Effect of Nintendo Wii (TM)-based motor and cognitive training on activities of daily living in patients with Parkinson's disease: A randomised clinical trial

Objectives To investigate the effect of Nintendo Wii (TM)-based motor cognitive training versus balance exercise therapy on activities of daily living in patients with Parkinson's disease. Design Parallel, prospective, single-blind, randomised clinical trial. Setting Brazilian Parkinson Association. Participants Thirty-two patients with Parkinson's disease (Hoehn and Yahr stages 1 and 2). Interventions Fourteen training sessions consisting of 30 minutes of stretching, strengthening and axial mobility exercises, plus 30 minutes of balance training. The control group performed balance exercises without feedback or cognitive stimulation, and the experimental group performed 10 Wii Fit (TM) games. Main outcome measure Section II of the Unified Parkinson's Disease Rating Scale (UPDRS-II). Randomisation Participants were randomised into a control group (n = 16) and an experimental group (n = 16) through blinded drawing of names. Statistical analysis Repeated-measures analysis of variance (RM-ANOVA). Results Both groups showed improvement in the UPDRS-II with assessment effect (RM-ANOVA P < 0.001, observed power = 0.999). There was no difference between the control group and the experimental group before training {8.9 [standard deviation (SD) 2.9] vs 10.1 (SD 3.8)}, after training [7.6 (SD 2.9) vs 8.1 (SD 3.5)] or 60 days after training [8.1 (SD 3.2) vs 8.3 (SD 3.6)]. The mean difference of the whole group between before training and after training was -0.9 (SD 2.3, 95% confidence interval -1.7 to -0.6). Conclusion Patients with Parkinson's disease showed improved performance in activities of daily living after 14 sessions of balance training, with no additional advantages associated with the Wii-based motor and cognitive training. Registered on http://www.clinicaltrials.gov (identifier: NCT01580787). (C) 2012 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

The interaction of postural and voluntary strategies for stability in Parkinson's disease

de Lima-Pardini AC, Papegaaij S, Cohen RG, Teixeira LA, Smith BA, Horak FB. The interaction of postural and voluntary strategies for stability in Parkinson's disease. J Neurophysiol 108: 1244-1252, 2012. First published June 6, 2012; doi:10.1152/jn.00118.2012.-This study assessed the effects of stability constraints of a voluntary task on postural responses to an external perturbation in subjects with Parkinson's disease (PD) and healthy elderly participants. Eleven PD subjects and twelve control subjects were perturbed with backward surface translations while standing and performing two versions of a voluntary task: holding a tray with a cylinder placed with the flat side down [low constraint (LC)] or with the rolling, round side down [high constraint (HC)]. Participants performed alternating blocks of LC and HC trials. PD participants accomplished the voluntary task as well as control subjects, showing slower tray velocity in the HC condition compared with the LC condition. However, the latency of postural responses was longer in the HC condition only for control subjects. Control subjects presented different patterns of hip-shoulder coordination as a function of task constraint, whereas PD subjects had a relatively invariant pattern. Initiating the experiment with the HC task led to 1) decreased postural stability in PD subjects only and 2) reduced peak hip flexion in control subjects only. These results suggest that PD impairs the capacity to adapt postural responses to constraints imposed by a voluntary task.

Subthalamic deep brain stimulation modulates small fiber-dependent sensory thresholds in Parkinson's disease

The effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms of Parkinson's disease (PD) rarely have been investigated. Among these, sensory disturbances, including chronic pain (CP), are frequent in these patients. The aim of this study was to evaluate the changes induced by deep brain stimulation in the perception of sensory stimuli, either noxious or innocuous, mediated by small or large nerve fibers. Sensory detection and pain thresholds were assessed in 25 PD patients all in the off-medication condition with the stimulator turned on or off (on- and off-stimulation conditions, respectively). The relationship between the changes induced by surgery on quantitative sensory testing, spontaneous CP, and motor abilities were studied. Quantitative sensory test results obtained in PD patients were compared with those of age-matched healthy subjects. Chronic pain was present in 72% of patients before vs 36% after surgery (P = .019). Compared with healthy subjects, PD patients had an increased sensitivity to innocuous thermal stimuli and mechanical pain, but a reduced sensitivity to innocuous mechanical stimuli. In addition, they had an increased pain rating when painful thermal stimuli were applied, particularly in the off-stimulation condition. In the on-stimulation condition, there was an increased sensitivity to innocuous thermal stimuli but a reduced sensitivity to mechanical or thermal pain. Pain provoked by thermal stimuli was reduced when the stimulator was turned on. Motor improvement positively correlated with changes in warm detection and heat pain thresholds. Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with PD and specifically modulates small fiber-mediated sensations. (C) 2012 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Different approaches, one target: understanding cellular mechanisms of Parkinson's and Alzheimer's diseases

