BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease.

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659). The primary measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and its motor component (UPDRS-III). Groups were divided by genotype and treatment regimen (levodopa monotherapy vs levodopa with other medications vs no levodopa). T allele carriers were associated with worse UPDRS outcomes compared to C/C subjects when treated with levodopa monotherapy (+ 6 points, p = 0.02) and to T allele carriers treated with no levodopa treatment strategies (UPDRS: + 8 points, p = 0.01; UPDRS-III: + 6 points, p = 0.01). Similar effects of worse outcomes associated with levodopa monotherapy were observed in the BDNF rs11030094, rs10501087, and rs1491850 SNPs. This study suggests the levodopa monotherapy strategy is associated with worse disease outcomes in BDNF rs6265 T carriers. Pending prospective validation, BDNF variants may be precision medicine factors to consider for symptomatic treatment decisions for early-stage PD patients.

The Functional Alterations in Top-Down Attention Streams of Parkinson's disease Measured by EEG.

Early and moderate Parkinson's disease patients seem to have attention dysfunctions manifested differentially in separate attention streams: top-down and bottom-up. With a focus on the neurophysiological underpinnings of such differences, this study evaluated source-localized regional activity and functional connectivity of regions in the top-down and bottom-up streams as well as any discordance between the two streams. Resting state electroencephalography was used for 36 Parkinson's disease patients and 36 healthy controls matched for age and gender. Parkinson's disease patients showed disproportionally higher bilateral gamma activity in the bottom-up stream and higher left alpha2 connectivity in the top-down stream when compared to age-matched controls. An additional cross-frequency coupling analysis showed that Parkinson's patients have higher alpha2-gamma coupling in the right posterior parietal cortex, which is part of the top-down stream. Higher coupling in this region was also associated with lower severity of motor symptoms in Parkinson's disease. This study provides evidence that in Parkinson's disease, the activity in gamma frequency band and connectivity in alpha2 frequency band is discordant between top-down and bottom-up attention streams.

Levodopa-carbidopa intestinal gel in advanced Parkinson's: Final results of the GLORIA registry.

INTRODUCTION: This registry evaluated the 24-month safety and efficacy of levodopa-carbidopa intestinal gel (LCIG) treatment in advanced Parkinson's disease (PD) patients under routine clinical care. METHODS: Motor fluctuations, dyskinesia, non-motor symptoms, quality of life, and safety were evaluated. Observations were fully prospective for treatment-naïve patients (60% of patients) and partially retrospective for patients with ≤12 months of pre-treatment with LCIG (40% of patients). Hours of "On" and "Off" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale part IV items 32 and 39. RESULTS: Overall, 375 patients were enrolled by 75 movement disorder centers in 18 countries and 258 patients completed the registry. At 24 months LCIG treatment led to significant reductions from baseline in "Off" time (hours/day) (mean ± SD = -4.1 ± 3.5, P < 0.001), "On" time with dyskinesia (hours/day) (-1.1 ± 4.8, P = 0.006), Non-Motor Symptom Scale total (-16.7 ± 43.2, P < 0.001) and individual domains scores, and Parkinson's Disease Questionnaire-8 item total score (-7.1 ± 21.0, P < 0.001). Adverse events deemed to have a possible/probable causal relationship to treatment drug/device were reported in 194 (54%) patients; the most frequently reported were decreased weight (6.7%), device related infections (5.9%), device dislocations (4.8%), device issues (4.8%), and polyneuropathy (4.5%). CONCLUSIONS: LCIG treatment led to sustained improvements in motor fluctuations, non-motor symptoms particularly sleep/fatigue, mood/cognition and gastrointestinal domains, as well as quality of life in advanced PD patients over 24 months. Safety events were consistent with the established safety profile of LCIG.

Verbal monitoring in Parkinson's disease: A comparison between internal and external monitoring.

