Desarrollo y validación de nuevas herramientas para la valoración cognitiva y funcional del deterioro cognitivo leve en la enfermedad de parkinson /

En los últimos años la investigación sobre la enfermedad de Parkinson (EP) ha dejado de centrarse exclusivamente en los aspectos motores de la misma, ampliando el espectro de acción sobre factores que suelen verse afectados en el transcurso de la enfermedad y que son muy limitantes para el paciente, como son los aspectos cognitivos, conductuales y funcionales. A pesar del notable interés hacia el deterioro cognitivo leve y la demencia en la EP, actualmente existen pocos instrumentos específicamente diseñados para valorar dichas alteraciones. La Parkinson's Disease-Cognitive Rating Scale (PD-CRS) se presentó en 2008 como un instrumento específico para valorar el deterioro cognitivo y la demencia en la EP. Dada la necesidad de poder realizar estudios longitudinales en intervalos cortos de tiempo o testar el efecto de productos farmacológicos candidatos a actuar sobre el deterioro cognitivo en fases de afectación tempranas de la EP, existe una urgencia por disponer de más datos sobre su habilidad discriminativa. Por ello, estudiar su rendimiento para detectar sutiles afectaciones en el terreno del deterioro cognitivo leve en EP se convierte en fundamental. Lo mismo ha ocurrido con la valoración funcional vinculada a estos aspectos. El uso de escalas diseñadas para ser empleadas en otras patologías dificulta la valoración de la afectación que en el día a día tiene la EP y no permite controlar en esencia los factores particulares que tienen lugar en ella, dejando muchos aspectos disfuncionales fuera de la valoración. El primer objetivo de este estudio ha sido proporcionar nueva información acerca de las capacidades psicométricas de la PD-CRS en el entorno del paciente con EP y la frontera entre normalidad cognitiva y deterioro cognitivo leve. La PD-CRS ha demostrado ser un instrumento válido y fiable para discriminar entre los niveles cognitivos en EP, lo que sugiere que los clínicos pueden hacer uso con confianza de las puntuaciones de corte propuestas para detectar casos de EP y deterioro cognitivo leve. Además, posee datos clinimétricos que permiten monitorizar los cambios cognitivos en pacientes con EP sin afectación cognitiva previa a lo largo del tiempo. El segundo objetivo ha sido el diseño y validación de una nueva escala, la Parkinson's Disease-Cognitive Functional Rating Scale (PD-CFRS), capaz de medir la afectación funcional que provocan las sutiles alteraciones cognitivas que se desarrollan desde los primeros estadíos de la EP, minimizando la interferencia derivada de aspectos meramente motores. La PD-CFRS se ha establecido como un instrumento recomendable para capturar el espectro de afectación funcional asociada al deterioro cognitivo en la EP y adecuado para usar tanto en la clínica como en investigación. Ambos estudios desarrollados en el contexto de este proyecto de tesis doctoral han cumplido con los objetivos establecidos, alcanzando una amplia difusión y un reconocimiento a nivel internacional.In recent years, research into Parkinson's disease (PD) has stopped focusing exclusively on its motor aspects, broadening the spectrum of action on factors that are often involved in the course of the disease and are very limiting for the patient, such as cognitive, behavioral and functional aspects. Despite the considerable interest to mild cognitive impairment and dementia in PD are currently few instruments specifically designed to assess these changes. Parkinson's Disease Rating Scale-Cognitive (PD-CRS) was presented in 2008 as a specific instrument to assess cognitive impairment and dementia in PD. Given the need to conduct longitudinal studies over short intervals of time or test the effect of pharmacological products aimed at acting on cognitive decline in early stages of involvement of PD, there is an urgency for more data on its discriminative ability. Therefore, studying its performance to detect subtle impacts on the field of mild cognitive impairment in PD becomes fundamental. The same has happened with the functional assessment linked to these aspects. Using scales designed to be applied in other pathologies difficult to assess the effects that the day has PD and does not control essentially particular factors that take place in it, leaving many dysfunctional aspects outside assessment. The first objective of this study was to provide new information about the psychometric capabilities of the PD-CRS in the environment of the patient with PD and cognitive border between normal and mild cognitive impairment. PD-CRS has proven a reliable and valid instrument to discriminate between cognitive levels in PD, suggesting that clinicians can use confidently cutoff scores proposed to detect cases of mild cognitive impairment and PD. It also has clinimetric data that allow monitoring of cognitive changes in PD patients without previous cognitive impairment over time. The second goal is the design and validation of a new scale, Parkinson's Disease-Cognitive Functional Rating Scale (PD-CFRS), capable of measuring functional impairment caused by subtle cognitive disorders which develop from the early stages of PD minimizing interference resulting from purely motor aspects. PD-CFRS is set as a recommended instrument to capture the spectrum of functional impairment associated with declining cognitive performance in PD and suitable for use in both clinical and research. Both studies developed in the context of this PhD project have met the established objectives, achieving international dissemination and recognition

Numerical simulation of the reverse field punch

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Neurophysiological Evidence of Compensatory Brain Mechanisms in Early-Stage Multiple Sclerosis

<div><p>Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by white matter inflammation, demyelination and neurodegeneration. Although cognitive dysfunction is a common manifestation, it may go unnoticed in recently-diagnosed patients. Prior studies suggest MS patients develop compensatory mechanisms potentially involving enhanced performance monitoring. Here we assessed the performance monitoring system in early-stage MS patients using the error-related negativity (ERN), an event-related brain potential (ERP) observed following behavioral errors. Twenty-seven early-stage MS patients and 31 controls were neuropsychologically assessed. Electroencephalography recordings were obtained while participants performed: a) a stop task and b) an auditory oddball task. Behavior and ERP measures were assessed. No differences in performance were found between groups in most neuropsychological tests or in behavior or ERP components in the auditory oddball task. However, the amplitude of the ERN associated with stop errors in the stop task was significantly higher in patients. ERN amplitude correlated positively with scores on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and negatively with the time since last relapse. Patients showed higher neuronal recruitment in tasks involving performance monitoring. Results suggest the development of compensatory brain mechanisms in early-stage MS and reflect the sensitivity of the ERN to detect these changes.</p></div

Neurophysiological evidence of compensatory brain mechanisms in early-stage multiple sclerosis

Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by white matter inflammation, demyelination and neurodegeneration. Although cognitive dysfunction is a common manifestation, it may go unnoticed in recently-diagnosed patients. Prior studies suggest MS patients develop compensatory mechanisms potentially involving enhanced performance monitoring. Here we assessed the performance monitoring system in early-stage MS patients using the error-related negativity (ERN), an event-related brain potential (ERP) observed following behavioral errors. Twenty-seven early-stage MS patients and 31 controls were neuropsychologically assessed. Electroencephalography recordings were obtained while participants performed: a) a stop task and b) an auditory oddball task. Behavior and ERP measures were assessed. No differences in performance were found between groups in most neuropsychological tests or in behavior or ERP components in the auditory oddball task. However, the amplitude of the ERN associated with stop errors in the stop task was significantly higher in patients. ERN amplitude correlated positively with scores on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and negatively with the time since last relapse. Patients showed higher neuronal recruitment in tasks involving performance monitoring. Results suggest the development of compensatory brain mechanisms in early-stage MS and reflect the sensitivity of the ERN to detect these changes

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients