Parkinsonian Motor Impairment Research Articles

Progression of parkinsonism in multiple system atrophy

Progression of parkinsonian motor impairment is usually rapid and relentless in multiple system atrophy (MSA). However, it may also be subject to considerable variation. Prospective natural history studies using validated rating scales are required to accurately determine the progression of parkinsonism in MSA. To assess the progression of parkinsonism in patients with the Parkinson variant of MSA. Parkinsonian motor impairment was assessed on regular therapy at two time points (mean follow-up 11.8 months, SD 1.4) using the Hoehn and Yahr scale (H&Y), the Schwab and England ADL scale (SES) and the motor examination section of the UPDRS (UPDRS-III) in 38 patients with clinically probable MSA-P. We examined 38 patients with probable MSA-P (mean age 63.2 years, SD 7.4; mean disease duration 4.1 years, SD 3.0). The mean difference of UPDRS-III between baseline and follow-up was 10.8 (95% CI 8.6-12.9), consistent with an average annual 28.3 % increase of UPDRS-III baseline scores. Several variables were associated with faster progression of parkinsonism including low baseline global motor disability as assessed by H&Y and SES, low baseline UPDRS-III score, and short disease duration. UPDRS-III progression was unrelated to gender, age at symptom onset, and age at baseline visit. This is the first observational study on UPDRS rates of decline in MSA. The observed 28.6% annual increase of UPDRS-III scores illustrates the rapid progression of motor impairment in MSA. Furthermore, motor progression appeared to be accelerated during the early disease stages. Our data allow sample size calculations that may be helpful for the planning of future therapeutic trials.

The Metabolic Substrates of Bradykinesia and Tremor in Uncomplicated Parkinson's Disease

The pathophysiological mechanisms of bradykinesia and resting tremor, i.e., two major features of Parkinson's disease (PD), remain incompletely understood despite extensive studies, including functional imaging investigations. Using high-resolution positron emission tomography (PET) and [ 18 F]fluoro-2-deoxyglucose (FDG) in 17 nondemented patients with uncomplicated PD on a stable therapeutic regimen, we measured the resting-state cerebral metabolic rate of glucose (CMRGlc), a validated marker of synaptic density/activity. Following formulation of distinct a priori hypotheses about potentially involved brain regions based on previous experimental and clinical literature, correlations between CMRGlc and objective scores of bradykinesia and tremor were searched in a voxel-based fashion using SPM99. Bradykinesia scores were significantly positively correlated with bilateral putamen and globus pallidum CMRGlc, while tremor scores were negatively correlated with bilateral putamen and cerebellar vermis CMRGlc. There was a large overlap of putamenal voxels significantly but inversely correlated with both extrapyramidal features. For both bradykinesia and tremor, the observed patterns of subcortical correlations largely concurred with our a priori hypotheses, and point to the major role of disruption of the striatofrontal and corticocerebellar pathways in the genesis of these extrapyramidal features. The direction of these correlations was not entirely expected, however, which may be due to the patients' being studied on medication, contrary to most studies performed to date. The observation that overlapping portions of the putamen inversely correlated with bradykinesia and tremor was a novel and striking finding which points to the complexity of the underlying pathophysiology of PD. Because it allows greater control of the neurological status, studying patients on medication may partly explain our findings. Voxel-based analysis of resting FDG-PET holds considerable potential for assessing the neural substrates of motor impairment in PD.

The Metabolic Substrates of Bradykinesia and Tremor in Uncomplicated Parkinson's Disease

The pathophysiological mechanisms of bradykinesia and resting tremor, i.e., two major features of Parkinson's disease (PD), remain incompletely understood despite extensive studies, including functional imaging investigations. Using high-resolution positron emission tomography (PET) and [ 18F]fluoro-2-deoxyglucose (FDG) in 17 nondemented patients with uncomplicated PD on a stable therapeutic regimen, we measured the resting-state cerebral metabolic rate of glucose (CMRGlc), a validated marker of synaptic density/activity. Following formulation of distinct a priori hypotheses about potentially involved brain regions based on previous experimental and clinical literature, correlations between CMRGlc and objective scores of bradykinesia and tremor were searched in a voxel-based fashion using SPM99. Bradykinesia scores were significantly positively correlated with bilateral putamen and globus pallidum CMRGlc, while tremor scores were negatively correlated with bilateral putamen and cerebellar vermis CMRGlc. There was a large overlap of putamenal voxels significantly but inversely correlated with both extrapyramidal features. For both bradykinesia and tremor, the observed patterns of subcortical correlations largely concurred with our a priori hypotheses, and point to the major role of disruption of the striatofrontal and corticocerebellar pathways in the genesis of these extrapyramidal features. The direction of these correlations was not entirely expected, however, which may be due to the patients' being studied on medication, contrary to most studies performed to date. The observation that overlapping portions of the putamen inversely correlated with bradykinesia and tremor was a novel and striking finding which points to the complexity of the underlying pathophysiology of PD. Because it allows greater control of the neurological status, studying patients on medication may partly explain our findings. Voxel-based analysis of resting FDG-PET holds considerable potential for assessing the neural substrates of motor impairment in PD.

