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Introduction: People with a Gly2019Ser mutation in the leucine-rich repeat kinase 2 (LRRK2 G2019S) are at increased risk of developing Parkinson's disease (PD). Recent evidence suggests that exercise may delay or prevent the development of clinically overt symptoms of PD in people at risk of PD. We determined whether LRRK2 G2019S mutation carriers with and without manifest PD are aware of the relationship between exercise and PD and how they differ in awareness, barriers and motivators to exercise., Methods: We deployed a survey among 4422 LRRK2 G2019S mutation carriers. In total, 505 (11.4%) of them completed the survey, of whom 105 had self-reported manifest PD., Results: Ninety-two percent of the LRRK2 G2019S mutation carriers with manifest PD and 63% of those with non-manifest PD were aware of the relationship between exercise and PD. Lack of motivation was the top barrier for those without manifest PD, while having an injury/disability was the most common barrier for those with manifest PD. Improvement of body functioning was the top motivator for both., Conclusion: The fact that many at-risk individuals are not aware of the importance of exercise and would exercise more with fewer barriers creates opportunities for trials using exercise as a possible prevention strategy for PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. D. Coker, J.F. Shelton, E. Chanoff, H.M. Rowbotham, P. Cannon and members of the 23andMe Research Team are employed by and hold stock or stock options in 23andMe, Inc. Prof. Bloem serves as the co-Editor in Chief for the Journal of Parkinson’s disease, serves on the editorial board of Practical Neurology and Digital Biomarkers, has received fees from serving on the scientific advisory board for UCB, Kyowa Kirin, Zambon and the Critical Path Institute (paid to the Institute), has received fees for speaking at conferences from AbbVie, Biogen, UCB, Zambon, Roche, GE Healthcare, Oruen and Bial (paid to the Institute), and has received research support from the Netherlands Organization for Health Research and Development, the Michael J Fox Foundation, UCB, the Stichting Parkinson Fonds, Hersenstichting Nederland, de Stichting Woelse Waard, Stichting Alkemade-Keuls, de Maag Lever Darm Stichting, Parkinson NL, Davis Phinney Foundation, the Parkinson’s Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, Nothing Impossible and the Parkinson Vereniging, outside the submitted work. Prof. Bloem does not hold any stocks or stock options with any companies that are connected to Parkinson’s disease or to any of the topics in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: There is little information on the late stages of parkinsonism., Methods: We conducted a multicentre study in 692 patients with late stage parkinsonism in six European countries. Inclusion criteria were disease duration of ≥7 years and either Hoehn and Yahr stage ≥4 or Schwab and England score of 50 or less., Results: Average disease duration was 15.4 (SD 7.7) years and mean total UPDRS score was 82.7 (SD 22.4). Dementia according to MDS-criteria was present in 37% of patients. Mean levodopa equivalence dose was 874.1 (SD 591.1) mg/d. Eighty two percent of patients reported falls, related to freezing (16%) or unrelated to freezing (21% of patients) or occurring both related and unrelated to freezing (45%), and were frequent in 26%. Moderate-severe difficulties were reported for turning in bed by 51%, speech by 43%, swallowing by 16% and tremor by 11%. Off-periods occurred in 68% and were present at least 50% of the day in 13%, with morning dystonia occurring in 35%. Dyskinesias were reported by 45% but were moderate or severe only in 7%. Moderate-severe fatigue, constipation, urinary symptoms and nocturia, concentration and memory problems were encountered by more than half of participants. Hallucinations (44%) or delusions (25%) were present in 63% and were moderate-severe in 15%. The association with overall disability was strongest for severity of falls/postural instability, bradykinesia, cognitive score and speech impairment., Conclusion: These data suggest that current treatment of late stage parkinsonism in the community remains insufficiently effective to alleviate disabling symptoms in many patients., Competing Interests: Declaration of competing interest The CLaSP study is funded by the European Commission (Joint Programme – Neurodegenerative Disease Research “European research projects for the evaluation of health care policies, strategies and interventions for Neurodegenerative Diseases”)., (Copyright © 2020. Published by Elsevier Ltd.)

Non-pharmacological interventions are increasingly being acknowledged as valuable treatment options to overcome or reduce functional problems in patients with Parkinson's disease (PD). There is a wide range of such non-pharmacological treatments for which the supportive evidence is emerging. Physiotherapy is one good example in this domain. However, there are also several promising non-pharmacological treatment strategies that have thus far received less research attention. Here, we describe two relatively new, but encouraging approaches. First, we focus on a hitherto largely overseen subgroup of PD, namely those with late-stage disease, a population that is often excluded from clinical studies. Importantly, the aims and therapeutic strategies in late-stage PD differ considerably from those in early-stage PD, and an emphasis on non-pharmacological management is particularly important for this vulnerable subgroup. Second, we focus on computer-based cognitive training, as an example of a relatively new intervention that includes innovative elements such as personalized training, artificial intelligence, and virtual reality. We review the latest evidence, practical considerations and future research perspectives, both for non-pharmacological approaches in late-stage PD and for computer-based cognitive training., (Copyright © 2017. Published by Elsevier Ltd.)

