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See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

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See detailSingle-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Smits, Lisa UL; Magni, Stefano UL; Grzyb, Kamil UL et al

E-print/Working paper (2019)

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an ... [more ▼]

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating these in vivo features makes hMOs an excellent tool for in vitro disease phenotyping and drug discovery. [less ▲]

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See detailAnodal tDCS modulates cortical activity and synchronization in Parkinson's disease depending on motor processing.
Schoellmann, Anna; Scholten, Marlieke; Wasserka, Barbara et al

in NeuroImage. Clinical (2019), 22

BACKGROUND: Transcranial direct current stimulation (tDCS) may alleviate motor symptoms in Parkinson's disease (PD). However, the neurophysiological effects of tDCS on cortical activation, synchronization ... [more ▼]

BACKGROUND: Transcranial direct current stimulation (tDCS) may alleviate motor symptoms in Parkinson's disease (PD). However, the neurophysiological effects of tDCS on cortical activation, synchronization, and the relation to clinical motor symptoms and motor integration need characterization. OBJECTIVE: We aimed to explore the effect of tDCS over the left sensorimotor area on clinical motor outcome, right hand fine motor performance as well as cortical activity and synchronization in the high beta range. METHODS: In this double-blind randomized sham-controlled clinico-neurophysiological study we investigated ten idiopathic PD patients and eleven matched healthy controls (HC) on two days during an isometric precision grip task and at rest before and after 'verum' and 'sham' anodal tDCS (20min; 1mA; anode [C3], cathode [Fp2]). We measured clinical outcome, fine motor performance, and analysed both cortical frequency domain activity and corticocortical imaginary coherence. RESULTS: tDCS improved PD motor symptoms. Neurophysiological features indicated a motor-task-specific modulation of activity and coherence from 22 to 27Hz after 'verum' stimulation in PD. Activity was significantly reduced over the left sensorimotor and right frontotemporal area. Before stimulation, PD patients showed reduced coherence over the left sensorimotor area during motor task compared to HC, and this increased after 'verum' stimulation in the motor task. The activity and synchronization modulation were neither observed at rest, after sham stimulation nor in healthy controls. CONCLUSION: Verum tDCS modulated the PD cortical network specifically during fine motor integration. Cortical oscillatory features were not in general deregulated in PD, but depended on motor processing. [less ▲]

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See detailThe Luxembourg Parkinson’s Study: A Comprehensive Approach for Stratification and Early Diagnosis
Hipp Epouse D'amico, Géraldine UL; Vaillant, Michel; Diederich, Nico J. et al

in Frontiers in Aging Neuroscience (2018), 10

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies ... [more ▼]

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson’s study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches. [less ▲]

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See detailReply: No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson’s disease
Fitzgerald, Julia C.; Zimprich, Alexander; Bobbili, Dheeraj Reddy UL et al

in Brain : A Journal of Neurology (2018)

Sir, In their letter in this issue, Gaare and colleagues (2018) state that TRAP1 may not be a Parkinson’s disease gene because of lack of genetic association. In response, we welcome their data analyses ... [more ▼]

Sir, In their letter in this issue, Gaare and colleagues (2018) state that TRAP1 may not be a Parkinson’s disease gene because of lack of genetic association. In response, we welcome their data analyses and we welcome any further genetic analyses of TRAP1 variants in additional Parkinson’s disease genetic datasets, including the reanalysis of open access datasets such as the Parkinson’s Progressive Markers Initiative (PPMI). Our point of view is that TRAP1 is an interesting effector protein that our study unequivocally showed is relevant to Parkinson’s disease signaling in the context of mitochondrial regulation. Furthermore, the overall contribution of TRAP1 genetic variants to Parkinson’s disease was not the focus of our recent paper in Brain (Fitzgerald et al., 2017). [less ▲]

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See detailThe genetic architecture of mitochondrial dysfunction in Parkinson's Disease
Krüger, Rejko UL; Larsen, Simone UL; Hanss, Zoé UL

in Cell and Tissue Research (2018)

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post mortem ... [more ▼]

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated to mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, it leads to cell death via apoptosis which defines the cellular level of quality control. Here we review how currently known PD-linked genetic variants interfere with the different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants such as GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants as candidates for PD, such as HSPA9, TRAP1 and RHOT1 complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches. [less ▲]