Neurodegenerative disorders are undoubtedly an increasing problem in the health sciences, given the increase of life expectancy and occasional vicious life style. Despite the fact that the mechanisms of such diseases are far from being completely understood, a large number of studies; that derive from both the basic science and clinical approaches have contributed substantial data in that direction. In this review, it is discussed several frontiers of basic research on Parkinson's and Alzheimer's diseases, in which research groups from three departments of the Institute of Biomedical Sciences of the University of Sao Paulo have been involved in a multidisciplinary effort. The main focus of the review involves the animal models that have been developed to study cellular and molecular aspects of those neurodegenerative diseases, including oxidative stress, insulin signaling and proteomic analyses, among others. We anticipate that this review will help the group determine future directions of joint research in the field and, more importantly, set the level of cooperation we plan to develop in collaboration with colleagues of the Nucleus for Applied Neuroscience Research that are mostly involved with clinical research in the same field.

Motor learning, retention and transfer after virtual-reality-based training in Parkinson's disease - effect of motor and cognitive demands of games: a longitudinal, controlled clinical study

Objectives To evaluate the learning, retention and transfer of performance improvements after Nintendo Wii Fit (TM) training in patients with Parkinson's disease and healthy elderly people. Design Longitudinal, controlled clinical study. Participants Sixteen patients with early-stage Parkinson's disease and 11 healthy elderly people. Interventions Warm-up exercises and Wii Fit training that involved training motor (shifts centre of gravity and step alternation) and cognitive skills. A follow-up evaluative Wii Fit session was held 60 days after the end of training. Participants performed a functional reach test before and after training as a measure of learning transfer. Main outcome measures Learning and retention were determined based on the scores of 10 Wii Fit games over eight sessions. Transfer of learning was assessed after training using the functional reach test. Results Patients with Parkinson's disease showed no deficit in learning or retention on seven of the 10 games, despite showing poorer performance on five games compared with the healthy elderly group. Patients with Parkinson's disease showed marked learning deficits on three other games, independent of poorer initial performance. This deficit appears to be associated with cognitive demands of the games which require decision-making, response inhibition, divided attention and working memory. Finally, patients with Parkinson's disease were able to transfer motor ability trained on the games to a similar untrained task. Conclusions The ability of patients with Parkinson's disease to learn, retain and transfer performance improvements after training on the Nintendo Wii Fit depends largely on the demands, particularly cognitive demands, of the games involved, reiterating the importance of game selection for rehabilitation purposes. (C) 2012 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Transcranial sonography in Parkinson's disease

Transcranial sonography has become a useful tool in the differential diagnosis of parkinsonian syndromes. This is a non-invasive, low cost procedure. The main finding on transcranial sonography in patients with idiopathic Parkinson's disease is an increased echogenicity of the mesencephalic substantia nigra region. This hyperechogenicity is present in more than 90% of cases, and reflects a dysfunction in the dopaminergic nigrostriatal pathway. This study discussed how the hyperechogenicity of the substantia nigra may facilitate the differential diagnosis of parkinsonian syndromes.

Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. A preliminary observation

Objective: Hyperechogenicity of the substantia nigra is a frequent observation on transcranial sonography in Parkinson's disease and Machado-Joseph disease patients. Additionally, restless legs syndrome is a sleep disorder that is also frequently found in both diseases. Autopsy studies have demonstrated increased SN iron content in hyperechogenic substantia nigra. Iron storage is also known to be involved in restless legs syndrome. We formally compared echogenicity of the substantia nigra with restless legs syndrome in Parkinson's disease and Machado-Joseph disease patients. Methods: Transcranial brain sonography was performed in a sample of Parkinson's disease and Machado-Joseph disease patients, and findings then correlated with the presence and severity of restless legs syndrome. Results: There was a continuum of substantia nigra echogenicity among groups (Parkinson's disease versus Machado-Joseph disease versus controls) and sub-groups (Parkinson's disease with and without restless legs syndrome versus Machado-Joseph disease with and without restless legs syndrome) as well as a statistically significant negative correlation between restless legs syndrome severity and substantia nigra echogenicity (p<0.001). Conclusions: These preliminary observations demonstrate that the severity of RLS may be influenced by nigral iron load reflected by substantia nigra echogenicity in different neurodegenerative movement disorders. (C) 2012 Elsevier B.V. All rights reserved.

Subgroup-specific structural variation across 1,000 medulloblastoma genomes

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4 alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappa B signalling in Group 4, suggest future avenues for rational, targeted therapy.

Validity of the Brazilian version of the freezing of gait questionnaire

Objective: To validate the freezing of gait questionnaire (FOG-Q) for a Brazilian population of Parkinson's disease (PD) patients. Methods: One hundred and seven patients with a diagnosis of PD were evaluated by shortened UPDRS motor scale (sUPDRm), Hoehn and Yahr (HY), Schwab and England scale (SE), Berg balance scale (BBS), falls efficacy scale international (FES-I), gait and balance scale (GABS), and the FOG-Q Brazilian version. Results: 47.7% of PD patients had FOG episodes; this group had worse scores on sUPDRSm, FOGQ, FES-I, BBS, GABS and FOG item of UPDRS when compared to the PD group without FOG. The internal consistency was 0.86, intra-rater 0.82 and inter-rater 0.78. The FOG-Q Brazilian version was significantly correlated with items related to gait and balance. The ROC curve was 0.94, the sensitivity was 0.90 and specificity was 0.92. Conclusion: Our study suggests that the FOG-Q Brazilian version is a reliable and valid instrument for assessing FOG in PD patients.

Olfactory impairment in familial ataxias

The main clinical manifestations of the spinocerebellar ataxias (SCAs) result from the involvement of the cerebellum and its connections. Cerebellar activity has been consistently observed in functional imaging studies of olfaction, but the anatomical pathways responsible for this connection have not yet been elucidated. Previous studies have demonstrated olfactory deficit in SCA2, Friedreich's ataxia and in small groups of ataxia of diverse aetiology. The authors used a validated version of the 16-item smell identification test from Sniffin' Sticks (SS-16) was used to evaluate 37 patients with genetically determined autosomal dominant ataxia, and 31 with familial ataxia of unknown genetic basis. This data was also compared with results in 106 Parkinson's disease patients and 218 healthy controls. The SS-16 score was significantly lower in ataxia than in the control group (p<0.001, 95% CI for beta=0.55 to 1.90) and significantly higher in ataxia than in Parkinson's disease (p<0.001, 95% CI for beta=-4.58 to -3.00) when adjusted for age (p=0.001, 95% CI for beta=-0.05 to -0.01), gender (p=0.19) and history of tobacco use (p=0.41). When adjusted for general cognitive function, no significant difference was found between the ataxia and control groups. This study confirms previous findings of mild hyposmia in ataxia, and further suggests this may be due to general cognitive deficits rather than specific olfactory problems.

Accuracy of Timed Up and Go Test for screening risk of falls among community-dwelling elderly