Background: The 'applause sign' a tendency to continue applauding in response to instructions to clap three times was described in 1995 and was considered specific to degenerative disease, especially to atypical parkinsonian disorders. In early phase Parkinson's disease (PD) the sign has been reported positive as well. In late stage PD it is unknown whether and to what extent the sign may be elicited and it remains unknown if and to what degree the sign correlates to cognitive impairment and PD related dementia., Methods: Nursing home residents with PD (MMSE >17) were included. All patients underwent the clapping test and were tested for cognitive disturbance by making use of accepted clinimetrics (MMSE and Scopa-cog). T-testing was performed with the hypothesis that patients expressing the applause sign would score lower on the MMSE or Scopa-cog., Results: Seventy three nursing home residents (mainly Hoehn and Yahr 4/5) with a mean disease duration of 10 years and a mean age of 78.7 years were included. The applause sign was found positive in 15 of 73 residents (20.5%). Residents expressing the applause sign had significantly lower mean scores on the MMSE (25.1 vs 22.9 points, p < 0.006) and Scopa-cog (14.8 vs 12.0 points, p < 0.039)., Conclusions: The applause sign is present in late stage PD and correlates with a higher degree of cognitive impairment as established with accepted clinimetric tests. A higher degree of frontal lobe involvement explains the presence of the applause sign., (Copyright © 2014. Published by Elsevier Ltd.)

Introduction: Management of Parkinson's disease (PD) and atypical parkinsonism in nursing homes depends on a timely and accurate diagnosis. However, little is known about the diagnostic accuracy of these parkinsonian syndromes in nursing homes. We examined this issue in a large group of Dutch nursing home residents., Methods: Twelve large nursing home organizations in the Netherlands accounting for 100 nursing homes with a total population of 5480 residents participated. Residents with PD or atypical parkinsonism were identified according to their nursing home medical chart diagnosis. Additionally, local pharmacists provided a list of all residents using antiparkinson medication. We compared the admission diagnosis to a clinical diagnosis made in the study, based upon interview and detailed neurological examination by movement disorders experts. Diagnoses were based on accepted clinical criteria for PD and atypical parkinsonism., Results: In the total population of 5480 residents, 258 had previously been diagnosed with a form of parkinsonism according to their medical record. In 53 of these residents (20.5%) we changed or rejected the diagnosis. Specifically, we found no parkinsonism in 22 of these 53 residents (8.5% of all patients with suspected parkinsonism). In the remaining 31 residents (12%), we established a new diagnosis within the parkinsonian spectrum., Conclusions: In a large population of Dutch nursing home residents, 20% of diagnoses within the parkinsonian spectrum were inaccurate. Almost 9% of residents had inadvertently received a diagnosis of parkinsonism. Better recognition of parkinsonism in nursing homes is important, because of the consequences for management and prognosis., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Dizziness is a frequent complaint of patients with Parkinson's disease (PD), and orthostatic hypotension (OH) is often thought to be the cause. We studied whether benign paroxysmal positional vertigo (BPPV) could also be an explanation., Aim: To assess the prevalence of benign paroxysmal positional vertigo in patients with Parkinson's disease, with and without dizziness., Methods: 305 consecutive outpatients with PD completed the Movement Disorders Society-sponsored revision of the Unified Parkinsons' Disease Rating Scale-motor score, the Dizziness Handicap Inventory, the Dix-Hallpike maneuver and a test for orthostatic hypotension. When positive for benign paroxysmal positional vertigo, a repositioning maneuver was performed. Patients were followed for three months to determine the clinical response., Results: 305 patients responded (186 men (61%), mean age 70.5 years (Standard Deviation 9.5 years)), of whom 151 (49%) complained of dizziness. 57 (38%) of the dizzy patients appeared to have orthostatic hypotension; 12 patients (8%) had a classical but previously unrecognized benign paroxysmal positional vertigo. A further four patients (3%) had a more atypical presentation of benign paroxysmal positional vertigo. Three months after treatment, 11 (92%) of patients with classical benign paroxysmal positional vertigo were almost or completely without complaints. We found no 'hidden' benign paroxysmal positional vertigo among patients without dizziness. The prevalence of benign paroxysmal positional vertigo among all patients with PD was 5.3%., Conclusion: Among Parkinson patients with symptoms of dizziness, up to 11% may have benign paroxysmal positional vertigo, which can be treated easily and successfully., (Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.)