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See detailBehavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial.
Lhommee, Eugenie; Wojtecki, Lars; Czernecki, Virginie et al

in The Lancet. Neurology (2018), 17(3), 223-231

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge ... [more ▼]

BACKGROUND: Although subthalamic stimulation is a recognised treatment for motor complications in Parkinson's disease, reports on behavioural outcomes are controversial, which represents a major challenge when counselling candidates for subthalamic stimulation. We aimed to assess changes in behaviour in patients with Parkinson's disease receiving combined treatment with subthalamic stimulation and medical therapy over a 2-year follow-up period as compared with the behavioural evolution under medical therapy alone. METHODS: We did a parallel, open-label study (EARLYSTIM) at 17 surgical centres in France (n=8) and Germany (n=9). We recruited patients with Parkinson's disease who were disabled by early motor complications. Participants were randomly allocated (1:1) to either medical therapy alone or bilateral subthalamic stimulation plus medical therapy. The primary outcome was mean change in quality of life from baseline to 2 years. A secondary analysis was also done to assess behavioural outcomes. We used the Ardouin Scale of Behavior in Parkinson's Disease to assess changes in behaviour between baseline and 2-year follow-up. Apathy was also measured using the Starkstein Apathy Scale, and depression was assessed with the Beck Depression Inventory. The secondary analysis was done in all patients recruited. We used a generalised estimating equations (GEE) regression model for individual items and mixed model regression for subscores of the Ardouin scale and the apathy and depression scales. This trial is registered with ClinicalTrials.gov, number NCT00354133. The primary analysis has been reported elsewhere; this report presents the secondary analysis only. FINDINGS: Between July, 2006, and November, 2009, 251 participants were recruited, of whom 127 were allocated medical therapy alone and 124 were assigned bilateral subthalamic stimulation plus medical therapy. At 2-year follow-up, the levodopa-equivalent dose was reduced by 39% (-363.3 mg/day [SE 41.8]) in individuals allocated bilateral subthalamic stimulation plus medical therapy and was increased by 21% (245.8 mg/day [40.4]) in those assigned medical therapy alone (p<0.0001). Neuropsychiatric fluctuations decreased with bilateral subthalamic stimulation plus medical therapy during 2-year follow-up (mean change -0.65 points [SE 0.15]) and did not change with medical therapy alone (-0.02 points [0.15]); the between-group difference in change from baseline was significant (p=0.0028). At 2 years, the Ardouin scale subscore for hyperdopaminergic behavioural disorders had decreased with bilateral subthalamic stimulation plus medical therapy (mean change -1.26 points [SE 0.35]) and had increased with medical therapy alone (1.12 points [0.35]); the between-group difference was significant (p<0.0001). Mean change from baseline at 2 years in the Ardouin scale subscore for hypodopaminergic behavioural disorders, the Starkstein Apathy Scale score, and the Beck Depression Inventory score did not differ between treatment groups. Antidepressants were stopped in 12 patients assigned bilateral subthalamic stimulation plus medical therapy versus four patients allocated medical therapy alone. Neuroleptics were started in nine patients assigned medical therapy alone versus one patient allocated bilateral subthalamic stimulation plus medical therapy. During the 2-year follow-up, two individuals assigned bilateral subthalamic stimulation plus medical therapy and one patient allocated medical therapy alone died by suicide. INTERPRETATION: In a large cohort with Parkinson's disease and early motor complications, better overall behavioural outcomes were noted with bilateral subthalamic stimulation plus medical therapy compared with medical therapy alone. The presence of hyperdopaminergic behaviours and neuropsychiatric fluctuations can be judged additional arguments in favour of subthalamic stimulation if surgery is considered for disabling motor complications. FUNDING: German Federal Ministry of Education and Research, French Programme Hospitalier de Recherche Clinique National, and Medtronic. [less ▲]

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See detailMitochondrial Morphology, Function and Homeostasis Are Impaired by Expression of an N-terminal Calpain Cleavage Fragment of Ataxin-3.
Harmuth, Tina; Prell-Schicker, Caroline; Weber, Jonasz J. et al

in Frontiers in molecular neuroscience (2018), 11

Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease and Huntington disease. Metabolic defects, resulting ... [more ▼]

