Parkinsoni tõbi kui multisüsteemne haigus: Parkinsoni tõve patsientide naha ja vere kogu transkriptoomi uuring

Väitekirja elektrooniline versioon ei sisalda publikatsiooneAlzheimeri tõve järel on Parkinsoni tõbi (PT) teine kõige levinum neurodegeneratiivne haigus, mille puhul esineb arvestatavalt palju kliinilist valediagnoosi. PT on liigutushäire, millele on iseloomulik tahtlike liigutuste aeglus (mida tuntakse bradükineesiana), rigiidsus ja rahutreemor, mida kokku nimetatakse parkinsoni triaadiks. PT patofüsioloogiale on iseloomulik dopaminergiliste närvirakkude hävimine kesknärvisüsteemi mustaines ja närvirakkudes patoloogilise valgu α-sünukleiini kuhjumine Lewy kehakesteks. Kindla diagnoosi saab anda alles peale surma, sest hetkel pole PT jaoks olemas usaldusväärseid biomarkereid. Enamik PT juhtumitest on sporaadilised ja suured genoomiülesed uuringud näitavad, et ainuüksi geenide varieeruvus ei ole PT peamine esinemise põhjus. Seetõttu uurib käesolev teadustöö PT geeniekspressiooni (transkriptoomikat), et leida kasutavaid diagnostilisi ja prognostilisi biomarkerid. Geeniekspressiooni koespetsiifilisuse tõttu on transkriptoomika puhul oluline, millisest koest proov võtta. PT on kanooniliselt keskaju dopaminergiliste närvirakkude haigus, kuid sellest koest ei saa eluspuhuselt proovi võtta. Arvestades, et transkriptoomikat saab keskajust teha ainult peale surma, on teiste ligipääsetavate kudede leidmine eluspuhuseks diagnostikaks oluline. Potentsiaalsete huvipakkuvate kudede alla võib lugeda naha, sest PT patsientidel esineb üldpopulatsioonist rohkem melanoomi ning teisi spetsiifilisi nahaprobleeme. Naha kõrval on teine huvipakkuv kude veri, sest see on kõige lihtsamini kogutav kude ja ringeldes kogu organismis, sisaldab ta endas palju süsteemset informatsiooni. Selgitamaks, kas PT on multisüsteemne haigus, kus on haigusspetsiifiliselt muutunud ka mitteneuronaalsed perifeersed koed, on käesoleva töö eesmärgiks kaardistada PT geeniekspressiooni RNA sekveneerimise abil nahas ja veres. PT naha tulemused näitavad, et valdava osa geenide ekspressioon on alla reguleeritud ja leitud muutused peegeldavad PT ajukoes leitud mustrit. Samuti selgitavad need muutused naha kõrgemat haavatavust mutageensete ohtude suhtes, mis võib põhjendada kõrgenenud melanoomi esinemist PT põdevate inimeste nahas. Teadustöö viitab sellele, et PT võib muuta naha kui perifeerse koe geeniekspressiooni haigusspetsiifiliselt. Tulemused PT põdevate inimeste vereproovidest näitavad oluliselt vähem muutusi, mida samas on varasemate PT uuringutes juba kirjeldatud. Muutuste vähesuse tõttu on verd raske kasutada biomarkerite avastamiseks, sest tegemist on heterogeense koega ja tulemused ei pruugi seega olla reprodutseeritavad. Kahe koe võrdluses ei leitud kattuvaid oluliselt muutunud geeniekspressioone. See asjaolu rõhutab koespetsiifiliste erinevuste tähtsust geeniekspressiooni uuringutes. Käesolev uuring toob välja geeniekspressioonid, mis näitasid kõige reprodutseeritavamaid muutusi ja vajavad täiendavaid funktsionaalseid uuringuid nende biomarkeripotentsiaali hindamiseks.Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease with a considerable rate of clinical misdiagnosis. PD is a movement disorder characterized by slowness of voluntary movement (known as bradykinesia), rigidity and resting tremor, together known as the parkinsonian triad. The pathophysiology of PD converges into pathognomonic loss of dopaminergic neurons in substantia nigra of the central nervous system and the accumulation of pathologic protein α-synuclein into Lewy bodies in neurons. The definite diagnosis can only be established post mortem, as there are currently no reliable biomarkers for PD. Most PD cases are sporadic and large genome wide association studies show that gene variance alone is not the main cause of PD occurrence. This work, therefore, investigates gene expression (transcriptomics) of PD in search of feasible diagnostic and prognostic biomarkers. The tissue which the sample is taken from is relevant in transcriptomics, because gene expression is tissue specific. PD has canonically seen as a disease of the dopaminergic neurons in the central nervous tissue, but this tissue cannot be sampled from living patients. It is, therefore, necessary to find other tissues that allow sampling in vivo for biomarker research. A potential tissue of interest is the skin because PD patients have more melanoma and other specific skin conditions compared to the general population. Another promising tissue next to skin is the blood, because it is the easiest to sample and circulating the whole organism carries a lot of systemic information. The current work profiles gene expression from skin and blood using RNA sequencing in order to explore the disease specific involvement of nonneuronal peripheral tissues in PD. The results from PD skin show a pattern of global downregulation of differentially expressed genes that mirrors the pathophysiology of PD in the brain. Changes that lead to vulnerability in PD skin to mutagenic hazards are also mapped that might explain the epidemiologically observed elevated prevalence of melanoma in PD patients. This suggests that gene expression in the skin, a peripheral nonneuronal tissue, is PD-specifically changed. The results from PD blood show notably fewer changes, however, most are previously described in PD. This highlights the difficulty in using blood for biomarker discovery as the tissue is heterogeneous and the results are not easily reproducible. No overlapping differentially changed gene expressions are found in comparison of the two tissues in PD, which underlines the importance of tissue specific differences in gene expression. The study highlights notable differential gene expressions that show most robust changes and warrant further functional studies to evaluate their biomarker potential.https://www.ester.ee/record=b542987

