Anna Negrotti

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.

Restless legs syndrome and polyneuropathy.

Restless legs syndrome (RLS), diagnosed according to the International RLS Study Group criteria, was investigated in 97 consecutive patients with polyneuropathy and found in 29 patients. RLS patients were more often women (22 of 29 vs. 33 of 68; P = 0.015), mainly with sensory neuropathy of small fiber type (15 of 29 vs. 16 of 68; P = 0.009). Changes of sensory action potentials were significantly less severe in RLS patients. In the RLS group, acquired neuropathies, and in particular dysimmune neuropathies, were significantly more frequent (27/29 vs. 46/68; P = 0.009). Thus, RLS is frequent in acquired polyneuropathy of sensory type and mild entity, mainly in women.

Planning an action

Abstract 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.

Case-control study of interactions between genetic and environmental factors in Parkinson's disease

Several environmental risk factors and some allelic variants of polymorphic drug-metabolising enzymes have been associated with sporadic Parkinson’s disease. No study has to date explored the possible interaction between individual susceptibility and exposure to chemical pollutants. We genotyped enzymes expressed by the human brain and involved in oxidative stress through the generation of free radicals (phase I enzymes) or involved in scavenging (phase II enzymes). Candidate genes were characterised by a genetic polymorphism that leads to lessened or abolished enzyme activity, and by fixed expression or homozygous allelic deletion (a theoretical correspondence between genotype and phenotype). Cytochrome P-450 2D6 (CYP2D6) is a non-inducible phase I enzyme involved in the biotransformation of various chemicals, including tetrahydroisoquinolines. Alleles CYP2D6*3 and CYP2D6*4 account for about 90% of the poor metaboliser autosomal recessive disorder, which has been associated with Parkinson’s disease. A meta-analysis of available studies showed an overall risk of borderline significance. Glutathione S-transferases (GSTs) are inducible phase II enzymes involved in the scavenging of many electrophilic reactive intermediates. Homozygous deletion of GSTM1 and GSTT1 loci affects, respectively, about 50% and 25% of white people (genotypes GSTM1*0 and GSTT1*0). We recruited 100 consecutive outpatients at the Institute of Neurology, University of Parma, with Parkinson’s disease (59 men, 41 women) aged 66·6 (SD 9·7) years, fulfilling the diagnostic criteria established by the UK Parkinson’s Disease Society Brain Bank. The mean age at the onset of Parkinson’s disease was 58·6 (9·7) years (mean duration of the disease 7·9 [4·6] years) and 15% of patients had a positive family history of the disease. We enrolled 200 controls (118 men, 82 women) aged 64·2 (9·2) years from outpatient specialist centres (nephrology clinic and taken on the same day as her baby’s and tested in parallel with her previous sera remained VZV IgG antibody positive and VZV IgM antibody negative. A month later, in February 1997, at another hospital in Surrey, the day after the birth of a healthy baby girl at term, birth weight 4·2 kg, her 2 –year-old sister developed chickenpox. The mother had had chickenpox 7 years previously (aged 24 years) and this was confirmed serologically by testing her stored antenatal booking serum (16 weeks’ gestation) which was VZV IgG antibody positive and VZV IgM antibody negative. Serological tests were not done on the infant at this time. Mother and baby were discharged home 2 days after delivery, with the baby well and breastfeeding. At 16 days of age the baby developed chickenpox. On day 4 of her illness the baby was seen in hospital and started on oral acyclovir. The typical rash involved the face and head, with a few lesions on the trunk and limbs. Serum from the baby at this time was VZV IgG positive and VZV IgM negative. A swab from the chickenpox lesions yielded VZV from routine tissue culture. Again, no illness or rash occurred in the mother and a repeat serum tested in parallel with her previous serum remained VZV IgG antibody positive and VZV IgM antibody negative. Although VZV was not isolated from the first baby the diagnosis was not in doubt. The strength of IgG reactivity of the mother and baby serum samples in the assay used are shown in the table. The first mother gave a test/positive control net absorbance ratio (T/P) of 1·2 (cutoff 0·8) for both early sera while that of the baby on day 4 of illness was significantly less at 0·46 (equivocal level). The 17 day postdelivery sample of the mother showed a boosted IgG response. The T/P ratios of the second mother/baby case were almost identical for the mother’s booking serum and the baby’s blood at 2·2 and 2·1, respectively—ie, both more than twice the reactivity of the positive control. In both babies the VZV IgG antibody detected (both at 4 days of illness) was likely to be entirely maternal and not their own. It is generally accepted that passively acquired maternal antibody protects neonates from varicella even in low-birthweight infants with neonatal titres of VZV IgG antibody usually matching maternal levels. We can only speculate that the reduced IgG titre in the first baby compared with his mother—possibly a result of being bottle fed—was a factor in his apparently failed immunity and more florid rash. Cell mediated immunity (CMI) was not studied in either baby. Non-specific, non-antibody-dependent cellmediated mechanisms, such as natural killer cells, are known to have a role in controlling the extent of disease due to primary varicella but cannot necessarily prevent infection in the first place. Although our two cases were of moderate severity, and both were treated with acyclovir, a defect in CMI might have been expected to have caused serious protracted disease which did not occur. There have been two previous reports of neonatal

Planning and executing an action in Parkinson's disease

We evaluated the possible impairment in planning and executing an action in patients with Parkinsons 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.

The control of an action in Parkinson’s disease

Abstract 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.

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

Abstract. 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” Alzheimers 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.

Absence of co-morbidity of Parkinson disease and restless legs syndrome: a case–control study in patients attending a movement disorders clinic

We have carried out a case–control survey of the prevalence of restless legs syndrome (RLS) in 118 Parkinson’s disease out-patients with different stage of disease severity by using the International restless legs syndrome Study Group clinical criteria. This study failed to demonstrate a significantly augmented prevalence of either primary and secondary restless legs syndrome pooled together or primary restless legs syndrome alone among Parkinson’s disease patients as compared to age and gender matched controls. The results of our survey do not confirm a significant co-morbid occurrence of the two disorders. However, an unavoidable limitation of this and all previous studies is that most of the patients examined were already treated with dopaminomimetic drugs, which could have abolished a mild unrecognized RLS anteceding the diagnosis of Parkinson’s disease or possibly masked the subsequent emergence of the sensory-motor disorder following the onset of Parkinson’s disease.

Reversible valproate-induced extrapyramidal disorders.

Summary: 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 dopa‐mine inhibition might be hypothesized.

A case-control study of Parkinson’s disease and tobacco use : gene-tobacco interactions

A case‐control study of genetic, environmental, and occupational risk factors for Parkinsons disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age‐matched and gender‐matched controls. Participants completed an interviewer‐administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene‐tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1‐1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.