Background: Although physical activity is beneficial for Parkinson's disease (PD) patients, many do not meet the recommended levels. The range of physical activity among sedentary PD patients is unknown, as are factors that determine this variability. Hence, we aimed to (1) assess daily physical activity in self-identified sedentary PD patients; (2) compare this with criteria of a daily physical activity guideline; and (3) identify determinants of daily physical activity., Methods: Daily physical activity of 586 self-identified sedentary PD patients was measured with a tri-axial accelerometer for seven consecutive days. Physical fitness and demographic, disease-specific, and psychological characteristics were assessed. Daily physical activity was compared with the 30-min activity guideline. A linear mixed-effects model was estimated to identify determinants of daily physical activity., Results: Accelerometer data of 467 patients who fulfilled all criteria revealed that >98% of their day was spent on sedentary to light-intensity activities. Eighty-two percent of the participants were 'physically inactive' (0 days/week of 30-min activity); 17% were 'semi-active' (1-4 days/week of 30-min activity). Age, gender, physical fitness, and scores on the Unified Parkinson's Disease Rating Scale explained 69% of the variability in daily physical activity., Conclusions: Performance-based measurements confirmed that most self-identified sedentary PD patients are 'physically inactive'. However, the variance in daily physical activity across subjects was considerable. Higher age, being female, and lower physical capacity were the most important determinants of reduced daily physical activity. Future therapeutic interventions should aim to improve daily physical activity in these high-risk patients, focusing specifically on modifiable risk factors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Startle pathways may contribute to rapid accomplishment of postural stability. Here we investigate the possible influence of a startling auditory stimulus (SAS) on postural responses. We formulated four specific questions: (1) can a concurrent SAS shorten the onset of automatic postural responses?; and if so (2) is this effect different for forward versus backward perturbations?; (3) does this effect depend on prior knowledge of the perturbation direction?; and (4) is this effect different for low- and high-magnitude perturbations? Balance was perturbed in 11 healthy participants by a movable platform that suddenly translated forward or backward. Each participant received 160 perturbations, 25% of which were combined with a SAS. We varied the direction and magnitude of the perturbations, as well as the prior knowledge of perturbation direction. Perturbation trials were interspersed with SAS-only trials. The SAS accelerated and strengthened postural responses with clear functional benefits (better balance control), but this was only true for responses that protected against falling backwards (i.e. in tibialis anterior and rectus femoris). These muscles also demonstrated the most common SAS-triggered responses without perturbation. Increasing the perturbation magnitude accelerated postural responses, but again with a larger acceleration for backward perturbations. We conclude that postural responses to backward and forward perturbations may be processed by different neural circuits, with influence of startle pathways on postural responses to backward perturbations. These findings give directions for future studies investigating whether deficits in startle pathways may explain the prominent backward instability seen in patients with Parkinson's disease and progressive supranuclear palsy., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Introduction: The startle reflex is an involuntary reaction to sudden sensory input and consists of a generalized flexion response. Startle responses in distal leg muscles occur more frequently during standing compared to sitting. We hypothesized that sensory input from load receptors modulates the occurrence of startle responses in leg muscles., Methods: We administered sudden startling auditory stimuli (SAS) to 11 healthy subjects while (1) sitting relaxed, (2) standing relaxed, (3) standing while bearing 60% of their weight on the right leg, (4) standing while bearing 60% of their weight on the left leg, and (5) standing with 30% body weight support ('bilateral unloaded'). The requested weight distribution for each condition was verified using force plates. Electromyography data were collected from both tibialis anterior (TA) and the left sternocleidomastoid muscles., Results: In the TA, startle responses occurred much more frequently during normal standing (26% of trials) compared to both sitting (6% of trials, p<0.01) and bilateral unloading (3% of trials, p<0.01). In the asymmetrical stance conditions, startle responses in the TA were more common in the loaded leg (21% of trials) compared to the unloaded leg (10% of trials, p<0.05)., Discussion: The occurrence of startle responses in the leg muscles was strongly influenced by load. Hence, it is likely that information from load receptors influences startle response activity. We suggest that, in a stationary position, startling stimuli result in a descending volley from brainstem circuits, which is gated at the spinal level by afferent input from load receptors., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) patients have an increased gait asymmetry and variability, which is most pronounced in patients with freezing of gait (FOG). We examined if stride time variability and deficits in interlimb coordination between the upper and lower limbs would increase during split-belt locomotion in PD, and particularly so in patients with FOG., Methods: Fourteen PD patients (seven with FOG, matched for disease severity with the seven non-freezers) and 10 healthy controls walked on a treadmill with split belts at different speeds (2 versus 3km/h). Gait was recorded by means of a video motion analysis system. Outcome measures were stride length asymmetry and variability, stride time asymmetry and variability, ipsilateral and contralateral interlimb coordination, and phase coordination index., Results: Both PD subjects and controls were able to adapt to split-belt walking by modulating their stride length. However, freezers showed a larger increase in stride time asymmetry and stride time variability due to split-belt walking compared to non-freezers. Furthermore, contralateral interlimb coordination improved in control subjects during split-belt walking, but not in PD patients (freezers and non-freezers). Phase coordination index did not change differently across the three groups., Conclusions: The ability to walk under split-belt conditions was preserved in PD. Non-freezers and controls compensated for the experimentally increased stride length asymmetry by decreasing their stride time asymmetry. This ability was lost in freezers, who in fact increased their stride time asymmetry during split-belt walking. As a result, stride time variability also increased in freezers. These findings support the hypothesis that FOG is related to gait asymmetries and to gait timing deficits., (Copyright © 2013. Published by Elsevier Ltd.)