Objective: To determine the accuracy of the Timed Up and Go Test (TUGT) for screening the risk of falls among community-dwelling elderly individuals. Method: This is a prospective cohort study with a randomly by lots without reposition sample stratified by proportional partition in relation to gender involving 63 community-dwelling elderly individuals. Elderly individuals who reported having Parkinson's disease, a history of transitory ischemic attack, stroke and with a Mini Mental State Exam lower than the expected for the education level, were on a wheelchair and that reported a single fall in the previous six months were excluded. The TUGT, a mobility test, was the measure of interested and the occurrence of falls was the outcome. The performance of basic activities of daily living (ADL) and instrumental activities of daily living (IADL) was determined through the Older American Resources and Services, and the socio-demographic and clinical data were determined through the use of additional questionnaires. Receiver Operating Characteristic Curves were used to analyze the sensitivity and specificity of the TUGT. Results: Elderly individuals who fell had greater difficulties in ADL and IADL (p<0.01) and a slower performance on the TUGT (p=0.02). No differences were found in socio-demographic and clinical characteristics between fallers and non- fallers. Considering the different sensitivity and specificity, the best predictive value for discriminating elderly individuals who fell was 12.47 seconds [(RR= 3.2) 95% CI: 1.3- 7.7]. Conclusions: The TUGT proved to be an accurate measure for screening the risk of falls among elderly individuals. Although different from that reported in the international literature, the 12.47 second cutoff point seems to be a better predictive value for Brazilian elderly individuals.

NADPH Oxidase and Neurodegeneration

NADPH oxidase (Nox) is a unique, multi-protein, electron transport system that produces large amounts of superoxide via the reduction of molecular oxygen. Nox-derived reactive oxygen species (ROS) are known to be involved in a variety of physiological processes, including host defense and signal transduction. However, over the past decade, the involvement of (Nox)-dependent oxidative stress in the pathophysiology of several neurodegenerative diseases has been increasingly recognized. ROS produced by Nox proteins contribute to neurodegenerative diseases through distinct mechanisms, such as oxidation of DNA, proteins, lipids, amino acids and metals, in addition to activation of redox-sensitive signaling pathways. In this review, we discuss the recent literature on Nox involvement in neurodegeneration, focusing on Parkinson and Alzheimer diseases.

New molecular targets for PET and SPECT imaging in neurodegenerative diseases

The pathophysiology of neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD) has not yet been completely elucidated. However, in the past few years, there have been great knowledge advances about intra-and extracellular proteins that may display impaired function or expression in AD, PD and other ND, such as amyloid beta (AB), alpha-synuclein, tau protein and neuroinfiammatory markers. Recent developments in the imaging techniques of positron emission tomography (PET) and single photon emission computed tomography (SPECT) now allow the non-invasive tracking of such molecular targets of known relevance to ND in vivo. This article summarizes recent findings of PET and SPECT studies using these novel methods, and discusses their potential role in the field of drug development for ND as well as future clinical applications in regard to differential diagnosis of ND and monitoring of disease progression.

Characterization of Heparin-induced Glyceraldehyde-3-phosphate Dehydrogenase Early Amyloid-like Oligomers and Their Implication in alpha-Synuclein Aggregation

Lewy bodies and Lewy neurites, neuropathological hallmarks of several neurological diseases, are mainly made of filamentous assemblies of alpha-synuclein. However, other macromolecules including Tau, ubiquitin, glyceraldehyde-3-phosphate dehydrogenase, and glycosaminoglycans are routinely found associated with these amyloid deposits. Glyceraldehyde-3-phosphate dehydrogenase is a glycolytic enzyme that can form fibrillar aggregates in the presence of acidic membranes, but its role in Parkinson disease is still unknown. In this work, the ability of heparin to trigger the amyloid aggregation of this protein at physiological conditions of pH and temperature is demonstrated by infrared and fluorescence spectroscopy, dynamic light scattering, small angle x-ray scattering, circular dichroism, and fluorescence microscopy. Aggregation proceeds through the formation of short rod-like oligomers, which elongates in one dimension. Heparan sulfate was also capable of inducing glyceraldehyde-3-phosphate dehydrogenase aggregation, but chondroitin sulfates A, B, and C together with dextran sulfate had a negligible effect. Aided with molecular docking simulations, a putative binding site on the protein is proposed providing a rational explanation for the structural specificity of heparin and heparan sulfate. Finally, it is demonstrated that in vitro the early oligomers present in the glyceraldehyde-3-phosphate dehydrogenase fibrillation pathway promote alpha-synuclein aggregation. Taking into account the toxicity of alpha-synuclein prefibrillar species, the heparin-induced glyceraldehyde-3-phosphate dehydrogenase early oligomers might come in useful as a novel therapeutic strategy in Parkinson disease and other synucleinopathies.