Clinical Features That Evoke the Concept of Disinhibition in Tourette Syndrome

The capacity to efficiently control motor output, by either refraining from prepotent actions or disengaging from ongoing motor behaviors, is necessary for our ability to thrive in a stimulus-rich and socially complex environment. Failure to engage in successful inhibitory motor control could lead to aberrant behaviors typified by an excess of motor performance. In tic disorders and Tourette syndrome (TS) - the most common tic disorder encountered in clinics - surplus motor output is rarely the only relevant clinical sign. A range of abnormal behaviors is often encountered which are historically viewed as "disinhibition phenomena". Here, we present the different clinical features of TS from distinct categorical domains (motor, sensory, complex behavioral) that evoke the concept of disinhibition and discuss their associations. We also present evidence for their consideration as phenomena of inhibitory dysfunction and provide an overview of studies on TS pathophysiology which support this view. We then critically dissect the concept of disinhibition in TS and illuminate other salient aspects, which should be considered in a unitary pathophysiological approach. We briefly touch upon the dangers of oversimplification and emphasize the necessity of conceptual diversity in the scientific exploration of TS, from disinhibition and beyond

Aggression Toward Others Misdiagnosed as Primary Tics

Background: 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. Cases: 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. Conclusions: 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

Looking beyond the brain to improve the pathogenic understanding of Parkinson's disease: implications of whole transcriptome profiling of Patients' skin

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12883-016-0784-z) contains supplementary material, which is available to authorized users

