Effects of disease progression and L-dopa therapy on the control of reaching-grasping in Parkinson's disease.

The present study aimed to determine whether the bradykinesia of Parkinson's disease (PD) patients during the execution of reaching-grasping movements (i) is related to an impaired implementation of movement parameters and (ii) selectively involves the control of reach and/or grasp movements. We compared the kinematics of reaching to grasp of differently sized objects placed at different positions, among PD patients in the early stage of disease (ESPD), in the advanced stage of disease (ASPD) without L-dopa medication (off-state), and in healthy controls. In addition, we analysed the effects of L-dopa replacement therapy by comparing the kinematics of the patients in the advanced stage of disease after L-dopa administration with those of the other groups. Bradykinesia increased with disease progression, but only in the initial phases of the reach and grasp components. However at both stages of the disease, the kinematics of reaching and grasping responded to extrinsic and intrinsic object properties just as in controls. L-dopa administration improved the performance of PD patients, though this was more evident for the reach than for the grasp. We suggest that the basal ganglia (BG) are involved in implementing kinematic parameters, but neither (or only marginally) in the initial movement parameterization itself, nor in the on-line control of movement. Specifically, the BG dysfunction in PD induces a slowed implementation of movement parameters. The lack of effect of L-dopa administration on grasp kinematics may be because the motor control of distal effectors is less represented in the motor circuitry formed by the supplementary motor area (SMA), thalamus and BG.

REM sleep behaviour disorder in Parkinson's disease: a questionnaire-based study.

The aim of the study was to determine the clinical frequency and features of REM sleep behaviour disorder (RBD) in a large population of Parkinson's disease (PD) patients using defined diagnostic criteria both for RBD and PD. Six trained neurologists used a semistructured questionnaire based on ICSD-R diagnostic criteria for RBD to evaluate 200 PD patients and their caregivers. Interobserver reliability for the diagnosis of RBD was "substantial" (Kappa 0.65). Five patients were excluded from the study because of an MMSE lower than 25. The demographic and PD clinical features were compared in the clinically defined RBD group and in those without RBD (NRBD). Then the RBD features during the last year were analysed in the affected group. Out of 195 patients, 66 fulfilled the ICSD-R criteria for RBD; 62 patients reported RBD during the last year (frequency 31.8%). RBD features: two or more episodes per week in 35.5%; upper limb movements in 87%; lower limb movements in 79%; vocalisations during events in 85%. RBD onset was before PD in 27% of patients; 69% of the RBD group had injured themselves or their caregivers during sleep. According to multivariate analysis, RBD was associated with male gender, age and PD duration. Brief training and the use of a semistructured questionnaire may help the neurologist in dealing with sleep disturbances in PD patients. The search for RBD symptoms in PD is highly recommended, especially in patients with a long disease duration, the risk of sleep-related injuries being high.

Frontal intermittent rhythmic delta activity (FIRDA) in patients with dementia with Lewy bodies: a diagnostic tool?

The accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) remains poor, especially in early phases of the disease, in spite of applying current consensus diagnostic criteria. The need for supportive diagnostic tools is therefore warranted. In this study EEG recordings showed a main pattern of bilateral frontal intermittent rhythmic delta activity (FIRDA) in 7 of 10 patients, aged 58-83 years, 8 of whom were diagnosed as affected by "probable" and 2 by "possible" DLB. Conversely, the same EEG abnormality was found only in 2 of 9 age-matched patients, 8 of whom had "probable" and 1 "possible" Alzheimer's disease, according to NINCDS-ADRDA criteria, taken as controls. The degree of cognitive impairment was comparable among the two groups of patients. If these findings will be confirmed in a larger series, FIRDA, even though an aspecific EEG pattern, could be of value in improving the diagnostic accuracy of DLB.

The status of dopamine nerve terminals in Parkinson's disease and essential tremor: a PET study with the tracer [11-C]FE-CIT.

