Factors impacting performance on the 6-minute walk test by people with late-onset Pompe disease.

INTRODUCTION/AIMS: Pompe disease is a progressive myopathy that combines motor, respiratory, and cardiac impairments. The 6-min walk test is the gold standard for assessing disease severity at the motor level. The objective of this study was to better determine the parameters that influence the total distance covered in patients with Pompe disease. METHODS: We performed a retrospective review of 15 patients with late-onset Pompe disease who were followed regularly at a single referral center. Logistic regression was used to investigate the links between motor, respiratory and cardiac variables and 6-min walk test performance. RESULTS: When considering baseline clinical and demographic variables, a seven-step backward elimination regression analysis yielded a model with two predictors (age and the use of an assistive device) that explained 85.5% of the variance. When considering the cardiorespiratory variables monitored during gait, a three-step backward elimination regression analysis showed that two predictors (heart rate recovery and the baseline partial pressure of carbon dioxide) explained 42.2% of the variance. DISCUSSION: Our results highlighted the importance of respiratory and cardiac adaptation during exercise (along with motor ability) during the 6-min walk test in patients with Pompe disease. Further studies of larger cohorts are necessary to validate the model, which might enable investigators to determine whether intra-individual fluctuations in 6-min walk test performance are related to physiological parameters and/or to other variables such as the patient's level of motivation during the test.

Repetitive transcranial magnetic stimulation for patients with functional paralysis: a randomized controlled study.

BACKGROUND AND PURPOSE: Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat functional neurological disorders. Here, the aim was to assess the efficacy of rTMS to treat functional paralysis in a controlled randomized trial. METHODS: Patients received two sessions of active or sham 0.25 Hz rTMS (60 stimuli each), with a 1-day interval, applied over the motor cortex contralateral to the paralysis. The primary outcome was the number of patients with an increase in motor score between baseline and after the second rTMS session, rated by two investigators blinded to the treatment allocation. Secondary outcomes were changes in global and fine motor scores between groups after rTMS, and the occurrence of adverse events. RESULTS: Sixty-two patients (46 female; mean [SD] age, 35.2 [13.9] years) were enrolled and randomized. Thirteen out of 32 (41%) and 11/30 (37%) patients had increased motor strength after active or sham rTMS, respectively (p = 0.80). Changes in both global and fine motor scores after rTMS relative to baseline were also not significantly different between treatment groups (median difference in the global motor score 0.62 [0.83] and 0.37 [0.61], and in the fine motor scores 0.12 [0.18] and 0.08 [0.11], in active and sham rTMS groups, respectively; p = 0.14). Six serious adverse events, consisting of three cephalalgia in the active group and two cephalalgia and one asthenia in the sham group, were observed. CONCLUSIONS: Two sessions of sham or active low frequency rTMS were effective to improve functional paralysis, suggesting a placebo effect of this non-invasive brain stimulation technique.

Parkinson's disease-related changes in the behavioural synergy between eye movements and postural movements.

Patients with Parkinson's disease (PD patients) have been shown to exhibit abnormally low levels of synergy in their posture control. The goal of this study was to determine how synergic interactions between vision and posture are affected in PD patients. These synergic interactions were expected to be impaired because PD affects the basal ganglia, which are involved in the modulation of both types of movement. Twenty patients (mean age: 60) on levodopa and 20 age-matched-controls (mean age: 61) performed a precise visual task (searching for targets in an image) and an unprecise control task (randomly looking at an image) in which images were projected onto a large panoramic display. Lower back, upper back, head and eye movements were recorded simultaneously. To test behavioural synergies, Pearson correlations between eye and postural movements were analysed. The relationships between eye movements and upper and lower back movements were impaired in the patients. The age-matched controls did not show any significant correlations between eye and postural movements. Overall, our results showed that the PD patients failed to adjust and control their postural stability for success in the visual task. The impaired synergy between eye and postural movements was not related to clinical variables-probably because our patients had early-stage PD. Our results showed that impairments in synergy can occur very early in PD. Hence, the analysis of this synergy might provide a better understanding of postural instability, visual task performance in the upright stance, and perhaps the risk of falls in PD patients.

New insight into Parkinson's disease-related impairment of the automatic control of upright stance.

