Parkinsonian Disability Research Articles

Concordance between severity of disease, prevalence of nonmotor symptoms, patient-reported quality of life and disability and use of medication in Parkinson’s disease

The aim of this study was to test the concordance between disease severity, prevalence of nonmotor symptoms, age, health-related quality of life (HRQoL), disability and medication use in patients with Parkinson's disease (PD). Severity was classified with the Hoehn and Yahr (HY) scale and Levodopa Equivalent Daily Dose (LEDD) calculated. HRQoL was evaluated with the SF-36, disability with the WHO-DAS II and nonmotor symptoms with the NMSQuest. Patients were clustered using SF-36 and WHO-DAS II into three groups covering the continuum from low disability and HRQoL, to severe disability and HRQoL decrement. Contingency Coefficient were used to verify the relationships between clusters and HY stage; ANOVA to evaluate differences in NMS, age and LEDD between clusters; odds ratio to test the likelihood of taking levodopa or dopamine agonist and being member of the three clusters; t test to evaluate differences in LEDD between patients with HY ≥3 or ≤2. Eighty-six patients were clustered: 48 had low disability and HRQoL decrement, 18 intermediate disability and HRQoL decrement and 20 high disability and HRQoL decrement. A significant relationship was found between PD severity groups, HRQoL and disability profiles. No differences for age and LEDD were observed in the three groups, and those with more disability and lower HRQoL reported a higher number of nonmotor symptoms; patients in HY ≥3 were prescribed higher doses of drugs. In conclusion, we found a substantial concordance between PD staging, prevalence of nonmotor symptoms and patient-reported HRQoL and disability measures. In our opinion, the SF-36 and the WHO-DAS II can be used for profiling patients.

Randomized Controlled Trial of Community-Based Dancing to Modify Disease Progression in Parkinson Disease

Background. Tango dancing has been effective in improving measures of physical function in people with Parkinson disease (PD). However, all previous studies were institution-based, tested participants on medication, and employed short-term interventions. Objective. To determine the effects of a 12-month community-based tango program for individuals with PD on disease severity and physical function. Methods. Sixty-two participants were randomly assigned to a twice weekly, community-based Argentine Tango program or a Control group (no intervention). Participants were assessed off anti-Parkinson medication at baseline, 3, 6, and 12 months. The primary outcome measure was the Movement Disorders Society–Unified Parkinson Disease Rating Scale 3 (MDS-UPDRS-3). Secondary outcome measures were the MDS-UPDRS-1, MDS-UPDRS-2, MiniBESTest balance test; Freezing of Gait Questionnaire (FOG_Q); 6-Minute Walk Test (6MWT); gait velocity for comfortable forward, fast as possible forward, dual task, and backward walking; and Nine-Hole Peg Test (9HPT). Results. Groups were not different at baseline. Overall, the Tango group improved whereas the Control group showed little change on most measures. For the MDS-UPDRS-3, there was no significant change in the Control group from baseline to 12 months, whereas the Tango group had a reduction of 28.7% (12.8 points). There were significant group by time interactions for MDS-UPDRS-3, MiniBESTest, FOG_Q, 6MWT, forward and dual task walking velocities, and 9HPT in favor of the dance group. Conclusions. Improvements in the Tango group were apparent off medication, suggesting that long-term participation in tango may modify progression of disability in PD.

Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease

L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia. The effects of topiramate (5-20 mg/kg) and amantadine (5-20 mg/kg) on abnormal involuntary movements (the rat homologue of dyskinesia) and Rotarod performance were assessed alone and in combination in the 6-hydroxydopamine-lesioned rat following chronic L-dopa treatment. Dyskinesia, parkinsonian disability, and "on-time" were assessed in the MPTP-lesioned nonhuman primate following administration of topiramate (5-20 mg/kg) and amantadine (0.1-1.0 mg/kg) alone and in combination. Topiramate and amantadine dose-dependently reduced dyskinesia in the 6-hydroxydopamine-lesioned rat, whereas topiramate reduced Rotarod performance; there was no effect on parkinsonian disability in the MPTP-lesioned nonhuman primate, in which both drugs reduced dyskinesia. Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg). Subthreshold doses of both drugs in combination had a synergistic effect on dyskinesia in the 6-hydroxydopamine-lesioned rat, with no worsening of motor performance; this effect was confirmed in the MPTP-lesioned nonhuman primate, with a selective reduction in "bad on-time." These data confirm the antidyskinetic potential of topiramate and suggest that combination with low-dose amantadine may allow better reduction of dyskinesia with no adverse motor effects.

