in genes encoding lysosomal proteins have been estimated to be associated with more than half of PD cases. The most common genetic risk factor for PD are variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. In this review we will describe the clinical symptoms and pathology of GBA-PD, and how this might be affected by the type of GBA variant. The putative mechanisms by which GCase deficiency in neurons and glia might contribute to PD pathogenesis will then be discussed, with particular emphasis on the accumulation of α-synuclein aggregates and the spread of pathogenic α-synuclein species between the cell types. The dysregulation of not only sphingolipids, but also phospholipids and cholesterol in the misfolding of α-synuclein is reviewed, as are neuroinflammation and the interaction of GCase with LRRK2 protein, another important contributor to PD pathogenesis. Study of both non-manifesting GBA carriers and GBA-PD cohorts provides an opportunity to identify robust biomarkers for PD progression as well as clinical trials for potential treatments. The final part of this review will describe preclinical studies and clinical trials for increasing GCase activity or reducing toxic substrate accumulation.


Asunto(s)
Glucosilceramidasa , Enfermedad de Parkinson , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Heterocigoto , Humanos , Lisosomas/metabolismo , Mutación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
6.
J Neurochem ; 159(5): 826-839, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34618942

RESUMEN

The glucocerebrosidase 1 gene (GBA1), bi-allelic variants of which cause Gaucher disease (GD), encodes the lysosomal enzyme glucocerebrosidase (GCase) and is a risk factor for Parkinson Disease (PD). GBA1 variants are linked to a reduction in GCase activity in the brain. Variants in Leucine-Rich Repeat Kinase 2 (LRRK2), such as the gain-of-kinase-function variant G2019S, cause the most common familial form of PD. In patients without GBA1 and LRRK2 mutations, GCase and LRRK2 activity are also altered, suggesting that these two genes are implicated in all forms of PD and that they may play a broader role in PD pathogenesis. In this review, we review the proposed roles of GBA1 and LRRK2 in PD, focussing on the endolysosomal pathway. In particular, we highlight the discovery of Ras-related in brain (Rab) guanosine triphosphatases (GTPases) as LRRK2 kinase substrates and explore the links between increased LRRK2 activity and Rab protein function, lysosomal dysfunction, alpha-synuclein accumulation and GCase activity. We also discuss the discovery of RAB10 as a potential mediator of LRRK2 and GBA1 interaction in PD. Finally, we discuss the therapeutic implications of these findings, including current approaches and future perspectives related to novel drugs targeting LRRK2 and GBA1.


Asunto(s)
Epistasis Genética/genética , Glucosilceramidasa/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Animales , Glucosilceramidasa/antagonistas & inhibidores , Glucosilceramidasa/metabolismo , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/genética , Aparato de Golgi/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Proteínas de Unión al GTP rab/antagonistas & inhibidores , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo
7.
BMC Neurol ; 20(1): 113, 2020 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-32228506

RESUMEN

BACKGROUND: Detection of brain-MRI T2/T2* gradient echo images (T2*GRE)-hypointensity can be compatible with iron accumulation and leads to a differential diagnosis work-up including neurodegeneration with brain iron accumulation (NBIA) and Wilson Disease. Idiopathic or secondary brain calcification can be also associated with neurological involvement and brain-MRI T2/T2*GRE-hypointensity. Hereditary hemochromatosis (HH), characterized by systemic iron loading, usually does not involve the CNS, and only sporadic cases of neurological abnormalities or brain-MRI T2/T2*GRE-hypointensity have been reported. CASE PRESENTATION: A 59-year-old man came to our observation after a diagnosis of HH carried out in another hospital 2 years before. First-level genetic test had revealed a homozygous HFE p.Cys282Tyr (C282Y) mutation compatible with the diagnosis of HFE-related HH, thus phlebotomy treatment was started. The patient had a history of metabolic syndrome, type-2 diabetes, autoimmune thyroiditis and severe chondrocalcinosis. Brain-MRI showed the presence of bilateral T2*GRE hypointensities within globus pallidus, substantia nigra, dentate nucleus and left pulvinar that were considered expression of cerebral siderosis. No neurological symptoms or family history of neurological disease were reported. Neurological examination revealed only mild right-sided hypokinetic-rigid syndrome. Vitamin D-PTH axis, measurements of serum ceruloplasmin and copper, and urinary copper were within the normal range. A brain computed tomography (CT) was performed to better characterize the suspected and unexplained brain iron accumulation. On the CT images, the hypointense regions in the brain MRI were hyperdense. DNA sequence analysis of genes associated with primary familial brain calcification and NBIA was negative. CONCLUSIONS: This report highlights the importance of brain CT-scan in ambiguous cases of suspected cerebral siderosis, and suggests that HH patients with a severe phenotype, and likely associated with chondrocalcinosis, may display also brain calcifications. Further studies are needed to confirm this hypothesis. So far, we can speculate that iron and calcium homeostasis could be reciprocally connected within the basal ganglia.


