Brain structural and functional signatures of impulsive-compulsive behaviours in Parkinson's disease.

This study assessed brain structural and functional alterations in patients with Parkinson's disease and impulsive-compulsive behaviours (PD-ICB) compared with controls and PD no-ICB cases. Eighty-five PD patients (35 PD-ICB) and 50 controls were recruited. All subjects underwent three-dimensional T1-weighted, diffusion tensor (DT), and resting state functional magnetic resonance imaging (RS fMRI). We assessed cortical thickness with surface-based morphometry, subcortical volumes using FIRST, DT MRI metrics using region of interest and tractography approaches, and RS fMRI using a model free approach. Compared with controls, both PD groups showed a pattern of brain structural alterations in the basal ganglia (more evident in PD no-ICB patients), sensorimotor and associative systems. Compared with PD no-ICB, PD-ICB cases showed left precentral and superior frontal cortical thinning, and motor and extramotor white matter tract damage. Compared with controls, all patients had an increased functional connectivity within the visual network. Additionally, PD no-ICB showed increased functional connectivity of bilateral precentral and postcentral gyri within the sensorimotor network compared with controls and PD-ICB. Severity and duration of PD-ICB modulated the functional connectivity between sensorimotor, visual and cognitive networks. Relative to PD no-ICB, PD-ICB patients were characterised by a more severe involvement of frontal, meso-limbic and motor circuits. These data suggest ICB in PD as the result of a disconnection between sensorimotor, associative and cognitive networks with increasing motor impairment, psychiatric symptoms, and ICB duration. These findings may have important implications in understanding the neural substrates underlying ICB in PD.

Transcranial sonography in dopa-responsive dystonia.

BACKGROUND AND PURPOSE: Mutations in the GCH1 gene, encoding GTP cyclohydrolase 1, the enzyme critically important for dopamine production in nigrostriatal neurons, are the most common cause of dopa-responsive dystonia (DRD), characterized predominantly by limb dystonia, although parkinsonian features may also be present. It has been suggested that DRD is a neurochemical rather than neurodegenerative disorder. METHODS: Transcranial brain sonography, which might be a risk marker for nigral injury, was obtained from 141 subjects divided into four groups: (i) 11 patients with genetically confirmed DRD; (ii) 55 consecutive patients with Parkinson's disease (PD); (iii) 30 patients diagnosed as isolated adult-onset focal dystonia; and (iv) 45 healthy controls (HCs). RESULTS: Substantia nigra hyperechogenicity was present in 63.6% of patients with DRD, which was significantly different in comparison to patients with dystonia (20%) and HCs (6.7%), but not in comparison to the PD group (87.3%). Also, values of the maximal areas of substantia nigra hyperechogenicity in patients with DRD were higher in comparison to HCs, but significantly lower than among the PD group. CONCLUSIONS: We suggested that the observed transcranial brain sonography features in patients with DRD might primarily be risk markers for particular clinical features (parkinsonism, dystonia) occurring in the specific genetic context (i.e. GCH1 mutations), or might reflect compensated neurodegenerative processes triggered by the long-lasting dopamine deficiency due to the profound delay in levodopa treatment in our patients with DRD.

Management of dystonia in Europe: a survey of the European network for the study of the dystonia syndromes.

BACKGROUND AND PURPOSE: Dystonia is difficult to recognize due to its large phenomenological complexity. Thus, the use of experts in dystonia is essential for better recognition and management of dystonia syndromes (DS). Our aim was to document managing strategies, facilities and expertise available in various European countries in order to identify which measures should be implemented to improve the management of DS. METHODS: A survey was conducted, funded by the Cooperation in Science and Technology, via the management committee of the European network for the study of DS, which is formed from representatives of the 24 countries involved. RESULTS: Lack of specific training in dystonia by general neurologists, general practitioners as well as other allied health professionals was universal in all countries surveyed. Genetic testing for rare dystonia mutations is not readily available in a significant number of countries and neurophysiological studies are difficult to perform due to a lack of experts in this field of movement disorders. Tetrabenazine is only readily available for treatment of dystonia in half of the surveyed countries. Deep brain stimulation is available in three-quarters of the countries, but other surgical procedures are only available in one-quarter of countries. CONCLUSIONS: Internationally, collaboration in training, advanced diagnosis, treatment and research of DS and, locally, in each country the creation of multidisciplinary teams for the management of dystonia patients could provide the basis for improving all aspects of dystonia management across Europe.