Pain due to osteoarthritis may impair the early outcome of deep brain stimulation in Parkinson's disease

Objective To analyse postoperative pain due to osteoarthritis in patients with Parkinson's disease submitted to bilateral subthalamic nucleus stimulation. Methods Fifty-three parkinsonian patients (mean age, 59.9 ± 8.3 years; mean disease duration, 11.5 ± 4.2 years) referred for subthalamic nucleus stimulation were enrolled. Patients were prospectively asked to refer and describe any pain due to osteoarthritis they experienced at any time during the preoperative period and within the 6 postoperative months. Pre-existing pain due to osteoarthritis, therapeutic changes, parkinsonian motor disability and weight gain were assessed as explanatory factors for occurrence pain due to osteoarthritis after surgery. Results After surgery, thirty patients (57%) complained of pain due to osteoarthritis whereas all demonstrated great functional improvement. Twenty (67%) among the 30 experienced similar pain sensation before surgery. Symptoms occurred rapidly, between 4 and 26 postoperative weeks. Multiple stepwise regression analysis showed that pre-existing pain due to osteoarthritis, 6-month postoperative UPDRS III motor score and axial sub-score improvements in the off-drug/ on-stimulation condition were accurate independent predictors of pain due to osteoarthritis after surgery ( F(8, 41) = 2.20, p < 0.047). Conclusion Our results highlight the high prevalence of pain due to osteoarthritis arising shortly after subthalamic implantation. An accurate pain and osteo-articular assessment should be performed preoperatively in parkinsonian candidates for subthalamic nucleus stimulation in order to limit occurrence of complications in the early postoperative period.

Self-awareness of Motor Dysfunction in Patients with Huntington's Disease in Comparison to Parkinson's Disease and Cervical Dystonia

Individuals suffering from Huntington's disease (HD) have been shown to present with poor self-awareness of a variety of symptoms. The aim of this study was to better assess the self-awareness of motor symptoms and activities of daily living (ADL) impairment in HD, in comparison to Parkinson's disease (PD) and cervical dystonia (CD). In particular, the anosognosia/anosodiaphoria of involuntary movements has been investigated. Self-awareness was tested in 23 patients with HD by comparing patient and caregiver ratings in reference to clinical control groups (25 PD with dyskinesias, PDdys; 21 PD without dyskinesias, PDndys; and 20 with CD). Patients were assessed neurologically by relevant rating scales. Self-awareness was tested using a scale based on 15 films demonstrating 3 types of motor symptoms (chorea/dyskinesias, parkinsonism, torticollis) as well as the Self-Assessment Parkinson's Disease Disability Scale. General cognitive status, verbal learning, cognitive control, and mood were also analyzed. Our results indicate that self-awareness of choreic movements was affected more severely in HD than in PDdys, despite comparable cognitive status. Patient-proxy agreement on ADL impairment was roughly similar in all clinical groups. The results are discussed in the context of orbitofrontal-limbic pathology as a potential trigger of anosognosia/anosodiaphoria in individuals with HD.

Investigating interactional competencies in Parkinson's disease: the potential benefits of a conversation analytic approach

Around 70% of people who develop Parkinson's disease (PD) experience speech and voice changes. Clinicians often find that when asked about their primary communication concerns, PD clients will talk about the difficulties they have 'getting into' conversations. This is an important area for clients and it has implications for quality of life and clinical management. To review the extant literature on PD and communication impairments in order to reveal key topic areas, the range of methodologies applied, and any gaps in knowledge relating to PD and social interaction and how these might be usefully addressed. A systematic search of a number of key databases and available grey literatures regarding PD and communication impairment was conducted (including motor speech changes, intelligibility, cognitive/language changes) to obtain a sense of key areas and methodologies applied. Research applying conversation analysis in the field of communication disability was also reviewed to illustrate the value of this methodology in uncovering common interactional difficulties, and in revealing the use of strategic collaborative competencies in naturally occurring conversation. In addition, available speech and language therapy assessment and intervention approaches to PD were examined with a view to their effectiveness in promoting individualized intervention planning and advice-giving for everyday interaction. A great deal has been written about the deficits underpinning communication changes in PD and the impact of communication disability on the self and others as measured in a clinical setting. Less is known about what happens for this client group in everyday conversations outside of the clinic. Current speech and language therapy assessments and interventions focus on the individual and are largely impairment based or focused on compensatory speaker-oriented techniques. A conversation analysis approach would complement basic research on what actually happens in everyday conversation for people with PD and their co-participants. The potential benefits of a conversation analysis approach to communication disability in PD include enabling a shift in clinical focus from individual impairment onto strategic collaborative competencies. This would have implications for client-centred intervention planning and the development of new and complementary clinical resources addressing participation. The impact would be new and improved support for those living with the condition as well as their families and carers.