Asunto(s)
Encefalopatías Metabólicas/etiología , Encefalopatías Metabólicas/patología , Calcinosis/patología , Hemocromatosis/complicaciones , Hemocromatosis/patología , Calcinosis/etiología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad
8.
Mov Disord ; 34(11): 1588-1601, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31449710

RESUMEN

Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related myoclonus-dystonia, these conditions can be collectively classified as "myoclonus-dystonia syndromes." In the present article, we present myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network. © 2019 International Parkinson and Movement Disorder Society.


Asunto(s)
Distonía/genética , Trastornos Distónicos/metabolismo , Red Nerviosa/metabolismo , Sarcoglicanos/metabolismo , Calcio/metabolismo , Proteínas del Citoesqueleto/metabolismo , Trastornos Distónicos/fisiopatología , Homeostasis/fisiología , Humanos , Mutación/genética , Mioclonía/metabolismo , Fenotipo , Sarcoglicanos/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
12.
CNS Drugs ; 38(5): 315-331, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38570412

RESUMEN

The concept of a 'microbiota-gut-brain axis' has recently emerged as an important player in the pathophysiology of Parkinson disease (PD), not least because of the reciprocal interaction between gut bacteria and medications. The gut microbiota can influence levodopa kinetics, and conversely, drugs administered for PD can influence gut microbiota composition. Through a two-step enzymatic pathway, gut microbes can decarboxylate levodopa to dopamine in the small intestine and then dehydroxylate it to m-tyramine, thus reducing availability. Inhibition of bacterial decarboxylation pathways could therefore represent a strategy to increase levodopa absorption. Other bacterial perturbations common in PD, such as small intestinal bacterial overgrowth and Helicobacter pylori infection, can also modulate levodopa metabolism, and eradication therapies may improve levodopa absorption. Interventions targeting the gut microbiota offer a novel opportunity to manage disabling motor complications and dopa-unresponsive symptoms. Mediterranean diet-induced changes in gut microbiota composition might improve a range of non-motor symptoms. Prebiotics can increase levels of short-chain fatty acid-producing bacteria and decrease pro-inflammatory species, with positive effects on clinical symptoms and levodopa kinetics. Different formulations of probiotics showed beneficial outcomes on constipation, with some of them improving dopamine levels; however, the most effective dosage and duration and long-term effects of these treatments remain unknown. Data from faecal microbiota transplantation studies are preliminary, but show encouraging trends towards improvement in both motor and non-motor outcomes.This article summarises the most up-to-date knowledge in pharmacomicrobiomics in PD, and discusses how the manipulation of gut microbiota represents a potential new therapeutic avenue for PD.


Asunto(s)
Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Microbioma Gastrointestinal/fisiología , Levodopa/farmacología , Dopamina
13.
Nutrients ; 16(14)2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-39064625

