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1.
Brain ; 146(8): 3258-3272, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36881989

RESUMEN

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.


Asunto(s)
Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Enfermedad por Cuerpos de Lewy/diagnóstico , Trastorno de la Conducta del Sueño REM/diagnóstico , Estudios Prospectivos , Progresión de la Enfermedad , Biomarcadores , Síntomas Prodrómicos
2.
Mov Disord ; 36(8): 1825-1834, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33772873

RESUMEN

BACKGROUND: Neuroinflammation plays a key role in PD pathogenesis, and allogeneic bone marrow-derived mesenchymal stem cells can be used as an immunomodulatory therapy. OBJECTIVE: The objective of this study was to prove the safety and tolerability of intravenous allogeneic bone marrow-derived mesenchymal stem cells in PD patients. METHODS: This was a 12-month single-center open-label dose-escalation phase 1 study of 20 subjects with mild/moderate PD assigned to a single intravenous infusion of 1 of 4 doses: 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg, evaluated 3, 12, 24, and 52 weeks postinfusion. Primary outcome safety measures included transfusion reaction, study-related adverse events, and immunogenic responses. Secondary outcomes included impact on peripheral markers, PD progression, and changes in brain perfusion. RESULTS: There were no serious adverse reactions related to the infusion and no responses to donor-specific human leukocyte antigens. Most common treatment-emergent adverse events were dyskinesias (20%, n = 4) with 1 emergent and 3 exacerbations; and hypertension (20%, n = 4) with 3 transient episodes and 1 requiring medical intervention. One possibly related serious adverse event occurred in a patient with a 4-year history of lymphocytosis who developed asymptomatic chronic lymphocytic leukemia. Peripheral inflammation markers appear to be reduced at 52 weeks in the highest dose including, tumor necrosis factor-α (P < 0.05), chemokine (C-C motif) ligand 22 (P < 0.05), whereas brain-derived neurotrophic factor (P < 0.05) increased. The highest dose seems to have demonstrated the most significant effect at 52 weeks, reducing the OFF state UPDRS motor, -14.4 (P < 0.01), and total, -20.8 (P < 0.05), scores. CONCLUSION: A single intravenous infusion of allogeneic bone marrow-derived mesenchymal stem cells at doses of 1, 3, 6, or 10 × 106 allogeneic bone marrow-derived mesenchymal stem cells/kg is safe, well tolerated, and not immunogenic in mild/moderate PD patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Células Madre Mesenquimatosas , Enfermedad de Parkinson , Médula Ósea , Humanos , Infusiones Intravenosas , Enfermedad de Parkinson/terapia
3.
JAMA ; 326(10): 926-939, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34519802

RESUMEN

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.


Asunto(s)
Progresión de la Enfermedad , Inosina/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Ácido Úrico/sangre , Anciano , Biomarcadores/sangre , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/deficiencia , Método Doble Ciego , Femenino , Humanos , Inosina/efectos adversos , Cálculos Renales/inducido químicamente , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/fisiopatología , Índice de Severidad de la Enfermedad , Insuficiencia del Tratamiento
4.
J Neurol Neurosurg Psychiatry ; 91(7): 740-749, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32404379

RESUMEN

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.


Asunto(s)
Ensayos Clínicos como Asunto , Trastorno de la Conducta del Sueño REM/tratamiento farmacológico , Sueño REM/efectos de los fármacos , Humanos , Proyectos de Investigación
5.
Neuromodulation ; 23(7): 996-1002, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31989725

