α-Synuclein Gene Hypomethylation in LRRK2 Parkinson's Disease Patients.

Background: α-Synuclein (SNCA) gene hypomethylation was reported in idiopathic Parkinson's disease (iPD). Based on a high clinical resemblance between iPD and leucine-rich repeat kinase 2 (LRRK2)-driven Parkinson's disease (L2PD), we investigated the epigenetic status of SNCA in an extensive LRRK2 clinical cohort from Spain.

Methods: We assessed the methylation levels of 23 CpG sites in the SNCA promoter region using peripheral blood DNA from L2PD patients (n = 151), LRRK2 nonmanifesting carriers (n = 55), iPD patients (n = 115), and healthy control subjects (n = 154) (total: N = 475).

DRD4 gene polymorphism and impulse control disorder induced by dopamine agonists in Parkinson's disease.

Impulse control disorders and their consequences display variability among individuals, indicating potential involvement of environmental and genetic factors. In this retrospective study, we analyzed a cohort of Parkinson's disease patients treated with dopamine agonists and investigated the influence of the dopamine D4 receptor gene polymorphism, DRD4 7R+, which is linked to psychiatric disorders, impulsive traits, and addictive behaviors. We found that DRD4 7R+ is a significant genetic risk factor associated with the severity of ICD.

Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders.

Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson's disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosing monogenic ND.

Brainstem neuromelanin and iron MRI reveals a precise signature for idiopathic and LRRK2 Parkinson's disease.

Neuromelanin (NM) loss in substantia nigra pars compacta (SNc) and locus coeruleus (LC) reflects neuronal death in Parkinson's disease (PD). Since genetically-determined PD shows varied clinical expressivity, we wanted to accurately quantify and locate brainstem NM and iron, to discover whether specific MRI patterns are linked to Leucine-rich repeat kinase 2 G2019S PD (LRRK2-PD) or idiopathic Parkinson's disease (iPD). A 3D automated MRI atlas-based segmentation pipeline (3D-ABSP) for NM/iron-sensitive MRI images topographically characterized the SNc, LC, and red nucleus (RN) neuronal loss and calculated NM/iron contrast ratio (CR) and normalized volume (nVol).

Elevated urine BMP phospholipids in LRRK2 and VPS35 mutation carriers with and without Parkinson's disease.

Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson's disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies.

Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson's disease.

The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson's disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years.

Cell-free mitochondrial DNA deletions in idiopathic, but not LRRK2, Parkinson's disease.

Mitochondrial dysfunction happens in both idiopathic (iPD) and LRRK2-related Parkinson's disease (LRRK2-PD). Nonetheless, previous studies suggested that a different type of mitochondrial pathology underlies the neurodegeneration in these two disorders. To further explore this hypothesis, we developed a novel multiplex digital PCR assay that allows the absolute quantification of cell-free mitochondrial DNA (cf-mtDNA) copy number and deletion ratio directly in cerebrospinal fluid (CSF) by simultaneously measuring two opposed regions of the mtDNA circular molecule, one of them in the commonly deleted major arc.

Serum MicroRNAs Predict Isolated Rapid Eye Movement Sleep Behavior Disorder and Lewy Body Diseases.

Background: Isolated rapid eye movement sleep behavior disorder (IRBD) is a well-established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB).

Objective: To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning-based modeling.

Methods: Using genome-wide miRNA analysis and real-time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single-photon emission computed tomography into DaT-negative IRBD (n = 17) and DaT-positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20).

Increased Phospho-AKT in Blood Cells from LRRK2 G2019S Mutation Carriers.

The purpose of this study was to investigate whether  differential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). We assessed phospho(P)-Ser-935-LRRK2 and P-Ser-473-AKT levels in peripheral blood cells from patients with G2019S LRRK2-associated PD (L2PD, n = 31), G2019S LRRK2 non-manifesting carriers (L2NMC, n = 26), idiopathic PD (iPD, n = 25), and controls (n = 40, total n = 122). We found no differences at P-Ser-935-LRRK2 between groups but detected a specific increase of P-Ser-473-AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD.

Utility of Postoperative Imaging Software for Deep Brain Stimulation Targeting in Patients with Movement Disorders.

Objective: The objective of this study was to evaluate the accuracy of the SureTune3 postoperative imaging software in determining the location of a deep brain stimulation (DBS) electrode based on clinical outcomes and the adverse effects (AEs) observed.

Methods: Twenty-six consecutive patients with Parkinson disease (n = 17), essential tremor (n = 8), and dystonia (n = 1) who underwent bilateral DBS surgery (52 electrodes) were included in this study. Presurgical assessments were performed in all patients prior to surgery and at 3 and 6 months after surgery, using quality-of-life and clinical scales in each case.

WHOPPA Enables Parallel Assessment of Leucine-Rich Repeat Kinase 2 and Glucocerebrosidase Enzymatic Activity in Parkinson's Disease Monocytes.