Background: Postural instability in Parkinson's disease (PD) can lead to falls, injuries and reduced quality of life. We investigated whether balance in PD can improve by offering patients feedback about their own trunk sway as a supplement to natural sensory inputs. Specifically, we investigated the effect of artificial vibrotactile biofeedback on trunk sway in PD., Methods: Twenty PD patients were assigned to a control group (n = 10) or biofeedback group (n = 10). First, all patients performed two sets of six gait tasks and six stance tasks (pre-training assessment). Subsequently, all subjects trained six selected tasks five times (balance training). During this training, the feedback group received vibrotactile feedback of trunk sway, via vibrations delivered at the head. After training, both groups repeated all twelve tasks (post-training assessment). During all tasks, trunk pitch and roll movements were measured with angular velocity sensors attached to the lower trunk. Outcomes included sway angle and sway angular velocity in the roll and pitch plane, and task duration., Results: Overall, patients in the feedback group had a significantly greater reduction in roll (P = 0.005) and pitch (P < 0.001) sway angular velocity. Moreover, roll sway angle increased more in controls after training, suggesting better training effects in the feedback group (P < 0.001)., Conclusions: One session of balance training in PD using a biofeedback system showed beneficial effects on trunk stability. Additional research should examine if these effects increase further after more intensive training, how long these persist after training has stopped, and if the observed effects carry over to non-trained tasks., (© 2012 Elsevier Ltd. All rights reserved.)

Background: Balance control in Parkinson's disease is often studied using dynamic posturography, typically with serial identical balance perturbations. Because subjects can learn from the first trial, the magnitude of balance reactions rapidly habituates during subsequent trials. Changes in this habituation rate might yield a clinically useful marker. We studied balance reactions in Parkinson's disease using posturography, specifically focusing on the responses to the first, fully unpractised balance disturbance, and on the subsequent habituation rates., Methods: Eight Parkinson patients and eight age- and gender-matched controls received eight consecutive toe-up rotations of a support-surface. Balance reactions were measured with a motion analysis system and converted to centre of mass displacements (primary outcome)., Results: Mean centre of mass displacement during the first trial was 51% greater in patients than controls (P=0.019), due to excessive trunk flexion and greater ankle plantar-flexion. However, habituated trials were comparable in both groups. Patients also habituated slower: controls were fully habituated at trial 2, whereas habituation in patients required up to five trials (P=0.004). The number of near-falls during the first trial was significantly correlated with centre of mass displacement during the first trial and with habituation rate., Conclusions: Higher first trial reactions and a slow habituation rate discriminated Parkinson's patients from controls, but habituated trials did not. Further work should demonstrate whether this also applies to clinical balance tests, such as the pull test, and whether repeated delivery of such tests offers better diagnostic value for evaluating fall risks in parkinsonian patients., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Dysphagia is a potentially harmful feature, also in Parkinson's disease (PD). As published prevalence rates vary widely, we aimed to estimate the prevalence of oropharyngeal dysphagia in PD in a meta-analysis. We conducted a systematic literature search in February 2011 and two independent reviewers selected the papers. We computed the estimates of the pooled prevalence weighted by sample size. Twelve studies were suitable for calculating prevalence rates. Ten studies provided an estimate based on subjective outcomes, which proved statistically heterogeneous (p < 0.001), with a pooled prevalence estimate with random effect analysis of 35% (95% CI 28-41). Four studies provided an estimate based on objective measurements, which were statistically homogeneous (p = 0.23), with a pooled prevalence estimate of 82% (95% CI 77-87). In controls the pooled subjective prevalence was 9% (95% CI 2-17), while the pooled objective prevalence was 23% (95% CI 13-32). The pooled relative risk was 3.2 for both subjective outcomes (95% CI 2.32-4.41) and objective outcomes (95% CI 2.08-4.98). Clinical heterogeneity between studies was chiefly explained by differences in disease severity. Subjective dysphagia occurs in one third of community-dwelling PD patients. Objectively measured dysphagia rates were much higher, with 4 out of 5 patients being affected. This suggests that dysphagia is common in PD, but patients do not always report swallowing difficulties unless asked. This underreporting calls for a proactive clinical approach to dysphagia, particularly in light of the serious clinical consequences., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The pathophysiology underlying freezing of gait (FOG) in Parkinson's disease remains incompletely understood. Patients with FOG ("freezers") have a higher temporal variability and asymmetry of strides compared to patients without FOG ("non-freezers"). We aimed to extend this view, by assessing spatial variability and asymmetry of steps and interlimb coordination between the upper and lower limbs during gait. Twelve freezers, 15 non-freezers, and 15 age-matched controls were instructed to walk overground and on a treadmill. Kinematic data were recorded with a motion analysis system. Both freezers and non-freezers showed an increased spatial variability of leg movements compared to controls. In addition, both patient groups had a deficit in interlimb coordination, not only between ipsilateral arms and legs, but also between diagonally positioned limbs. The only difference between freezers and non-freezers was a decreased step length during treadmill walking. We conclude that parkinsonian gait-regardless of FOG-is irregular, not only in the legs, but also with respect to interlimb coordination between the arms and legs. FOG is reflected by abnormal treadmill walking, presumably because this provides a greater challenge to the defective supraspinal control than overground walking, hampering the ability of freezers to increase their stride length when necessary., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

