Estudio de asociación de la enfermedad de Parkinson con genes que codifican sustratos de la parkina y las subunidades del proteasoma en una muestra de población gallega

La enfermedad de Parkinson (EP) se incluye dentro de las enfermedades comunes o complejas, que ocurren por la acción conjunta de una serie de genes con variables ambientales Los estudios de asociación permiten relacionar genes de susceptibilidad con enfermedades complejas. Se basan en el análisis de polimorfismos, principalmente SNP (polimorfismos de base única, de los genes en estudio. Se compara si hay diferencias significativas en las frecuencias de cada alelo del SNP en casos (pacientes) y en controles (sujetos sanos). Se planteó un estudio que buscase asociación con genes relacionados con vías implicadas en la patogenia molecular de la EP. Para ello se reclutaron pacientes que cumpliesen los criterios de Gelb para EP probable y que fuesen de ascendencia gallega. Los pacientes se evaluaron por el mismo neurólogo en el Servicio de Neurología del Hospital Clínico de Santiago de Compostela. Los pacientes con algún determinante monogénico se excluyeron del estudio de asociación. Los controles, pertenecientes a la misma población, se reclutaron tanto en la consulta como en visitas a centros de salud y geriátricos. No se incluyeron familiares de pacientes con EP u otras enfermedades degenerativas. La selección de genes se realizó centrándose en el sistema ubicuitina proteasoma. Así se incluyeron todos los genes que codifican cada una de las subunidades del proteasoma, junto con los genes que codifican la mayoría de los sustratos conocidos de parkina. Como control de calidad del estudio se incluyeron genes MAPT y SNCA, cuya asociación con EP se ha descrito ampliamente en la literatura. Los SNP se seleccionaron empleando las bases de datos disponibles en la red (dbSNP, HapMap, FEES). Las asociaciones positivas halladas en la muestra de población gallega, salvo las de los genes MAPT y SNCA, se intentaron replicar en una muestra de tamaño similar de población mestiza mexicana. Se incluyeron 267 pacientes y 274 controles en la muestra inicial de población gallega. Se analizaron 312 SNP, pertenecientes a 43 genes. Se realizaron 2 estudios separados, uno con los genes del proteasoma y otro con los SNP del resto de los genes incluidos. Se encontraron asociaciones nominales con polimorfismos de los genes SNCA, MAPT, SYT11, que codifica un sustrato de la parkina, y de los genes que codifican subunidades del proteasoma PSMA1, PSMA3, PSMA6, PSMC3, PSMD1, PSMD6 y PSMD7. Uno de los SNP de MAPT superó las pruebas de corrección múltiple. El estudio de replicación con una muestra de población mestiza mexicana de 260 pacientes y 273 controles reprodujo la asociación nominal con SYT11 pero no las halladas en los genes de las subunidades del proteasoma. Apenas se han publicado estudios de asociación en los que se hayan analizado genes del proteasoma. No obstante, dado el papel de UPS en la EP es una vía interesante para seguir estudiando. La asociación nominal con SYT11 ya se había descrito en 3 trabajos publicado

An ontology-aware integration of clinical models, terminologies and guidelines: an exploratory study of the Scale for the Assessment and Rating of Ataxia (SARA)