Neuroimaging studies of the striatal dopamine transporter (DAT) are useful in the assessment of the dopaminergic system in Parkinson's disease (PD). We used positron emisson tomography (PET) and the tracer [11C]FE-CIT to measure DAT binding in the caudate nucleus and putamen of 31 patients with PD, 5 with essential tremor and 8 healthy control subjects. Of the patients with PD, 17 were drug naive, while the others were either on levodopa or dopamine agonist monotherapy. DAT binding was significantly reduced in the caudate nucleus and to a greater extent in the putamen of PD patients compared to both healthy controls and essential tremor individuals. No overlap was observed between putamen values in PD and normals. No differences were found between controls and essential tremor subjects. These data confirm that measurements of DAT binding can provide an accurate and highly sensitive measure of degeneration in the dopamine system in PD.

Long-term persistence of symptomatic effect of selegiline in Parkinson's disease. A two-months placebo-controlled withdrawal study.

Following a two-months of placebo-controlled withdrawal, the MAO-B inhibitor selegiline was found to maintain a long term significant mild to moderate symptomatic effect on bradykinesia and tremor at rest in nine patients with Parkinson's disease (stage II and III of H&Y), whose functional impairment had also required a dopaminergic therapy with low-dose bromocriptine. Both motor signs found worsened during the wash-out showed a full recovery to pre-withdrawal condition within two months after reinstitution of the drug.

Impaired control of an action after supplementary motor area lesion: a case study.

The kinematics of the action formed by reaching-grasping an object and placing it on a second target was studied in a patient who suffered from an acute vascular left brain lesion, which affected the Supplementary Motor Area proper (SMA-proper) (Matelli M, Luppino G. Thalamic input to mesial and superior area 6 in the macaque monkey. Journal of Comparative Neurology 1996;372:59-87, Matelli M, Luppino G, Fogassi L, Rizzolatti G. Thalamic input to inferior area 6 and area 4 in the macaque monkey. Journal of Comparative Neurology 1989;280:468-488), and in five healthy control subjects. The reach kinematics of the controls was affected by the positions of both the reaching-grasping and the placing targets (Gentilucci M, Negrotti A, Gangitano M. Planning an action. Experimental Brain Research 1997;115:116-28). In contrast, the reach kinematics of the patient was affected only by the position of the reaching-grasping target. By comparing these results with those previously found in Parkinson's disease patients executing the same action (Gentilucci M, Negrotti A. Planning and executing an action in Parkinson's disease patients. Movement Disorders 1999;1:69-79, Gentilucci M, Negrotti A. The control of an action in Parkinson's disease. Experimental Brain Research 1999;129:269-277), we suggest that the anatomical "motor" circuit formed by SMA-proper (see above), Basal Ganglia (BG) and Thalamus (Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends in the Neurosciences 1990;13:266-271, Hoover JE, Strick PL. Multiple output channels in the basal ganglia. Nature 1993;259:819-821) may be involved in the control of actions: SMA-proper assembles the sequence of the action, whereas BG updates its parameters and stores them.

The control of an action in Parkinson's disease.

We studied, in Parkinson's disease (PD) patients and healthy control subjects, the kinematics of the action formed by two successive motor acts: reaching-grasping an object (first target) and placing it on a second target. We examined the effects of extrinsic (i.e., distance) and intrinsic (i.e., size) properties of the second target on the various kinematic phases of reaching-grasping. We randomly varied distance and size of both stimuli across the experimental session. The kinematics of the reach initial phase of both patients and controls was influenced by the distance of both the first and the second target. In particular, peak acceleration increased for farther position of the second target. However, in the subsequent phase, patients, differently from controls, modified their reaching kinematics, removing the effects of second target position. These results were due neither to a visual interference effect of the second target on reaching-grasping nor to the complexity of movement sequence. Finally, the size of the second target did not affect grasp kinematics of both patients and controls. The results of the present study support the hypothesis that PD patients are able to compute the general program of an action in which extrinsic properties of both the actual and the final target are computed. However, PD patients re-program movement during its execution. This suggests a decay of the motor program. That is, basal ganglia can be involved in storing the plan of an action and in controlling its correct execution.

Planning and executing an action in Parkinson's disease.