Charting the progression of disability in Parkinson disease: study protocol for a prospective longitudinal cohort study.

BackgroundPeople with Parkinson disease (PD), even in the presence of symptomatic relief from medical, surgical, and rehabilitative interventions, face a persistent worsening of disability. This disability is characterized by diminished quality of life, reduced functional mobility, declining performance in activities of daily living and worsening neurological impairments. While evidence has emerged supporting the clinically meaningful benefits of short-term exercise programs on these underlying factors, assertions regarding the effects of sustained programs of exercise and physical activity on the trajectory of disablement in PD are made in the absence of direct evidence. Indeed, the natural decline in quality of life and functional mobility in people diagnosed with PD is poorly understood. Moreover, outcome measures commonly used in clinical exercise trials typically do not capture the full spectrum of disability as defined by the World Health Organization (WHO).Methods/DesignThe objective of this multicenter prospective study will be to examine the 2-year trajectory of disablement in a cohort of persons with PD. Two hundred sixty participants will be recruited to produce an expected final sample size of 150 individuals. Participants will be included if they are greater than 40 years of age, have a neurologist confirmed diagnosis of idiopathic PD, and are at Hoehn and Yahr stages 1 through 4. Data will be collected every 6 months during the study period. Primary outcome measures reflecting a broad spectrum of disablement will include, but will not be limited to, MDS-UPDRS, Timed Up and Go, Berg Balance Test, Nine Hole Peg Test, PDQ-39, and directly monitored ambulatory activity. Self-reported exercise and physical activity data also will be recorded. Statistical analyses will be used to characterize the trajectory of disablement and examine the influence of its underlying contributing factors.DiscussionTertiary prevention is an important component of contemporary healthcare for individuals living with degenerative disease. For individuals with PD, there is growing recognition that exercise and/or physical activity efforts to slow the rate of functional mobility decline, in particular, may be critical for optimizing quality of life. By describing the natural trajectory of disablement, exercise habits, and physical activity in a cohort of persons with PD, this investigation will establish an important foundation for future intervention research. Specifically, through the evaluation of the influence of sustained exercise and physical activity on disablement, the study will serve as a preliminary step toward developing a randomized controlled trial of long-term exercise in persons with PD.

Experimental Deep Brain Stimulation in Animal Models

DEEP BRAIN STIMULATION (DBS) as a therapy in neurological and psychiatric disorders is widely applied in the field of functional and stereotactic neurosurgery. In this respect, experimental DBS in animal models is performed to evaluate new indications and new technology. In this article, we review our experience with the concept of experimental DBS, including its development and validation. An electrode construction was developed using clinical principles to perform DBS unilaterally or bilaterally in freely moving rats. The stimulation parameters were adjusted for the rat using current density calculations. We performed validation studies in 2 animal models: a rat model of Parkinson's disease (bilateral 6-hydroxydopamine infusion in the striatum) and a rat model of Huntington's disease (transgenic rats). The effects of DBS were evaluated in different behavioral tasks measuring motor and cognitive functions. The electrode construction developed allows experimental DBS to be performed in freely moving rats. With the current setup, electrodes are placed in the target in 70% to 95% of the cases. Using a rat model, we showed that bilateral DBS of the subthalamic nucleus improves parkinsonian motor disability, but can induce behavioral side effects, similar to the clinical situation. In addition, we showed that DBS of the globus pallidus can improve motor and cognitive symptoms in a rat model of Huntington's disease. Nevertheless, during the process of the development and validation of experimental DBS, we encountered specific problems. These are discussed in detail. Experimental DBS in freely moving animals is an adequate tool to explore new indications for DBS and to refine DBS technology.

F11 Self-awareness of involuntary movements and daily living disability in huntington's disease in comparison to Parkinson's disease and cervical dystonia

BackgroundInvoluntary movements are one of the features of Huntington's disease (HD), Parkinson's disease (PD) and cervical dystonia (CD). Self-awareness of symptoms is overally deficient in HD, while in PD poor...