Background: Electronic rating scales represent an important resource for standardized data collection. However, the ability to exploit reasoning on rating scale data is still limited. The objective of this work is to facilitate the integration of the semantics required to automatically interpret collections of standardized clinical data. We developed an electronic prototype for the Scale of the Assessment and Rating of Ataxia (SARA), broadly used in neurology. In order to address the modeling challenges of the SARA, we propose to combine the best performances from OpenEHR clinical archetypes, guidelines and ontologies. Methods: A scaled-down version of the Human Phenotype Ontology (HPO) was built, extracting the terms that describe the SARA tests from free-text sources. This version of the HPO was then used as backbone to normalize the content of the SARA through clinical archetypes. The knowledge required to exploit reasoning on the SARA data was modeled as separate information-processing units interconnected via the defined archetypes. Each unit used the most appropriate technology to formally represent the required knowledge. Results: Based on this approach, we implemented a prototype named SARA Management System, to be used for both the assessment of cerebellar syndrome and the production of a clinical synopsis. For validation purposes, we used recorded SARA data from 28 anonymous subjects affected by Spinocerebellar Ataxia Type 36 (SCA36). When comparing the performance of our prototype with that of two independent experts, weighted kappa scores ranged from 0.62 to 0.86. Conclusions: The combination of archetypes, phenotype ontologies and electronic information-processing rules can be used to automate the extraction of relevant clinical knowledge from plain scores of rating scales. Our results reveal a substantial degree of agreement between the results achieved by an ontology-aware system and the human experts.This work presented in this paper was supported by the National Institute of Health Carlos III [grant no. FIS2012-PI12/00373: OntoNeurophen], FEDER for national and European funding; PEACE II, Erasmus Mundus Lot 2 Project [grant no. 2013-2443/001-001-EMA2]; and the Modern University for Business and Science (M.U.B.S)S

MNCD: A New Tool for Classifying Parkinson’s Disease in Daily Clinical Practice

Background and objective: Parkinson's disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study

Staging Parkinson’s Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life

Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL: 1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). Results: Four hundred and thirty-nine PD patients (62.05 +/- 7.84 years old; 59% males) were included. MNCD stage was: stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advanced MNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p < 0.0001) and EUROHIS-QOL8 (p < 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD

Staging Parkinson’s Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life

© 2023 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0).Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD).Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity.Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8).Results: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages.Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.COPPADIS and the present study were developed with the help of Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético (https://fundaciondegen.org/) and Alpha Bioresearch (www.alphabioresearch.com). Also, we received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesión de subvenciones de Proyectos de Investigación en Salud de la convocatoria 2020 de la Acción Estratégica en Salud 2017-2020 por el Proyecto “PROGRESION NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) to develop a part of the COPPADIS project.Peer reviewe

Parkinson&rsquo;s Disease Symptoms Associated with Developing On-State Axial Symptoms Early after Subthalamic Deep Brain Stimulation

Background: The relationship between axial symptoms in Parkinson&rsquo;s disease (PD) and subthalamic deep brain stimulation (STN-DBS) is still unclear. Purpose: We searched for particular clinical characteristics before STN-DBS linked to on-state axial problems after surgery. Methods: We retrospectively analyzed baseline motor, emotional and cognitive features from PD patients with early axial symptoms (within 4 years after STN-DBS) and late axial symptoms (after 4 years). We also considered a group of PD patients without axial symptoms for at least 4 years after surgery. Results: At baseline, early-axial PD patients (n = 28) had a higher on-state Unified Parkinson&rsquo;s Disease Rating Scale III (15.0 &plusmn; 5.6 to 11.6 &plusmn; 6.2, p = 0.020), higher axial score (2.4 &plusmn; 1.8 to 0.7 &plusmn; 1.0, p &lt; 0.001) and worse dopaminergic response (0.62 &plusmn; 0.12 to 0.70 &plusmn; 0.11, p = 0.005), than non-axial PD patients (n = 51). Early-axial PD patients had short-term recall impairment, not seen in non-axial PD (36.3 &plusmn; 7.6 to 40.3 &plusmn; 9.3, p = 0.041). These variables were similar between late-axial PD (n = 18) and non-axial PD, but late-axial PD showed worse frontal dysfunction. Conclusions: PD patients with early axial symptoms after DBS may have a significantly worse presurgical motor phenotype, poorer dopaminergic response and memory impairment. This may correspond to a more severe form of PD

Additional file 3: of An ontology-aware integration of clinical models, terminologies and guidelines: an exploratory study of the Scale for the Assessment and Rating of Ataxia (SARA)

Contains the openEHR observation archetype related to the SARA scale. (ADL 29 kb

MNCD: A New Tool for Classifying Parkinson’s Disease in Daily Clinical Practice

Background and objective: Parkinson’s disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed stud