RESUMEN

OBJECTIVE: To assist in the assessment of intrathecal baclofen (ITB) therapy risks and benefits by providing surgical intervention rate, safety, and elective device replacement rate data. MATERIALS AND METHODS: An ongoing prospective, long-term, multicenter Product Surveillance Registry (PSR) (NCT01524276) enrolled consented patients implanted with the SynchroMed II infusion system. Pump and catheter performance data were collected, with patients followed prospectively for events related to the device, procedure, and therapy. Investigators provided event descriptions, patient symptoms, and patient outcomes. RESULTS: We analyzed registry data from 1743 patients (77% adult, 46.8% female) treated with ITB for severe spasticity at 53 registry sites between August 2003 and October 2017, for an accumulated 6481 patient-years. Discontinuation from the registry was largely (58.6% of discontinued patients) due to study site closure and patient relocation; exit due to an adverse event was limited to 0.3%. After 10 years, 87.2% of adult and 76.3% of pediatric patients continued with ITB. Overall, 99.1% of pumps reaching end of battery life were replaced at the time of explant. CONCLUSIONS: ITB therapy for the treatment of severe spasticity requires surgical implantation of a programmable infusion system for chronic drug delivery. If complications arise, many necessitate surgical intervention for correction. For spinal and cerebral spasticity in pediatric and adult patients, discontinuation rates due to an adverse event were low (0.3%), and there was high acceptance (99.1%) of surgical intervention for therapy continuation. Patient/caregiver willingness to accept surgical and other risks for therapy continuation was extremely high.


Asunto(s)
Baclofeno , Inyecciones Espinales , Relajantes Musculares Centrales , Espasticidad Muscular , Adulto , Baclofeno/uso terapéutico , Niño , Femenino , Humanos , Bombas de Infusión Implantables , Masculino , Relajantes Musculares Centrales/uso terapéutico , Espasticidad Muscular/tratamiento farmacológico , Estudios Prospectivos , Sistema de Registros
6.
Mov Disord ; 33(12): 1895-1901, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30187527

RESUMEN

BACKGROUND: Direct targeting of the dentato-rubro-thalamic tract is efficacious in DBS for tremor suppression. OBJECTIVES: We sought to compare outcomes and optimal stimulation parameters for tremor control using the technique of directly targeting the dentato-rubro-thalamic tract to those who underwent indirect targeting of the ventral intermediate nucleus thalamus. METHODS: Twenty consecutive essential tremor patients obtained preoperative diffusion MRIs, where the dentato-rubro-thalamic tract was individually drawn and used to directly target the ventral intermediate nucleus of the thalamus during surgery. These patients were compared to an earlier cohort of 20 consecutive patients who underwent surgery using atlas-based coordinates. Baseline and 1-year postsurgery tremor amplitude using The Essential Tremor Rating Assessment Scale was recorded, as were the parameters needed for successful tremor control. RESULTS: The indirectly targeted group had greater baseline and postop tremor severity relative to those directly targeted (baseline, 2.9 vs. 2.6; P = 0.02; postop, 1.1 vs. 0.8; P = 0.03). Mean voltage, pulse width, and frequency for optimal tremor control in the directly targeted group (38 electrodes) = 2.8 V, 80 µs, 153 Hz; the parameters for the indirectly targeted group (38 electrodes) = 2.9 V, 86 µs, 179 Hz (significantly greater, P < 0.001). Both groups had significant improvement in arm tremor amplitude from baseline (P < 0.001) without sustained side effects. CONCLUSION: Direct targeting of the dentato-rubro-thalamic tract provides excellent tremor control, comparable to indirectly targeting the ventral intermediate nucleus of the thalamus. Use of lower stimulation parameters, especially frequency, to control tremor in the directly targeted group suggests that it is a more efficient targeting methodology, which may minimize battery depletion. © 2018 International Parkinson and Movement Disorder Society.


Asunto(s)
Estimulación Encefálica Profunda , Temblor Esencial/terapia , Adulto , Anciano , Anciano de 80 o más Años , Núcleos Cerebelosos/fisiopatología , Estimulación Encefálica Profunda/métodos , Imagen de Difusión Tensora/métodos , Temblor Esencial/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/fisiopatología , Tálamo/fisiopatología , Tálamo/cirugía , Resultado del Tratamiento
7.
Cerebellum ; 16(2): 421-426, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27491538

