Role of the ERK pathway in psychostimulant-induced locomotor sensitization

BACKGROUND: Repeated exposure to psychostimulants results in a progressive and long-lasting facilitation of the locomotor response that is thought to have implications for addiction. Psychostimulants and other drugs of abuse activate in specific brain areas extracellular signal-regulated kinase (ERK), an essential component of a signaling pathway involved in synaptic plasticity and long-term effects of drugs of abuse. Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain-penetrating selective inhibitor of MAP-kinase/ERK kinase (MEK), the enzyme that selectively activates ERK. RESULTS: A dose of SL327 (30 mg/kg) that reduced the number of activated ERK-positive neurons by 62 to 89% in various brain areas, had virtually no effect on the spontaneous locomotor activity or the acute hyperlocomotion induced by cocaine or D-amphetamine. Pre-treatment with SL327 (30 mg/kg) prior to each drug administration prevented the locomotor sensitization induced by repeated injections of D-amphetamine or cocaine. The SL327 pre-treatment abolished also conditioned locomotor response of mice placed in the context previously paired with cocaine or D-amphetamine. In contrast, SL327 did not alter the expression of sensitized response to D-amphetamine or cocaine. CONCLUSION: Altogether these results show that ERK has a minor contribution to the acute locomotor effects of psychostimulants or to the expression of sensitized responses, whereas it is crucial for the acquisition of locomotor sensitization and psychostimulant-conditioned locomotor response. This study supports the important role of the ERK pathway in long-lasting behavioral alterations induced by drugs of abuse

Learning disease progression models with longitudinal data and missing values

International audienceStatistical methods have been developed for the analysis of longitudinal data in neurodegenerative diseases. To cope with the lack of temporal markers-i.e. to account for subject-specific disease progression in regard to age-a common strategy consists in realigning the individual sequence data in time. Patient's specific trajectories can indeed be seen as spatiotemporal perturbations of the same normative disease trajectory. However, these models do not easily allow one to account for multimodal data, which more than often include missing values. Indeed, it is rare that imaging and clinical examinations for instance are performed at the same frequency in clinical protocols. Multimodal models also need to allow a different profile of progression for data with different structure and representation. We propose to use a generative mixed effect model that considers the progression trajectories as curves on a Rieman-nian Manifold. We use the concept of product manifold to handle multimodal data, and leverage the generative aspect of our model to handle missing values. We assess the robuste-ness of our methods toward missing values frequency on both synthetic and real data. Finally we apply our model on a real-world dataset to model Parkinson's disease progression from data derived from clinical examination and imaging

Learning disease progression models with longitudinal data and missing values

International audienceStatistical methods have been developed for the analysis of longitudinal data in neurodegenerative diseases. To cope with the lack of temporal markers-i.e. to account for subject-specific disease progression in regard to age-a common strategy consists in realigning the individual sequence data in time. Patient's specific trajectories can indeed be seen as spatiotemporal perturbations of the same normative disease trajectory. However, these models do not easily allow one to account for multimodal data, which more than often include missing values. Indeed, it is rare that imaging and clinical examinations for instance are performed at the same frequency in clinical protocols. Multimodal models also need to allow a different profile of progression for data with different structure and representation. We propose to use a generative mixed effect model that considers the progression trajectories as curves on a Rieman-nian Manifold. We use the concept of product manifold to handle multimodal data, and leverage the generative aspect of our model to handle missing values. We assess the robuste-ness of our methods toward missing values frequency on both synthetic and real data. Finally we apply our model on a real-world dataset to model Parkinson's disease progression from data derived from clinical examination and imaging

Longitudinal comparison of subjects with and without Sleep Disorders in Parkinson's Disease

International audiencePatients with Parkinson’s Disease (PD) may have very different patterns of progression, corresponding to distinct disease subtypes. Here, we describe quantitatively the overall pattern of progression in subgroups of PD by using a Bayesian non-linear mixed effect model that describes the continuous progression of biomarkers at both population and individual level. This approach allows to model variability in progression patterns and disease stage between patients. We analyzed two subgroups of patients, with (RBD+) and without sleep disorders (RBD-), that are known to present different patterns of progression [1]. We compared the two groups by extracting the ordering of abnormalities that occurred over the disease course, and by studying their disease onset and speed of progression

A comparison between early presentation of dementia with Lewy Bodies, Alzheimer's disease and Parkinson's disease: evidence from routine primary care and UK Biobank data