Alterations in mitochondrial morphology and function have been linked to neurodegenerative diseases, including Parkinson disease, Alzheimer disease and Huntington disease. Metabolic defects, resulting from dysfunctional mitochondria, have been reported in patients and respective animal models of all those diseases. Spinocerebellar Ataxia Type 3 (SCA3), another neurodegenerative disorder, also presents with metabolic defects and loss of body weight in early disease stages although the possible role of mitochondrial dysfunction in SCA3 pathology is still to be determined. Interestingly, the SCA3 disease protein ataxin-3, which is predominantly localized in cytoplasm and nucleus, has also been associated with mitochondria in both its mutant and wildtype form. This observation provides an interesting link to a potential mitochondrial involvement of mutant ataxin-3 in SCA3 pathogenesis. Furthermore, proteolytic cleavage of ataxin-3 has been shown to produce toxic fragments and even overexpression of artificially truncated forms of ataxin-3 resulted in mitochondria deficits. Therefore, we analyzed the repercussions of expressing a naturally occurring N-terminal cleavage fragment of ataxin-3 and the influence of an endogenous expression of the S256 cleavage fragment in vitro and in vivo. In our study, expression of a fragment derived from calpain cleavage induced mitochondrial fragmentation and cristae alterations leading to a significantly decreased capacity of mitochondrial respiration and contributing to an increased susceptibility to apoptosis. Furthermore, analyzing mitophagy revealed activation of autophagy in the early pathogenesis with reduced lysosomal activity. In conclusion, our findings indicate that cleavage of ataxin-3 by calpains results in fragments which interfere with mitochondrial function and mitochondrial degradation processes. [less ▲]

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See detailLong-Term Effect of GPi-DBS in a Patient With Generalized Dystonia Due to GLUT1 Deficiency Syndrome.
Hanci, Idil; Kamm, Christoph; Scholten, Marlieke et al

in Frontiers in neurology (2018), 9

Treatment outcomes from pallidal deep brain stimulation are highly heterogeneous reflecting the phenotypic and etiologic spectrum of dystonia. Treatment stratification to neurostimulation therapy ... [more ▼]

Treatment outcomes from pallidal deep brain stimulation are highly heterogeneous reflecting the phenotypic and etiologic spectrum of dystonia. Treatment stratification to neurostimulation therapy primarily relies on the phenotypic motor presentation; however, etiology including genetic factors are increasingly recognized as modifiers of treatment outcomes. Here, we describe a 53 year-old female patient with a progressive generalized dystonia since age 25. The patient underwent deep brain stimulation of the globus pallidus internus (GPi-DBS) at age 44. Since the clinical phenotype included mobile choreo-dystonic features, we expected favorable therapeutic outcome from GPi-DBS. Although mobile dystonia components were slightly improved in the long-term outcome from GPi-DBS the overall therapeutic response 9 years from implantation was limited when comparing "stimulation off" and "stimulation on" despite of proper electrode localization and sufficient stimulation programming. In order to further understand the reason for this limited motor symptom response, we aimed to clarify the etiology of generalized dystonia in this patient. Genetic testing identified a novel heterozygous pathogenic SLC2A1 mutation as cause of glucose transporter type 1 deficiency syndrome (GLUT1-DS). This case report presents the first outcome of GPi-DBS in a patient with GLUT1-DS, and suggests that genotype relations may increasingly complement phenotype-based therapy stratification of GPi-DBS in dystonia. [less ▲]

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See detailLateralisation in Parkinson disease.
Riederer, P.; Jellinger, K. A.; Kolber, Pierre Luc UL et al

in Cell and tissue research (2018), 373(1), 297-312

Asymmetry of dopaminergic neurodegeneration and subsequent lateralisation of motor symptoms are distinctive features of Parkinson's disease compared to other forms of neurodegenerative or symptomatic ... [more ▼]