Quantification of the dopaminergic response in Parkinson's disease

Background: Various investigators have developed complex quantitative procedures for objective assessment of parkinsonian motor impairment, since drawbacks of rating scales are interrater variability, subjective impression, insensitivity to subtle modifications. Objectives: To determine whether standardized performance of inserting pegs (i) differentiates between parkinsonian subjects and healthy controls and (ii) reflects quantification of the dopaminergic response with rating scales within a levodopa challenge test design. Subjects and methods: We used an easy-to-operate Purdue Pegboard-like apparatus, which measures the total time taken to insert 25 pegs from a rack into a series of appropriate holes by a computer to 100 ms accuracy, and simultaneous rating with part III of the Unified Parkinson's Disease Rating Scale for assessment of motor impairment in 28 idiopathic parkinsonian patients before and during a levodopa challenge test. Additionally we compared data of the instrumental task to age- and sex-matched healthy controls. Results: We found significant differences between parkinsonian subjects and controls and significant correlations to the rated severity of Parkinson's disease. Within-subject comparisons and correlation analysis demonstrated the ability of this tool to reflect scored motor improvement after intake of levodopa. Conclusion: Inserting pegs provides an objective quantitative estimation of changes in motor impairment within a typical levodopa challenge test design.

Correlation between Tapping and Inserting of Pegs in Parkinson's Disease

Various investigators have developed complex quantitative instrumental procedures for objective assessment of parkinsonian motor impairment, since drawbacks of rating scales are interrater variability, subjective impression, and insensitivity to subtle modifications. To determine whether performance of inserting of pegs and tapping (i) correlates with each other (ii) differentiates between parkinsonian subjects and healthy controls and (iii) reflects severity of Parkinson's disease (PD). In 157 previously untreated idiopathic parkinsonian patients and healthy controls, we measured (i) the total time taken to insert 25 pegs from a rack into a series of appropriate holes in a Purdue pegboard-like apparatus and (ii) the number of taps on a contact board with a contact pencil for a period of 32 seconds for assessment of fine motor skills. Results of both tests correlated with each other, differed between parkinsonian subjects and controls and reflected scored severity of PD. Better correlation with intensity of PD was noted with the Purdue pegboard-like task. Both tapping and inserting of pegs represent useful tools for objective evaluation of severity of PD. Peg insertion correlated better with disease severity. Both approaches may be useful in future clinical studies.

Differential progression of motor impairment in levodopa-treated Parkinson's disease

To monitor comparative progression of clinical impairment over 4 years in patients with Parkinson's disease (PD) who present on levodopa at two different levels of Hoehn and Yahr (HY) stages, II and III. The rate of clinical impairment progression in patients with PD being treated with levodopa has not been studied in detail using current, standardized assessment tools. Sample size estimates for all levodopa adjunctive treatment studies and proper definition of study groups require a solid estimate of longitudinal motor impairment progression. From our computer database, we identified two groups of patients with PD being treated with levodopa based on their initial HY stage at presentation to our center (II or III). Fifty randomly selected subjects in each stage were monitored in the ON state with annual Unified Parkinson's Disease Rating Scale (UPDRS) motor scores, dyskinesia ratings, and antiparkinsonian medication doses using a repeated measures analysis of variance. The stage II and stage III subjects had similar disease duration. In stage II subjects, parkinsonian impairment was maintained without progression over 4 years, but in association with significantly higher dyskinesia scores and dopaminergic medication doses. In stage III subjects, UPDRS motor scores deteriorated despite more medication and increased dyskinesias. Of the established six factors comprising the UPDRS motor scale, bradykinesia accounted for the increased impairment. Initial UPDRS motor score and disease duration did not influence progression of motor impairment. In subjects with similar disease duration, progression of PD motor impairment differs significantly between stage II and stage III subjects over 4 years. Whereas in stage II subjects, parkinsonian impairment can be stabilized at the expense of increased dyskinesia and dopaminergic drugs, once subjects reach stage III, motor impairment progresses. Power estimates and sample size calculations for these groups of patients should be calculated separately.