OBJECTIVE: To simultaneously contrast prediagnostic clinical characteristics of individuals with a final diagnosis of dementia with Lewy Bodies, Parkinson's disease, Alzheimer's disease compared to controls without neurodegenerative disorders. METHODS: Using the longitudinal THIN database in the UK, we tested the association of each neurodegenerative disorder with a selected list of symptoms and broad families of treatments, and compared the associations between disorders to detect disease-specific effects. We replicated the main findings in the UK Biobank. RESULTS: We used data of 28,222 patients with PD, 20,214 with AD, 4,682 with DLB and 20,214 controls. All neurodegenerative disorders were significantly associated with the presence of multiple clinical characteristics before their diagnosis including sleep disorders, falls, psychiatric symptoms and autonomic dysfunctions. When comparing DLB patients with patients with PD and AD patients, falls, psychiatric symptoms and autonomic dysfunction were all more strongly associated with DLB in the five years preceding the first neurodegenerative diagnosis. The use of statins was lower in patients who developed PD and higher in patients who developed DLB compared to AD. In PD patients, the use of statins was associated with the development of dementia in the five years following PD diagnosis. INTERPRETATION: Prediagnostic presentations of falls, psychiatric symptoms and autonomic dysfunctions were more strongly associated with DLB than PD and AD. This study also suggests that whilst several associations with medications are similar in neurodegenerative disorders, statin usage is negatively associated with Parkinson's Disease but positively with DLB and AD as well as development of dementia in PD

The myelin-weighted connectome in Parkinson’s disease

Background Even though Parkinson's disease (PD) is typically viewed as largely affecting gray matter, there is growing evidence that there are also structural changes in the white matter. Traditional connectomics methods that study PD may not be specific to underlying microstructural changes, such as myelin loss. Objective The primary objective of this study is to investigate the PD-induced changes in myelin content in the connections emerging from the basal ganglia and the brainstem. For the weighting of the connectome, we used the longitudinal relaxation rate as a biologically grounded myelin-sensitive metric. Methods We computed the myelin-weighted connectome in 35 healthy control subjects and 81 patients with PD. We used partial least squares to highlight the differences between patients with PD and healthy control subjects. Then, a ring analysis was performed on selected brainstem and subcortical regions to evaluate each node's potential role as an epicenter for disease propagation. Then, we used behavioral partial least squares to relate the myelin alterations with clinical scores. Results Most connections (~80%) emerging from the basal ganglia showed a reduced myelin content. The connections emerging from potential epicentral nodes (substantia nigra, nucleus basalis of Meynert, amygdala, hippocampus, and midbrain) showed significant decrease in the longitudinal relaxation rate (P < 0.05). This effect was not seen for the medulla and the pons. Conclusions The myelin-weighted connectome was able to identify alteration of the myelin content in PD in basal ganglia connections. This could provide a different view on the importance of myelination in neurodegeneration and disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Genome-wide Analysis of Motor Progression in Parkinson Disease

BACKGROUND AND OBJECTIVES: The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets. METHODS: We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores. RESULTS: We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (β = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode). DISCUSSION: Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression

European Academy of Neurology/Movement Disorder Society - European Section guideline on the treatment of Parkinson's disease: I. Invasive therapies

BACKGROUND AND PURPOSE: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway. METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered. RESULTS: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended. CONCLUSIONS: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups

Phosphoproteomic screening identifies Rab GTPases as novel downstream targets of PINK1

International audienceMutations in the PTEN-induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser 65) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1-dependent phosphorylation targets in HEK (human embry-onic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub-family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser 111) in response to PINK1 activation. Using phospho-specific antibodies raised against Ser 111 of each of the Rabs, we demonstrate that Rab Ser 111 phosphoryla-tion occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient-derived fibroblasts stimulated by mitochondrial depolari-sation. We provide evidence that Rab8A GTPase Ser 111 phosphory-lation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser 111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser 65. We further show mechanistically that phosphorylation at Ser 111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/ 8B/13 at Ser 111 may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase-mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease

Clustering of Alzheimer's and Parkinson's disease based on genetic burden of shared molecular mechanisms

One of the visions of precision medicine has been to re-define disease taxonomies based on molecular characteristics rather than on phenotypic evidence. However, achieving this goal is highly challenging, specifically in neurology. Our contribution is a machine-learning based joint molecular subtyping of Alzheimer’s (AD) and Parkinson’s Disease (PD), based on the genetic burden of 15 molecular mechanisms comprising 27 proteins (e.g. APOE) that have been described in both diseases. We demonstrate that our joint AD/PD clustering using a combination of sparse autoencoders and sparse non-negative matrix factorization is reproducible and can be associated with significant differences of AD and PD patient subgroups on a clinical, pathophysiological and molecular level. Hence, clusters are disease-associated. To our knowledge this work is the first demonstration of a mechanism based stratification in the field of neurodegenerative diseases. Overall, we thus see this work as an important step towards a molecular mechanism-based taxonomy of neurological disorders, which could help in developing better targeted therapies in the future by going beyond classical phenotype based disease definitions