Patients with Parkinson's disease (PD) display a variety of impairments in motor and non-motor language processes; speech is decreased on motor aspects such as amplitude, prosody and speed and on linguistic aspects including grammar and fluency. Here we investigated whether verbal monitoring is impaired and what the relative contributions of the internal and external monitoring route are on verbal monitoring in patients with PD relative to controls. Furthermore, the data were used to investigate whether internal monitoring performance could be predicted by internal speech perception tasks, as perception based monitoring theories assume. Performance of 18 patients with Parkinson's disease was measured on two cognitive performance tasks and a battery of 11 linguistic tasks, including tasks that measured performance on internal and external monitoring. Results were compared with those of 16 age-matched healthy controls. PD patients and controls generally performed similarly on the linguistic and monitoring measures. However, we observed qualitative differences in the effects of noise masking on monitoring and disfluencies and in the extent to which the linguistic tasks predicted monitoring behavior. We suggest that the patients differ from healthy subjects in their recruitment of monitoring channels.

Mindfulness Training among Individuals with Parkinson's Disease: Neurobehavioral Effects.

Objective. To investigate possible neurobehavioral changes secondary to a mindfulness based intervention (MBI) training for individuals living with Parkinson's disease (PD). Background. In the context of complementary medicine, MBIs are increasingly being used for stress reduction and in patient populations coping with chronic illness. The use of alternative and complementary medicine may be higher in patients with chronic conditions such as PD. However, behavioral effects of mindfulness training in PD have not yet been reported in the literature and this points to an unmet need and warrants further examination. Methods. A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Questionnaires and the UPDRS I-IV were obtained at baseline and 8-week follow-up. Results. Significant changes after the MBI were found including a 5.5 point decrease on the UPDRS motor score, an increase of 0.79 points on Parkinson's disease questionnaire (PDQ-39) pain item, and a 3.15 point increase in the Five Facet Mindfulness Questionnaire observe facet. Conclusions. To the best of our knowledge, this is the first quantitative analysis of neurobehavioral effects of MBI in PD.

Impulse control disorders in Parkinson's disease: an overview from neurobiology to treatment.

Parkinson's disease (PD) is the second most common neurodegenerative brain disorder and is characterized by motor symptoms such as tremor, bradykinesia, rigidity and postural instability. A majority of the patients also develop non-motor symptoms. Impulse control disorders (ICD) are behavioural changes that often fail to be detected in clinical practice. The prevalence of ICD in PD varies widely from 6.1 to 31.2 % and treatment with dopaminergic medication is considered to be the greatest risk factor. Management consists mainly of reducing dopaminergic medication. In our experience, ICD has a tremendous impact on the quality of life of the patients and their families and should therefore not be disregarded. Studies addressing the role of ICD in PD caregiver strain are imperative. We attempt to give a comprehensive overview of the literature on the complicated neurobiology of ICD and discuss risk factors, genetic susceptibility, screening modalities and management.

Intestinal levodopa infusion: the Belgian experience.

Data concerning efficacy, safety, and patient satisfaction of levodopa/carbidopa intestinal gel (LCIG, Duodopa, AbbVie, Wavre, Belgium) infusion in routine clinical practice were needed to maintain reimbursement of the drug in Belgium. Patients with advanced Parkinson's disease in 27 neurology centers across Belgium were included. Of 100 patients who underwent naso-intestinal (NI) evaluation with LCIG, 67 received permanent treatment with LCIG via percutaneous endoscopic gastrostomy and jejunal tube (PEG/J). Efficacy was evaluated at baseline (on levodopa) and during a follow-up (FU) visit (on LCIG) using the Unified Parkinson's Disease Rating Scale (UPDRS) IV. Patient appraisal of the Duodopa system was evaluated using a visual analog scale for therapy compliance, user-friendliness, and global appreciation. Safety was assessed by reporting suspected adverse drug reactions (ADRs) and medical device-related complaints. FU evaluations were conducted in 37 patients. Significant improvement at FU was observed for motor complications (UPDRS IV) as the mean change from baseline to FU was -6.3 (95 % CI -8.1 to -4.5). Patient appraisal showed high scores for hospital delivery, user-friendliness, and patient global appreciation, as well as family appreciation of the system on daily life. Few ADRs and system malfunctions were reported, with no unexpected ADRs. In conclusion, the symptoms and impact of Parkinsonism improved markedly when LCIG PEG/J was initiated.

Mindfulness based intervention in Parkinson's disease leads to structural brain changes on MRI: a randomized controlled longitudinal trial.