Pramipexole versus bromocriptine for levodopa-induced complications in Parkinson's disease.

To compare the efficacy and safety of adjuvant pramipexole versus bromocriptine therapy in patients with Parkinson's disease, already established on levodopa and suffering from motor complications. Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn and Boehringer Ingelheim. Randomised controlled trials of pramipexole versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy. Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, 'off' time measurements and the frequency of drop outs and adverse events. One randomised controlled trial has compared pramipexole with bromocriptine using a double-blind, parallel group, multicentre design. It was not powered to examine differences between active treatment arms. There was a larger reduction in off time with pramipexole therapy compared with bromocriptine (weighted mean difference 1.4 hours; 0, 2.8, 95% CI). No differences occurred in dyskinesia rating scale, dyskinesia as an adverse event or UPDRS complication score. The UPDRS ADL and motor scores showed similar improvements compared to placebo with both agonists. Levodopa dose reduction was similar with both agonists. Subscales of the Functional Status Questionnaire showed significant improvements compared to placebo with both agonists. The finding that the EuroQol improved significantly compared with placebo with pramipexole but not bromocriptine should be treated with caution. Dopaminergic adverse events were similar with each agonist, as was the all cause withdrawal rate. Although pramipexole and bromocriptine improved off time and reduced parkinsonian motor impairments and disability compared with placebo, no conclusions regarding their comparative effectiveness and safety can be drawn as this single trial did not have adequate power to assess such differences. Further larger trials are required to examine this issue in the future.

Functional effects of striatal dysfunction in Parkinson disease.

Concepts of basal ganglia organization suggest structually and functionally segregated pathways that link putamen and caudate function to motor and cognitive performance, respectively. To investigate whether motor and cognitive impairment in Parkinson disease is attributable to selective disturbance in nigrostriatal, dopaminergic function and regional cerebral glucose metabolism. Twenty patients with probable Parkinson disease underwent positron emission tomographic measurements of dopaminergic, nigrostriatal function (positron emission tomography with fluorodopa F 18), regional glucose metabolism (positron emission tomography with fludeoxyglucose F 18), memory testing, and evaluation of locomotor disability. Memory performance in the patient cohort strongly correlated with the individual disease duration and degree of locomotor disability (P < .05). Striatal uptake rates of fluorodopa F 18 were significantly reduced in all patients (P < .05) compared with those in normal control subjects, and putaminal rates correlated significantly with the patients' degree of locomotor disability (P < .01) but not with memory performance. In the patients with an advanced stage of disease, there was a significant correlation between reduced caudate uptake rates of fluorodopa F 18 and the patients' impairment in delayed recall performance of the memory task (P < .05) but not with the individual degree of locomotor disability. No changes were found for regional glucose metabolic rates in the patients compared with the controls. The present study provides evidence for the hypothesis that on the level of the striatum, motor impairment in Parkinson disease may be assigned to altered dopamine neuronal integrity in the putamen but not in the caudate, whereas memory impairment in the more advanced cases may be attributed to caudate but not putaminal dysfunction.

PET imaging of neocortical monoaminergic terminals in Parkinson's disease.

Post-mortem neurochemical studies in Parkinson's disease (PD) have shown that, in addition to the typical nigro-striatal dopamine denervation, there exists a concomitant neocortical monoamine fibre deafferentation (of variable severity) whose role in motor, and especially in associated cognitive and affective impairment, remains elusive. We have extensively examined whether PET imaging with 11C-S-Nomifensine (11C-NMF), a radioligand of the dopamine and norepinephrine presynaptic reuptake sites which has been used so far to investigate the striatum, could provide a method for assessing in vivo the neocortical monoamine terminal loss in PD; previously, this has been a little addressed and controversial issue. To this end, we prospectively selected a highly homogeneous sample of nine non-demented, non-depressed idiopathic PD patients with mild to marked side-to-side asymmetry in motor impairment. In addition to recovering the previously-reported correlations with putaminal 11C-NMF specific uptake asymmetries, the clinical motor asymmetries also significantly correlated in the clinically expected direction to neocortical (especially frontal) 11C-NMF asymmetries, suggesting the monoamine neocortical denervation might play a direct role in motor impairment in PD. These results demonstrate that it is possible to assess in vivo the neocortical monoamine terminal loss, and to elucidate its potential role in the complex cognitive and affective impairment, in both PD and atypical degenerative parkinsonism.

