Reliability of clinical diagnosis of dystonia.

BACKGROUND: There is only one small single-center study on the reliability of the diagnosis of focal dystonia. The aim of this study was to assess the inter-rater reliability of dystonia diagnosis among neurologists with different professional experience. METHODS: Twenty-nine adults (18 with dystonia, 9 with other movement disorders, and 2 healthy controls) were videotaped while undergoing neurological examination and during the process of collecting information on the history of their condition. Each case was diagnosed by 35 blind raters (12 general neurologists, 21 neurology residents, and 2 experts in movement disorders) from different hospitals. Sensitivity and specificity were calculated confronting raters with the gold standard (the caring physician). Inter-rater agreement was measured by the Kappa statistic. RESULTS: Specificity and sensitivity were 95.2 and 66.7%, 76.3 and 75.2%, 84.6 and 71.6% for experts, general neurologists, and residents, respectively. Kappa values on dystonia diagnosis ranged from 0.30 to 0.46. The agreement was moderate for experts and residents (0.40-0.60) and fair for general neurologists (0.20-0.40). Kappas were the highest among experts for cranial and laryngeal dystonia (0.61-1), but not for cervical dystonia (0.37). CONCLUSIONS: The diagnosis of dystonia is difficult and only partially mirrors a physician's background.

Association analysis of PARP1 polymorphisms with Parkinson's disease.

Alpha-synuclein accumulation in intracellular inclusions, oxidative stress and microglia-mediated inflammation in the substantia nigra are crucial events in the pathogenesis of Parkinson's disease (PD). Poly (ADP-ribose) polymerase-1 (PARP1), a DNA-binding enzyme and transcriptional regulator, plays an important role in modulating the cellular response to oxidative stress, inflammatory stimuli, and in apoptotic cell death. Inhibition of PARP1 results in significant neuroprotection in PD animal models; moreover PARP1 has a physiological role in the regulation of alpha-synuclein expression. A previous study had demonstrated that variants located within the PARP1 gene promoter reduce the risk of PD and delay the disease age at onset. In light of these data, we carried out an association study to investigate whether variability within this gene is associated with PD risk and disease age at onset in an Italian cohort composed of 600 PD patients and 592 healthy controls. To this purpose, we used a comprehensive tag SNP approach spanning the entire gene and the upstream and downstream regions. We did not detect any significant association of the PARP1 gene with PD either at genotypic or haplotypic level; none of the 11 genotyped SNPs was significantly associated with PD age at onset. We conclude that, despite previous evidence, PARP1 is not a susceptibility gene for PD in our population.

Alpha-synuclein nitration and autophagy response are induced in peripheral blood cells from patients with Parkinson disease.

Several lines of evidence implicate a central role for alpha-synuclein (aSN) in the pathogenesis of Parkinson's disease (PD). Besides rare genetic mutations, post-translational mechanisms, such as oxidative stress-related nitration, may alter the protein properties in terms of propensity to aggregate or be degraded. Our group previously described increased reactive oxygen species (ROS) production within easily accessible peripheral blood mononuclear cells (PBMCs) in PD patients compared to healthy elderly subjects. In the present work, we demonstrated a significant induction of nitrotyrosine (NT)-modifications of aSN within PBMCs derived from individuals with idiopathic PD compared to controls, while aSN protein appeared similarly expressed in the two populations. The amount of NT-modified aSN within PBMCs was positively correlated with intracellular ROS concentration and inversely related to daily dosage of levodopa, making its measurement potentially relevant for disease-intervention studies. Neither aSN expression nor its NT-modifications showed any correlation to specific REP1 genotypes, polymorphic variants within aSN gene promoter whose association to PD susceptibility may occur through the modulation of aSN protein expression. Moreover, although NT-modified aSN has been linked to enhanced propensity to aggregate, we failed to detect an increased presence of insoluble aSN aggregates in PBMCs from PD subjects relative to controls, despite a lack of changes in the ubiquitin-proteasome expression or activity. Nonetheless, a significant activation of the autophagy response was identified within PBMCs from PD individuals, which could represent a protective mechanism against abnormal protein accumulation and may explain the lack of aSN aggregation. We discuss the relevance of these findings with respect to PD pathogenesis and biomarker development.

Lymphomonocyte alpha-synuclein levels in aging and in Parkinson disease.

In this study we employed an ELISA assay to measure alpha-synuclein protein in lymphomonocytes from 78 PD patients and 78 controls. We correlated protein levels with demographic and clinical characteristics and with the chymotryptic and tryptic activities of the 20S proteasome. Alpha-synuclein levels were not significantly different between patients and controls. In control subjects, alpha-synuclein protein levels increased significantly with age and were significantly higher in men compared to women. Proteasome activity was not significantly different between cases and controls. In control group, the 20S chymotryptic activity tended to decrease significantly with increasing age, though it was not correlated to alpha-synuclein levels. The 20S tryptic activity was not significantly correlated to age, but was inversely correlated to alpha-synuclein levels. Our findings suggest that alpha-synuclein levels in lymphomonocytes are affected by age, gender, and by the 20S proteasome activity in control subjects, but they are not useful as a diagnostic biomarker for PD.

Oxidative stress in peripheral blood mononuclear cells from patients with Parkinson's disease: negative correlation with levodopa dosage.

Oxidative stress, resulting from the imbalance between reactive oxygen species (ROS) formation and antioxidant defenses, plays a major role in the pathogenesis of Parkinson's disease (PD). However, the contribution of levodopa (LD) therapy to oxidative damage is still debated. We investigated oxidative stress in peripheral blood mononuclear cells (PBMCs) from LD-treated PD patients and healthy subjects. Increased ROS production associated with unaltered glutathione reductase activity was detected in PBMC from PD patients. LD daily dosage appeared to be inversely correlated with ROS levels and positively associated with GR activity, suggesting a protective role for LD on PBMCs redox status. Our data support the view of systemic oxidative stress involvement in PD and give further rationale for using PBMCs as an easily accessible ex-vivo dopaminergic model for exploring the biological effects of LD therapy.

Clinical, neuropsychological, and morphometric correlates of apathy in Parkinson's disease.

Apathy is a salient feature of various neuropsychiatric disorders, from depression to Alzheimer's disease. We formally assess its prevalence in idiopathic Parkinson's disease (PD) together with its clinical, neuropsychological, and morphometric correlates. Thirty patients with PD and 25 normal controls were assessed using an extensive neuropsychological battery and Marin's Apathy Scale; parkinsonian patients also underwent MRI scan, followed by linear measurement of various frontotemporal structures. Approximately 45% of the PD sample showed apathy. For comparison analysis, given the unimodal distribution of the apathy scores, the PD sample was divided into three groups on the basis of the apathy tertiles. All three PD groups had worse cognitive and depression scores than controls, whereas they did not differ in terms of demographic, neurological, general cognitive, or affective features. By contrast, a significant positive association was found between apathy scores and performance on tests of executive function. As regards the morphometric data, we failed to find any specific measure of frontotemporal atrophy correlating with the presence or severity of apathy. Thus, apathy seems to be a frequent and important companion of PD, in many cases probably due to a primary motivational impairment, possibly related to a frontosubcortical dysfunction.