We evaluated the possible impairment in planning and executing an action in patients with Parkinson's disease (PD). The action considered in the present study was formed by two successive motor acts: reaching-grasping an object (first target) and placing it on a second target of the same shape and size. We examined the effects of extrinsic properties of the second target (that is, distance) on the various kinematic phases of reaching-grasping movements. Distance, position, and size of both stimuli were randomly varied across the experimental session. Movements were executed with and without visual control of both targets and arm. The performance of six patients with PD was compared with an age-matched control group. The kinematics of the initial phase of reaching was influenced by position and size of the first target and by distance of the second target in both patients and control subjects. In particular, peak acceleration was higher for farther position of the second target. However, in the subsequent phase patients, differently from control subjects, removed the effects of the second target distance by modifying their reaching kinematics. This was obtained by varying the duration of the acceleration phase. In summary, the patients reprogrammed the reaching component by taking into account only the properties of the first target. The decreasing influence of second-target distance on reaching kinematics of patients was more evident during movements executed under visual control. Moreover, their movements executed without visual control were slowed down from the beginning. The second target affected the grasping kinematics only of the control subjects. Globally, these results indicate that PD patients are able to compute the general program of an action that takes into account extrinsic properties of the final target. However, the finding that PD patients reprogrammed the movement during its execution suggests a decay of the program during its time course, that is, basal ganglia can be involved in storing the plan of an action and in controlling its correct execution.

A case-control study of occupational and environmental risk factors for Parkinson's disease in the Emilia-Romagna region of Italy.

A questionnaire-based case-control study was carried out on 86 patients with neurologist-confirmed idiopathic Parkinson's disease (PD) and 86 controls similar in sex and age. The control group was recruited in outpatient specialist centers of the same University Hospital (glaucoma, psoriasis vulgaris, essential arterial hypertension and renal diseases). Exposure was defined as occupational or residential contact with a given factor for at least 10 consecutive years prior to the onset of PD. Smoking habits were defined by exclusion of those subjects who never smoked. The following risk factors were identified: cranial trauma (OR: 2.88; 95% CI: 0.98-8.49), well water use (OR: 2.78; 95% CI: 1.46-5.28) and occupational exposure to industrial chemicals (OR: 2.13; 95% CI: 1.16-3.91). Among industrial chemicals, only organic solvents were identified as significant risk factors for PD (O.R. : 2.78, 95% C.I. : 1.23-6.26). Whereas no exposure to neurotoxic metals occurred among controls, making the assessment of the O.R. impossible, exposure pesticides and herbicides was similar in the two groups (O.R. : 1.15; 95% C. : 0.56-2-36). Smoking habits was negatively associated with PD (OR: 0.41; 95% CI: 0.22-0.75), confirming the "protective" role of tobacco smoking suggested by many studies. As a whole, these results support the role of environmental factors in the etiology of PD.

Clinical and genetic study of a family with spinocerebellar ataxia type 1 (SCA1) and beta-thalassemia.

We report a family affected by autosomal dominant ataxia, in which numerous members also showed microcytosis. Genetic analysis demonstrated a CAG expansion in the SCA1 locus in five members, while all subjects with microcytosis revealed a C-T substitution at codon 39 of the beta-globin gene. A pure cerebellar syndrome with prominent gait ataxia characterized the first stages of the neurological disease. The fully developed disease included additional clinical findings such as dysarthria and dysphagia, and instrumental signs of axonal involvement of the peripheral nerves. Ophthalmoplegia was not observed. The coexistence of hereditary spinocerebellar degeneration and erythropathies or hemoglobinopathies has been previously described. We discuss the possible linkages between these two pathologies.

Planning an action.