The spectrum of involuntary vocalizations in humans: A video atlas

In clinical practice, involuntary vocalizing behaviors are typically associated with Tourette syndrome and other tic disorders. However, they may also be encountered throughout the entire tenor of neuropsychiatry, movement disorders, and neurodevelopmental syndromes. Importantly, involuntary vocalizing behaviors may often constitute a predominant clinical sign, and, therefore, their early recognition and appropriate classification are necessary to guide diagnosis and treatment. Clinical literature and video-documented cases on the topic are surprisingly scarce. Here, we pooled data from 5 expert centers of movement disorders, with instructive video material to cover the entire range of involuntary vocalizations in humans. Medical literature was also reviewed to document the range of possible etiologies associated with the different types of vocalizing behaviors and to explore treatment options. We propose a phenomenological classification of involuntary vocalizations within different categorical domains, including (1) tics and tic-like vocalizations, (2) vocalizations as part of stereotypies, (3) vocalizations as part of dystonia or chorea, (4) continuous vocalizing behaviors such as groaning or grunting, (5) pathological laughter and crying, (6) vocalizations resembling physiological reflexes, and (7) other vocalizations, for example, those associated with exaggerated startle responses, as part of epilepsy and sleep-related phenomena. We provide comprehensive lists of their associated etiologies, including neurodevelopmental, neurodegenerative, neuroimmunological, and structural causes and clinical clues. We then expand on the pathophysiology of the different vocalizing behaviors and comment on available treatment options. Finally, we present an algorithmic approach that covers the wide range of involuntary vocalizations in humans, with the ultimate goal of improving diagnostic accuracy and guiding appropriate treatment

Autochthonous West Nile virus infection in Germany: Increasing numbers and a rare encephalitis case in a kidney transplant recipient.

West Nile Virus (WNV) infections are increasingly detected in birds and horses in central Europe, with the first mosquito-borne autochthonous human infection detected in Germany in 2019. Human infections are typically asymptomatic, with occasional severe neurological disease. Because of a low number of cases in central Europe, awareness regarding potential cases is low and WNV diagnostic testing is not routine. We tested cerebrospinal fluid (CSF) samples from unsolved encephalitis and meningitis cases from Berlin from 2019 to 2020, and describe a WNV-encephalitis case in a 33-year-old kidney transplant recipient. The infectious course was resolved by serology, RT-PCR and sequencing of stored samples. Phylogenetic sequence analysis revealed a close relationship of the patient's WNV strain to German sequences from 2019 and 2020. A lack of travel history and patient self-isolation during the SARS-CoV-2 pandemic suggest the infection was acquired in the patient's home or garden. Serological tests of four people sharing the living space were negative. Retrospective RT-PCR and WNV-IgM testing of 671 CSF samples from unsolved encephalitis and meningitis cases from Berlin detected no additional infections. The recent increase of WNV cases illustrates the importance of considering WNV in cases of meningoencephalitis, especially in immunocompromised patients, as described here. Proper education and communication and a revised diagnostic strategy will help to raise awareness and to detect future WNV infections

Clinical Practice Patterns in Tic Disorders Among Movement Disorder Society Members

[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.CG is supported by the Freigeist Fellowship of the VolkswagenStiftung. He has served as ad hoc advisory board to Biomarin and received honoraria from the International Parkinsons Disease and Movement Disorders Society for educational activities

Aggression Toward Others Misdiagnosed as Primary Tics

BACKGROUND: 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. CASES: 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. CONCLUSIONS: 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

No evidence of impaired visual and tactile metacognition in adults with tourette disorder

International audienceIntroduction: Premonitory urges in Tourette disorder are often linked to altered somatosensory processing, which might include deficits in metacognition. We explored tactile and visual metacognitive ability in people with Tourette disorder and healthy control participants.Methods: Patients with Tourrete disorder and healthy control participants completed a tactile and a visual metacognitive task. On each trial, participants did a forced choice discrimination and then rated their confidence in their decision. To quantify metacognitive ability, we used m-ratio — a bias-free measure that allows for comparisons across modalities. Correlations between severity of tics and premonitory urges with tactile metacognitive sensitivity were also performed.Results: Metacognitive ability in both tactile and visual domains was comparable between adults with Tourette disorder and healthy controls. We also found no evidence for correlations between tactile metacognitive ability and severity of premonitory urges or tic severity.Conclusions: Tactile and visual metacognition is not impaired in adults with Tourette disorder. These results question the role of altered tactile metacognition in pathophysiology of tic disorders

Clinical Practice Patterns in Tic Disorders Among Movement Disorder Society Members

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