Reduction of l-DOPA-Induced Dyskinesia by the Selective Metabotropic Glutamate Receptor 5 Antagonist 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Lesioned Macaque Model of Parkinson's Disease

Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 +/- 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of l-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.

Neuropsychiatric Behaviors in the MPTP Marmoset Model of Parkinson’s Disease

Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to 'sensitisation' following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms. Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d, was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day. The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment. The data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy.

The clinical progression of Parkinson's disease

Parkinson's disease (PD) is known as a chronic neurodegenerative disorder with a relentlessly progressive course of illness. Although in recent decades there have been many advances in symptomatic therapy, there is still no established therapy that will halt or slow progression in a clinically meaningful way. So far, disease-modification trials have focused on indices of progression of cardinal motor features such as bradykinesia, rigidity and tremor as captured by the Unified Parkinson's Disease Rating Scale, and the emerging need for effective symptomatic dopaminergic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation, leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites inevitably leads to poorly l-dopa-responsive motor symptoms such as postural instability, freezing and falls, or non-motor symptoms. Furthermore, treatment-induced motor complications also contribute to PD disability. Progression of PD is multidimensional with superimposed age-related co-morbidities. Hence there is no consensus on how to best implement more clinically meaningful end-points for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers identifying preclinical stages of illness and describing disease progression – thus faithfully reflecting early and advancing neurodegeneration – that could be used in short-term clinical trials testing putative disease-modifying agents.

Serum levels of interleukin-6 are elevated in patients with Parkinson's disease and correlate with physical performance

Some studies have demonstrated altered circulating levels of cytokines, including IL-6, in Parkinson's disease (PD), implying a possible involvement of inflammatory and immune-mediated mechanisms in its pathogenesis. Moreover, the increased production of inflammatory cytokines has been associated with cognitive impairment and poor physical performance in the elderly. We compared serum levels of IL-6 in 44 PD patients and 22 healthy subjects, and correlated them with PD specific instruments and functional tests. Serum levels of IL-6 were significantly increased in PD ( p = 0.015). There was no correlation between serum levels of IL-6 and instruments traditionally used to assess PD severity. However, we found that PD patients with higher serum levels of IL-6 spent more time at functional mobility tests and had lower gait speed. Also, these patients had major problems to keep balance during functional tasks that required postural changes and that had a reduced base support. These results showed that high levels of IL-6 can be involved with an acceleration of muscle catabolism leading to sarcopenia, therefore contributing to weakness and fatigue, and may also be associated with functional disability in PD.

The selective D3 receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect l-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats

Despite evidence linking dopamine D(3) receptors to the etiology of Parkinson's disease and L-DOPA-induced dyskinesia, the potential therapeutic utility of D(3) receptor ligands remains unclear. In the present study, we investigated whether the selective D(3) receptor antagonist, S33084, affects development and expression of abnormal involuntary movements (AIMs), a behavioural correlate of dyskinesia, in rats hemi-lesioned with 6-hydroxydopamine and chronically treated with L-DOPA. The ability of S33084, alone or in combination with L-DOPA, to attenuate 6-hydroxydopamine induced motor deficits was also investigated employing a battery of behavioural tests. Acute administration of S33084 (0.64 mg/kg, s.c.) did not attenuate the induction of AIMs in dyskinetic rats upon challenge with L-DOPA (6 mg/kg, s.c.). Moreover, S33084 (0.64 mg/kg) did not prevent the development of AIMs affecting axial, limb and orolingual muscles when chronically administered together with L-DOPA (6 mg/kg for 21 days). However, both acute and chronic administration of S33084 enhanced L-DOPA-induced contralateral turning, suggesting potential antiparkinsonian properties. Furthermore, S33084 (0.01-0.64 mg/kg) dose-dependently attenuated parkinsonian disabilities, including bradykinesia, in drag and rotarod tests, although, in these procedures, the combination of S33084 with L-DOPA did not produce synergistic effect. It is concluded that sustained D(3) receptor blockade does not blunt L-DOPA-induced dyskinesia in hemiparkinsonian rats. However, D(3) receptor antagonism may be associated with antiparkinsonian properties. The clinical relevance of these observations will be of interest to explore further.