Asymmetry of dopaminergic neurodegeneration and subsequent lateralisation of motor symptoms are distinctive features of Parkinson's disease compared to other forms of neurodegenerative or symptomatic parkinsonism. Even 200 years after the first description of the disease, the underlying causes for this striking clinicopathological feature are not yet fully understood. There is increasing evidence that lateralisation of disease is due to a complex interplay of hereditary and environmental factors that are reflected not only in the concept of dominant hemispheres and handedness but also in specific susceptibilities of neuronal subpopulations within the substantia nigra. As a consequence, not only the obvious lateralisation of motor symptoms occurs but also patterns of associated non-motor signs are defined, which include cognitive functions, sleep behaviour or olfaction. Better understanding of the mechanisms contributing to lateralisation of neurodegeneration and the resulting patterns of clinical phenotypes based on bilateral post-mortem brain analyses and clinical studies focusing on right/left hemispheric symptom origin will help to develop more targeted therapeutic approaches, taking into account subtypes of PD as a heterogeneous disorder. [less ▲]

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See detailDopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.
Burbulla, Lena F.; Song, Pingping; Mazzulli, Joseph R. et al

in Science (New York, N.Y.) (2017), 357(6357), 1255-1261

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains ... [more ▼]

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and alpha-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or alpha-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis. [less ▲]

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See detailMetformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Fitzgerald, Julia C.; Zimprich, Alexander; Carvajal-Berrio, Daniel A. et al

in Brain : A Journal of Neurology (2017), 140(9), 2444-2459

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 ... [more ▼]

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HtrA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HtrA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HtrA2 and PINK1. HtrA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HtrA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HtrA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies. [less ▲]

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See detailAn Observational Study of the Effect of Levodopa-Carbidopa Intestinal Gel on Activities of Daily Living and Quality of Life in Advanced Parkinson's Disease Patients.
Krüger, Rejko UL; Lingor, Paul; Doskas, Triantafyllos et al

in Advances in therapy (2017)

INTRODUCTION: Continuous delivery of levodopa-carbidopa intestinal gel (LCIG) by percutaneous endoscopic gastrojejunostomy (PEG-J) in advanced Parkinson's disease (PD) patients reduces variability in ... [more ▼]

INTRODUCTION: Continuous delivery of levodopa-carbidopa intestinal gel (LCIG) by percutaneous endoscopic gastrojejunostomy (PEG-J) in advanced Parkinson's disease (PD) patients reduces variability in plasma levels, providing better control of motor fluctuations ("on" and "off" states). The MONOTREAT study assessed the effect of LCIG on activities of daily living, motor and non-motor symptoms, and quality of life in advanced PD patients. METHODS: This prospective, observational study included patients with advanced, levodopa-responsive PD with either 2-4 h of "off" time or 2 h of dyskinesia daily. Patients received LCIG via PEG-J for 16 h continuously. Effectiveness was assessed using Unified PD Rating Scale parts II and III, the Non-Motor Symptom Scale, and the PD Questionnaire-8. RESULTS: The mean (SD) treatment duration was 275 (157) days. Patients experienced significant improvement from baseline in activities of daily living at final visit (p < 0.05) as well as at months 3 and 6 (p < 0.0001). Patients also experienced significant improvements from baseline in quality of life and non-motor symptoms at all time points (p < 0.001 for all). Specifically, patients manifested significant improvements in mean change from baseline at every study visit in five of nine non-motor symptom score domains: sleep/fatigue, mood/cognition, gastrointestinal tract, urinary, and miscellaneous. One-third of patients (32.8%) experienced an adverse event; 21.9% experienced a serious adverse event; 11.1% discontinued because of an adverse event. CONCLUSION: This study demonstrated significant and clinically relevant improvements in measures of activities of daily living, quality of life, and a specific subset of non-motor symptoms after treatment with LCIG. FUNDING: AbbVie Inc. [less ▲]

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See detailRare variant analysis of the PPMI dataset to uncover the complex genetic architecture of Parkinson’s disease
Bobbili, Dheeraj Reddy UL; May, Patrick UL; Krüger, Rejko UL

in Movement Disorders : Official Journal of the Movement Disorder Society (2017, June 02), 322(Supplement S2), 405

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s ... [more ▼]