Non-motor symptoms, such as fear of falling and anxiety, are frequently reported in Parkinson's disease (PD). Recent evidence of anxiety and fear directly influencing balance control in healthy young and older adults, raises the question whether fear of falling and anxiety also directly contribute to the balance deficits observed in PD. The goal of the current study was to examine whether PD patients and controls responded similarly or differently to experimentally induced increases in anxiety. For this purpose, 14 PD patients (tested during a subjective optimal ON state) and 16 healthy age-matched control subjects stood in three conditions of different levels of postural threat: normal threat (quiet standing at ground level); medium threat (standing at the edge of a surface elevated to 80 cm); and high threat (same, but to 160 cm). Outcome measures included mean position, mean power of frequency (MPF) and root mean square (RMS) of centre of pressure (COP) displacements in the anterior-posterior (AP) and medial-lateral (ML) directions. Physiological and psychosocial measures of fear and anxiety were also recorded. Increased threat changed postural control similarly in PD patients and controls; MPF of AP and ML COP increased and the mean COP position was shifted backward in both groups. These results indicate that during the ON state, static balance in PD patients and controls is equally susceptible to the influence of anxiety. Significant correlations observed between COP changes and measures of fear and anxiety provide evidence to support the proposed neural links between structures controlling emotion and postural control. Future studies should further address this issue by including more severely affected patients, by testing the influence of dopaminergic medication, by including more anxious patients, and by using dynamic measures of balance., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

The healthy brain appears to have an asymmetric dopamine distribution, with higher levels of dopamine in the left than in the right striatum. Here, we test the hypothesis that this neurochemical asymmetry renders the right striatum relatively more vulnerable to the effects of dopaminergic denervation in Parkinson's disease (PD). Using the pegboard dexterity test, we compared motor performance of both hands between healthy subjects (n=48), PD patients with predominantly right-hemispheric dopamine depletion (PD-RIGHT; n=83) and PD patients with more severe left-hemispheric dopamine depletion (PD-LEFT; n=103). All subjects were right-handed. After adjusting for hand-dominance effects, we found that PD-RIGHT patients exhibited a 55% larger difference between right and left dexterity scores than PD-LEFT patients. This effect could be attributed to greater motor dysfunction of the more-affected hand in PD-RIGHT patients, while the less-affected hand performed similarly in both groups. We conclude that the side of symptom onset affects motor dysfunction in PD, and suggest that the non-dominant right hemisphere may be more susceptible to dopaminergic denervation than the dominant left hemisphere., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Previous dynamic posturography studies demonstrated clear abnormalities in balance responses in Parkinson's disease (PD) patients compared to controls at the group level, but its clinical value in the diagnostic process and fall risk estimation in individual patients leaves for improvement. Therefore, we investigated whether a new approach, focusing on the balance responses to the very first and fully unpractised trial rather than a pooled mean response to a series of balance perturbations, could further improve the diagnostic utility of dynamic posturography. Following the first trial, subjects were exposed to repeated balance perturbations, which also permitted us to investigate the training responses. Fourteen patients with PD and 18 age-matched controls were enrolled, who received a series of multidirectional postural perturbations, induced by support surface rotations. We measured trunk and upper arm kinematics and electromyographic responses, and evaluated group differences at three levels: the postural response to the very first backward perturbation; pooled first and habituated postural responses; and habituation rates. Analysis of the first trial responses yielded similar results as evaluation of the mean response over trials: forward flexion of the trunk induced by backward perturbations was decreased in patients, accompanied by increased muscle responses present. Moreover, trunk movement and muscle activity were equally present in both groups-suggesting a preserved training response in PD patients. Early masseter activity in both groups might be indicative of a startle-like component to the balance response. In terms of diagnostic utility, focusing on the first trial response or habituation rate is no better than analysis of pooled responses to a series of perturbations. The apparently preserved training response in PD patients suggests that balance reactions in PD can be improved by repeated exposure, and this may have implications for future exercise studies. Early masseter activity warrants further studies to evaluate a potential startle component in the pathophysiology of balance disorders., (2010. Published by Elsevier Ltd.)

