Background and aims: Next to characteristic motor triad of Parkinson’s Disease (PD) due to loss of nigrostriatal neurons, more symptoms associated with non-neuronal tissues are emerging. Little is known about the molecular alterations underlying dermatologic issues or epidemiologic associations like increased incidence of melanoma in PD. The aim is to give an overview of the altered gene expression profiles of PD skin and blood using the novel method of RNA Sequencing. Networks of different genes are analyzed to map affected pathways that contribute to pathomolecular mechanism of PD in the periphery.
Methods: Whole transcriptomic profiling of 12+12 idiopathic PD patients’ and matched controls’ skin biopsies and venous whole blood was performed with highthroughput RNA-sequencing analysis. Followingly, pathway analysis of differentially changed gene expressions was performed. The results were validated using RT-qPCR.
Results: PD skin RNA-Seq resulted in a large collection of over 1000 differentially expressed genes, among which a clear pattern of global downregulation appeared. In blood, the differential changes were more subtle, blood being a heterogenous tissue. Pathways associated with mitochondrial metabolism and protein degradation by the ubiquitin-proteasome system were dysregulated in both.
Conclusion: The concordance of these results with previous gene expression profiling studies demonstrate that the molecular alterations in PD leading to neurodegeneration in the CNS are systemic and manifest also in peripheral tissues. Major affected pathways include dysfunction in protein metabolism, mitochondrial dysfunction and impaired immune system. Homeostatic imbalance in the skin can lead to increased susceptibility to mutagenic hazards and provide a possible molecular link between melanoma and PD.
Tics describe a wide range of sudden and repetitive behaviors. Their multifaceted clinical features may resemble other explosive behaviors, including repetitive episodes of aggression toward others (allo-aggression) reported by subjects without tics. Here, we document 3 exemplary cases that help disentangle allo-aggressive behaviors from tics.We report 3 cases who presented with an array of complex repetitive behaviors, most notably allo-aggression (eg, sudden kicking, hitting, slapping and biting others, or pushing someone off a bike), which were misdiagnosed as primary tics. In all cases, additional symptoms, such as blackouts, feeling of being controlled by different personalities, or being empowered by repetitive behaviors, and examination pointed toward different neuropsychiatric diagnoses.Repetitive allo-aggressive behaviors are not part of the range of motor manifestations of tics. This observation not only has important medico-legal implications but is also relevant for the overall perception of Tourette syndrome and other primary tic disorders.
Background: Tic disorders belong to the broad spectrum of pediatric and adult movement disorders. The wide variability in clinical presentations, applied assessment tools, and treatments are poorly understood. Objectives: To map practices and knowledge base of movement disorder clinicians concerning clinical features, pathophysiology, and treatment approaches in tic disorders. Methods: A 33-item survey was developed by the Tic Disorders and Tourette syndrome Study Group members of the Movement Disorder Society. The survey was distributed to the complete society membership and included responses from 346 members, 314 of whom reported treating tic disorders. Results: Approximately one third of survey respondents (35%) frequently evaluated patients with tics. The data revealed widespread use of existing guidelines (about 70%) and screening for comorbid disorders (>90%). The most common investigations used to rule out secondary causes of tics were imaging (92%), laboratory tests (66%) and neurophysiology (38%). Functional tics were the second most common tic etiology following primary tics. Only 27% of respondents reported confidence in knowledge about tic pathogenesis. Top rated interventions to treat tics were psychoeducation, cognitive behavioral intervention for tics (CBIT) and treatment for neuropsychiatric comorbidities. Antipsychotics were ranked as the most effective pharmacologic tic intervention. Conclusions: The majority of movement disorders specialists do not frequently encounter tics. There was sparse knowledge about tic pathophysiology. Psychoeducation, CBIT, the treatment of neuropsychiatric comorbidities and use of antipsychotics emerged as the most common interventions to treat tics. These results provide insight into what will be needed to improve the diagnosis and treatment of tic disorders.
Abstract Tic disorders are characterized by a surplus of brief movements and sounds that share some of the characteristics of voluntary actions but occur repetitively and are inapposite to discernable context. Tics are most commonly observed in primary tic disorders, and are often accompanied by additional neuropsychiatric features, including impulsive and socially disruptive behaviors. This lends support to the hypothesis of a core inhibitory deficit at different organization levels of brain structure and function. This chapter dissects evidence supporting the disinhibition model, starting from neuronal composition aberrations within the cortico-basal-ganglia-thalamo-cortical loops to their putative consequences in behavioral output. Specifically, it provides an overview of the neuropathological and functional neuroanatomic changes of different cell populations within the basal ganglia, with a focus in GABA-ergic and cholinergic interneurons, dopaminergic neurotransmission, and the glutamate–glutamine-GABA cycle. Evidence from animal models of tic disorders, alongside studies of cortical neurophysiology are also discussed. Finally, an account of behavioral studies related both to control of voluntary actions and tics is provided, and knowledge gaps are listed to motivate future studies in the field.