The motor control of a sequence of two motor acts forming an action was studied in the present experiment. The two analysed motor acts were reaching-grasping an object (first target) and placing it on a second target of the same shape and size (experiment 1). The aim was to determine whether extrinsic properties of the second target (i.e. target distance) could selectively influence the kinematics of reaching and grasping. Distance, position and size of both targets were randomly varied across the experimental session. The kinematics of the initial phase of the first motor act, that is, velocity of reaching and hand shaping of grasping, were influenced by distance of the second target. No kinematic difference was found between movements executed with and without visual control of both hand and targets. These results could be due to computation of the general program of an action that takes into account extrinsic properties of the final target. Conversely, they could depend on a visual interference effect produced by the near second target on the control of the first motor act. In order to dissociate the effects due to second target distance from those due to visual interference, two control experiments were carried out. In the first control experiment (experiment 2) subjects executed movements directed towards spatial locations at different distances from the first target, as in experiment 1. However, the near second target was not presented and subjects were required to place the object on an arbitrary near position. Distance of the second (either real or arbitrary) target affected the reaching component of the first motor act, as in experiment 1, but not the grasp component. In the second control experiment (experiment 3), the pure visual interference effect was tested. Subjects were required to reach and grasp the object and to lift it in either presence or absence of a second near stimulus. No effect on the initial phase of the first motor act was observed. The results of the this study suggest a dissociation in the control of reaching and grasping, concerning not only visual analysis of extrinsic properties of the immediate target but also visual analysis of the final target of the action. In other words, the notion of modularity for the motor control can be extended to the construction of an entire action.

A long-term follow-up study of cinnarizine- and flunarizine-induced parkinsonism.

The natural course of calcium-entry blocker-induced parkinsonism was evaluated in 13 elderly patients previously exposed to cinnarizine or flunarizine or both for a median period of 7 months. Clinical assessments were carried out before drug discontinuation and twice thereafter over a period lasting < or = 7 years. None of the patients showed a full recovery of extrapyramidal signs, indicating that the long-term prognosis of the parkinsonism is less benign than previously reported. Two main patterns of clinical outcome were recognized (i.e., "remittent" and "persistent and not progressive" parkinsonism), whereas the development of a progressive disorder was observed only in one patient. No significant correlation was found between the patterns of outcome and some clinical variables, such as total duration of exposure to cinnarizine and flunarizine, cumulative drug dosages, and age at onset of parkinsonism. There was no significant difference in terms of family history of essential tremor or parkinsonism or both among patients with the two main patterns of clinical course.

Mechanisms for distance reproduction in perceptual and motor tasks.

Two experiments were carried out: the control experiment and the doubling-distance experiment. In the control experiment subjects were presented with two visual stimuli whose distance was randomly varied. Subjects were required to reproduce the interstimulus remembered distance in two conditions. In one condition (reproduction by pointing) they pointed to a virtual position in space. In the other condition (visual reproduction) they matched the distance by using two other visual stimuli. In the doubling-distance experiment, distances between the two randomly presented stimuli were half of the distances used in the control experiment. Subjects were required to reproduce the double of the presented distance. As in the control experiment, reproduction was executed in two conditions: reproduction by pointing and visual reproduction. In both experiments variable and constant errors were measured. Pointing kinematics were also analysed. The results of the control experiment showed that subjects underestimated distance in reproduction by pointing, whereas they overestimated distance in visual reproduction. Variable errors increased with increasing distance, whereas they were not influenced by the type of reproduction. In the doubling-distance experiment, subjects generally overestimated distance by the same amount in both conditions. However, overestimation decreased with distance during reproduction by pointing. Pointing kinematics varied between the two experiments. The results of the control experiment confirm the hypothesis that perceptual judgement and visuo-motor transformation are two separate processes during which the same object attributes are independently analysed. However, the results of the doubling-distance experiment suggest that perceptual judgement and visuo-motor transformation use the same mechanisms when object attributes are deduced by mental elaboration.

L-deprenyl as an adjunct to low-dose bromocriptine in early Parkinson's disease: a short-term, double-blind, and prospective follow-up study.