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s disease (PD) is a complex disease. Besides variants in high-risk genes such as LRRK2 and PARK2, multiple genes associated to sporadic PD were discovered via genome-wide association studies. Yet, there is a large number of genetic factors that need to be deciphered. Methods: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). The dataset comprised of 435 PD cases and 162 ethnically matched controls, respectively. We performed burden tests at single variant, gene and geneset levels on common and rare exonic and splice-variants. We also looked for severity of rare highly deleterious variants (CADD phred score>30) using the CADD score as well as singleton (variants seen in only one individual across cases and controls) rare variants. Additionally, we performed the functional enrichment analysis with the genes harboring rare highly deleterious variants (case uniq genes) that are only present in cases. Results: We observed an increased mutational burden of singleton variants in PD cases compared to the controls in nonsynonymous+LOF variants (empirical P-value 0.005) but not in the synonymous variants (empirical P-value 0.09). We observed a higher significant burden (P-value 0.028) as well as higher significant severity (empirical P-value 0.027) of rare, highly deleterious nonsynonymous variants, but not in the synonymous variants of the candidate genes (P-value 0.686, empirical P-value 0.556 for burden and severity respectively). The network analysis of genes having deleterious variants only present in cases (Case uniq) showed a significant increase in connectivity compared to random networks (P-value 0.0002). Pathway analysis of those genes showed a significant enrichment of pathways and biological process implicated in the nervous system functioning and the etiology of PD. Conclusions: Our study supports the complex disease notion of PD by highlighting the convoluted architecture of PD where case uniq genes including LRRK2 are implicated in several biological processes and pathways related to PD. The main finding of this study is to discover the complex genetics of PD at an exome wide level. [less ▲]

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See detailInvolvement of the cerebellum in Parkinson disease and dementia with Lewy bodies.
Seidel, Kay; Bouzrou, Mohamed; Heidemann, Nina et al

in Annals of neurology (2017), 81(6), 898-903

Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha-synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable ... [more ▼]

Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha-synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait, and impaired balance, which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha-synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, whereas lobules were mildly affected. Cerebellar aggregation pathology may suggest a prionlike spread originating from affected precerebellar structures, and the high homogeneity between patients with dementia with Lewy bodies and Parkinson disease shows that both diseases likely belong to the same neuropathological spectrum. Ann Neurol 2017;81:898-903. [less ▲]

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See detailNeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases
Blauwendraat, Cornelis; Faghri, Faraz; Pihlstrom, Lasse et al

in Neurobiology of Aging (2017)

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina ... [more ▼]

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array, and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases. [less ▲]

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See detailClassification of advanced stages of Parkinson's disease: translation into stratified treatments.
Krüger, Rejko UL; Klucken, Jochen; Weiss, Daniel et al

in Journal of neural transmission (Vienna, Austria : 1996) (2017), 124(124), 1015-1027

Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain ... [more ▼]

Advanced stages of Parkinson's disease (advPD) still impose a challenge in terms of classification and related stage-adapted treatment recommendations. Previous concepts that define advPD by certain milestones of motor disability apparently fall short in addressing the increasingly recognized complexity of motor and non-motor symptoms and do not allow to account for the clinical heterogeneity that require more personalized approaches. Therefore, deep phenotyping approaches are required to characterize the broad-scaled, continuous and multidimensional spectrum of disease-related motor and non-motor symptoms and their progression under real-life conditions. This will also facilitate the reasoning for clinical care and therapeutic decisions, as neurologists currently have to refer to clinical trials that provide guidance on a group level; however, this does not always account for the individual needs of patients. Here, we provide an overview on different classifications for advPD that translate into critical phenotypic patterns requiring the differential therapeutic adjustments. New concepts refer to precision medicine approaches also in PD and first studies on genetic stratification for therapeutic outcomes provide a potential for more objective treatment recommendations. We define novel treatment targets that align with this concept and make use of emerging device-based assessments of real-life information on PD symptoms. As these approaches require empowerment of patients and integration into treatment decisions, we present communication strategies and decision support based on new technologies to adjust treatment of advPD according to patient demands and safety. [less ▲]

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See detailEvaluation of the interaction between LRRK2 and PARK16 loci in determining risk of Parkinson's disease: analysis of a large multicenter study.
Wang, Lisa; Heckman, Michael G.; Aasly, Jan O. et al

in Neurobiology of aging (2017), 49

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed ... [more ▼]