Transcranial brain sonography findings in two main variants of progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) can occur with two main clinical presentations, classified as classical Richardson's syndrome (PSP-RS) and as PSP-parkinsonism (PSP-P), the most common atypical PSP variant. The differential diagnosis between them is challenging. Therefore, we studied different ultrasound markers by transcranial sonography in individuals with PSP-RS and PSP-P, to test their value in the diagnostic work up of these patients. METHODS: Transcranial sonography was performed in 21 patients with PSP-RS and 11 patients with PSP-P. Echogenic sizes of the substantia nigra (SN) and the lenticular nuclei (LN), as well as the width of the third ventricle, were measured. RESULTS: Among the patients with PSP-RS and PSP-P, three (14%) and eight (73%) patients had a hyperechogenic SN (P = 0.020), respectively. Uni- or bilateral hyperechogenicity of the LN was observed in 67% and 36% of patients with PSP-RS and PSP-P, respectively (P = 0.101). Third ventricle was significantly wider in patients with PSP-RS (11.2 ±â€…2.3 mm) when compared with patients with PSP-P (7.5 ±â€…1.4 mm; P = 0.001). CONCLUSION: Our data, possibly reflecting pathological differences, primarily contribute supporting the view that the neurodegenerative process differs in the two PSP variants.

Long-term outcome in Serbian patients with Wilson disease.

BACKGROUND AND PURPOSE: To investigate survival rates, prognostic factors, and causes of death in Wilson disease (WD). METHODS: In the years 1980-2007, a cohort of 142 patients with WD was prospectively registered (54 presented with neurologic symptoms, 49 with hepatic symptoms, 33 had mixed form, and data were missing for six patients). The duration of follow-up for patients alive was 11.1 +/- 8.8 years. RESULTS: After initiation of treatment (d-penicillamine and zinc salts), 79% of patients had a stable or improved course of disease. Despite early diagnosis and appropriate therapy, 15 patients still had a relentlessly progressive course. Thirty patients died. The cumulative probability of survival in a 15-year period for the whole group was 76.7 +/- 4.9%. Better prognosis of WD was associated with male sex, younger age at onset, neurologic form of the disease, and treatment continuity. Causes of death were predominantly related to hepatic failure (16 patients), but also suicide (four patients) and cancer (three patients). CONCLUSION: Despite the relatively early diagnosis and treatment of our patients with WD, mortality was still considerably high.

Prolactin and cortisol responses to fenfluramine in Parkinson's disease.

Dysfunction of the central serotonergic system has been associated with depression in Parkinson's disease. To evaluate central serotonergic function in Parkinson's disease in relation to depression, we examined prolactin and cortisol responses to a single-dose challenge with fenfluramine (60 mg orally), a serotonin releasing/uptake-inhibiting agent, in the course of 5 hours in 11 patients with Parkinson's disease associated with major depression (SADS-RDC), 22 nondepressed parkinsonians, and 20 age- and gender-matched healthy controls. No difference in cortisol responses were observed between the groups; however, prolactin responses to fenfluramine were significantly impaired in patients with Parkinson's disease compared to controls, and the response was significantly more blunted in parkinsonian patients with major depression in comparison with the nondepressed ones. These findings indicate that there is a diminished serotonergic responsivity in depression associated with Parkinson's disease.

Sudden hearing loss as the initial monosymptom of multiple sclerosis.