Parkinson's disease (PD) affects the automatic control of body movements. In our study, we tested PD-related impairments in automatic postural control in quiet upright stance. Twenty PD patients (mean age: 60 ± 8 years; Hoehn and Yahr: 2.00 ± 0.32, on-drug) and twenty age-matched controls (61 ± 7 years) were recruited. We studied interrelations between center-of-pressure movements, body movements (head, neck, and lower back), eye movements and variability of pupil size. Participants performed two fixation tasks while standing, during which they looked at: (a) a cross surrounded by a white background; and (b) a cross surrounded by a structured visual background (images used: rooms in houses). PD patients exhibited stronger and weaker correlations between eye and center-of-pressure/body movement variables than age-matched controls in the white and structured fixation tasks, respectively. Partial correlations, controlling for variability of pupil size showed that PD patients used lower and greater attentional resources than age-matched controls to control their eye and center-of-pressure/body movements simultaneously in the white fixation and structured fixation tasks, respectively. In the white fixation task, PD patients used attentional resources to optimize visuomotor coupling between eye and body movements to control their posture. In the structured fixation task, the salient visual stimuli distracted PD patients' attention and that possibly affected postural control by deteriorating the automatic visuomotor coupling. In contrast, age-matched controls were able to use surrounding visual background to improve the automatic coupling between eye and center-of-pressure movements to control their posture. These results suggest that cluttered environments may distract PD patients and deteriorate their postural control.

Excessive buccal saliva in patients with Parkinson's disease of the French COPARK cohort.

We describe excessive buccal saliva (EBS) prevalence in patients with Parkinson's Disease (PD) and controls of the COPARK study, its changes between "ON" and OFF" conditions and over time, its impact on Health-related Quality of life (HRQoL), and factors associated with this condition. We studied 671 ambulatory PD patients and 177 age/sex-matched controls. We defined "sialorrhea" as UPDRS item #6 (salivation) = 1 or 2; and "drooling" as item #6 = 3 or 4. SCOPA-Aut drooling score (item #2) was also available in a subset (45%) of the cohort. HRQoL was assessed by the PDQ-39 and SF-36 scales. Twenty-four months' follow-up data were available in 401/671 patients. EBS as assessed by UPDRS was present in 38% of PD patients in the "ON" condition ("Sialorrhea": 35%; "drooling": 3%). There were also more PD patients reporting "drooling" than controls according to the SCOPA-Aut (49% vs 19%, p < 0.01). UPDRS salivation score was worse in the "OFF" vs "ON" condition in PD patients with motor fluctuations (0.90 ± 0.94 vs 0.54 ± 0.79, p < 0.01). UPDRS salivation score worsened after ~ 24 months of follow-up (0.47 ± 0.70 vs 0.64 ± 0.81, p < 0.01). Worse PDQ-39 scores were observed in PD patients with EBS in bivariate but not in multivariate analyses. EBS was directly related to PD duration and severity, male gender, dysphagia, hypomimia, and autonomic dysfunction (logistic regression). EBS was more frequent in PD patients than controls, worsened in the "OFF" condition and after ~ 24 months of follow-up, moderately affected HRQoL, and was correlated with indices of bradykinesia, dysphagia, and autonomic dysfunction.

A new paradigm to study the influence of attentional load on cortical activity for motor preparation of step initiation.

Motor programme for gait initiation can vary as a function of attentional resources. The objective of the present study was to determine whether alertness, orientation and executive control can modulate cortical activation during step initiation. The attention network test (ANT) was used to control the influence of different attentional components on kinetic characteristics of step initiation and the associated cortical activity. Thirty healthy adults performed ANT combined with step initiation. The step execution time (SET) and anticipatory postural adjustments (APAs) were recorded. Movement-related cortical potentials (MRCPs) and event-related spectral perturbations (ERSPs) after response emission were analysed according to the presence or absence of cueing or conflict resolution. Step reaction time and thus SET were significantly shorter with cueing, whereas APA duration and SET were longer during conflict resolution. Moreover, alertness was related to a higher rate of anticipated responses, and conflicting situations were associated with a greater amount of multiple APAs. Attentional load did not affect MRCPs but ERSPs: trials with a cue showed earlier posterior alpha and beta desynchronisations before APA onset. Furthermore, we found earlier, more pronounced and longer alpha- and beta-band desynchronisations over the sensorimotor cortex for trials with incongruent flankers. Our results showed that attention has an impact on step initiation. A specific pattern of response-locked ERSPs seems to mirror behavioural effects of attentional load on step initiation. This new paradigm combining ANT and step initiation is, therefore, promising to investigate the interaction between attention and gait initiation in pathological populations.