The impact of treatment of depression on quality of life, disability and relapse in patients with Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease affecting up to one million individuals in the United States. Depression is found in 40 to 50% of these patients and is associated with a variety of poor outcomes for both patients and their families. Despite this, there are few evidence-based data to guide clinical care. This was an NIH-funded, randomized, controlled trial of paroxetine, nortriptyline, and placebo. It included an 8 week acute phase and a 16 week blind extension phase. This report details the impact of depression treatment on quality of life (QoL) and disability in the acute and extension phase of this study. Secondary outcomes included relapse, tolerability, safety, and the impact of depression treatment on PD physical functioning. Patients who had improvement in depression, compared with those who did not, had significant gains in measures of QoL and disability (PDQ-8, P = 0.0001; SF-36, P = 0.0001) at 8 weeks and maintained their gains in the extension phase. Patients who were on active drug were significantly less likely to relapse in the extension phase than those on placebo (P = 0.041). Though relatively modest in size, this trial provides the first controlled data on the impact of treatment of depression on QoL and disability in PD. It suggests that successfully treating depression in PD leads to important, sustained improvements in these outcomes and that patients who improve on antidepressants are less likely to relapse than are patients who initially improve on placebo.

Factors contributing to the development of restless legs syndrome in patients with Parkinson disease

Although restless legs syndrome (RLS) commonly accompanies Parkinson disease (PD), the mechanism of RLS development in PD is still unclear. We investigated the prevalence of RLS in Korean patients with PD, and the possible contributing factors to the development of RLS in those patients. Four hundred forty-seven consecutive patients with PD were interviewed and examined. Among them, 73 patients (16.3%) were diagnosed with RLS. PD patients with RLS had a longer duration of PD symptoms, more severe PD disability, a greater degree of cognitive decline, and a longer duration of antiparkinson therapy than those without RLS. Multivariate logistic regression analysis revealed that the duration of antiparkinson therapy was the most significant factor contributing to the development of RLS in patients with PD. The present results support a higher prevalence of RLS in patients with PD and suggest that long-term antiparkinson therapy, rather than PD itself, may contribute to the development of RLS.

Clinical measures of progression in Parkinson's disease

Despite all recent advances in symptomatic therapy Parkinson's disease (PD) continues to be a relentlessly progressive neurodegenerative disorder. Therefore therapies that will slow or hold disease progression are a major medical unmet need in PD. Clinical measures of disease progression that have been used in disease modification trials so far have focused on indices of progression of cardinal motor features like bradykinesia, rigidity, and tremor as captured by the UPDRS and the emerging need for effective dopaminergic symptomatic therapy. Progression of global disability in PD, however, is driven by additional factors beyond progressive nigrostriatal denervation leading to increasing severity of cardinal motor features. Progressive pathology in extranigral sites in the brain or peripheral autonomic nervous system contribute to poorly levodopa responsive motor symptoms like postural instability, freezing and falls or nonmotor symptoms. In addition treatment-induced motor complications also impact on PD disability. Although it is widely accepted that clinical progression of PD is multidimensional and in addition includes effects of aging, there is no consensus how to best implement more clinically meaningful endpoints for disease progression trials that would reflect these complex interactions impacting on the evolution of global disability in PD. There is an urgent need for biomarkers for disease progression that would faithfully reflect advancing neurodegeneration and resulted clinical disability in PD and that could be used in shorter term clinical trials testing putative disease modifying agents.

Effects of nigral stimulation on locomotion and postural stability in patients with Parkinson's disease

The physiopathology of gait and balance disorders in Parkinson's disease patients is still poorly understood. Levodopa treatment and subthalamic nucleus (STN) stimulation improve step length and walking speed, with less effect on postural instability. These disorders have been linked to dysfunction of the descending basal ganglia outputs to brainstem structures. In this study, we evaluated the effects of stimulation of the substantia nigra pars reticulata (SNr), on locomotion and balance in Parkinson's disease patients. Biomechanical parameters and leg muscle activity were recorded during gait initiation in seven selected patients operated for bilateral STN stimulation, out of 204 stimulated patients, with one contact of each electrode located within the SNr. Step length, anteroposterior and vertical velocities of the centre of gravity were studied, with special reference to the subjects' ability to brake the centre of gravity fall before foot-contact, and compared to seven controls. In Parkinson's disease patients, five treatment conditions were tested: (i) no treatment, (ii) levodopa treatment, (iii) STN stimulation, (iv) SNr stimulation and (v) combined levodopa treatment and STN stimulation. The effects of these treatments on motor parkinsonian disability were assessed with the UPDRS III scale, separated into 'axial' (rising from chair, posture, postural stability and gait) and 'distal' scores. Whereas levodopa and/or STN stimulation improved 'axial' and 'distal' motor symptoms, SNr stimulation improved only the 'axial' symptoms. Compared to controls, untreated Parkinson's disease patients showed reduced step length and velocity, and poor braking just prior to foot-contact, with a decrease in both soleus (S) and anterior tibialis (AT) muscle activity. Step length and velocity significantly increased with levodopa treatment alone or in combination with STN stimulation in both natural and fast gait conditions, and with STN stimulation alone in the fast gait condition. Conversely, SNr stimulation had no significant effect on these measures in either condition. In the natural gait condition, no fall in the centre of gravity occurred as step length was low and active braking was unnecessary. In the fast gait condition, braking was improved with STN or SNr stimulation but not with levodopa treatment, with an increase in the stance leg S muscle activity. These results suggest that anteroposterior (length and velocity) and vertical (braking capacity) gait parameters are controlled by two distinct systems within the basal ganglia circuitry, representing respectively locomotion and balance. The SNr, a major basal ganglia output known to project to pontomesencephalic structures, is postulated as being particularly involved in balance control during gait.