RESUMEN

To determine if the use of intraoperative microelectrode recording (MER) influences the final location of lead implant in deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM), and to evaluate the incidence of associated complications. The usefulness of intraoperative MER in DBS is debated, some centers suggesting it increases complications without additional benefit. We conducted a retrospective chart review of all patients who underwent VIM DBS with MER at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013. Initial (MRI determined) and final (intraoperative MER determined) coordinates of implant were compared. To assess incidences of hemorrhagic and infectious complications, we reviewed postoperative CT scans and follow-up notes. Forty-five lead implants on 24 patients were reviewed. The mean age at implantation was 62.42 years (range 18-83). The average duration from diagnosis to surgery was 21.5 years (range 1-52). A statistically significant mean difference was observed in the superior-inferior plane (0.52 ± 0.80 mm inferiorly, p < 0.05) and the anterior-posterior plane (0.45 ± 0.86 mm posteriorly, p < 0.05). A non-statistically significant difference was also observed in the medial-lateral plane (0.02± 0.15 mm, p > 0.05). One patient developed an infectious complication (4.2 %) that required removal of leads; two patients had minimal asymptomatic intra-ventricular bleeding (8.3 %). In our DBS center, intraoperative MER in VIM DBS implant does not seem to have a higher rate of surgical complications compared to historical series not using MER, and might also be useful in determining the final lead location.


Asunto(s)
Estimulación Encefálica Profunda , Monitorización Neurofisiológica Intraoperatoria , Microelectrodos , Procedimientos Neuroquirúrgicos , Núcleos Talámicos Ventrales/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Humanos , Monitorización Neurofisiológica Intraoperatoria/efectos adversos , Monitorización Neurofisiológica Intraoperatoria/métodos , Persona de Mediana Edad , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
8.
Stereotact Funct Neurosurg ; 95(2): 86-92, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28208150

RESUMEN

BACKGROUND/AIMS: Postoperative cerebral edema around a deep brain stimulation (DBS) electrode is an uncommon reported complication. The goal of this study was to identify instances of postoperative edema based on clinical presentation, and to remark on their management. METHODS: A retrospective chart review was performed on all patients who underwent DBS electrode implantation over a 3-year period. Routine CT imaging on postoperative day (POD) 1 was negative. Patients were identified based on clinical neurological changes, leading to imaging and subsequent diagnosis. RESULTS: Five of 145 patients (3.4%) presented with new neurological symptoms from POD 1 to 14, which were confirmed by CT imaging to show perilead and/or subcortical edema around 6 of 281 electrodes (2.1%). Four of 5 patients had unilateral edema despite bilateral implantation. Clinical presentations varied widely. Two patients presenting on POD 1 with deteriorating conditions required longer inpatient stays with supportive measures than those presenting later (p = 0.0002). All patients were treated with corticosteroids and returned to baseline by 3 months after surgery. CONCLUSIONS: Acute instances of DBS lead edema may occur as early as POD 1 and can rapidly progress into profound deficits. Treatment with supportive care and corticosteroids is otherwise identical to those cases presenting later.


Asunto(s)
Edema Encefálico/diagnóstico por imagen , Edema Encefálico/cirugía , Estimulación Encefálica Profunda/efectos adversos , Estimulación Encefálica Profunda/instrumentación , Electrodos Implantados/efectos adversos , Complicaciones Posoperatorias/diagnóstico por imagen , Enfermedad Aguda , Adulto , Anciano , Estimulación Encefálica Profunda/tendencias , Electrodos Implantados/tendencias , Femenino , Humanos , Masculino , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos
9.
Neuromodulation ; 20(5): 429-436, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28256785

RESUMEN

OBJECTIVES: Targeting the dentato-rubro-thalamic tract (DRTt) has been suggested to be efficacious in deep brain stimulation (DBS) for tremor suppression, both in case reports and post-hoc analyses. This prospective observational study sought to analyze outcomes after directly targeting the DRTt in tremor patients. METHODS: 20 consecutively enrolled intention tremor patients obtained pre-operative MRI with diffusion tensor (dTi) sequences. Mean baseline tremor amplitude based on The Essential Tremor Rating Assessment Scale was recorded. The DRTt was drawn for each individual on StealthViz software (Medtronic) using the dentate nucleus as the seed region and the ipsilateral pre-central gyrus as the end region and then directly targeted during surgery. Intraoperative testing confirmed successful tremor control. Post-operative analysis of electrode position relative to the DRTt was performed, as was post-operative assessment of tremor improvement. RESULTS: The mean age of patients was 66.8 years; mean duration of tremor was 16 years. Mean voltage for the L electrode = 3.4 V; R = 2.6 V. Mean distance from the center of the active electrode contact to the DRTt was 0.9 mm on the L, and 0.8 mm on the R. Improvement in arm tremor amplitude from baseline after DBS was significant (P < 0.001). CONCLUSION: Direct targeting of the DRTt in DBS is an effective strategy for tremor suppression. Accounting for hardware, software, and model limitations, depiction of the DRTt allows for placement of electrode contacts directly within the fiber tract for modulation despite any anatomical variation, which reproducibly resulted in good tremor control.