Hearing loss is an uncommon symptom in multiple sclerosis. We report two patients in whom unilateral sudden hearing loss was the first monosymptomatic manifestation of multiple sclerosis. We confirmed the initial central auditory dysfunction suggested by audiometric findings and brainstem auditory evoked potentials by MRI, which showed a unilateral pontine lesion in one patient and a lesion in the medulla oblongata in the other.

Insulin increases entrance of 2-deoxy-D-[3H]glucose in isolated rat brain microvessels.

Insulin in a dose of 0.5 U ml-1 in the incubation medium did not change ATP and phosphocreatine contents in the isolated rat brain microvessels, when energy production was supported by 5.5 mmol l-1 glucose. However, the entrance of non-metabolizable glucose analogue, 2-deoxy-D-[3H]glucose into the microvessel cells was strongly enhanced, almost 18-fold.

A genetic study of idiopathic focal dystonias.

The inheritance of focal dystonias was investigated in 43 families containing 43 index cases with torticollis (n = 21), blepharospasm (n = 18) and writer's cramp (n = 4). They generated a potential population of 235 first-degree relatives, and 168 out of 179 living first-degree relatives were examined. Ten relatives with dystonia were identified in ten families. Another two parents from two of the same group of ten families were affected according to the family history. The majority of the secondary cases (six patients, five siblings, and one child) were not aware of any dystonia. The tendency for affected relatives to have the same type of dystonia as index patients was observed only for torticollis. Overall, 23% of index patients had relatives with dystonia. Segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrance underlying focal dystonia.

Degenerative neurological disorders associated with deficiency of glutamate dehydrogenase.

The activity of glutamate dehydrogenase, the enzyme of glutamate degradation, was measured in platelets of 27 healthy controls and 85 patients with different degenerative cerebellar and/or basal ganglia disorders. A group of 7 patients was selected with slowly progressive multiple-system atrophy, in whom a clinical diagnosis of olivopontocerebellar atrophy appeared tenable, with decreased activity of glutamate dehydrogenase (38% of the mean control value). In 4 patients data on inheritance were compatible with the genetic pattern of autosomal recessive inheritance, while 3 patients were sporadic cases. In an effort to define this group of patients more precisely, it is suggested that decreased activity of glutamate dehydrogenase induces an increase in extracellular glutamate levels in the central nervous system with subsequent development of excitotoxicity.

DYT1 mutation in primary torsion dystonia in a Serbian population.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. A GAG deletion at position 946 in the DYT1 gene is responsible for most cases of autosomal dominant early-onset PTD. We analysed the DYT1 mutation in 50 patients from a Serbian population, selected according to the proposed guidelines for diagnostic testing: (a) 38 patients with PTD onset < 26 years, and (b) 12 patients with the disease onset +/- 26 years, but with at least one affected family member with early-onset dystonia. Only three apparently sporadic patients among the 50 individuals tested were positive for the GAG deletion in the DYT1 gene: one with typical, generalized, one with long-lasting, non-progressive segmental, and one with multifocal dystonia. Molecular analysis of relatives in 2 families revealed that the lack of family history was due to reduced penetrance.

Depression and Parkinson's disease: possible role of serotonergic mechanisms.

Depression is frequently encountered in Parkinson's disease and was seen to occur in 14 of 26 patients studied. The levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin (5-HT), in CSF samples of the patients were significantly lower than in those of controls. However, within the group of patients the levels of 5-HIAA in CSF samples were significantly lower in the depressive subgroup compared with the non-depressive patients. Moreover, no correlation was recorded between motor disability and depression. The results indicate that disturbed 5-HT metabolism may possibly play a role in Parkinson's disease as a predisposing factor in the development of depression.

Reduced rapid eye movement sleep latency in patients with Parkinson's disease.