OBJECTIVE: The aim of the current study is to investigate structural changes on brain MRI using voxel based morphometry (VBM) related to an eight-week mindfulness based intervention (MBI) in Parkinson's Disease (PD). METHODS: A total of 27 out of 30 PD patients completed a randomized controlled longitudinal trial. Fourteen patients participated in a structured eight-week program of MBI. Thirteen patients received usual care (UC) alone. MRI data sets of the brain were obtained at baseline and after eight weeks follow-up. VBM analysis was performed using DARTEL from the SPM8 software. The resulting difference maps were statistically compared to examine gray matter density (GMD) differences. Results were reported at p<0.001, uncorrected for multiple comparisons. RESULTS: Increased GMD was found in the MBI compared to the UC group in the region of interest (ROI) analysis in the right amygdala, and bilaterally in the hippocampus. Whole brain analysis showed increased GMD in the left and right caudate nucleus, the left occipital lobe at the lingual gyrus and cuneus, the left thalamus, and bilaterally in the temporo-parietal junction. In contrast, GMD differences were found in the UC group in the left anterior lobe and dentate nucleus of the cerebellum. CONCLUSIONS: To the best of our knowledge this is the first quantitative analysis of neurobiological effects of MBI in PD. Increased GMD was found in the MBI group in the neural networks that have been postulated to play an important role in PD. These areas have also been implicated in the functional networks mediating the benefits of meditation.

Guanosine triphosphate cyclohydrolase 1 promoter deletion causes dopa-responsive dystonia.

BACKGROUND: Autosomal dominant dopa-responsive dystonia (AD-DRD) is caused by a biochemical defect primarily resulting from guanosine triphosphate cyclohydrolase 1 gene (GCH1) mutations. Few families have been reported without mutations in GCH1. METHODS: Genome-wide linkage analysis and positional cloning to identify the genetic defect in a Belgian AD-DRD family was carried out. RESULTS AND CONCLUSION: In this study, we report on the identification and characterization of a novel 24-kb deletion spanning exon 1 and the 5' regulatory region of GCH1 causing a wide spectrum of motor and nonmotor symptoms in a large Belgian AD-DRD family. This large-scale deletion of regulatory sequences leads to decreased GCH1 activity in all carriers, most probably resulting from allelic loss of transcription. We mapped the breakpoints of this deletion to the nucleotide level, allowing the development of a straightforward polymerase chain reaction assay for fast, efficient detection of this large deletion, which will prove valuable for preimplantation genetic diagnosis.

Contribution of VPS35 genetic variability to LBD in the Flanders-Belgian population.

VPS35 was recently identified as a novel autosomal dominant gene for Parkinson disease. In this study, we aimed to determine the contribution of simple and complex VPS35 variations to the genetic etiology of the spectrum of Lewy body disorders (LBD) in a Flanders-Belgian patient cohort (n = 677). We identified 3 novel missense variations in addition to 1 silent and 1 intronic variation predicted to activate a cryptic splice site, but no copy number variations. Despite the absence of these rare variations in the control group (n = 800), we could not attain convincing evidence for pathogenicity by segregation analysis or in silico predictions. Hence, our data do not support a major role for VPS35 variations in the genetic etiology of Lewy body disorders in the Flanders-Belgian population.

DLB and PDD: a role for mutations in dementia and Parkinson disease genes?

Based on the substantial overlap in clinical and pathological characteristics of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) with Alzheimer disease (AD) and Parkinson disease (PD) we hypothesized that these disorders might share underlying genetic factors. The contribution of both sequence and copy number variants (CNVs) in known AD and PD genes to the genetic etiology of DLB and PDD however is currently unclear. Therefore, we performed a gene-based mutation analysis of all major AD and PD genes in 99 DLB and 75 PDD patients, including familial and sporadic forms, from Flanders, Belgium. Also, copy number variants in APP, SNCA, and PARK2 were determined. In the AD genes we detected proven pathogenic missense mutations in PSEN1 and PSEN2, and 2 novel missense variants in PSEN2 and MAPT. In the PD genes we identified 1 SNCA duplication, the LRRK2 R1441C founder mutation and 4 novel heterozygous missense variants with unknown pathogenicity. Our results suggest a contribution of established AD and PD genes to the genetic etiology of DLB and PDD though to a limited extent. They do support the hypothesis of a genetic overlap between members of the Lewy body disease spectrum, but additional genes still have to exist.