Muscle weakness is consistently associated with falls in the elderly people, typically when present along with other risk factors. However, it remains unknown whether and how muscle weakness alone affects balance. This hampers development of more effective fall prevention strategies. Clinical observations suggest that the amount and distribution of muscle weakness influences balance control. We therefore investigated balance corrections in patients with either predominantly proximal (limb girdle muscular dystrophy (LGMD); n=8) or distal (distal spinal muscular atrophy; n=5) leg weakness, and 27 matched healthy controls. Balance was perturbed using surface tilt rotations that were delivered randomly in eight directions. Balance measures were full body kinematics and surface electromyographic activity (EMG) of leg, arm, and trunk muscles. Both patient groups were more unstable than controls, as reflected by greater excursions of the centre of mass (COM), especially in the pitch (anterior-posterior (AP)) plane. COM displacements were greater in distal weakness patients. Patients with distal weakness had excessive and unstable trunk, knee and ankle movements, and this was present following both forward and backward directed balance perturbations, possibly reflecting the greater use of distal leg muscles in these directions. In contrast, the less weak proximal weakness patients demonstrated unstable trunk and ankle movements only for backward directed balance perturbations. Both patient groups used arm movements to compensate for their instability. We conclude that primarily distal but also proximal muscle weakness leads to significant postural instability. This observation, together with the retained ability of patients to use compensatory arm movements, provides targets that may be amenable to improvement with therapeutic intervention.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a complex phenotype, featuring a wide variety of both motor and non-motor symptoms. Current medical management is usually monodisciplinary, with an emphasis on drug treatment, sometimes supplemented with deep brain surgery. Despite optimal medical management, most patients become progressively disabled. Allied health care may provide complementary benefits to PD patients, even for symptoms that are resistant to pharmacotherapy or surgery. This notion is increasingly supported by scientific evidence. In addition, the role of allied health care is now documented in recent clinical practice guidelines that are available for physiotherapy, occupational therapy and speech-language therapy. Unfortunately, adequate delivery of allied health care is threatened by the insufficient expertise among most therapists, and the generally low patient volumes for each individual therapist. Moreover, most allied health interventions are used in isolation, with insufficient collaboration and communication with other disciplines involved in the care for PD patients. Clinical experience suggests that optimal management requires a multidisciplinary approach, with multifactorial health plans tailored to the needs of each individual patient. Although the merits of specific allied health care interventions have been scientifically proven for other chronic disorders, only few studies have tried to provide a scientific basis for a multidisciplinary care approach in PD. The few studies published so far were not yet convincing. We conclude by providing recommendations for current multidisciplinary care in PD, while highlighting the need for future clinical trials to evaluate the cost-effectiveness of a multidisciplinary team approach.

Although Parkinson's disease (PD) has traditionally been considered to be a non-genetic disorder, recent progress in the neurogenetics of PD provided converging evidence that genetic factors play a relevant role in the etiology of PD. The strongest case for a genetic contribution to PD was made by the discovery of mutations in single genes that can cause autosomal dominant (alpha-synuclein (SNCA)) and leucine rich repeat kinase 2 (LRRK2) gene) or recessive (Parkin, PTEN-induced putative kinase 1 (PINK1), DJ-1, and ATP13A2 gene) forms of PD. Here, we review how structural and functional neuroimaging of individuals carrying a mutation in one of the PD genes has offered a unique avenue of research into the pathogenesis of PD. In symptomatic mutation carriers (i.e. those with overt disease), brain mapping can help to link the molecular pathogenesis of PD more directly with functional and structural changes in the intact human brain. In addition, neuroimaging of presymptomatic (i.e. non-manifesting) mutation carriers has emerged as a valuable tool to identify mechanisms of adaptive motor reorganization at the preclinical stage that may prevent or delay clinical manifestation. In addition to mutations causing monogenic forms of PD, common polymorphisms in genes that influence mono-aminergic signaling or synaptic plasticity may have modifying effects on distinct aspects of PD. We also discuss how functional and structural neuroimaging can be used to better characterize these genotype-phenotype correlations.