Asunto(s)
Núcleos Cerebelosos/diagnóstico por imagen , Estimulación Encefálica Profunda/métodos , Núcleo Rojo/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Temblor/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Núcleos Cerebelosos/cirugía , Imagen de Difusión Tensora/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/cirugía , Estudios Prospectivos , Núcleo Rojo/cirugía , Tálamo/cirugía , Resultado del Tratamiento , Temblor/cirugía
10.
Neuroimmunomodulation ; 23(5-6): 301-308, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-28395279

RESUMEN

OBJECTIVE: Chronic inflammatory processes contribute to the eventual death of motor neurons and the development of symptoms in both idiopathic Parkinson disease (PD) and multiple system atrophy (MSA). Given the faster rate of progression and more severe symptoms associated with MSA, we hypothesized that markers of inflammation would be more evident in the peripheral blood of MSA than PD patients, and that evidence of this inflammation might assist early diagnosis of MSA versus PD. METHODS: We performed multiplex analysis to determine the concentrations of 37 immune-associated cytokines and chemokines isolated from the plasma of patients with PD (n = 25) and MSA (n = 14) and compared our results to those of age-matched controls (n = 15). We then applied a mixed-effect multiple regression model to determine if the concentration of cytokines in the plasma of patients with PD and MSA changed significantly over time. RESULTS: Patients with MSA had a trend towards overall lower levels of immune-associated cytokines, while serum cytokine levels were increased in patients with PD. Statistically adjusted comparisons of overall changes in cytokine concentrations between the PD and MSA groups revealed higher concentrations of T-cell-associated cytokines TNFß and IL-7 in PD. Comparison of samples taken over time revealed significantly faster rates of change in 4 different cytokine concentrations (IL-4, IL-15, IL-2, and IL-9) in patients with MSA versus patients with PD. CONCLUSIONS: Our results suggest that single measurements of plasma concentrations of inflammation-associated cytokines cannot be used to distinguish disease states. However, measurements made over time may correlate with pathogenesis. The significant changes in T-cell-associated cytokines may shed light on immune mechanisms that contribute to PD and MSA disease progression.


Asunto(s)
Citocinas/sangre , Linfocitos/metabolismo , Atrofia de Múltiples Sistemas/sangre , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/patología , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo
11.
Semin Neurol ; 34(5): 591-6, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25520030

RESUMEN

Severe spastic tone and/or spastic hypertonia can be the most disabling consequences of a neurologic insult, resulting from an excess of muscle tone. Baclofen, a GABA-B agonist, is one of the most widely used drugs in treating abnormal or disabling spastic tone. However, the effectiveness of baclofen taken orally is often limited by its systemic side effects, including sedation, confusion, and lethargy. Intrathecal baclofen (ITB) delivered by an implanted catheter can work directly at the spinal cord level to reduce spastic tone through presynaptic inhibition. Several decades after Penn and Kroin (1984) proved that continuous infusion of intrathecal baclofen reduced spinal cord spasticity, numerous studies have demonstrated the benefits of ITB therapy and proven its effectiveness in modulating and reducing spastic tone. In this article the authors review current methods of management with ITB therapy; summarize the current knowledge, controversies, and available scientific literature; illustrate through different clinical cases treatment strategies and their outcomes; and lastly, provide a synopsis of current clinical practice in ITB therapy with insights into new therapeutic developments.