Event related potentials, reaction time, and cognitive performance in idiopathic Parkinson's disease

Sixteen non-demented patients with idiopathic Parkinson's disease (PD) with varying degrees of cognitive impairment and sixteen age-, sex- and education-matched normal controls were examined with (1) an auditory oddball paradigm requiring counting or a motor response in separate determinations, (2) a reaction time task with movement time component and (3) a detailed clinical and neuropsychological test battery. Patients were impaired on a number of neuropsychological tests. They also showed an increased P2 and N2 latency, but no significant increase in P3 latency. Their response initiation times and reaction times during the oddball experiment were not different from controls, whereas movement time was significantly increased. Increased peak latencies, particularly for N2, were moderately associated with Parkinsonian motor impairment in patients and with the Benton Multiple Choice Visual Retention Test in patients and controls. Movement time was associated with P3 latency only in controls and in both groups with the Benton Multiple Choice Visual Retention Test. The observed pattern of results suggests that in non-demented PD patients ERP peak latencies, visuo-spatial task performance and Parkinsonian motor impairment share a significant degree of variance. While impairments in neuropsychological tests and delay in the earlier peaks P2 and N2 do not appear to be sensitive to medication with L-DOPA, normal P3 latencies might indicate good pharmacological symptom control in the absence of dementia.

The prediction of stress in carers: The role of behaviour, reported self care and dementia in patients with idiopathic Parkinson's disease

AbstractStress scores were elicited from relatives living with Parkinsonian patients and correlated with various aspects of the patients' impairment. The (usually female) relatives looking after male patients reported higher levels of stress than husbands looking after their wives. In general, the best predictor of relatives' stress was the behavioural rating scale of the CAPE and a reported selfcare scale designed for the study. The relative contribution of Parkinsonian motor impairment and cognitive impairment to relatives' stress scores was examined. While motor impairment was still associated with relatives' stress after controlling for sex and cognitive deterioration, both dementia and cognitive impairment measured by the Mini‐Mental State Examination were not associated with relatives' stress if Parkinsonian disability was controlled for.

TASK-DEPENDENT VARIATIONS IN PARKINSONIAN MOTOR IMPAIRMENTS

Studies of visually-guided arm movements in patients with Parkinson's disease (PD) have suggested a relationship between slowness of movement and a reduction in the ratio of movement amplitude and peak velocity. Recent studies indicate, however, that PD impairments may be different for well-learned, natural movements performed without visual guidance, or movements associated with sequential motor behaviours such as speech. To address this issue, PD subjects and age/sex-matched controls were compared on the performance of three tasks, all of which required lowering the jaw: (1) single, rapid, visually-guided movements; (2) equivalent movements associated with a single speech syllable (inherently without visual guidance), and (3) well-learned speech movements produced in a natural sequence. PD subjects manifested similar deficits for visually-guided jaw lowering as those previously reported for arm movements, namely reduced velocity/amplitude ratios and increased movement durations. By contrast, analogous jaw movements during the sequential speech tasks were unimpaired on these measures. These results suggest that PD motor impairments are influenced by a variety of factors, including the degree to which tasks are familiar and natural, and the availability of visual information.

Orofacial motor control impairment in Parkinson's disease.

Motor impairments in lip, jaw, and tongue muscles in patients with idiopathic Parkinson's disease (PD) were quantified. These orofacial muscle groups are nonuniformly endowed with muscle afferents, thus permitting evaluation of the hypothesis that certain PD motor symptoms are due to aberrations in muscle afferent function. Tongue muscles, devoid of stretch reflexes, were most impaired, while jaw-closing muscles, with numerous spindles and a monosynaptic stretch reflex, manifested the least impairment. Seemingly, PD motor impairments are independent of fusimotor or muscle afferent dysfunctions.