Influence of Motor Deficiency and Spatial Neglect on the Contralesional Posterior Parietal Cortex Functional and Structural Connectivity in Stroke Patients.

The posterior parietal cortex (PPC) is a key structure for visual attention and upper limb function, two features that could be impaired after stroke, and could be implied in their recovery. If it is well established that stroke is responsible for intra- and interhemispheric connectivity troubles, little is known about those existing for the contralesional PPC. In this study, we aimed at mapping the functional (using resting state fMRI) and structural (using diffusion tensor imagery) networks from 3 subparts of the PPC of the contralesional hemisphere (the anterior intraparietal sulcus), the posterior intraparietal sulcus and the superior parieto-occipital cortex to bilateral frontal areas and ipsilesional homologous PPC parts in 11 chronic stroke patients compared to 13 healthy controls. We also aimed at assessing the relationship between connectivity and the severity of visuospatial and motor deficiencies. We showed that interhemispheric functional and structural connectivity between PPCs was altered in stroke patients compared to controls, without any specificity among seeds. Alterations of parieto-frontal intra- and interhemispheric connectivity were less observed. Neglect severity was associated with several alterations in intra- and interhemispheric connectivity, whereas we did not find any behavioral/connectivity correlations for motor deficiency. The results of this exploratory study shed a new light on the influence of the contralesional PPC in post-stroke patients, they have to be confirmed and refined in further larger studies.

Electroencephalography-based machine learning for cognitive profiling in Parkinson's disease: Preliminary results.

BACKGROUND: Cognitive symptoms are common in patients with Parkinson's disease. Characterization of a patient's cognitive profile is an essential step toward the identification of predictors of cognitive worsening. OBJECTIVE: The aim of this study was to investigate the use of the combination of resting-state EEG and data-mining techniques to build characterization models. METHODS: Dense EEG data from 118 patients with Parkinson's disease, classified into 5 different groups according to the severity of their cognitive impairments, were considered. Spectral power analysis within 7 frequency bands was performed on the EEG signals. The obtained quantitative EEG features of 100 patients were mined using 2 machine-learning algorithms to build and train characterization models, namely, support vector machines and k-nearest neighbors models. The models were then blindly tested on data from 18 patients. RESULTS: The overall classification accuracies were 84% and 88% for the support vector machines and k-nearest algorithms, respectively. The worst classifications were observed for patients from groups with small sample sizes, corresponding to patients with the severe cognitive deficits. Whereas for the remaining groups for whom an accurate diagnosis was required to plan the future healthcare, the classification was very accurate. CONCLUSION: These results suggest that EEG features computed from a daily clinical practice exploration modality in-that it is nonexpensive, available anywhere, and requires minimal cooperation from the patient-can be used as a screening method to identify the severity of cognitive impairment in patients with Parkinson's disease. © 2018 International Parkinson and Movement Disorder Society.

Freezing/festination during motor tasks in early-stage Parkinson's disease: A prospective study.

BACKGROUND: Parkinsonian patients have a tendency to speed up during repetitive motor tasks (festination) and to experience sudden motor blocks (freezing). In this article, we prospectively studied the appearance and progression of these phenomena in 30 early-stage PD patients. METHODS: A total of 30 controls and early-stage PD patients were assessed in the "off-drug" condition at baseline and 2 years later. Freezing of gait was evaluated using a standardized gait trajectory with the usual triggers. Patients also performed diadochokinetic tasks with 3 different effectors (repetitive, antiphase movements for the hands and feet, and repetitive syllable production for the orofacial effector) at frequencies ranging from 1 to 7 Hz (in random order). The primary endpoint was the occurrence of freezing and festination. RESULTS: At baseline, freezing was observed in 6.5% of the trials in PD patients (43% of the patients) and 2.3% of the trials in controls, and festination was observed in 5.7% of the trials in patients (53% of the patients) and 0.8% of the trials in controls. These proportions were slightly higher in patients 2 years later. None of the patients presented freezing of gait at baseline, but 2 displayed this condition 2 years later. These phenomena occurred more frequently for the limb effectors than for the orofacial effector. Freezing and festination were associated with the akinetic-rigid subtype, although tremor-dominant patients displayed greater rhythm variability outside episodes. CONCLUSION: Freezing and festination of the upper and lower limbs are observed soon after the diagnosis of PD and may be early biomarkers for disease progression. © 2016 International Parkinson and Movement Disorder Society.

How does visuospatial attention modulate motor preparation during gait initiation?