A comparative study of physical performance measures in Parkinson's disease

The objective of this study is to compare physical performance measures for their ability to discriminate between levels of disability and disease severity in Parkinson's disease (PD). Disability in PD is commonly assessed by patient self-report, which may be limited by patient insight. Seventy-nine patients with PD were tested with seven performance measures: Physical Performance Test (PPT), modified Physical Performance Test (mPPT), Short Physical Performance Battery (SPPB), Performance Test of Activities of Daily Living (PADL), Berg Balance Scale (BBS), Timed Up and Go (TUG), and Functional Reach (FR). These measures were compared with patient-reported disability on the Older Americans Resource and Services Disability subscale (OARS) and disease severity on the Unified Parkinson's Disease Rating Scale (UPDRS). The performance measures were more sensitive to levels of disease severity than disability. Four measures discriminated across quartiles of disability (PPT, mPPT, BBS, TUG: P < 0.05), whereas all seven measures discriminated across quartiles of the Total UPDRS (PPT, mPPT, BBS, TUG, FR: P < 0.01; SPPB, PADL: P < 0.05). However, no measure consistently discriminated between subgroups with a range of early and advanced disease severity. The seven physical performance measures showed different profiles of strengths and weaknesses in assessing disability and disease severity. The results of this study will facilitate choosing performance measures for clinical care and clinical trials in PD.

An ambulatory persistence power curve: Motor planning affects ambulatory persistence in Parkinson's disease

Background/objectives: When performing activity associated with walking, the amount of walking a person does often will depend on their plans. This study was designed to evaluate the relationship between motor planning and ambulatory persistence in participants with Parkinson's disease (PD) and to see if ambulatory persistence was related to the ability to perform activities of daily living (ADL). Methods: 20 individuals with idiopathic PD were recruited to perform the Trail making Test (a test of motor planning) and to wear a step activity monitor for 48h. The measurement of persistence of an ambulatory event consisted of the number of steps taken during an event and an ambulatory event was defined as continuous ambulation (taking step) without pausing for 3 or more seconds. The resumption of taking step (ambulation) after 3 or more seconds counted as a new ambulatory event. UPDRS-motor and ADL scale were also obtained. Analysis and results: The cumulative percentage of the total ambulatory events at each number of steps was plotted for each subject which when plotted could be described as a sigmoid curve. We found that this sigmoidal curve defined by the equation y=xn/(kn+xn), fit the data well, where k represents a constant specific to each subject, x represents the number of steps during each ambulatory event, and y represents the projected percentage of movement events containing x number of steps or less. (Root Mean Square Error (RMSE)=0.02, R2=0.98). Trail making test part A was highly associated with the constant k (R=−0.74, p<0.001). The constant k was also highly associated with the UPDRS ADL subscale (R=−0.81, p=0.0001). A forward bivariate regression model including Part A of the Trail making test, and the UPDRS-ADL subscale predicted 66% of the variability of the constant k. The overall number of steps taken per day, and the UPDRS motor subscale did not contribute to the model. Conclusions: Defective motor planning in Parkinson's disease as measured by poor performance on a Trail making test is associated with a measurable alteration in ambulatory persistence, and altered ambulatory persistence, quantified by our proposed model parameter, correlates highly with the UPDRS ADL score. Thus, cognitive-motor planning defects might be a major source of disability in PD. We suggest that in future clinical practice gait tests can be used in order to quantify short-term planning ability in neurodegenerative diseases.