Tiago Mestre

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.

Cerebral venous thrombosis in Behçet’s disease: a systematic review

Behçet’s disease (BD) is a chronic inflammatory multisystem disorder which can involve the central nervous system (CNS). Cerebral venous thrombosis (CVT) is one of its major neurological manifestations. We aimed to review the epidemiologic and clinical features of CVT in patients with BD, as well as the available data on therapeutic interventions and prognosis. Systematic review of all observational studies of BD patients was done. Search strategy included electronic searches of MEDLINE (1966-August 2009). Occurrence of CVT in BD and Neuro-Behçet patients, occurrence of CVT as the inaugural manifestation of BD, clinical and neuro-imaging characteristics of CVT, prothrombotic evaluation, treatment options and prognosis were extracted. A meta-analysis of available results was performed when feasible. Twenty-three studies were included, with 290 cases of CVT in patients with BD. The incidence of CVT per 1,000 person-years was 3 (95% CI: 1–8), being higher in retrospective studies (3.2, 95% CI: 1–10) than in prospective studies (2.7, 95% CI: 1–13). Among patients with neurologic involvement, the incidence rate was 15.1/1,000 person-years. The onset was progressive in 77% of the patients. Intracranial hypertension syndrome was a frequent presentation of CVT in BD. The most frequent sites of occlusion were the superior sagittal and the transverse sinus. Most of the studies did not evaluate the prevalence of prothrombotic disorders. Treated CVT was associated with a good prognosis. CVT is a frequent neurological manifestation of BD. When treated, BD-associated CVT bears a good prognosis. There is insufficient information regarding the role of concomitant prothrombotic disorders and specific treatments.

An evidence-based approach in the treatment of Huntington's disease.

Huntingtons disease (HD) is a neurodegenerative disease with diverse symptoms for which there is no curative or disease-modifying treatment available. Currently, tetrabenazine is the only drug approved for HD by a regulatory agency, and only for the treatment of chorea. In the current review, we present updated results from recent clinical trials and ongoing clinical research efforts to find effective and safe treatments for HD motor, and neuropsychiatric and cognitive symptoms. We used a systematic review approach that included data from well-designed randomised controlled trials. The authors conclude that there is weak evidence to support most of the treatment decisions in HD and thus clinicians may be guided only by expert opinion-based therapeutic recommendations. Ongoing research is considerable and is expected to have an impact in the management of HD in upcoming years.

Subthalamic nucleus-deep brain stimulation for early motor complications in Parkinson's disease—the EARLYSTIM trial: Early is not always better

Subthalamic nucleus deep brain stimulation (STN‐DBS) has revolutionized the management of disabling motor complications in Parkinsons disease. The EARLYSTIM trial applied this treatment to patients who had been experiencing motor complications for less than three years. STN‐DBS significantly improved all primary and secondary outcome measures while best medical therapy failed to provide any improvement at the two‐year follow‐up time point. On face value these results strongly favor the application of STN‐DBS far earlier than is currently applied, when patients are just beginning to experience problems with motor complications. Here we review the application of early DBS and the EARLYSTIM trial from the perspectives of clinical issues, health economics and study design and patient expectation of benefit. We conclude that the most relevant issue is not when to operate but on whom and that early is not always better.

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.

Motor and nonmotor heterogeneity of LRRK2‐related and idiopathic Parkinson's disease

Parkinsons disease (PD) associated with LRRK2 mutations has been described as similar to idiopathic PD with minor clinical differences. No study has compared the clinical features of LRRK2‐associated PD due to different mutations. The objective of this study was to compare LRRK2‐associated PD due to G2019S and G2385R mutations and to compare each to idiopathic PD.

Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing.

Objective: To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic. Methods: The patients’ initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively. Results: Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP’s enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced. Conclusion: Exome sequencing provides a powerful and elegant tool in the specific diagnosis of “mild” or “atypical” neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features.