Gait initiation is an automatized motor program that is preceded by anticipatory postural adjustments (APAs). These adjustments create the propulsive forces required to reach the steady-state gait at the end of the first step and can be studied by the displacement of the centre of pressure. The objective of this study was to demonstrate that APAs can be modulated by visuospatial attentional processes prior to motor execution. An adaptation of the Posner paradigm was used to assess attention during step initiation. Twelve healthy subjects performed a gait initiation task under three conditions: a no-cue condition (the control experiment), a double-cue condition (alerting attention) and a single-cue condition (orienting attention). The kinetic and kinematic parameters of the APAs and step initiation were recorded. The time to step initiation was significantly shorter in the alerting condition than in the control condition. This effect was associated with the earlier occurrence of APAs. Orienting condition also had an effect and was associated with the modulation of APA errors (defined as a contralateral shift of the CoP on the cue side before corrective shifting to the target side). Behavioural measurements (such as postural preparation of step initiation) may reflect the interaction between attention and locomotion. Our results show that the different components of attention each have a specific influence on step initiation parameters.

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson's disease.

After more than 50 years of treating Parkinson's disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinson's disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinson's disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinson's Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinson's Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinson's disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Falls in ambulatory non-demented patients with Parkinson's disease.

This study aimed at determining the prevalence of falling in PD patients, to assess generic and disease-specific clinical and pharmacological factors, relationship with health-related quality of life (HR-QoL) and changes in falls from OFF to ON in patients with motor fluctuations. Six-hundred and eighty-three PD patients of the COPARK survey were evaluated (11 had missing data and were excluded from the analysis). Patients with falls were identified as those with a UPDRS Item 13 ≥ 1 in the ON condition. All patients were assessed in a standardized manner [demographics, treatments, Unified PD Rating Scale (UPDRS), Hospital Anxiety and Depression Scale, Pittsburg questionnaire and HR-QoL scales (SF36, PDQ39)]. Falling was reported by 108/672 (16%) PD patients during the ON state and prevalence increased according to PD severity, from 5% in Hoehn and Yahr stage 1-60% in stage 4. Falling was significantly related to lower HR-QoL. Falling correlated with (1) generic factors such as female gender, age at the end of academic studies and diuretics consumption, (2) motor PD-specific factors including disease severity, frozen gait, difficulties when arising from a chair, dyskinesia and higher levodopa daily equivalent dose and (3) non-motor PD-specific factors such as orthostatic hypotension and hallucinations. Falling was more frequent in OFF than in ON in 48/74 (64%) patients with motor fluctuations and remained unchanged in 27 patients (36%). In summary, falling affected a significant proportion of PD patients, especially in advanced stages. It was associated with a variety of generic and PD-specific factors and was related to reduced HR-QoL.

Interest of active posturography to detect age-related and early Parkinson's disease-related impairments in mediolateral postural control.

Patients with Parkinson's disease display impairments of postural control most particularly in active, challenging conditions. The objective of the present study was to analyze early signs of disease-related and also age-related impairments in mediolateral body extension and postural control. Fifty-five participants (18 Hoehn and Yahr stage 2 patients in the off-drug condition, 18 healthy elderly control subjects, and 19 young adults) were included in the study. The participants performed a quiet stance task and two active tasks that analyzed the performance in mediolateral body motion: a limit of stability and a rhythmic weight shift task. As expected, the patients displayed significantly lower and slower body displacement (head, neck, lower back, center of pressure) than elderly control subjects when performing the two body excursion tasks. However, the behavioral variability in both tasks was similar between the groups. Under these active conditions, the patients showed significantly lower contribution of the hip postural control mechanisms compared with the elderly control subjects. Overall, the patients seemed to lower their performance in order to prevent a mediolateral postural instability. However, these patients, at an early stage of their disease, were not unstable in quiet stance. Complementarily, elderly control subjects displayed slower body performance than young adults, which therefore showed an additional age-related impairment in mediolateral postural control. Overall, the study illustrated markers of age-related and Parkinson's disease impairments in mediolateral postural control that may constrain everyday activities in elderly adults and even more in patients with Parkinson's disease.

Qualitative versus quantitative assessment of electroencephalography in cognitive decline: Comparison in a clinical population.