The comparative gene expression list from RNA-sequencing analysis of skin samples from Parkinson’s Disease patients and controls. An excel file of all regulated genes between Parkinson’s Disease patients and control skin samples from RNA-sequencing analysis, which includes a column form of data including the geneID, log2FC, logCPM, p-value, FDR, the HGNC identifier and the name of the gene. (XLSX 1752 kb)
Transcriptomics in Parkinson’s disease offers insights into the pathogenesis of Parkinson’s disease but obtaining brain tissue has limitations. In order to bypass this issue, we profile and compare differentially expressed genes and enriched pathways (KEGG) in two peripheral tissues (blood and skin) of 12 Parkinson’s disease patients and 12 healthy controls using RNA-sequencing technique and validation with RT-qPCR. Furthermore, we compare our results to previous Parkinson’s disease post mortem brain tissue and blood results using the robust rank aggregation method. The results show no overlapping differentially expressed genes or enriched pathways in blood vs. skin in our sample sets (25 vs. 1068 differentially expressed genes with an FDR ≤ 0.05; 1 vs. 9 pathways in blood and skin, respectively). A meta-analysis from previous transcriptomic sample sets using either microarrays or RNA-Seq yields a robust rank aggregation list of cortical gene expression changes with 43 differentially expressed genes; a list of substantia nigra changes with 2 differentially expressed genes and a list of blood changes with 1 differentially expressed gene being statistically significant at FDR ≤ 0.05. In cortex 1, KEGG pathway was enriched, four in substantia nigra and two in blood. None of the differentially expressed genes or pathways overlap between these tissues. When comparing our previously published skin transcription analysis, two differentially expressed genes between the cortex robust rank aggregation and skin overlap. In this study, for the first time a meta-analysis is applied on transcriptomic sample sets in Parkinson’s disease. Simultaneously, it explores the notion that Parkinson’s disease is not just a neuronal tissue disease by exploring peripheral tissues. The comparison of different Parkinson’s disease tissues yields surprisingly few significant differentially expressed genes and pathways, suggesting that divergent gene expression profiles in distinct cell lineages, metabolic and possibly iatrogenic effects create too much transcriptomic noise for detecting significant signal. On the other hand, there are signs that point towards Parkinson’s disease-specific changes in non-neuronal peripheral tissues in Parkinson’s disease, indicating that Parkinson’s disease might be a multisystem disorder.
Early research suggested that compulsive sexual behavior (CSB) and paraphilic interests (PI) are more prevalent in adults with primary tic disorders compared to the general population. However, recent data on this topic remain scarce. We conducted an anonymous online survey capturing data on CSB and PI in adult patients with primary tic disorders. We also explored the role of antipsychotic tic medication and the impact of neuropsychiatric comorbidities like attention-deficit hyperactivity disorder and depression. In total, 62 participants (26 females/36 males) completed the survey. The prevalence of CSB and PI were 12.9% and 19.4%, respectively. There was no association with antipsychotic medication nor with symptoms of depression. However, the presence of attention-deficit hyperactivity disorder was associated with a higher prevalence of both CSB and PI. The current results contrast with earlier reports and show that in adults with primary tic disorders, the prevalence of CSB and PI is not overly prominent.
Parkinson's Disease is a progressive neurodegenerative disease, characterized by symptoms of motor impairment, resulting from the loss of dopaminergic neurons in the midbrain, however non-neuronal symptoms are also common. Although great advances have been made in the pathogenic understanding of Parkinson's Disease in the nervous system, little is known about the molecular alterations occurring in other non-neuronal organ systems. In addition, a higher rate of melanoma and non-melanoma skin cancer has been observed in the Parkinson's Disease population, indicating crosstalk between these diseases.To understand the molecular pathogenesis and gene expression alterations of Parkinson's Disease in peripheral tissues, and in order to explore the possible link between skin cancer and neurodegeneration, whole transcriptomic profiling of patients' skin was performed. Skin biopsies from 12 patients and matched controls were collected, and processed with high-throughput RNA-sequencing analysis.This analysis resulted in a large collection of over 1000 differentially expressed genes, among which clear biological and functional networks could be distinguished. The central functional processes altered in patients skin can be grouped into six broad categories: impaired cellular metabolism and mitochondrial dysfunction, defective protein metabolism, disturbed skin homeostasis, dysfunctional nuclear processes, altered signalling and tumour pathways, as well as disordered immune regulation.These results demonstrate that the molecular alterations leading to neurodegeneration in the CNS are systemic and manifest also in peripheral tissues, thereby indicating the presence of "skin-brain" crosstalk in Parkinson's Disease. In addition, the extensive homeostatic imbalance and basal stress can lead to increased susceptibility to external and internal mutagenic hazards in these patients, and thus provide a possible molecular link for the crosstalk between skin cancer and Parkinson's Disease.
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