Loss of Nogo-A-expressing neurons in a rat model of Parkinson's disease

The myelin-associated protein Nogo-A is among the most potent neurite growth inhibitors in the adult CNS. Recently, Nogo-A expression was demonstrated in a number of neuronal subpopulations of the adult and developing CNS but at present, little is known about the expression of Nogo-A in the nigrostriatal system, a brain structure severely affected in Parkinson's disease (PD). The present study sought to characterize the expression pattern of Nogo-A immunoreactive (ir) cells in the adult ventral mesencephalon of control rats and in the 6-hydroxydopamine (6-OHDA) rat model of PD. Immunohistochemical analyses of normal adult rat brain showed a distinct expression of Nogo-A in the ventral mesencephalon, with the highest level in the substantia nigra pars compacta (SNc) where it co-localized with dopaminergic neurons. Analyses conducted 1week and 1 month after unilateral striatal injections of 6-OHDA disclosed a severe loss of the number of Nogo-A-ir cells in the SNc. Notably, at 1week after treatment, more dopaminergic neurons expressing Nogo-A were affected by the 6-OHDA toxicity than Nogo-A-negative dopaminergic neurons. However, at later time points more of the surviving dopaminergic neurons expressed Nogo-A. In the striatum, both small and large Nogo-A-positive cells were detected. The large cells were identified as cholinergic interneurons. Our results suggest yet unidentified functions of Nogo-A in the CNS beyond the inhibition of axonal regeneration and plasticity, and may indicate a role for Nogo-A in PD.

Dopaminergic denervation severity depends on COMT Val158Met polymorphism in Parkinson's disease.

BACKGROUND Catecholamine-O-methyl-tranferase (COMT) initiates dopamine degradation. Its activity is mainly determined by a single nucleotide polymorphism in the COMT gene (Val158Met, rs4680) separating high (Val/Val, COMT(HH)), intermediate (Val/Met, COMT(HL)) and low metabolizers (Met/Met, COMT(LL)). We investigated dopaminergic denervation in the striatum in PD patients according to COMT rs4680 genotype. METHODS Patients with idiopathic PD were assessed for motor severity (UPDRS-III rating scale in OFF-state), dopaminergic denervation using [123I]-FP-CIT SPECT imaging, and genotyped for the COMT rs4680 enzyme. [123I]-FP-CIT binding potential (BP) for each voxel was defined by the ratio of tracer-binding in the region of interest (striatum, caudate nucleus and putamen) to that in a region of non-specific activity. Genotyping was performed using TaqMan(®) SNP genotyping assay. We used a regression model to evaluate the effect of COMT genotype on the BP in the striatum and its sub-regions. RESULTS Genotype distribution was: 11 (27.5%) COMT(HH), 26 (65%) COMT(HL) and 3 (7.5%) COMT(LL). There were no significant differences in disease severity, treatments, or motor scores between genotypes. When adjusted to clinical severity, gender and age, low and intermediate metabolizers showed significantly higher rates of striatal denervation (COMT(HL+LL) BP = 1.32 ± 0.04) than high metabolizers (COMT(HH), BP = 1.6 ± 0.08; F(1.34) = 9.0, p = 0.005). Striatal sub-regions showed similar results. BP and UPDRS-III motor scores (r = 0.44, p = 0.04) (p < 0.001) were highly correlated. There was a gender effect, but no gender-genotype interaction. CONCLUSIONS Striatal denervation differs according to COMT-Val158Met polymorphism. COMT activity may play a role as a compensatory mechanism in PD motor symptoms.

Elizabeth Parkina, Mary Parkinson, Gaw, {[N.N.], Gruppenbildnis, Engelberg, 1901

Signatur des Originals: S 36/F05687

The illness experience of persons with Parkinson's Disease

Background. Parkinson's disease is a chronic, progressive, age-related, neurodegenerative disorder with no known cause or promising cure. While substantial information is known about the pathophysiology of Parkinson's disease, little is known about the illness experience of persons living with the disease. The purpose of this study was to understand how persons with Parkinson's disease construct their illness experience and manage living with their illness on a daily basis. ^ Method. A qualitative study with an ethnographic approach employed the strategies of participant observations and fieldwork. Field data were generated from a two year exposure to two Parkinson's disease support groups in east Texas. Open-ended semi-structured interviews with seven men and seven women with Parkinson's disease were also conducted. These data were combined and analyzed using thematic analysis. ^ Findings. The illness experience is described through the metaphor "Sailing the Sea in The Eye of the Storm." This metaphor served as the overarching theme that covered the two interacting content themes of the voyage of Daily Negotiations in the Midst of Uncertainty and Reconstruction of the Self with Parkinson's Disease. Daily negotiations incorporated navigating daily activities with the uncertainty of both the progression and daily vicissitudes of the disease. Participants described their symptoms as progressive imprisonment that interfered with daily activities. The progressive nature of the disease required the participants to reconstruct their perceptions of themselves. Reconstructing the self involved the paradoxical balancing of preserving the self while simultaneously releasing aspects of the former self to reconstruct the self with Parkinson's disease. This process was reflected in four exemplars: I Know Me." "It's Still Me," "See Me." and "Remember Me." ^ Conclusions. This qualitative study illuminated the struggle of persons in dealing with the uncertainties and fluctuations of Parkinson's disease and the process of reconstructing their perceptions of themselves. The meaning and reconstruction of the illness experience expressed by participants will inform understanding beyond the disease itself to the illness experience that these participants must deal with on a daily basis. ^

