Cortical thickness in de novo patients with Parkinson disease and mild cognitive impairment with consideration of clinical phenotype and motor laterality.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, including cognitive deficits. Several magnetic resonance imaging approaches have been applied to investigate brain atrophy in PD. The aim of this study was to detect early structural cortical and subcortical changes in de novo PD whilst distinguishing cognitive status, clinical phenotype and motor laterality. METHODS: Eighteen de novo PD with mild cognitive impairment (PD-MCI), 18 de novo PD without MCI (PD-NC) and 18 healthy control subjects were evaluated. In the PD-MCI group, nine were tremor dominant and nine were postural instability gait disorder (PIGD) phenotype; 11 had right-sided symptom dominance and seven had left-sided symptom dominance. FreeSurfer was used to measure cortical thickness/folding, subcortical structures and to study group differences as well as the association with clinical and neuropsychological data. RESULTS: Parkinson's disease with MCI showed regional thinning in the right frontal, right middle temporal areas and left insula compared to PD-NC. A reduction of the volume of the left and right thalamus and left hippocampus was found in PD-MCI compared to PD-NC. PD-MCI PIGD showed regional thinning in the right inferior parietal area compared to healthy controls. A decreased volume of the left thalamus was reported in PD-MCI with right-sided symptom dominance compared to PD-NC and PD-MCI with left-sided symptom dominance. CONCLUSIONS: When MCI was present, PD patients showed a fronto-temporo-parietal pattern of cortical thinning. This cortical pattern does not appear to be influenced by motor laterality, although one-sided symptom dominance may contribute to volumetric reduction of specific subcortical structures.

Increased risk for heart valve disease associated with antiphospholipid antibodies in patients with systemic lupus erythematosus: meta-analysis of echocardiographic studies.

BACKGROUND: Heart valve disease (HVD) is frequent in patients with systemic lupus erythematosus (SLE), and the role of antiphospholipid antibodies (aPL) is controversial. Thus, our objective was to estimate the risk of HVD, including Libman-Sacks endocarditis, associated with aPL in patients with SLE. METHODS AND RESULTS: Studies were selected if they investigated the association between aPL and HVD in SLE patients and if aPL-negative patients were included for comparison. Data sources were MEDLINE, Embase, Cochrane Library, hand search, contact with investigators, and reference lists of studies, without language restrictions. Data on study and patient characteristics, risk estimates, and study quality were independently extracted by 2 investigators. Pooled effect estimates were obtained by using the DerSimonian-Laird method. Of 234 identified abstracts, 23 primary studies (15 cross-sectional, 7 cohort, 1 case-control) met inclusion criteria, including 1656 SLE patients and 508 cases of HVD. Compared with SLE patients without aPL (n=988), the overall pooled odds ratios for HVD and Libman-Sacks endocarditis in aPL-positive patients (n=668) were 3.13 (95% confidence interval, 2.31 to 4.24) and 3.51 (95% confidence interval, 1.93 to 6.38), respectively. The risk of HVD depending on aPL subtypes was the highest for lupus anticoagulant at 5.88 (95% confidence interval, 2.92 to 11.84) and IgG anticardiolipin antibodies at 5.63 (95% confidence interval, 3.53 to 8.97). CONCLUSIONS: Overall, the presence of aPL in SLE patients is significantly associated with an increased risk for HVD including Libman-Sacks endocarditis. The risk conferred by IgG anticardiolipin antibodies is as strong as by lupus anticoagulant. Systematic echocardiographic examinations in SLE patients with aPL should be performed.

[New systems of mapping and navigation in electrophysiology]. / Nouveaux systèmes de cartographie et de navigation en électrophysiologie.

The indications of radiofrequency ablation of arrhythmias have considerably increased since the introduction of the technique in the early 1990s. Interventional rhythmologists now treat arrhythmias which are more and more complex by their mechanism. This requires accurate representation of the ablation catheter position and the integration of spatial and temporal data to identify the arrhythmogenic substrate. The systems of mapping and navigation developed over the last ten years are important tools for interventional rhythmologists. They are very useful for the identification of complex arrhythmogenic substrates which require "individualised" ablations in specific cases. The aim of this article is to review different systems of mapping, and/or navigation currently on the market and their principal characteristics without entering into the details of their use in interventional electrophysiology.