Asunto(s)
Baclofeno/administración & dosificación , Relajantes Musculares Centrales/administración & dosificación , Espasticidad Muscular/diagnóstico , Espasticidad Muscular/tratamiento farmacológico , Adulto , Anciano , Humanos , Inyecciones Espinales , Persona de Mediana Edad
12.
Clin Park Relat Disord ; 8: 100187, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36793590

RESUMEN

Introduction: Motor classifications of Parkinson's Disease (PD) have been widely used. This paper aims to update a subtype classification using the MDS-UPDRS-III and determine if cerebrospinal neurotransmitter profiles (HVA and 5-HIAA) differ between these subtypes in a cohort from the Parkinson's Progression Marker Initiative (PPMI). Methods: UPDRS and MDS-UPDRS scores were collected for 20 PD patients. Akinetic-rigid (AR), Tremor-dominant (TD), and Mixed (MX) subtypes were calculated using a formula derived from UPDRS, and a new ratio was developed for subtyping patients with the MDS-UPDRS. This new formula was subsequently applied to 95 PD patients from the PPMI dataset, and subtyping was correlated to neurotransmitter levels. Data were analyzed using receiver operating characteristic models and ANOVA. Results: Compared to previous UPDRS classifications, the new MDS-UPDRS TD/AR ratios produced significant areas under the curve (AUC) for each subtype. The optimal sensitivity and specificity cutoff scores were ≥0.82 for TD, ≤0.71 for AR, and >0.71 and <0.82 for Mixed. Analysis of variance showed that the AR group had significantly lower HVA and 5-HIAA levels than the TD and HC groups. A logistic model using neurotransmitter levels and MDS-UPDRS-III could predict the subtype classification. Conclusions: This MDS-UPDRS motor classification system provides a method to transition from the original UPDRS to the new MDS-UPDRS. It is a reliable and quantifiable subtyping tool for monitoring disease progression. The TD subtype is associated with lower motor scores and higher HVA levels, while the AR subtype is associated with higher motor scores and lower 5-HIAA levels.

13.
J Parkinsons Dis ; 13(4): 501-513, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37212075

RESUMEN

BACKGROUND: Parkinson's disease is a heterogeneous neurodegenerative disorder with distinctive gut microbiome patterns suggesting that interventions targeting the gut microbiota may prevent, slow, or reverse disease progression and severity. OBJECTIVE: Because secretory IgA (SIgA) plays a key role in shaping the gut microbiota, characterization of the IgA-Biome of individuals classified into either the akinetic rigid (AR) or tremor dominant (TD) Parkinson's disease clinical subtypes was used to further define taxa unique to these distinct clinical phenotypes. METHODS: Flow cytometry was used to separate IgA-coated and -uncoated bacteria from stool samples obtained from AR and TD patients followed by amplification and sequencing of the V4 region of the 16 S rDNA gene on the MiSeq platform (Illumina). RESULTS: IgA-Biome analyses identified significant alpha and beta diversity differences between the Parkinson's disease phenotypes and the Firmicutes/Bacteroides ratio was significantly higher in those with TD compared to those with AR. In addition, discriminant taxa analyses identified a more pro-inflammatory bacterial profile in the IgA+ fraction of those with the AR clinical subclass compared to IgA-Biome analyses of those with the TD subclass and with the taxa identified in the unsorted control samples. CONCLUSION: IgA-Biome analyses underscores the importance of the host immune response in shaping the gut microbiome potentially affecting disease progression and presentation. In the present study, IgA-Biome analyses identified a unique proinflammatory microbial signature in the IgA+ fraction of those with AR that would have otherwise been undetected using conventional microbiome analysis approaches.