Effects of treatment on orienting in Parkinson disease

Parkinson disease (PD) is a movement disorder affecting over one million Americans, and 1% of our population over 60 years of age. Currently, PD has an unknown cause, no predictive biomarker, and no cure, yet there are effective treatments (medicine and surgery) to chronically manage the motor symptoms. But, PD patients also develop cognitive symptoms (e.g., distractibility, executive dysfunction) that remain untreated or may decline as a result of treating the motor symptoms. To address this important issue, I measured covert orienting of attention and overt eye movements in PD patients to assess the patients' ability to automatically detect stimuli in their visual field, to predict and attend to where the stimuli would appear, and to volitionally look somewhere else. ^ PD patients completed the cognitive tasks under multiple treatment conditions, and their performance was compared to healthy adults. PD patients first completed the tasks after they had withdrawn from medication. Their unmedicated performance revealed exaggerated automatic orienting, poor predictability, and weak volitional orienting. PD patients then repeated the tasks while medication was giving its peak benefit. The medication returned automatic covert orienting toward normal but did not improve volitional covert orienting. Several PD patients completed the tasks a third time after receiving surgery (specifically, implantation of stimulating electrodes in a subcortical brain region to alleviate motor symptoms). The stimulation (without medication) returned automatic orienting toward normal, did not change predictability, and further impaired volitional orienting. Taken together, treatments prescribed to alleviate the motor symptoms (a patient's primary concern) only improve some cognitive functions. Future studies may establish criteria to predict which patients are more likely to have cognitive benefit from medication over surgery, or vice versa. ^ I have also hypothesized an anatomical model relating orienting circuitry to abnormal PD circuitry and the therapeutic targets. My results suggest medication is more effective restoring the orienting circuitry than stimulation. Further, automatic and volitional orienting abilities seem to be modulated independently, which differs from an earlier model proposing a dependent, inverse relationship. My results are further discussed in terms of response inhibition, response selection, and the location of the selection. ^

A comparison of adherence with minocycline treatment in Parkinson's disease and rheumatoid arthritis clinical trials

Background: Little is known about the effects on patient adherence when the same study drug is administered in the same dose in two populations with two different diseases in two different clinical trials. The Minocycline in Rheumatoid Arthritis (MIRA) trial and the NIH Exploratory Trials in Parkinson's disease (NET-PD) Futility Study I provide a unique opportunity to do the above and to compare methods measuring adherence. This study may increase understanding of the influence of disease and adverse events on patient adherence and will provide insights to investigators selecting adherence assessment methods in clinical trials of minocycline and other drugs in future.^ Methods: Minocycline adherence by pill count and the effect of adverse events was compared in the MIRA and NET-PD FS1 trials using multivariable linear regression. Within the MIRA trial, agreement between assay and pill count was compared. The association of adverse events with assay adherence was examined using multivariable logistic regression.^ Results: Adherence derived from pill count in the MIRA and NET-PD FS1 trials did not differ significantly. Adverse events potentially related to minocycline did not appear useful to predict minocycline adherence. In the MIRA trial, adherence measured by pill count appears higher than adherence measured by assay. Agreement between pill count and assay was poor (kappa statistic = 0.25).^ Limitations: Trial and disease are completely confounded and hence the independent effect of disease on adherence to minocycline treatment cannot be studied.^ Conclusion: Simple pill count may be preferred over assay in the minocycline clinical trials to measure adherence. Assays may be less sensitive in a clinical setting where appointments are not scheduled in relation to medication administration time, given assays depend on many pharmacokinetic and instrument-related factors. However, pill count can be manipulated by the patient. Another study suggested that self-report method is more sensitive than pill count method in differentiating adherence from non-adherence. An effect of medication-related adverse events on adherence could not be detected.^

Markov blanket-based approach for learning multi-dimensional Bayesian network classifiers: An application to predict the European Quality of Life-5 Dimensions (EQ-5D) from the 39-item Parkinson's Disease Questionnaire (PDQ-39)

Multi-dimensional Bayesian network classifiers (MBCs) are probabilistic graphical models recently proposed to deal with multi-dimensional classification problems, where each instance in the data set has to be assigned to more than one class variable. In this paper, we propose a Markov blanket-based approach for learning MBCs from data. Basically, it consists of determining the Markov blanket around each class variable using the HITON algorithm, then specifying the directionality over the MBC subgraphs. Our approach is applied to the prediction problem of the European Quality of Life-5 Dimensions (EQ-5D) from the 39-item Parkinson’s Disease Questionnaire (PDQ-39) in order to estimate the health-related quality of life of Parkinson’s patients. Fivefold cross-validation experiments were carried out on randomly generated synthetic data sets, Yeast data set, as well as on a real-world Parkinson’s disease data set containing 488 patients. The experimental study, including comparison with additional Bayesian network-based approaches, back propagation for multi-label learning, multi-label k-nearest neighbor, multinomial logistic regression, ordinary least squares, and censored least absolute deviations, shows encouraging results in terms of predictive accuracy as well as the identification of dependence relationships among class and feature variables.