Interpretation of expression-profiling results obtained from different platforms and tissue sources: examples using prostate cancer data.

The analysis of expression signatures is a powerful tool for the classification of cancer and other tissue samples. Several protocols and platforms are available on the market, and these lead to both confirmatory and complementary results. We review the main processing techniques for cross-platform comparisons and the different tissue sources for cancer profiling. Some examples and the cross-interpretation of bibliographic data related to prostate cancer are also presented.

[A multicentre trial of the diagnostic value and cost of electrocardiography in symptoms suggesting arrhythmia with a new event recorder with transtelephonic transmission]. / Etude multicentrique sur l'intérêt et le coût du diagnostic électrocardiographique de symptômes présumés rythmiques utilisant un nouvel enregistreur d'événements avec transmission transtéléphonique.

Events recorders are used for electrocardiographic documentation of symptoms of arrhythmia too sporadic and short lasting to be recorded by 24 hour Holter monitoring. However, there are no French studies comparing the value and cost of event recorders with conventional diagnostic methods. Recently, a new telediagnostic device has become available in France leading to an assessment of the technique. The aim of this study was to determine the value of this event recorder and the cost of diagnostic ECG in the assessment of presumed arrhythmic symptoms such as palpitations or rare tachycardia (<3 episodes per week) of short duration, compared with conventional techniques. Fifty-eight patients with these criteria were randomised, 30 to Survcard (Group I) and 28 to conventional diagnostic methods (Group II). The patients were comparable with respect to age, sex distribution, type of symptoms and associated cardiac disease. The ECG diagnosis of the symptoms was established in 20 cases (66.6%) of patients in Group I in 17 +/- 16 days, and in 14 cases (50.0%) of Group II in 23 +/- 28 days. The difference between the two groups was not statistically significant. The cost of a positive diagnosis for Group I (Survcard) varied from 0 to 228.47 Euro with an average of 71.22 +/- 117.02 Euro. The cost of positive diagnosis in Group II varied from 76.80 to 2340.41 Euro with an average of 480.39 +/- 797.41 Euro. In conclusion, this study showed that the percentage of patients with a positive diagnosis was comparable in the two groups but that the cost was 6 times higher in the group investigated by conventional methods than in the Survcard group because of more costly medical intervention.

Bedtime cabergoline in Parkinson's disease patients with excessive daytime sleepiness induced by dopamine agonists.

Excessive daytime somnolence is a common adverse effect of dopamine-agonist treatment of Parkinson's disease (PD). Many factors, such as age and sleep disturbances, could be involved in the pathogenesis of this phenomenon. However, pharmacokinetic factors have never been considered. In this open, prospective, pilot study, nine consecutive non-demented PD patients in early disease stages on monotherapy treatment with dopamine agonists and with no significant sleep problems, were enrolled. They were selected based on the presence of excessive daytime sleepiness induced by the dopaminergic treatment. A fast switch-over from the dopamine agonist currently used to a single equivalent dose of cabergoline, a long-acting dopamine agonist, administered at bedtime was performed. All patients were evaluated by means of UPDRS and Epworth Sleepiness Scale (ESS). A significant 70% reduction of daytime sleepiness was observed during the 3-month study compared with baseline. Data from this study suggest that both pharmacodynamic and pharmacokinetic mechanisms are involved in the pathophysiology of dopamine agonist-induced sleepiness.

IV amantadine improves chorea in Huntington's disease: an acute randomized, controlled study.

The acute antidyskinetic effects of IV amantadine in HD were evaluated. A 2-hour IV infusion of amantadine or placebo was administered to nine patients with HD on two different days in a double-blind, randomized crossover fashion. All patients subsequently received oral amantadine unblinded for a 1-year period. A reduction of dyskinesia scores was reported during both IV and oral amantadine treatment (p < 0.05). No significant changes were observed in neuropsychological tests or psychiatric rating scales.

Correlation between electrogram morphology and standard criteria to validate bidirectional cavotricuspid block in common atrial flutter ablation.