RESUMEN

BACKGROUND: There is mounting evidence to suggest that high adherence to the Mediterranean diet (MedDiet) may reduce the risk of age-related diseases, including Parkinson's disease (PD). However, evidence for the role of the MedDiet in the relief of motor and non-motor symptoms in patients with PD remains limited and inconclusive. We provide a systematic review of the effects of the MedDiet on the clinical features of PD using data from randomised controlled trials (RCT) and prospective observational studies. METHODS: We searched MEDLINE, EMCare, EMBASE, Scopus and PubMed from inception until June 2023. Reference lists and the grey literature were also searched. Human studies with no restriction on language or publication date, examining associations between MedDiet adherence and the symptoms of PD, were included. We employed standard methodological procedures for data extraction and evidence synthesis and used the Quality Criteria Checklist for assessing the studies included. RESULTS: Four studies from three unique cohorts, including two observational studies (n = 1213) and one RCT (n = 70), met the inclusion criteria. Despite the short study duration reported in all included reports, high MedDiet adherence was associated with changes in the gut microbiota (e.g., increased abundance of short-chain fatty acids producers). These outcomes correlated with a significant improvement in several non-motor symptoms including cognitive dysfunction, dyspepsia and constipation. However, there were no significant changes in diarrhoea, gastrointestinal reflux, abdominal pain and motor symptoms. CONCLUSION: High MedDiet adherence may be associated with significant improvement in global cognition and several gastrointestinal symptoms, possibly associated to changes in gut microbiota composition. Further studies are warranted to clarify potential cause-and-effect relationships and to elucidate MedDiet impact on motor symptoms.


Asunto(s)
Dieta Mediterránea , Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/dietoterapia , Cooperación del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Femenino , Masculino , Estudios Observacionales como Asunto , Anciano
14.
Pharmacol Ther ; 246: 108419, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37080432

RESUMEN

The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants in GBA1 cause Gaucher disease (GD), a lysosomal storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation of GCase substrates. Carriers of GBA1 variants have an increased risk of developing Parkinson disease (PD), with odds ratio ranging from 2.2 to 30 according to variant severity. GBA1 variants which do not cause GD in homozygosis can also increase PD risk. Patients with PD carrying GBA1 variants show a more rapidly progressive phenotype compared to non-carriers, emphasising the need for disease modifying treatments targeting the GBA1 pathway. Several mechanisms secondary to GCase dysfunction are potentially responsible for the pathological changes leading to PD. Misfolded GCase proteins induce endoplasmic reticulum stress and subsequent unfolded protein response and impair the autophagy-lysosomal pathway. This results in α-synuclein accumulation and spread, and promotes neurodegenerative changes. Preclinical evidence also shows that products of GCase activity can promote accumulation of α-synuclein, however there is no convincing evidence of substrate accumulation in GBA1-PD brains. Altered lipid homeostasis secondary to loss of GCase activity could also contribute to PD pathology. Treatments that target the GBA1 pathway could reverse these pathological processes and halt/slow the progression of PD. These range from augmentation of GCase activity via GBA1 gene therapy, restoration of normal intracellular GCase trafficking via molecular chaperones, and substrate reduction therapy. This review discusses the pathways associated with GBA1-PD and related novel GBA1-targeted interventions for PD treatment.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/uso terapéutico , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Glucosilceramidasa/uso terapéutico , Encéfalo/metabolismo , Mutación
15.
Brain Commun ; 5(6): fcad285, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37953845

RESUMEN

Caudo-rostral migration of pathological forms of α-synuclein from the gut to the brain is proposed as an early feature in Parkinson's disease pathogenesis, but the underlying mechanisms remain unknown. Intestinal epithelial enteroendocrine cells sense and respond to numerous luminal signals, including bacterial factors, and transmit this information to the brain via the enteric nervous system and vagus nerve. There is evidence that gut bacteria composition and their metabolites change in Parkinson's disease patients, and these alterations can trigger α-synuclein pathology in animal models of the disorder. Here, we investigated the effect of toll-like receptor and free fatty acid receptor agonists on the intracellular level of α-synuclein and its release using mouse secretin tumour cell line 1 enteroendocrine cells. Secretin tumour cell line 1 enteroendocrine cells were treated for 24 or 48 h with toll-like receptor agonists (toll-like receptor 4 selective lipopolysaccharide; toll-like receptor 2 selective Pam3CysSerLys4) and the free fatty acid receptor 2/3 agonists butyrate, propionate and acetate. The effect of selective receptor antagonists on the agonists' effects after 24 hours was also investigated. The level of α-synuclein protein was measured in cell lysates and cell culture media by western blot and enzyme-linked immunosorbent assay. The level of α-synuclein and tumour necrosis factor messenger RNA was measured by quantitative reverse transcription real-time polymerase chain reaction. Stimulation of secretin tumour cell line 1 enteroendocrine cells for 24 and 48 hours with toll-like receptor and free fatty acid receptor agonists significantly increased the amount of intracellular α-synuclein and the release of α-synuclein from the cells into the culture medium. Both effects were significantly reduced by antagonists selective for each receptor. Toll-like receptor and free fatty acid receptor agonists also significantly increased tumour necrosis factor transcription, and this was effectively inhibited by corresponding antagonists. Elevated intracellular α-synuclein increases the likelihood of aggregation and conversion to toxic forms. Factors derived from bacteria induce α-synuclein accumulation in secretin tumour cell line 1 enteroendocrine cells. Here, we provide support for a mechanism by which exposure of enteroendocrine cells to specific bacterial factors found in Parkinson's disease gut dysbiosis might facilitate accumulation of α-synuclein pathology in the gut.