Both leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase) are promising targets for the treatment of Parkinson's disease (PD). Evidence suggests that both proteins are involved in biological pathways involving the lysosome. However, studies to date have largely investigated the enzymes in isolation and any relationship between LRRK2 and GCase remains unclear.

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson's Disease.

The association between Parkinson's disease (PD) and mutations in genes involved in lysosomal and mitochondrial function has been previously reported. However, little is known about the involvement of other genes or cellular mechanisms. We aim to identify novel genetic associations to better understand the pathogenesis of PD.

Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson's disease patients.

Neuroinflammation, in which activated microglia are involved, appears to contribute to the development of Parkinson's disease (PD). However, the role of microglial activation and the mechanisms governing this process remain uncertain. We focused on one inhibitory mechanism involved in the control of microglial activation, the microglia inhibitory receptor CD200R1, and its ligand CD200, mainly expressed by neurons.

Differential Phospho-Signatures in Blood Cells Identify LRRK2 G2019S Carriers in Parkinson's Disease.

Background: The clinicopathological phenotype of G2019S LRRK2-associated Parkinson's disease (L2PD) is similar to idiopathic Parkinson's disease (iPD), and G2019S LRRK2 nonmanifesting carriers (L2NMCs) are at increased risk for development of PD. With various therapeutic strategies in the clinical and preclinical pipeline, there is an urgent need to identify biomarkers that can aid early diagnosis and patient enrichment for ongoing and future LRRK2-targeted trials.

Objective: The objective of this work was to investigate differential protein and phospho-protein changes related to G2019S mutant LRRK2 in peripheral blood mononuclear cells from G2019S L2PD patients and G2019S L2NMCs, identify specific phospho-protein changes associated with the G2019S mutation and with disease status, and compare findings with patients with iPD.

Disrupted functional connectivity in PD with probable RBD and its cognitive correlates.

Recent studies associated rapid eye movement sleep behavior disorder (RBD) in Parkinson's disease (PD) with severe cognitive impairment and brain atrophy. However, whole-brain functional connectivity has never been explored in this group of PD patients. In this study, whole-brain network-based statistics and graph-theoretical approaches were used to characterize resting-state interregional functional connectivity in PD with probable RBD (PD-pRBD) and its relationship with cognition.

Differentiation of multiple system atrophy subtypes by gray matter atrophy.

Background And Purpose: Multiple system atrophy(MSA) is a rare adult-onset synucleinopathy that can be divided in two subtypes depending on whether the prevalence of its symptoms is more parkinsonian or cerebellar (MSA-P and MSA-C, respectively). The aim of this work is to investigate the structural MRI changes able to discriminate MSA phenotypes.

Methods: The sample includes 31 MSA patients (15 MSA-C and 16 MSA-P) and 39 healthy controls.

Prediabetes, type 2 diabetes mellitus and risk of Parkinson's disease: A population-based cohort study.

Background: Association of type 2 diabetes mellitus (T2D) with subsequent Parkinson's disease (PD) has supported the link between glucose metabolism and PD. We assessed the risk of PD not only in T2D but also in prediabetes.

Methods: We conducted a retrospective cohort study of the population attended in primary care centres of the Catalan Health Institute in Catalonia between 2006 and 2018.

R1441G but not G2019S mutation enhances LRRK2 mediated Rab10 phosphorylation in human peripheral blood neutrophils.

Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1-2% of all cases of Parkinson's disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2-either in its kinase domain (e.g.

Non-motor symptoms in spasmodic dysphonia: A case control-study.

Objective: Non-motor symptoms (NMS) have been identified in some focal adult-onset dystonia. In the present study we aimed to evaluate the presence of NMS in patients with spasmodic dysphonia (SD), a focal action-induced dystonia that affects intrinsic laryngeal muscle control.

Methods: Seventeen SD patients and 17 control subjects not significantly different in age and sex were evaluated for the presence of NMS.

Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson's disease.

Parkinson's disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD.

Falls Predict Acute Hospitalization in Parkinson's Disease.

Background: There is a need for identifying risk factors for hospitalization in Parkinson's disease (PD) and also interventions to reduce acute hospital admission.

Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort.

Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study.

Impaired Structural Connectivity in Parkinson's Disease Patients with Mild Cognitive Impairment: A Study Based on Probabilistic Tractography.

Probabilistic tractography, in combination with graph theory, has been used to reconstruct the structural whole-brain connectome. Threshold-free network-based statistics (TFNBS) is a useful technique to study structural connectivity in neurodegenerative disorders; however, there are no previous studies using TFNBS in Parkinson's disease (PD) with and without mild cognitive impairment (MCI). Sixty-two PD patients, 27 of whom classified as PD-MCI, and 51 healthy controls (HC) underwent diffusion-weighted 3T magnetic resonance imaging.