Asunto(s)
Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Temblor/etiología , Microbioma Gastrointestinal/fisiología , Progresión de la Enfermedad , Inmunoglobulina A
14.
Front Neurol ; 14: 1104759, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36937520

RESUMEN

Background and purpose: The intestinal microbiome plays a primary role in the pathogenesis of neurodegenerative disorders and may provide an opportunity for disease modification. We performed a pilot clinical study looking at the safety of fecal microbiota transplantation (FMT), its effect on the microbiome, and improvement of symptoms in Parkinson's disease. Methods: This was a randomized, double-blind placebo-controlled pilot study, wherein orally administered lyophilized FMT product or matching placebo was given to 12 subjects with mild to moderate Parkinson's disease with constipation twice weekly for 12 weeks. Subjects were followed for safety and clinical improvement for 9 additional months (total study duration 12 months). Results: Fecal microbiota transplantation caused non-severe transient upper gastrointestinal symptoms. One subject receiving FMT was diagnosed with unrelated metastatic cancer and was removed from the trial. Beta diversity (taxa) of the microbiome, was similar comparing placebo and FMT groups at baseline, however, for subjects randomized to FMT, it increased significantly at 6 weeks (p = 0.008) and 13 weeks (p = 0.0008). After treatment with FMT, proportions of selective families within the phylum Firmicutes increased significantly, while proportion of microbiota belonging to Proteobacteria were significantly reduced. Objective motor findings showed only temporary improvement while subjective symptom improvements were reported compared to baseline in the group receiving FMT. Constipation, gut transient times (NS), and gut motility index (p = 0.0374) were improved in the FMT group. Conclusions: Subjects with Parkinson's disease tolerated multi-dose-FMT, and experienced increased diversity of the intestinal microbiome that was associated with reduction in constipation and improved gut transit and intestinal motility. Fecal microbiota transplantation administration improved subjective motor and non-motor symptoms. Clinical trial registration: ClinicalTrial.gov, identifier: NCT03671785.

15.
Mult Scler J Exp Transl Clin ; 9(4): 20552173231208271, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38021452

RESUMEN

Background: Tremor affects up to 45% of patients with Multiple Sclerosis (PwMS). Current understanding is based on insights from other neurological disorders, thus, not fully addressing the distinctive aspects of MS pathology. Objective: To characterize the brain white matter (WM) correlates of MS-related tremor using diffusion tensor imaging (DTI). Methods: In a prospective case-control study, PwMS with tremor were assessed for tremor severity and underwent MRI scans including DTI. PwMS without tremor served as matched controls. After tract selection and segmentation, the resulting diffusivity measures were used to calculate group differences and correlations with tremor severity. Results: This study included 72 PwMS. The tremor group (n = 36) exhibited significant changes in several pathways, notably in the right inferior longitudinal fasciculus (Cohen's d = 1.53, q < 0.001) and left corticospinal tract (d = 1.32, q < 0.001), compared to controls (n = 36). Furthermore, specific tracts showed a significant correlation with tremor severity, notably in the left medial lemniscus (Spearman's coefficient [rsp] = -0.56, p < 0.001), and forceps minor of corpus callosum (rsp = -0.45, p < 0.01). Conclusion: MS-related tremor is associated with widespread diffusivity changes in WM pathways and its severity correlates with commissural and sensory projection pathways, which suggests a role for proprioception or involvement of the dentato-rubro-olivary circuit.

16.
Neuromodulation ; 14(2): 176-7; discussion 178, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21992207

RESUMEN

OBJECTIVES: Evaluate the benefit of intrathecal baclofen (ITB) therapy on function, quality of life, and progression in patients with multiple system atrophy (MSA). METHODS: We report on three MSA patients at different stages treated with ITB therapy. MSA patients were staged using Watanabe et al. ADL milestones for disease progression and by scales for tone (modified Ashworth scale) ambulation (Hauser ambulation index) and disability (expanded disability status scale) RESULTS: All three patients had an improvement in the modified Ashworth scale and none had progression in their disability or ambulatory outcomes and did not progress as predicted by Watanabe et al. CONCLUSIONS: Our results suggest that ITB can maintain (or improve function) and maintain quality of life in patients with MSA. ITB is currently not indicated for patients with MSA but should be studied further for the quality of life benefits and delay in disease progression it potentially provides.