16.
Front Neurol ; 14: 1213772, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37533469

RESUMEN

Background: Very few studies have assessed the presence of a possible correlation between speech variables and limb bradykinesia in patients with Parkinson's disease (PD). The objective of this study was to find correlations between different speech variables and upper extremity bradykinesia under different medication conditions in advanced PD patients. Methods: Retrospective data were collected from a cohort of advanced PD patients before and after an acute levodopa challenge. Each patient was assessed with a perceptual-acoustic analysis of speech, which included several quantitative parameters [i.e., maximum phonation time (MPT) and intensity (dB)]; the Unified Parkinson's Disease Rating Scale (UPDRS) (total scores, subscores, and items); and a timed test (a tapping test for 20 s) to quantify upper extremity bradykinesia. Pearson's correlation coefficient was applied to find correlations between the different speech variables and the tapping rate. Results: A total of 53 PD patients [men: 34; disease duration: 10.66 (SD 4.37) years; age at PD onset: 49.81 years (SD 6.12)] were included. Levodopa intake increased the MPT of sustained phonation (p < 0.01), but it reduced the speech rate (p = 0.05). In the defined-OFF condition, MPT of sustained phonation positively correlated with both bilateral mean (p = 0.044, r-value:0.299) and left (p = 0.033, r-value:0.314) tapping. In the defined-ON condition, the MPT correlated positively with bilateral mean tapping (p = 0.003), left tapping (p = 0.003), and right tapping (p = 0.008). Conclusion: This study confirms the presence of correlations between speech acoustic variables and upper extremity bradykinesia in advanced PD patients. These findings suggest common pathophysiological mechanisms.

17.
Biomolecules ; 13(10)2023 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-37892187

RESUMEN

Recent attention has highlighted the importance of oral microbiota in human health and disease, e.g., in Parkinson's disease, notably using shotgun metagenomics. One key aspect for efficient shotgun metagenomic analysis relies on optimal microbial sampling and DNA extraction, generally implementing commercial solutions developed to improve sample collection and preservation, and provide high DNA quality and quantity for downstream analysis. As metagenomic studies are today performed on a large number of samples, the next evolution to increase study throughput is with DNA extraction automation. In this study, we proposed a semi-automated DNA extraction protocol for human salivary samples collected with a commercial kit, and compared the outcomes with the DNA extraction recommended by the manufacturer. While similar DNA yields were observed between the protocols, our semi-automated DNA protocol generated significantly higher DNA fragment sizes. Moreover, we showed that the oral microbiome composition was equivalent between DNA extraction methods, even at the species level. This study demonstrates that our semi-automated protocol is suitable for shotgun metagenomic analysis, while allowing for improved sample treatment logistics with reduced technical variability and without compromising the structure of the oral microbiome.