Background and Purpose: Impairments in gait and autonomic function are common in patients with Parkinson's disease (PD). These are likely independent symptoms, based on different etiologic mechanisms. However, a few recent reports have observed an association between motor function, in particular gait impairment, and autonomic function in PD. In those studies, the Unified Parkinson's Disease Rating Scale (UPDRS) was used to evaluate gait and motor function. The present study was performed to further examine this putative relationship using quantitative measures of autonomic function and gait in order to shed light on the underlying pathophysiology of these symptoms., Methods: Nine healthy young, 15 healthy elderly and 18 PD patients were studied. Heart rate variability (HRV) measures were collected during rest. Gait speed, swing time and swing time variability were measured during a 1-min walk at comfortable speed. The motor portion of the UPDRS was also evaluated in all subjects., Results: HRV values were highest in the young adults, intermediate in the healthy elderly controls, and lowest in the PD patients. Gait measures tended to deteriorate with age and were significantly worse in the PD patients, compared to the elderly controls. HRV was not correlated with any measure of gait performance (p>0.129) nor with the UPDRS-motor score (p>0.147)., Discussion and Conclusions: The present findings support the idea that gait and autonomic function impairments co-exist in PD, but their etiology is based on distinct pathophysiological pathways, with minimal overlap.

We characterized upper trunk and pelvis motion in normal subjects and in subjects with vestibular or proprioceptive loss, to document upper body movement modes in the pitch and roll planes during quiet stance. Six bilateral vestibular loss (VL), six bilateral lower-leg proprioceptive loss (PL) and 28 healthy subjects performed four stance tasks: standing on firm or foam surface with eyes open or closed. Motion of the upper body was measured using two pairs of body-worn gyroscopes, one mounted at the pelvis and the other pair at the shoulders. Pitch and roll angular velocities recorded from the gyroscopes were analyzed separately for low-frequency (<0.7 Hz) and high-frequency (>3 Hz) motion. Low-frequency pitch motion was similar for all groups, consisting of in-phase pelvis and shoulder motion. High-frequency pitch motion in controls and VL subjects was dominated by pelvis motion with little shoulder motion, but vice versa in PL subjects. Low-frequency roll motion changed for all groups from mainly shoulder and little pelvis motion to in-phase pelvis and shoulder motion after moving from a firm to foam surface. In contrast, high-frequency roll motion changed from mainly shoulder motion to mainly pelvis motion with the change to a foam surface, except for PL subjects with eyes closed. Coherent low-frequency sway between pelvis and shoulder was only pronounced in VL patients. These results indicate that relative motion between the pelvis and shoulder depends on the support surface, the type of sensory loss, and whether the motion is in roll or pitch plane. Furthermore, relative motion between the pelvis and upper trunk is an integral part of movement modes used to control quiet stance. Vestibular loss patients showed very similar movement modes as controls, with larger amplitudes. Proprioceptive loss patients, however, used more shoulder motion and stabilized the pelvis for the high-frequency mode. We conclude that there is relative motion between the upper trunk and pelvis during quiet stance and suggest that it may contribute to balance control.

Objective: The Parkinson Activity Scale (PAS) is designed for functional assessment in Parkinson's disease (PD), but the scale has - in its current form - several drawbacks. The objectives of the present study are to (a) introduce a Modified PAS, with unambiguous scoring options and without ceiling effect; (b) evaluate the inter-rater agreement, using physiotherapists with and without PD-specific expertise; and (c) examine the concurrent validity with the VAS-Global Functioning and the UPDRS-III., Methods: The Modified PAS was developed based on the results of a recent pilot feasibility study [Keus SHJ, Bloem BR, van Hilten JJ, Ashburn A, Munneke M. Effectiveness of physiotherapy in Parkinson's disease: The feasibility of a randomised controlled trial. Parkinsonism Relat Disord 2007; 13(2):115-21.]. To evaluate inter-rater agreement, the Modified PAS was scored by a large number of raters (n=13) in 15 patients (Hoehn and Yahr stage 2-4), thus yielding a high number of observations (n=195) and creating adequate power. To ascertain broad applicability of the results, both physiotherapists with and without PD-specific expertise participated., Results: The interquartile range of the Modified PAS total scores was 40-51, within a possible range of 0 (optimal performance) to 56 (worst performance), suggesting lack of ceiling effect. The precision of these scores was 2.6 points, with an inter-rater error of 1.3 and a patient-induced error of 2.3. There were no differences between experts and non-experts. Correlation to Global Functioning (0.79) and UPDRS-III (0.64) was good., Conclusion: The Modified PAS showed no ceiling effect, good concurrent validity, good inter-rater agreement and no differences between experts and non-experts.