Rapid eye movement (REM) sleep latency (time from sleep onset to the first REM episode) was measured in 39 patients with idiopathic Parkinson's disease. Reduced REM sleep latency (less than or equal to 65.0 min) was found in a high proportion of patients (69%). Since reduced REM sleep latency may be a trait-like abnormality relatively specific to primary depression, we evaluated this parameter in two groups of parkinsonian patients: depressed (16 patients) and non-depressed (23 patients). Its incidence was significantly higher in depressed patients with Parkinson's disease.

Effect of unilateral perinatal hypoxic-ischemic brain injury on striatal dopamine uptake sites and D1 and D2 receptors in adult rats.

The effect of unilateral perinatal hypoxic-ischemic brain injury on striatal dopamine uptake sites and on D1 and D2 receptors was investigated in rat by using in vitro quantitative receptor binding autoradiography, 9-11 weeks after the insult. Saturation experiments revealed a significant 20% decrease in maximal binding capacity (Bmax) for [3H]spiperone-labeled D2 receptors on the side of the lesion in comparison to the non-lesioned contralateral side or to either side of control animals. There was no significant change in [3H]mazindol-labeled dopamine uptake sites or in [3H]SCH 23390-labeled D1 receptor characteristics (Bmax and Kd) on the lesioned side. We conclude that the decrease in D2 receptor binding previously observed in immature animals is persistent, whereas the decrease in D1 binding is not.

Impairment of cortical inhibition in writer's cramp as revealed by changes in electromyographic silent period after transcranial magnetic stimulation.

Changes in silent period (SP) duration following transcranial magnetic stimulation (TMS) set at 20% above the motor threshold were studied in six subjects suffering from writer's cramp, while performing dystonic movement and during voluntary isometric contraction of the muscles mostly involved in the dystonic movement. Dependency of SP duration on the intensity of preceding muscle contraction was compared on both affected and healthy side. In all subjects SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the same hand. Also, in five subjects, SP duration during dystonic contraction was shorter than during voluntary contraction of the similar strength performed with the healthy hand. In addition, the SP duration on the affected side was negatively associated with the intensity of the preceding contraction (i.e. the stronger contraction the shorter SP), while on the healthy side it was not the case. It is concluded that central inhibitory mechanisms are abnormal in writer's cramp.

Utility of auditory P300 in detection of presenile dementia.

The significance of P300 in investigation of the cognitive changes characteristic of aging and dementia is well established. But some controversies about sensitivity and specificity of P300 latency prolongation in detection of dementia still exist, and its predictive value and specificity in "real" clinical situations (i.e., in mixed population of neurological patients, both demented and nondemented but potentially cognitively impaired) were seldom estimated. In order to elucidate these questions, we recorded auditory event-related potentials ("oddball" paradigm) in 40 demented patients, 58 nondemented neurological patients, and 39 healthy subjects aged < or = 65 years. In addition, for the qualitative analysis of the data, we calculated three normality ranges of different width (i.e., control group's mean +/- 3 SD, 2.5 SD, and 2 SD, respectively). Our results showed that P300 latency was significantly longer in demented patients as compared to both controls and nondemented patients. Sensitivity of the P300 latency prolongation in detection of dementia depends on the width of the selected normality range, and is greatest for the narrowest range (70%), and diminishes with its widening. Specificity of this parameter, when only demented patients and controls were considered (approach used in the majority of the previous studies) was 100%, regardless of the range used. However, when the assessment was done in a mixed population of neurological patients, the P300 latency prolongation showed smaller but still very high specificity (from 86.2 to 100%) and the predictive value (from 77.8 to 100%). Depending on the width of the normality range selected, the rise of sensitivity was associated with fall of specificity and predictive value (and vice versa).

Correlation between Bereitschaftspotential and reaction time measurements in patients with Parkinson's disease. Measuring the impaired supplementary motor area function?

