Mário M. Rosa

Convergence of miRNA expression profiling, α-synuclein interacton and GWAS in Parkinson's disease.

miRNAs were recently implicated in the pathogenesis of numerous diseases, including neurological disorders such as Parkinsons disease (PD). miRNAs are abundant in the nervous system, essential for efficient brain function and play important roles in neuronal patterning and cell specification. To further investigate their involvement in the etiology of PD, we conducted miRNA expression profiling in peripheral blood mononuclear cells (PBMCs) of 19 patients and 13 controls using microarrays. We found 18 miRNAs differentially expressed, and pathway analysis of 662 predicted target genes of 11 of these miRNAs revealed an over-representation in pathways previously linked to PD as well as novel pathways. To narrow down the genes for further investigations, we undertook a parallel approach using chromatin immunoprecipitation-sequencing (ChIP-seq) analysis to uncover genome-wide interactions of α-synuclein, a molecule with a central role in both monogenic and idiopathic PD. Convergence of ChIP-seq and miRNomics data highlighted the glycosphingolipid biosynthesis and the ubiquitin proteasome system as key players in PD. We then tested the association of target genes belonging to these pathways with PD risk, and identified nine SNPs in USP37 consistently associated with PD susceptibility in three genome-wide association studies (GWAS) datasets (0.46≤OR≤0.63) and highly significant in the meta-dataset (3.36×10−4<p<1.94×10−3). A SNP in ST8SIA4 was also highly associated with PD (p = 6.15×10−3) in the meta-dataset. These findings suggest that several miRNAs may act as regulators of both known and novel biological processes leading to idiopathic PD.

Worldwide frequency of G2019S LRRK2 mutation in Parkinson's disease: A systematic review

BACKGROUND The LRRK2 G2019S mutation is the most frequent known cause of familial and sporadic Parkinsons disease. Knowledge of its worldwide frequency distribution is essential for clinical and molecular research as well as genetic counseling. OBJECTIVES To conduct a systematic review of the reported frequency of G2019S in different populations and to assess critically the quality of the clinical studies. METHODS We conducted a systematic review of all published papers on G2019S frequency in homogeneous ethnic groups or sub-groups of patients. Selected papers were analyzed for methodological quality. RESULTS 68 studies from 32 countries were included in the analysis. A heterogeneous distribution was observed with high frequencies in North African Arab countries, the Middle East, southern Europe, North American Ashkenazi Jewish populations and in South American countries with known European ethnic influence. Frequencies ranged from the no cases to 35.7% in sporadic and 42% in familial North-African Arab patients. Only one paper from one sub-Saharan country was found. Methodological pitfalls were identified. CONCLUSIONS Estimated frequencies were found to be variable, which may reflect ethnic differences and methodological discrepancies. We make recommendations on the methods of selection of participants and on the definition of familial Parkinsons disease to improve the quality of frequency studies on LRRK2 mutations.

High prevalence of LRRK2 mutations in familial and sporadic Parkinson's disease in Portugal

Mutations in the Leucine‐Rich Repeat Kinase 2 (LRRK2) gene are the most frequent known cause of Parkinsons disease (PD), but their prevalence varies markedly between populations. Here we studied the frequency and associated phenotype of four recurrent LRRK2 mutations (R1441C, R1441G, R1441H, and G2019S) in familial and sporadic PD from a single referral center in Lisbon, Portugal. Among 138 unrelated PD probands, we identified 9 heterozygous G2019S carriers (6.52%) and 1 heterozygous R1441H carrier (0.72%). The G2019S mutation was present in 4 of the 107 sporadic (3.74%) and in 5 of the 31 familial probands (16.1%). Mutations were not found among 101 Portuguese controls. The G2019S mutation was present on a single haplotype and displayed reduced penetrance. Heterozygous parkin gene mutations were also found in 2 G2019S‐positive probands, but their pathogenic role is unclear. The clinical phenotype in patients with LRRK2 mutations was indistinguishable from that of typical PD, including impaired sense of smell. The G2019S mutation is a very common genetic determinant among the Portuguese patients with PD, and the R1441H mutation is also present in this population. These data have important implications for the diagnostic work‐up and genetic counseling of patients with this disease in Portugal.

Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson's disease patients

Depigmentation of the substantia nigra (SN) and locus coeruleus (LC) is a conspicuous pathological feature of Parkinsons disease (PD) and is related to the loss of neuromelanin, whose paramagnetic properties result in high signal on specific T1‐weighted magnetic resonance imaging (MRI). Recent studies have suggested that neuromelanin decrease in the SN and LC of PD patients may emerge as a possible diagnostic biomarker. The SN neuromelanin signal in de novo and early stage PD patients was studied to assess its diagnostic accuracy. This is the first study based on a semi‐automated MRI analysis of the neuromelanin signal in de novo PD patients.

Skin cancer and Parkinson's disease

The report of an increased frequency of melanoma during the clinical development of rasagiline prompted a renewed interest in a possible association between skin cancer and Parkinsons disease (PD). The evaluation of this risk ended in a recommendation to perform a periodic dermatological examination as a follow‐up measure of their treatment. The recognition of this safety concern lead to the need to clarify if the risk of skin cancer is indeed associated with PD and if levodopa or other anti‐parkinsonian drugs might contribute to increase such risk. To answer these questions, we critically reviewed all clinical studies available concerning the association between skin cancer and PD. We found 26 studies on cancer occurrence in PD. The best data available suggest the risk of cancer is reduced in PD patients. However, specific cancers like thyroid and the female breast were reported at higher‐than‐expected rates. Additionally, it was suggested that PD patients have a higher frequency of melanoma and non‐melanoma skin cancers than the general population. The data on non‐melanoma skin cancer are less robust than the data on melanoma. Causal factors remain unknown. Due to the weak association between skin cancer and PD, no robust recommendation can be made regarding the need for periodic dermatological screening.