Non-motor symptoms in a Flanders-Belgian population of 215 Parkinson's disease patients as assessed by the Non-Motor Symptoms Questionnaire.

BACKGROUND: Non-motor symptoms (NMS) in Parkinson's disease (PD) are frequent, increase the patients' disability and have an important negative impact on their quality of life. METHODS: We used a Dutch translation of the Non-Motor Symptoms Questionnaire (NMSQuest) to identify NMS in a population of 215 Belgian PD patients. RESULTS: A median number of 8 NMS was reported per patient. Urinary urgency (59.2 %), nocturia (56.9 %), insomnia (45.8 %), attention problems (45.5 %) and orthostatism (41.2 %) were the most frequently denoted NMS. A higher number of NMS was present with more severe Hoehn and Yahr stages. Longer disease duration was associated with more NMS. Furthermore, clinical markers of disease progression were also associated with a higher number of NMS. However, early-onset patients (< 50 years) reported less NMS than late-onset patients after correction for disease duration. Interestingly, in early-onset patients we observed more unexplained pain and more hyperhydrosis. CONCLUSION: We confirm the high prevalence of NMS in PD patients. A long disease duration and more severe disease are associated with a higher number of NMS. Importantly, even if late-onset patients generally report more NMS, unexplained pain and hyperhydrosis are more frequent in early-onset patients.

Assessment of prosodic communicative efficiency in Parkinson's disease as judged by professional listeners.

This study examines the impact of Parkinson's disease (PD) on communicative efficiency conveyed through prosody. A new assessment method for evaluating productive prosodic skills in Dutch speaking dysarthric patients was devised and tested on 36 individuals (18 controls, 18 PD patients). Three professional listeners judged the intended meanings in four communicative functions of Dutch prosody: Boundary Marking, Focus, Sentence Typing, and Emotional Prosody. Each function was tested through reading and imitation. Interrater agreement was calculated. Results indicated that healthy speakers, compared to PD patients, performed significantly better on imitation of Boundary Marking, Focus, and Sentence Typing. PD patients with a moderate or severe dysarthria performed significantly worse on imitation of Focus than on reading of Focus. No significant differences were found for Emotional Prosody. Judges agreed well on all tasks except Emotional Prosody. Future research will focus on elaborating the assessment and on developing a therapy programme paralleling the assessment.

GIGYF2 has no major role in Parkinson genetic etiology in a Belgian population.

Missense mutations were identified in the Grb10-Interacting GYF Protein-2 gene (GIGYF2), located in the chromosomal region 2q36-q37, in familial Parkinson disease (PD) patients of European descent. To determine the contribution of GIGYF2 mutations in an extended (N=305) Belgian series of both familial and sporadic PD patients, we sequenced all 32 coding and non-coding exons of GIGYF2. In three sporadic PD patients we identified two novel heterozygous missense mutations (c.1907A>G, p.Tyr636Cys and c.2501G>A, p.Arg834Gln), that were absent from control individuals (N=360). However, since we lack genetic as well as functional data supporting their pathogenic nature, we cannot exclude that these variants are benign polymorphisms. Together, our results do not support a role for GIGYF2 in the genetic etiology of Belgian PD.

Contribution of TARDBP to Alzheimer's disease genetic etiology.

The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD patients (n=485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val substitution in two patients. One extra p.Ala90Val carrier was observed by sequencing exon 3 of an additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and haplotype analysis using microsatellite markers suggested that the three patients might share a common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further, genetic association analyses using five single nucleotide polymorphisms did not detect significant differences between AD patients and control individuals. In conclusion, the genetic contribution of TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic nature that affects the nuclear localization signal in TDP-43.

Treatments for progressing Parkinson's disease: a clinical case scenario study.