Asunto(s)
Baclofeno/administración & dosificación , Baclofeno/uso terapéutico , Progresión de la Enfermedad , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Atrofia de Múltiples Sistemas/fisiopatología , Relajantes Musculares Centrales/administración & dosificación , Relajantes Musculares Centrales/uso terapéutico , Humanos , Bombas de Infusión Implantables , Inyecciones Espinales , Espasticidad Muscular/tratamiento farmacológico , Espasticidad Muscular/fisiopatología , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
17.
Neuromodulation ; 14(1): 38-45; discussion 45, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21992161

RESUMEN

OBJECTIVES: To assess the effects of intrathecal baclofen (ITB) therapy for the treatment of poststroke spastic hemiparesis on quality of life, functional independence, and upper, lower extremity (UE, LE) motor functions. MATERIALS AND METHODS: Prospective observational study of adult men and women with a minimum 6-month stroke-related spastic hemiparesis graded as ≥2 in UE and LE on Modified Ashworth Scale (MAS). Patients served as their own controls with measures compared pre-implant with 12 months post ITB including: MAS, manual muscle test (MMT), gait distance/velocity, Functional Independence Measures (FIM), stroke-specific quality of life scale (SSQL), and upper extremity manual activity log. RESULTS: After 12-month ITB therapy, 26 patients (poststroke=6.4±9 years) demonstrated 1) reduced MAS/increased MMT for most LE muscle groups (p≤0.0001); 2) reduced MAS/increased MMT most UE muscle groups (p≤0.01); 3) FIM scores improved (p≤0.05) except bed mobility and lower body dressing; 4) gait distance and velocity improved (p≤0.05); 5) SSQL domains of family roles, mobility, personality, self-care, social roles, thinking, UE function, and work/productivity improved (p≤0.05); 6) amount of use and quality of movement of the spastic UE in performing common activities of daily living increased (p<0.0001). CONCLUSIONS: Regardless of duration of spastic hemiparesis, a reduction in tone with ITB therapy facilitates motor strength improvement and is associated with clinically significant improvements in functional independence and quality of life.


Asunto(s)
Baclofeno/uso terapéutico , Relajantes Musculares Centrales/uso terapéutico , Paraparesia Espástica/tratamiento farmacológico , Paraparesia Espástica/etiología , Paraparesia Espástica/rehabilitación , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/tratamiento farmacológico , Actividades Cotidianas , Adulto , Anciano , Baclofeno/administración & dosificación , Femenino , Humanos , Inyecciones Espinales , Extremidad Inferior/fisiología , Extremidad Inferior/fisiopatología , Masculino , Persona de Mediana Edad , Fuerza Muscular , Tono Muscular , Estudios Prospectivos , Autocuidado , Rehabilitación de Accidente Cerebrovascular , Resultado del Tratamiento , Extremidad Superior/fisiología , Extremidad Superior/fisiopatología
18.
Front Neurosci ; 15: 744190, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35046766

RESUMEN

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is one of the leading sources of morbidity and mortality in the aging population AD cardinal symptoms include memory and executive function impairment that profoundly alters a patient's ability to perform activities of daily living. People with mild cognitive impairment (MCI) exhibit many of the early clinical symptoms of patients with AD and have a high chance of converting to AD in their lifetime. Diagnostic criteria rely on clinical assessment and brain magnetic resonance imaging (MRI). Many groups are working to help automate this process to improve the clinical workflow. Current computational approaches are focused on predicting whether or not a subject with MCI will convert to AD in the future. To our knowledge, limited attention has been given to the development of automated computer-assisted diagnosis (CAD) systems able to provide an AD conversion diagnosis in MCI patient cohorts followed longitudinally. This is important as these CAD systems could be used by primary care providers to monitor patients with MCI. The method outlined in this paper addresses this gap and presents a computationally efficient pre-processing and prediction pipeline, and is designed for recognizing patterns associated with AD conversion. We propose a new approach that leverages longitudinal data that can be easily acquired in a clinical setting (e.g., T1-weighted magnetic resonance images, cognitive tests, and demographic information) to identify the AD conversion point in MCI subjects with AUC = 84.7. In contrast, cognitive tests and demographics alone achieved AUC = 80.6, a statistically significant difference (n = 669, p < 0.05). We designed a convolutional neural network that is computationally efficient and requires only linear registration between imaging time points. The model architecture combines Attention and Inception architectures while utilizing both cross-sectional and longitudinal imaging and clinical information. Additionally, the top brain regions and clinical features that drove the model's decision were investigated. These included the thalamus, caudate, planum temporale, and the Rey Auditory Verbal Learning Test. We believe our method could be easily translated into the healthcare setting as an objective AD diagnostic tool for patients with MCI.