A recent study MacLeod et al. has shown that an interaction between variants at the LRRK2 and PARK16 loci influences risk of development of Parkinson's disease (PD). Our study examines the proposed interaction between LRRK2 and PARK16 variants in modifying PD risk using a large multicenter series of PD patients (7715) and controls (8261) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Our data does not support a strong direct interaction between LRRK2 and PARK16 variants; however, given the role of retromer and lysosomal pathways in PD, further studies are warranted. [less ▲]

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See detailThe GBAP1 pseudogene acts as a ceRNA for the glucocerebrosidase gene GBA by sponging miR-22-3p.
Straniero, Letizia; Rimoldi, Valeria; Samarani, Maura et al

in Scientific reports (2017), 7(1), 12702

Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson's disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD ... [more ▼]

Mutations in the GBA gene, encoding lysosomal glucocerebrosidase, represent the major predisposing factor for Parkinson's disease (PD), and modulation of the glucocerebrosidase activity is an emerging PD therapy. However, little is known about mechanisms regulating GBA expression. We explored the existence of a regulatory network involving GBA, its expressed pseudogene GBAP1, and microRNAs. The high level of sequence identity between GBA and GBAP1 makes the pseudogene a promising competing-endogenous RNA (ceRNA), functioning as a microRNA sponge. After selecting microRNAs potentially targeting both transcripts, we demonstrated that miR-22-3p binds to and down-regulates GBA and GBAP1, and decreases their endogenous mRNA levels up to 70%. Moreover, over-expression of GBAP1 3'-untranslated region was able to sequester miR-22-3p, thus increasing GBA mRNA and glucocerebrosidase levels. The characterization of GBAP1 splicing identified multiple out-of-frame isoforms down-regulated by the nonsense-mediated mRNA decay, suggesting that GBAP1 levels and, accordingly, its ceRNA effect, are significantly modulated by this degradation process. Using skin-derived induced pluripotent stem cells of PD patients with GBA mutations and controls, we observed a significant GBA up-regulation during dopaminergic differentiation, paralleled by down-regulation of miR-22-3p. Our results describe the first microRNA controlling GBA and suggest that the GBAP1 non-coding RNA functions as a GBA ceRNA. [less ▲]

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See detailEffects of Subthalamic and Nigral Stimulation on Gait Kinematics in Parkinson's Disease.
Scholten, Marlieke; Klemt, Johannes; Heilbronn, Melanie et al

in Frontiers in neurology (2017), 8

Conventional subthalamic deep brain stimulation for Parkinson's disease (PD) presumably modulates the spatial component of gait. However, temporal dysregulation of gait is one of the factors that is ... [more ▼]

Conventional subthalamic deep brain stimulation for Parkinson's disease (PD) presumably modulates the spatial component of gait. However, temporal dysregulation of gait is one of the factors that is tightly associated with freezing of gait (FOG). Temporal locomotor integration may be modulated differentially at distinct levels of the basal ganglia. Owing to its specific descending brainstem projections, stimulation of the substantia nigra pars reticulata (SNr) area might modulate spatial and temporal parameters of gait differentially compared to standard subthalamic nucleus (STN) stimulation. Here, we aimed to characterize the differential effect of STN or SNr stimulation on kinematic gait parameters. We analyzed biomechanical parameters during unconstrained over ground walking in 12 PD patients with subthalamic deep brain stimulation and FOG. Patients performed walking in three therapeutic conditions: (i) Off stimulation, (ii) STN stimulation (alone), and (iii) SNr stimulation (alone). SNr stimulation was achieved by stimulating the most caudal contact of the electrode. We recorded gait using three sensors (each containing a tri-axial accelerometer, gyroscope, and magnetometer) attached on both left and right ankle, and to the lumbar spine. STN stimulation improved both the spatial features (stride length, stride length variability) and the temporal parameters of gait. SNr stimulation improved temporal parameters of gait (swing time asymmetry). Correlation analysis suggested that patients with more medial localization of the SNr contact associated with a stronger regularization of gait. These results suggest that SNr stimulation might support temporal regularization of gait integration. [less ▲]

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