This study aimed to compare the diagnostic performance of visual assessment of electroencephalography (EEG) using the Grand Total EEG (GTE) score and quantitative EEG (QEEG) using spectral analysis in the context of cognitive impairment. This was a retrospective study of patients with mild cognitive impairment, with (MCI+V) or without (MCI) vascular dysfunction, and patients with dementia including Alzheimer's disease, Lewy Body Dementia and vascular dementia. The results showed that the GTE is a simple scoring system with some potential applications, but limited ability to distinguish between dementia subtypes, while spectral analysis appeared to be a powerful tool, but its clinical development requires the use of artificial intelligence tools.

Association between caffeine intake and age at onset in Huntington's disease.

Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinson's and Alzheimer's diseases. Experimental evidence support that ARs play a role in Huntington's disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables.

Memantine for axial signs in Parkinson's disease: a randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Given that memantine is thought to decrease N-methyl-D-aspartic-acid-related (NMDA) glutamatergic hyperactivity and improve locomotion in rats, we sought to assess the drug's impact on axial symptoms in advanced Parkinson's disease (PD). METHODS: We performed a 90-day, randomised, double-blind, study with two parallel arms: 20 mg/day memantine versus placebo (ClinicalTrials.gov:NCT01108029). The main inclusion criterion was the presence of a severe gait disorder and an abnormal, forward-leaning stance. The following parameters were analysed under standardised conditions before and after acute administration of L-dopa: gait (stride length as primary criterion), the United-Parkinson's-Disease-Rating-Scale (UPDRS) motor score and its axial subscore, the hypertonia and strength of the axial extensors and flexors (isokinetic dynamometer), the Dyskinesia Rating Scale score (DRS) and its axial subscore. RESULTS: Twenty-five patients were included. The memantine and placebo group did not differ significantly in terms of stride length. However, in the memantine group, we observed significantly better results (vs placebo) for the overall UPDRS score (F(1,21)=4.9; p=0.039(-1)) and its axial subscore (F(1,21)=7.2; p=0.014(-1.1)), axial hypertonia, the axial and overall DRS and axial strength. CONCLUSIONS: Memantine treatment was associated with lower axial motor symptom and dyskinesia scores but did not improve gait. These benefits must be confirmed in a broader population of patients.

Pain and Parkinson's disease: Current mechanism and management updates.

The aim of this comprehensive review was to provide an overview of pain in Parkinson's disease (PD) by identifying different clinical features and potential mechanisms, and presenting some data on the evaluation and management of pain in PD. PD is a multifocal degenerative and progressive disease, which could affect the pain process at multiple levels. Pain in PD has a multifactorial aetiology, with a dynamic process based on pain intensity, complexity of symptoms, pain pathophysiology and presence of comorbidities. In fact, pain in PD responds to the concept of multimorphic pain, which can evolve, in relation to the different factors, whether they are linked to disease and its management. Understanding the underlying mechanisms will help in guiding of treatment choices. Providing scientific support useful for clinicians and health professionals involved in management of PD, the aim of this review was to bringing practical suggestions and clinical perspectives on the development of a multimodal approach guided by a multidisciplinary clinical intervention through a combination of pharmacological and rehabilitative approaches, to manage pain to improve the quality of life on individuals with PD.

The contribution of executive control dysfunction to freezing of gait in Parkinson's disease.

OBJECTIVE: An executive dysfunction is supposed to contribute to freezing of gait (FoG) in Parkinson's disease. We aimed to investigate at a behavioral and cortical levels whether an attentional load (particularly, a conflicting situation) can specifically impact preparation and execution phases of step initiation in parkinsonian patients with FoG. METHODS: Fifteen patients with FoG, 16 without and 15 controls performed an adapted version of the Attention Network Test, with step initiation as response instead of the standard manual keypress. Kinetic and kinematic features of gait initiation as well as high-resolution electroencephalography were recorded during the task. RESULTS: Patients with FoG presented an impaired executive control. Step execution time was longer in parkinsonian patients. However, the executive control effect on step execution time was not different between all groups. Compared to patients, controls showed a shorter step initiation-locked alpha desynchronization, and an earlier, more intense and shorter beta desynchronization over the sensorimotor cortex. Even though controls were faster, the induced alpha and beta activity associated with the effect of executive control didn't differ between patients and controls. CONCLUSIONS: Tasks of conflict resolution lead to a comparable alteration of step initiation and its underlying brain activity in all groups. Links between executive control, gait initiation and FoG seem more complex than expected. SIGNIFICANCE: This study questions the cognitive hypothesis in the pathophysiology of freezing of gait. Executive dysfunction is associated with FoG but is not the main causal mechanism since the interaction between attention and motor preparation didn't provoke FoG.