For a long time, reaction time (RT) testing has been used for objective assessment of characteristics of the movement impairments in patients with Parkinson's disease (PD). On the other hand, it is supposed that Bereitschaftspotential (BP) reflects CNS preparatory activity for the execution of voluntary movements, and amplitudes of BP are generally smaller in PD. In order to analyze possible correlations between two methods, we studied 15 drug-naive patients with idiopathic PD (Hoehn and Yahr stage from 1 to 2.5). BP was recorded from three scalp locations: Cz, C3, and C4, and Lateralized Potential (LP) was additionally calculated as a C3-C4 difference waveform. We recorded amplitudes of the initial part of BP (at 650 ms before movement-NS1), the maximal amplitude immediately before movement onset (N1), and the N1-NS1 difference (NS2), from the Cz and LP recordings. Two RT testing paradigms were used: Simple Reaction Time (SRT) and Choice Reaction Time (ChRT). The only significant correlation between RT parameters and BP amplitudes from Cz was negative correlation between dT (difference time between Choice Reaction Time and Simple Reaction Time), on one hand, and NS1 (P = 0.006) and N1 (P = 0.026), on the other. However, Cz-NS2 did not correlate with any of the RT parameters. Our data suggest that PD patients with smaller difference between ChRT and SRT, that is presumably caused by the lesser capacity of the movement pre-programming, have smaller (i.e., less negative) BP amplitudes. This association is especially pronounced for the earlier, NS1 amplitude that is supposed to reflect the activity of the supplementary motor area (SMA). The diminished capacity of SMA activation may be the cause of the both, smaller early BP amplitudes, and smaller ChRT-SRT difference, in PD patients.

Clozapine in hemiballismus: report of two cases.

Hemiballism is a relatively rare hyperkinetic disorder; treatment is based mainly on neuroleptics and drugs that decrease release of dopamine. We report the cases of two patients with hemiballism. After a period of 1 month of nonresponsiveness to haloperidol, amelioration of ballistic movements was observed only a few days after the initiation of clozapine therapy (50 mg/day). Our report suggests that clozapine may be a valuable alternative for patients with hemiballism.

The therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, in Parkinson's disease.

In this open study, the therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, was tested in 20 patients with Parkinson's disease who developed levodopa-induced motor response complications. Moclobemide as adjunct therapy reduced "off" time duration for 27%, without an overall motor and functional improvement during their "on" periods. Since it was well tolerated, moclobemide may be specially indicated in elderly or depressed fluctuating parkinsonian patients.

Depression in Parkinson's disease: an EEG frequency analysis study.

Although depression is a common finding in Parkinson's disease (PD), its neurobiological mechanism is still unknown. The purpose of this study was to determine whether there are specific spectral electroencephalographic (EEG) characteristics that distinguish depressed from non-depressed PD patients. The study was performed in 24 patients with idiopathic PD whose antiparkinson medication was stopped 24h beforehand. They were divided into two groups of 12 patients each, one with depressive symptomatology, and one without. The groups did not differ with respect to age, sex distribution, and disease severity and duration. All recordings were conducted using a 16-channel electroencephalograph, and artifact-free EEG was processed using a Fast Fourier Transformation. The EEG of depressed PD patients showed significantly less absolute and relative power in spectral band 7.5-10Hz (alpha1), and slightly more relative power in spectral band 10.513Hz (alpha2), while there was no difference in other spectral bands. Topographic analysis of the alpha1 absolute power revealed that, while in non-depressed patients this activity has a clear occipital maximum (and thus corresponds to the standard background activity), in depressed patients its maximum was shifted anteriorally toward the parietal region. Topographic analysis of the significance of the difference between the groups in the relative power of alpha1 and alpha2 bands revealed opposite gradients, posterior to anterior and anterior to posterior directions, respectively. The spectral EEG characteristics of the depressed PD patients not only differed from the spectral EEG characteristics of non-depressed PD patients, but they were also different from the usually reported spectral EEG characteristics of depressed patients without neurological disease. We propose that our data are sufficient to raise the possibility for the existence of a distinctive neurobiological substrate of depression in PD. This is not just a simple addition of two neurobiological substrata, one of depression (as it is determined in non-neurological patients) and one of PD, but rather a complex product of their interaction.