The aim of this study was to investigate the correlations between body segment movements and center of mass (COM) velocity during pathological balance corrections of spinocerebellar ataxia (SCA) patients compared with controls, and to relate correlations indicating instability to EMG activity differences. Eighteen SCA patients and 21 age-matched controls were tested. Upright standing was perturbed using rotations of the support surface. We recorded body motion and surface EMG. For lateral perturbations peaks in COM lateral velocity were larger in SCA patients than controls. These peaks were correlated with increased ("hypermetric") trunk roll downhill and reduced uphill knee flexion velocity. Subsequent arm abduction partially corrected the lateral instability. Early balance correcting responses in knee and paraspinal muscles showed reduced amplitudes compared with normal responses. Later responses were consistent with compensation mechanisms for the lateral instability created by the stiffened knee and pelvis. We conclude that truncal hypermetria coupled with insufficient uphill knee flexion is the primary cause of lateral instability in SCA patients. Holding the knees and pelvis more rigid possibly permits a reduction in the controlled degrees of freedom and concentration on arm abduction to improve lateral instability. For backwards perturbations excessive posterior COM velocity coincided with marked trunk hypermetric flexion forwards. We concluded that this flexion and the ensuing backwards shift of the pelvis result from rigidity which jeopardizes posterior stability. Timing considerations and the lack of confirmatory changes in amplitudes of EMG activity suggest that lateral and posterior instability in SCA is primarily a biomechanical response to pelvis and knee rigidity resulting from increased muscle background activity rather than changed evoked responses.

Stereotactic surgical interventions for Parkinson's disease (PD) can considerably improve appendicular motor signs, but their effect on axial motor signs--especially balance control under optimal drug therapy--remains unclear. Here, we investigated the effect of bilateral subthalamic nucleus (STN) stimulation on levodopa-resistant axial and appendicular postural impairment in PD. Fourteen patients (11 with young-onset PD) and 18 age-matched controls were included. Patients were tested after intake of a suprathreshold levodopa dose, ensuring optimal response to drug therapy, and with stimulators both turned on and off. Balance control was assessed using multidirectional dynamic posturography. Outcome measures included full body kinematics and surface electromyography of paraspinal and deltoid muscles. Patients with stimulators turned off showed early decreased trunk roll with a loss of directional dependency, followed by increased and abnormally directed--i.e. destabilizing--trunk roll. Pelvis pitch motion showed decreased directional dependency in these patients. The abnormal trunk motion was not corrected by STN stimulation, but directional dependency of both trunk and pelvis motion partially improved, along with a general decrease in muscle activity. Even with stimulators off, protective arm movements were similar in the optimally treated patients and controls, indicating that these appendicular signs respond better to dopaminergic treatment than axial motor control. Our findings indicate that instability in PD results from a reduced flexibility of the trunk and pelvis that is largely resistant to STN stimulation combined with optimal drug treatment. These postural abnormalities are therefore likely associated with non-dopaminergic pathology. In contrast, protective arm movements did appear to be levodopa-responsive. Future studies should focus on identifying subgroups of optimal responders, particularly patients with levodopa-induced dyskinesias.

Sleep disturbances occur in 70% of the patients with multiple system atrophy (MSA). Disturbances of the hypothalamic hypocretin neurotransmission have been suggested as a possible cause. Since a systematic study of CSF hypocretin-1 levels in MSA has not yet been performed, we analysed CSF hypocretin-1 concentrations in 6 MSA-P and 6 MSA-C patients and 11 age-matched controls. We did not observe any differences from control values.

Background: Multiple system atrophy (MSA) can clinically be divided into the cerebellar (MSA-C) and the parkinsonian (MSA-P) variants. It is unknown whether the variation in clinical expression is also reflected by a different underlying neurochemical profile., Methods: We analyzed brain specific proteins and neurotransmitter metabolites in cerebrospinal fluid (CSF) of 26 patients with MSA-C and 19 with MSA-P., Results: No differences were found between MSA-C and MSA-P., Conclusion: Our results suggest that the clinical and in part pathological distinction between the two clinical MSA phenotypes is not reflected by the neurochemical composition of CSF.

To study the feasibility of a large randomised controlled trial (RCT) evaluating the effectiveness of physiotherapy in Parkinson's disease (PD), 173 patients were asked to participate in a study with random allocation to best practice physiotherapy, or to no physiotherapy. The primary outcome measures were the Parkinson's disease questionnaire-39, the Parkinson activity scale, and a patient preference outcome scale (PPOS). Only 14% of the patients could be included in the study. The PPOS showed the largest effect size (0.74) with a significant group effect (p<0.05). Specific alterations to the study design to ensure successful RCTs in this field are recommended.

Allied health care and complementary therapies are used by many patients with Parkinson's disease (PD). For allied health care, supportive scientific evidence is gradually beginning to emerge, and interventions are increasingly integrated in the treatment programs for PD patients. To evaluate whether such multidisciplinary programs are justifiable, we review the literature of allied health care and complementary therapies in PD. According to the level of available evidence, we provide recommendations for clinical practice. Finally, we discuss the need for an improved organization of allied health care, and identify topics for future research to further underpin the pros and cons of allied health care and complementary therapies in PD.