Substantia nigra neuromelanin-MR imaging differentiates essential tremor from Parkinson's disease.

Essential tremor (ET) is a very common movement disorder that has no diagnostic markers. Differentiation with Parkinsons disease (PD) can be clinically challenging in some cases, with a high rate of misdiagnosis. Magnetic resonance imaging (MRI) studies have been able to identify neuromelanin changes in the substantia nigra (SN) of PD patients, but they have thus far not been investigated in ET. In this study, we aimed to characterize neuromelanin‐MR signal changes in ET and evaluate its diagnostic accuracy in the differential diagnosis with PD.

What motivates Parkinson’s disease patients to enter clinical trials?

INTRODUCTION Limited data is available regarding motivations and concerns of Parkinsons disease (PD) patients when participating in clinical trials (CTs). Knowledge of these factors may improve the recruitment and quality of future trials. OBJECTIVES To assess the motivations and concerns of PD patients concerning participation in CTs and to evaluate the extent to which patients understand informed consent materials and placebo effect concept. METHODS Cross-sectional study in PD patients enrolled in CTs between 2002 and 2007. Two questionnaires designed for placebo-controlled and active-controlled studies were mailed to patients. RESULTS From the 93/127 replied questionnaires (response rate: 73.2%) 91 were evaluable. Fifty-nine percent of the participants were women with a mean age of 66.8 years. The main reasons for participating in CTs were to help the advance of science (63.7%), to gain access to a better treatment (56.0%), and to benefit others (51.6%). Risk of adverse events (49.5%) and negative effects of treatment (35.2%) were the major concerns. Ninety percent reported they had understood the informed consent. Of 80 patients included in placebo-controlled studies, 63.9% understood the placebo effect concept. Globally, 66% of patients would participate in another CT and 41.6% in a placebo-controlled trial. CONCLUSIONS The main motivations of PD patients to participate in CTs were the benefit to the patient himself and to others. The major concern was safety. PD patients understood the informed consent, but more educational efforts must be made to explain the placebo effect. Most PD patients were very positive toward CTs and would participate in another trial.

Skin cancers and precancerous lesions in Parkinson's disease patients

Our objective was to evaluate the frequency of neoplastic and preneoplastic skin lesions in Parkinsons disease (PD) patients when compared with an aged‐matched population. We performed a cross‐sectional survey in PD patients and in an age‐matched control group. Patients and controls were examined by a movement disorder specialist and a dermatologist. 150 PD patients and 146 controls were included. Thirty‐five PD patients (23.3%) presented skin lesions that could be classified as neoplastic or preneoplastic vs. 20 subjects in the control group (13.7%) (OR 95%, CI 1.92 [1.05, 3.51]). However, this difference lost statistical significance when adjusted for gender (recruitment of controls was matched just for age with an over representation of males in the PD group). Twenty‐nine PD patients (19%) presented actinic keratosis and basal cell carcinoma was diagnosed in 4 patients (3%). Although nonconclusive, our results are in agreement with previous studies suggesting an increased risk of skin cancer in PD patients. The frequency of actinic keratosis in PD patients and the associated risk to develop melanoma recommends its screening in future epidemiological studies.

Dementia and severity of parkinsonism determines the handicap of patients in late-stage Parkinson's disease: the Barcelona−Lisbon cohort

Handicap has not been explored as a patient‐centred outcome measure in Parkinsons disease (PD). The clinical features and medication use in late stages of PD (LS‐PD) were reported previously.

STN-DBS does not change emotion recognition in advanced Parkinson's disease

UNLABELLED Deep brain stimulation of the subthalamic nuclei (STN-DBS) for the treatment of levodopa-induced motor complications in advanced Parkinsons disease (APD) has been associated with neuropsychiatric disorders. It has been suggested that a postoperative decline in visual emotion recognition is responsible for those adverse events, although there is also evidence that emotional processing deficits can be present before surgery. The aim of the present study is to compare the ability to recognize emotions before and one year after surgery in APD. METHODS Consecutively operated APD patients were tested pre-operatively and one year after STN-DBS by the Comprehensive Affect Testing System (CATS), which evaluates visual recognition of 7 basic emotions (happiness, sadness, anger, fear, surprise, disgust and neutral) on facial expressions and 4 emotions on prosody (happiness, sadness, anger and fear). RESULTS In a sample of 30 patients 6 had depression or apathy at baseline that significantly increased to 14 post-surgery. There were no significant changes in the tests of identity discrimination, discrimination of emotional faces, naming of emotional faces, recognition of emotional prosody, and naming of emotional prosody after STN-DBS. The results of emotion tests could not predict the development of the neuropsychiatric symptoms. DISCUSSION This study does not support the hypothesis of an acquired change in emotion recognition, either in faces or in prosody, after STN-DBS in APD patients. Neuropsychiatric symptoms appearing after STN-DBS should not be attributed to new deficits in emotional recognition.