Servicio ubicuo de estimulación cognitiva orientado a personas con enfermedad de Parkinson

Este trabajo de investigación detalla el diseño y evaluación de un servicio de e-salud cuyo objetivo es mejorar la estimulación y seguimiento de personas con un trastorno cognitivo. Con este fin, se ha desarrollado un protocolo de transferencia de mensajes que facilita la provisión de un servicio telemático para personas afectadas de Parkinson, pudiendo así realizar estimulación cognitiva personalizada, de forma ubicua, mediante un dispositivo fácil de usar como un tablet Android. Asimismo, este servicio permite a los terapeutas adaptar y monitorizar de forma segura la terapia, vía web, beneficiándose así de una mejor calidad en el seguimiento efectivo de cada paciente. El sistema ha sido evaluado satisfactoriamente durante tres meses con 10 pacientes entre 59 y 77 años. La solución resultante es fácilmente integrable con otras terapias complementarias y puede ser adaptada para otros deterioros cognitivos, como el debido a la enfermedad de Alzheimer o el deterioro cognitivo leve.

A telehealth system for Parkinson's disease remote monitoring. The PERFORM approach.

This paper summarizes the experience and the lessons learned from the European project PERFORM (A sophisticated multi-parametric system FOR the continuous effective assessment and monitoring of motor status in Parkinson's disease and other neurodegenerative diseases). PERFORM is aimed to provide a telehealth system for the remote monitoring of Parkinson's disease patients (PD) at their homes. This paper explains the global experience with PERFORM. It summarizes the technical performance of the system and the feedback received from the patients in terms of usability and wearability.

A telehealth system for Parkinson's disease remote monitoring. The PERFORM approach

This paper summarizes the experience and the lessons learned from the European project PERFORM (A sophisticated multi-parametric system FOR the continuous effective assessment and monitoring of motor status in Parkinson s disease and other neurodegenerative diseases). PERFORM is aimed to provide a telehealth system for the remote monitoring of Parkinson s disease patients (PD) at their homes. This paper explains the global experience with PERFORM. It summarizes the technical performance of the system and the feedback received from the patients in terms of usability and wearability.

Preliminary results of ON/OFF detection using an integrated system for Parkinson's disease monitoring

This paper describes the experimental set up of a system composed by a set of wearable sensors devices for the recording of the motion signals and software algorithms for the signal analysis. This system is able to automatically detect and assess the severity of bradykinesia, tremor, dyskinesia and akinesia motor symptoms. Based on the assessment of the akinesia, the ON-OFF status of the patient is determined for each moment. The assessment performed through the automatic evaluation of the akinesia is compared with the status reported by the patients in their diaries. Preliminary results with a total recording period of 32 hours with two PD patients are presented, where a good correspondence (88.2 +/- 3.7 %) was observed. Best (93.7 por ciento) and worst (87 por ciento) correlation results are illustrated, together with the analysis of the automatic assessment of the akinesia symptom leading to the status determination. The results obtained are promising, and if confirmed with further data, this automatic assessment of PD motor symptoms will lead to a better adjustment of medication dosages and timing, cost savings and an improved quality of life of the patients.

Predicting EQ-5D from the Parkinson's disease questionnaire PDQ-8 using multi-dimensional Bayesian network classifiers

The impact of the Parkinson's disease and its treatment on the patients' health-related quality of life can be estimated either by means of generic measures such as the european quality of Life-5 Dimensions (EQ-5D) or specific measures such as the 8-item Parkinson's disease questionnaire (PDQ-8). In clinical studies, PDQ-8 could be used in detriment of EQ-5D due to the lack of resources, time or clinical interest in generic measures. Nevertheless, PDQ-8 cannot be applied in cost-effectiveness analyses which require generic measures and quantitative utility scores, such as EQ-5D. To deal with this problem, a commonly used solution is the prediction of EQ-5D from PDQ-8. In this paper, we propose a new probabilistic method to predict EQ-5D from PDQ-8 using multi-dimensional Bayesian network classifiers. Our approach is evaluated using five-fold cross-validation experiments carried out on a Parkinson's data set containing 488 patients, and is compared with two additional Bayesian network-based approaches, two commonly used mapping methods namely, ordinary least squares and censored least absolute deviations, and a deterministic model. Experimental results are promising in terms of predictive performance as well as the identification of dependence relationships among EQ-5D and PDQ-8 items that the mapping approaches are unable to detect