19.
Sci Rep ; 11(1): 9313, 2021 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-33927277

RESUMEN

Our objective is to derive a sequential decision-making rule on the combination of medications to minimize motor symptoms using reinforcement learning (RL). Using an observational longitudinal cohort of Parkinson's disease patients, the Parkinson's Progression Markers Initiative database, we derived clinically relevant disease states and an optimal combination of medications for each of them by using policy iteration of the Markov decision process (MDP). We focused on 8 combinations of medications, i.e., Levodopa, a dopamine agonist, and other PD medications, as possible actions and motor symptom severity, based on the Unified Parkinson Disease Rating Scale (UPDRS) section III, as reward/penalty of decision. We analyzed a total of 5077 visits from 431 PD patients with 55.5 months follow-up. We excluded patients without UPDRS III scores or medication records. We derived a medication regimen that is comparable to a clinician's decision. The RL model achieved a lower level of motor symptom severity scores than what clinicians did, whereas the clinicians' medication rules were more consistent than the RL model. The RL model followed the clinician's medication rules in most cases but also suggested some changes, which leads to the difference in lowering symptoms severity. This is the first study to investigate RL to improve the pharmacological approach of PD patients. Our results contribute to the development of an interactive machine-physician ecosystem that relies on evidence-based medicine and can potentially enhance PD management.


Asunto(s)
Quimioterapia Combinada , Aprendizaje Automático , Enfermedad de Parkinson/tratamiento farmacológico , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Cadenas de Markov , Persona de Mediana Edad
20.
BMC Neurosci ; 11: 151, 2010 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-21114836

RESUMEN

BACKGROUND: Excessive and abnormal accumulation of alpha-synuclein (α-synuclein) is a factor contributing to pathogenic cell death in Parkinson's disease. The purpose of this study, based on earlier observations of Parkinson's disease cerebrospinal fluid (PD-CSF) initiated cell death, was to determine the effects of CSF from PD patients on the functionally different microglia and astrocyte glial cell lines. Microglia cells from human glioblastoma and astrocytes from fetal brain tissue were cultured, grown to confluence, treated with fixed concentrations of PD-CSF, non-PD disease control CSF, or control no-CSF medium, then photographed and fluorescently probed for α-synuclein content by deconvolution fluorescence microscopy. Outcome measures included manually counted cell growth patterns from day 1-8; α-synuclein density and distribution by antibody tagged 3D model stacked deconvoluted fluorescent imaging. RESULTS: After PD-CSF treatment, microglia growth was reduced extensively, and a non-confluent pattern with morphological changes developed, that was not evident in disease control CSF and no-CSF treated cultures. Astrocyte growth rates were similarly reduced by exposure to PD-CSF, but morphological changes were not consistently noted. PD-CSF treated microglia showed a significant increase in α-synuclein content by day 4 compared to other treatments (p ≤ 0.02). In microglia only, α-synuclein aggregated and redistributed to peri-nuclear locations. CONCLUSIONS: Cultured microglia and astrocytes are differentially affected by PD-CSF exposure compared to non-PD-CSF controls. PD-CSF dramatically impacts microglia cell growth, morphology, and α-synuclein deposition compared to astrocytes, supporting the hypothesis of cell specific susceptibility to PD-CSF toxicity.


Asunto(s)
Astrocitos/patología , Proteínas del Líquido Cefalorraquídeo/efectos adversos , Microglía/patología , Enfermedad de Parkinson/líquido cefalorraquídeo , Astrocitos/fisiología , Muerte Celular/fisiología , Diferenciación Celular/fisiología , Línea Celular Tumoral , Proliferación Celular , Forma de la Célula/fisiología , Células Cultivadas , Humanos , Cuerpos de Lewy/metabolismo , Microglía/fisiología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/fisiología
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