AIM: Assessment of a bidirectional conduction block within the cavotricuspid isthmus (CTI) is critical during radiofrequency (RF) atrial flutter (AF) ablation. We investigated the use of bipolar atrial electrogram (BAE) morphology as an additional criterion identifying CTI block and tested it against two recognized criteria: differential pacing and reversal of the right atrial depolarization sequence during coronary sinus (CS) pacing. METHODS AND RESULTS: An RF ablation procedure was performed during 600 ms CS pacing in 100 consecutive patients with a common AF. BAE recorded along the CTI were continuously monitored. CTI conduction block was achieved by RF ablation in all patients and a clear change in BAE polarity in the Electrogram recorded by the dipoles located on the CTI and immediately lateral to the intended line of block (RS to QR pattern) associated with a confirmed CTI conduction block was observed in all cases. BAE morphology changes predicted bidirectional CTI conduction blocks with a 100% positive and a 100% negative predictive value. At a mean follow-up of 33 +/- 11 months, there was a 5% AF recurrence rate. CONCLUSIONS: Our study suggests that morphological changes in BAE recorded at sites lateral and adjacent to the target line of block may be used as a unique and robust criterion to validate CTI conduction block during AF ablation procedure.

What is the 'true' function of skin?

Conventional textbook wisdom portrays the skin as an organ that literally enwraps whatever each of us stands for as a more or less functional, individual member of the mammalian species, and has it that the skin primarily establishes, controls and transmits contacts with the external world. In addition, the skin has long been recognized to protect the organism from deleterious environmental impacts (physical, chemical,microbiological), and is well-known as crucial for the maintenance of temperature, electrolyte and fluid balance. Now, ever more studies are being published that show the skin to also operate as a huge and highly active biofactory for the synthesis,processing and/or metabolism of an astounding range of e.g. structural proteins, glycans, lipids and signaling molecules. Increasingly, it becomes appreciated that the skin, furthermore, is an integral component of the immune, nervous and endocrine systems, with numerous lines of cross-talk between these systems established intracutaneously (e.g. Ann NY Acad Sci Vol 885, 1999; Endocrine Rev 21:457-487, 2000; Physiol Rev 80:980-1020, 2001; Exp Dermatol 10: 349-367, 2001). All these emerging cutaneous functions beyond the classical image of the skin as a barrier and sensory organ are immediately relevant for many of the quandaries that clinical dermatology, dermatopathology, and dermatopharmacology are still struggling with to-date, and offer the practising dermatologist attractive new targets for therapeutic intervention. Yet, many of these skin functions are not even mentioned in dermatology textbooks and await systematic therapeutic targeting. Following a suggestion by Enno Christophers, the current 'Controversies' feature brings together an unusually diverse council of biologists and clinicians, who share their thought-provoking views with the readers and allow us to peek into the future of research in cutaneous biology, not the least by reminding us of the -- often ignored -- evolutionary and embryonal origins of our favorite organ. Hopefully, this unique discussion feature will foster an understanding of the 'true' skin functions that is both more comprehensive and more profound than conventional teaching on this topic, and will stimulate more than 'skin-deep' reflections on the full range of skin functions.

Cytogenetic alterations in lymphocytes of Alzheimer's disease and Parkinson's disease patients.

We investigated the presence of cytogenetic alterations in peripheral blood lymphocytes of Alzheimer's disease (AD) and Parkinson's disease (PD) patients. Detection of spontaneous structural and/or numerical chromosome damage has been assessed by micronucleus (MN) assay coupled with fluorescence in situ hybridization (FISH). The cytogenetic investigation was performed on 22 AD patients, 18 PD patients, and 20 controls. The spontaneous frequencies of micronuclei (MN) in human lymphocytes of both AD and PD patients were significantly higher than in controls. The majority of MN was composed of whole chromosomes in AD patients, while a prevalence of MN arising from chromosome breakage was observed in PD patients. Different molecular mechanisms underlie cytogenetic alterations observed in peripheral lymphocytes of AD and PD patients.

Proton magnetic resonance spectroscopy (1H-MRS) of motor cortex and basal ganglia in de novo Parkinson's disease patients.