The therapeutic efficacy of L-deprenyl (10 mg daily) as an adjunct to low-dose bromocriptine monotherapy (up to 25 mg daily) in patients with early Parkinson's disease (PD) was evaluated in a double-blind placebo-controlled short-term study (11 patients) and subsequently in a long-term prospective open follow-up (21 patients) until L-dopa was required, over a 4-year period. The combined regimen of bromocriptine plus L-deprenyl produced a mildly significant improvement, as shown by the majority of clinical rating scales used after 6 weeks of sustained treatment (as compared to bromocriptine alone and bromocriptine plus placebo). In the prospective long-term study, a stabilization of the clinical status was observed until 12 months of sustained treatment, whereas after that, a gradual worsening of the scores on all motor rating scales occurred. However, at 24 months, fewer than one third of the patients had required L-dopa, a proportion comparatively smaller than that reported in the literature with bromocriptine alone. This finding could be related to the persistence of initial symptomatic effect of L-deprenyl, but a slowing action on the course of the disease process exerted by the monoamine oxidase typeB (MAO-B) inhibitor cannot be ruled out.

Dissociation between perception and visuomotor transformation during reproduction of remembered distances.

1. In complete darkness subjects were presented with two visual stimuli whose distance was randomly varied. The subjects were required to reproduce the interstimulus remembered distance in two conditions. In one condition (reproduction by pointing) they pointed to a virtual position in space. In the other condition (visual reproduction) they used two other visual stimuli. One of them was fixed, and the other could be manually moved. Constant and variable errors were measured in the two conditions. 2. Constant error varied between the two conditions. In the pointing task subjects slightly overestimated the shorter distances, and underestimated the longer ones. During visual reproduction, they consistently overestimated all distances, and the error of overestimation tended to increase with distance. Statistical comparison between the errors in the two conditions was significant. Variable error increased with distance in both conditions, but did not show any significant difference between the two tasks. 3. The results of the present experiment support the hypothesis that perception and visuo-motor transformation are two separate processes in which the same object attributes are independently analysed. However, the finding that variable error did not change between the two tasks suggests that some stages are common to the two processes.

Reversible valproate-induced extrapyramidal disorders.

We observed transient parkinsonism in 2 young epileptic patients with valproate (VPA) therapy. Complete recovery from extrapyramidal disorder occurred spontaneously in a few weeks. The lack of apparent susceptibility related to age and to VPA dosage, the rapid recovery from the extrapyramidal reaction, and the prevalence of negative signs such as bradykinesia and bradyphrenia can be considered the main clinical findings of this disease process. Pathophysiologic mechanisms of this rare "toxic" reaction remain unknown, although a transient imbalance between functionally reciprocal subgroups of GABA pathways leading to remediable dopamine inhibition might be hypothesized.

Effect of propranolol in head tremor: quantitative study following single-dose and sustained drug administration.

The effect of the beta-adrenoceptor antagonist propranolol has been investigated in nine patients suffering from isolated (six patients) or prominent (three patients) essential tremor of the head. In a double-blind, placebo-controlled study the tremorolytic efficacy of propranolol has been assessed by a quantitative accelerometric method after a single oral dose (120 mg) and following 2 weeks of sustained treatment with two different dosage regimens of the drug (120 and 240 mg daily). As compared with placebo, a significant reduction in tremor magnitude was found following a single oral dose but not on sustained administration of the beta-blocker at either dosage. The results suggest that the efficacy of sustained propranolol on isolated or prominent essential head tremor is less predictable and satisfactory than expected on the basis of the single-dose response, as compared with hand tremor.

Calcium-entry blockers-induced parkinsonism: possible role of inherited susceptibility.

The risk of developing drug-induced parkinsonism (DIP) has been related to a number of factors but it remains up to now poorly defined. The aim of this survey has been to evaluate retrospectively the possible role of inherited components in 25 patients with parkinsonism induced by chronic exposure to the calcium-entry blockers cinnarizine and flunarizine. The finding of higher occurrence of a positive family history for Parkinson's disease (PD) and/or essential tremor (ET) and of higher frequency of secondary cases with PD and/or ET among close relatives of the patients as compared to age-matched controls, suggests the involvement of genetic susceptibility in developing this drug-induced disorder. DIP could be regarded as a multifactorial disease process resulting from potential neurotoxicity of drugs on a background of inherited predisposition.