Asunto(s)
ADN , Microbiota , Humanos , Análisis de Secuencia de ADN/métodos , ARN Ribosómico 16S/genética , ADN/genética , ADN/química , Microbiota/genética , Metagenoma
18.
Sci Rep ; 13(1): 11462, 2023 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-37454168

RESUMEN

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson's Disease (PD). However, the effects of STN-DBS on speech are still debated, particularly in the long-term follow-up. The objective of this study was to evaluate the long-term effects of bilateral STN-DBS on speech in a cohort of advanced PD patients treated with bilateral STN-DBS. Each patient was assessed before surgery through a neurological evaluation and a perceptual-acoustic analysis of speech and re-assessed in the long-term in different stimulation and drug conditions. The primary outcome was the percentage change of speech intelligibility obtained by comparing the postoperative on-stimulation/off-medication condition with the preoperative off-medication condition. Twenty-five PD patients treated with bilateral STN-DBS with a 5-year follow-up were included. In the long-term, speech intelligibility stayed at the same level as preoperative values when compared with preoperative values. STN-DBS induced a significant acute improvement of speech intelligibility (p < 0.005) in the postoperative assessment when compared to the on-stimulation/off-medication and off-stimulation/off-medication conditions. These results highlight that STN-DBS may handle speech intelligibility even in the long-term.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/cirugía , Estimulación Encefálica Profunda/métodos , Resultado del Tratamiento , Inteligibilidad del Habla/fisiología
19.
J Neurol ; 270(9): 4342-4353, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37208527

RESUMEN

OBJECTIVE: To assess the long-term effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on gait in a cohort of advanced Parkinson's Disease (PD) patients. METHODS: This observational study included consecutive PD patients treated with bilateral STN-DBS. Different stimulation and drug treatment conditions were assessed: on-stimulation/off-medication, off-stimulation/off-medication, and on-stimulation/on-medication. Each patient performed the instrumented Timed Up and Go test (iTUG). The instrumental evaluation of walking ability was carried out with a wearable inertial sensor containing a three-dimensional (3D) accelerometer, gyroscope, and magnetometer. This device could provide 3D linear acceleration, angular velocity, and magnetic field vector. Disease motor severity was evaluated with the total score and subscores of the Unified Parkinson Disease Rating Scale part III. RESULTS: Twenty-five PD patients with a 5-years median follow-up after surgery (range 3-7) were included (18 men; mean disease duration at surgery 10.44 ± 4.62 years; mean age at surgery 58.40 ± 5.73 years). Both stimulation and medication reduced the total duration of the iTUG and most of its different phases, suggesting a long-term beneficial effect on gait after surgery. However, comparing the two treatments, dopaminergic therapy had a more marked effect in all test phases. STN-DBS alone reduced total iTUG duration, sit-to-stand, and second turn phases duration, while it had a lower effect on stand-to-sit, first turn, forward walking, and walking backward phases duration. CONCLUSIONS: This study highlighted that in the long-term after surgery, STN-DBS may contribute to gait and postural control improvement when used together with dopamine replacement therapy, which still shows a substantial beneficial effect.


Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Masculino , Humanos , Persona de Mediana Edad , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/tratamiento farmacológico , Núcleo Subtalámico/fisiología , Estimulación Encefálica Profunda/métodos , Equilibrio Postural , Resultado del Tratamiento , Estudios de Tiempo y Movimiento , Marcha
20.
Front Neurol ; 13: 971252, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36034282

RESUMEN

Variants in the GBA1 and LRRK2 genes are the most common genetic risk factors associated with Parkinson disease (PD). Both genes are associated with lysosomal and autophagic pathways, with the GBA1 gene encoding for the lysosomal enzyme, glucocerebrosidase (GCase) and the LRRK2 gene encoding for the leucine-rich repeat kinase 2 enzyme. GBA1-associated PD is characterized by earlier age at onset and more severe non-motor symptoms compared to sporadic PD. Mutations in the GBA1 gene can be stratified into severe, mild and risk variants depending on the clinical presentation of disease. Both a loss- and gain- of function hypothesis has been proposed for GBA1 variants and the functional consequences associated with each variant is often linked to mutation severity. On the other hand, LRRK2-associated PD is similar to sporadic PD, but with a more benign disease course. Mutations in the LRRK2 gene occur in several structural domains and affect phosphorylation of GTPases. Biochemical studies suggest a possible convergence of GBA1 and LRRK2 pathways, with double mutant carriers showing a milder phenotype compared to GBA1-associated PD. This review compares GBA1 and LRRK2-associated PD, and highlights possible genotype-phenotype associations for GBA1 and LRRK2 separately, based on biochemical consequences of single variants.

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