Proton MR spectroscopy (1H-MRS) has been previously performed in Parkinson's disease (PD) and parkinsonian syndromes to evaluate in vivo concentrations of basal ganglia and cerebral cortex metabolites such as N-acetylaspartate (NAA), choline (Cho), and creatine (Cr). However, this technique has never been used to evaluate motor cortex in untreated PD patients. In this study, single-voxel 1H-MRS of basal ganglia and motor cortex was carried out in 10 de novo patients with PD and 10 age-matched healthy controls. A significant reduction in the NAA/Cr ratio was observed in the motor cortex of PD patients compared with controls (p)<(0.01). Basal ganglia spectra did not allow any evaluation due to the presence of artefacts related to inorganic paramagnetic substances. The motor cortex reduction of the NAA/Cr ratio in de novo PD patients may reflect an altered neuronal functioning due to a loss of thalamocortical excitatory inputs and may represent an in vivo marker for the diagnosis of PD.

Cytogenetic analysis oxidative damage in lymphocytes of Parkinson's disease patients.

Several lines of evidence support the presence of DNA damage in somatic cells of Parkinson's disease (PD) patients due to the formation of free radical species. In order to detect spontaneous chromosome and primary or oxidative DNA damage, we performed the human lymphocyte micronucleus assay (HLMNA) and comet assay in 19 PD patients and 16 healthy controls. Compared with controls, PD patients showed a significant increase in: (I) spontaneous micronucleus (MN) frequency (p<0.001); (2) single strand break (SSB) levels (p<0.001); and (3) oxidized purine base levels (p<0.05). The chromosome damage and the increased levels of oxidized purine bases observed in our patients support the hypothesis of oxidative stress as a relevant factor in the pathogenesis of PD.

Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study.

Experimental evidence suggests that glutamatergic receptor blockade may improve the motor response complications associated with long-term levodopa treatment in Parkinson's disease (PD) patients. Our objective was to evaluate the acute effect of amantadine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, on levodopa-induced dyskinesias, and to gain further insights into the antidyskinetic mechanism of this drug. Nine PD patients with motor fluctuations and severely disabling peak of dose dyskinesias received their first morning levodopa dose, followed by a 2-hour intravenous amantadine (200 mg) or placebo infusion, on two different days. Parkinsonian symptoms and dyskinesias were assessed every 15 minutes during the infusion and for 3 hours thereafter, while patients were taking their usual oral antiparkinsonian therapy, by means of Unified Parkinson's Disease Rating Scale (UPDRS, motor examination), tapping test, and a modified Abnormal Involuntary Movement Scale (AIMS). Intravenous amantadine acutely improved levodopa-induced dyskinesias by 50%without any loss of the anti-parkinsonian benefit from levodopa. This study confirms the antidyskinetic effect of amantadine and strengthens the rationale for using antiglutamatergic drugs in the treatment of parkinsonian motor fluctuations.

Diurnal motor variations to repeated doses of levodopa in Parkinson's disease.

Patients with Parkinson's disease (PD) in long-term levodopa therapy often complain of worsening of motor symptoms in the afternoon and evening. The pathophysiology of this phenomenon is not known. We evaluated the motor response to repeated doses of levodopa during a 12-hour period in 52 parkinsonian patients (19 de novo, 20 stable, and 13 wearing-off). On the day of the study, all patients received standard doses of levodopa/carbidopa at 8:00 a.m., 12:00 noon, and 4:00 p.m. Motor measurements such as tapping test, walking time, and tremor score, and blood samples for levodopa and 3-O-methyldopa (3OMD) plasma analysis, were performed hourly. Mean motor scores and pharmacokinetic data, evaluated for a period of 3 hours after each levodopa dose, were compared. In de novo patients, we did not observe diurnal changes in motor score, whereas a progressive daytime worsening was visible in stable and wearing-off patients. No significant difference in levodopa pharmacokinetics after each levodopa dose was observed within each patient group, whereas 3OMD plasma levels significant increased with repeated levodopa administrations. However, no significant correlation between motor scores and 3OMD plasma levels was observed, suggesting that the diminishing motor response to afternoon and evening doses of levodopa in patients in long-term levodopa therapy does not relate to the pharmacokinetics of the drug. It is possible that this phenomenon may be an expression of the occurrence of tolerance to repeated doses of levodopa.

Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.

BACKGROUND: In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. OBJECTIVE: To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. DESIGN: One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. SETTING: National Institutes of Health Clinical Center. PATIENTS: Seventeen of the original 18 patients with advanced Parkinson disease complicated by dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. INTERVENTIONS: Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. MAIN OUTCOME MEASURES: Parkinsonian symptoms and dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. RESULTS: One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). CONCLUSION: The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.

Pharmacokinetics and pharmacodynamics of L-Dopa after acute and 6-week tolcapone administration in patients with Parkinson's disease.

Tolcapone, a central and peripheral catechol O-methyltransferase (COMT) inhibitor, reduces the conversion of L-Dopa into 3-O-methyl-Dopa (3-OMD), thus leading to more stable and sustained L-Dopa plasma levels. This study was designed to evaluate the effects of acute and 6-week tolcapone administration on L-Dopa pharmacokinetics and pharmacodynamics in Parkinson's disease (PD) patients with predictable motor fluctuations. Tapping test, walking time, and tremor, as well as L-Dopa and 3-OMD plasma levels, were assessed before and for 5 hours after the administration of a single L-Dopa dose, alone or in combination with 200 mg tolcapone, in seven patients with PD. This clinical and pharmacokinetic study was repeated after 6 weeks of tolcapone therapy (200 mg three times daily). It was observed that tolcapone, after both acute and chronic administration, prolonged the motor improvement induced by L-Dopa. As a result, at week 6 of tolcapone therapy, the daily hours spent "off" were significantly decreased. Tolcapone significantly increased the area under the curve of L-Dopa plasma levels by slowing down the elimination of L-Dopa from plasma, whereas the maximal concentration of L-Dopa was not modified. 3-OMD levels decreased significantly after acute tolcapone administration, and after 6 weeks of tolcapone therapy, they were approximately one sixth of pre-tolcapone values. The data confirm that tolcapone decreases L-Dopa clearance and prolongs motor response in PD patients with motor fluctuations, and that this effect is maintained after 6 weeks of tolcapone therapy.

Thyroid function and autoimmunity in Parkinson's disease: a study of 101 patients.

Thyroid disease is the endocrine dysfunction most frequently reported in association with idiopathic Parkinson's disease (PD). The aim of this study was to assess thyroid autoimmunity and function in PD, and to verify the effect of long term l-dopa and/or dopamine therapy on thyroid function. We studied 101 consecutive PD outpatients and seventy age- and sex-matched neurological non-PD patients as controls. They were evaluated for free thyroid hormones, TSH and thyroid autoantibodies. No significant difference in the prevalence of thyroid autoimmunity and dysfunction was found between PD patients and neurological controls (10.8% in PD patients vs 10% in neurological controls). Further, treatment with l-dopa and/or dopaminergic drugs and the stage of Parkinson's disease did not affect thyroid function. In conclusion, the prevalence of thyroid autoimmunity in PD patients appeared similar to that as described in the general population, though thyroid dysfunction was observed in over than 10% of PD patients. Indeed, neurologists should be alerted to the possible complications arising from thyroid dysfunction in Parkinson's disease, but thyroid function tests should be performed only when justified on clinical grounds.

Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease.

OBJECTIVE: This study assessed the effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on levodopa-induced dyskinesias in Parkinson's disease (PD). BACKGROUND: Recent experimental evidence suggests that increased synaptic efficacy of NMDA receptors expressed on basal ganglia neurons may play a role in the pathophysiology of levodopa-induced motor response complications. METHODS: DM was given to six PD patients with motor fluctuations in a double-blind, placebo-controlled, cross-over study. At the end of each 3-week study arm, patients received several brief i.v. levodopa infusions while parkinsonian symptoms and dyskinesias were frequently scored. Levodopa dose-response curves for antiparkinsonian and dyskinetic effects were then compared for each study arm. RESULTS: With DM, average and maximum dyskinesia scores improved by >50%, without compromising the antiparkinsonian response magnitude or duration of levodopa, although in some subjects the levodopa threshold dose was slightly higher with DM than with placebo. CONCLUSIONS: These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptors can ameliorate levodopa-associated dyskinesias.