Associated movement disorders in orthostatic tremor

Introduction Orthostatic tremor is a rare tremor syndrome triggered exclusively by standing, with pathognomonic neurophysiological features. More recently, it has been suggested that orthostatic tremor can present either in isolation (pure orthostatic tremor) or associated with other movement disorders (orthostatic tremor-plus). The present study aims at expanding the knowledge concerning orthostatic tremor associated with other movement disorders. Methods A retrospective case review of the clinical and neurophysiological data of patients diagnosed with orthostatic tremor. Results Median age of onset was 61 years with a median diagnostic delay of 4.5 years. Orthostatic tremor-plus accounted for eight cases (30.8%). The associated movement disorders were Parkinsons disease (n=1), parkinsonism (n=1), progressive supranuclear palsy (n=1), restless leg syndrome (n=1), multifocal action tremor (n=2), pathological proven dementia with Lewy bodies (n=1) and focal dystonia of the arm (n=1). There were no significant differences between primary orthostatic tremor and orthostatic tremor-plus in demographics, clinical presentation of orthostatic tremor, findings in neurophysiological studies and response to treatment. In the majority of cases (n=18, 72%), there was a progressive and disabling course with refractoriness to medical therapy without significant differences between pure orthostatic tremor and orthostatic tremor-plus. Conclusion One of the largest series on orthostatic tremor is presented and the second only focused on additional movement disorders. A progressive course was found, with increasing disability associated with orthostatic tremor. Dementia with Lewy bodies and task specific arm dystonia are reported for the first time as associated movement disorders.

5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders

Introduction: 5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are widely expressed in the brain and have been implicated in mood and behavior. Based on the use of atypical antipsychotics in schizophrenia, antagonism of 5-HT2A-Rs initially emerged as a potential intervention capable of reducing the incidence of extrapyramidal symptoms, while exerting an effective antipsychotic action. More recently, highly selective 5-HT2A-R antagonists have been evaluated in the treatment of a wide range of other psychiatric disorders. Areas covered: The aim of the current review is to present important clinical studies investigating the potential therapeutic effects of 5-HT2A-R antagonists in both primary psychiatric disorders, such as schizophrenia and mood disorders, as well as in psychiatric manifestations of neurodegenerative disorders. We present an overview of 5-HT2A-Rs in normal brain function and the rationale for use in (neuro) psychiatric disease based on significant findings from genetic association studies, neuroimaging data and postmortem studies. The majority of the studies relate to schizophrenia, depression, anxiety, obsessive compulsive disorder and psychosis in Parkinsons disease and Alzheimers disease. To date, there is sparse literature on 5-HT2A-Rs in Gilles de la Tourette syndrome, attention deficit hyperactivity disorder, eating disorders and autism spectrum disorders. The authors conclude by reviewing recent clinical trials investigating highly selective 5-HT2A-R antagonists in schizophrenia, psychosis in Parkinsons disease, insomnia and generalized anxiety. Expert opinion: Despite the potential, to date, 5-HT2A-R antagonists have not made an impact in the management of psychiatric disorders and psychiatric symptoms of neurodegenerative conditions.

The long-term outcome of orthostatic tremor

Objectives Orthostatic tremor is a rare condition characterised by high-frequency tremor that appears on standing. Although the essential clinical features of orthostatic tremor are well established, little is known about the natural progression of the disorder. We report the long-term outcome based on the largest multicentre cohort of patients with orthostatic tremor. Methods Clinical information of 68 patients with clinical and electrophysiological diagnosis of orthostatic tremor and a minimum follow-up of 5 years is presented. Results There was a clear female preponderance (76.5%) with a mean age of onset at 54 years. Median follow-up was 6 years (range 5–25). On diagnosis, 86.8% of patients presented with isolated orthostatic tremor and 13.2% had additional neurological features. At follow-up, seven patients who initially had isolated orthostatic tremor later developed further neurological signs. A total 79.4% of patients reported worsening of orthostatic tremor symptoms. These patients had significantly longer symptom duration than those without reported worsening (median 15.5 vs 10.5 years, respectively; p=0.005). There was no change in orthostatic tremor frequency over time. Structural imaging was largely unremarkable and dopaminergic neuroimaging (DaTSCAN) was normal in 18/19 cases. Pharmacological treatments were disappointing. Two patients were treated surgically and showed improvement. Conclusions Orthostatic tremor is a progressive disorder with increased disability although tremor frequency is unchanged over time. In most cases, orthostatic tremor represents an isolated syndrome. Drug treatments are unsatisfactory but surgery may hold promise.