OBJECTIVE: A 'case scenario' study on clinical decisions in progressing Parkinson's disease (PD) was developed to complement scientific evidence with the collective judgment of a panel of experts. METHODS: The opinions of 9 experts in movement disorders on the appropriateness of 9 common pharmacological treatments for 33 hypothetical patient profiles were compared to those of 14 general neurologists. Before rating the case scenarios, all participants received a document integrating European and US guidelines for the treatment of patients with advanced PD. Case scenarios showing disagreement or with inconsistencies in appropriateness ratings were discussed at a feedback meeting. A tool for interactive discussion on the clinical case scenarios included was developed based on the outcome of the study. RESULTS: Current guidelines are often insufficient to adequately guide the management of patients with progressing PD. The case scenario study did not reveal major differences in opinions between experts in movement disorders and general neurologists about the appropriateness of certain drug choices for specific case scenarios. However in about 1 out of 5 treatment decisions where experts stated appropriateness or inappropriateness, the general neurologists panel had no or dispersed opinions. CONCLUSIONS: This study reveals more uncertainty about treatment of advanced PD in general neurologists compared with experts in movement disorders and underlines the need for additional support for guiding treatment decisions in clinical practice.

Relative contribution of simple mutations vs. copy number variations in five Parkinson disease genes in the Belgian population.

The relative contribution of simple mutations and copy number variations (CNVs) in SNCA, PARK2, PINK1, PARK7, and LRRK2 to the genetic etiology of Parkinson disease (PD) is still unclear because most studies did not completely analyze each gene. In a large group of Belgian PD patients (N = 310) and control individuals (N = 270), we determined the mutation frequency of both simple mutations and CNVs in these five PD genes, using direct sequencing, multiplex amplicon quantification (MAQ), and real-time PCR assays. Overall, we identified 14 novel heterozygous variants, of which 11 were absent in control individuals. We observed eight PARK2 (multiple) exon multiplications in PD patients and one exon deletion in a control individual. Furthermore, we identified one SNCA whole-gene duplication. The PARK2 and LRRK2 mutation frequencies in Belgian PD patients were similar to those reported in other studies. However, at this stage the true pathogenic nature of some heterozygous mutations in recessive genes remains elusive. Furthermore, though mutations is SNCA, PINK1, and PARK7 are rare, our identification of a SNCA duplication confirmed that screening of these genes remains meaningful.

Reversal of head drop after discontinuation of olanzapine in a DLB patient.

We present a 72-year-oldpatient with probable diffuse Lewy body disease and visual hallucinations, who developed subacute reversible "dropped head syndrome" and parkinsonian signs after the introduction of olanzapine at a total daily dose of 10 mg. One week after olanzapine was withdrawn, the patient's posture started to improve. Further improvement was achieved after dopaminergic substitution. Clinical and electrophysiological observations might indicate neck extensor myopathy due to axial rigidity or focal neck dystonia, induced by dopamine receptor blockade.

Genetic variability in the mitochondrial serine protease HTRA2 contributes to risk for Parkinson disease.

In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5' and 3' regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration.

Founder mutation p.R1441C in the leucine-rich repeat kinase 2 gene in Belgian Parkinson's disease patients.

We determined the prevalence of mutations in two major functional domains of the leucine-rich repeat kinase 2 gene (LRRK2) in Belgian Parkinson's disease (PD) patients (N=304) of which 18.1% were familial PD patients. Ten patients were heterozygous for five different missense mutations (3.29%) of whom six carried the same mutation p.R1441C (1.97%). All six p.R1441C carriers were familial PD patients explaining 10.7% of familial PD in the Belgian patient group. Moreover, they shared a common disease haplotype of 21 consecutive markers in a region of 438 kb, suggesting that they are distant descendants of a single common ancestor. Clinically, p.R1441C carriers had typical levodopa-responsive parkinsonism with tremor as the most common presenting feature. Their age at onset was highly variable and ranged from 39 to 73 years, suggesting the influence of modifying factors. The remaining four patients were heterozygous each for a novel missense mutation located in the Roc or kinase domain. The pathogenic nature of these mutations remains to be determined, though we have genetic evidence that at least some represent rare but benign variants rather than causal mutations. The latter observation indicates that prudence is needed in diagnostic testing of LRRK2 in PD patients. Functional data should underlie a conclusion on the pathogenic nature of some mutations that have not been conclusively linked to disease.