This thesis presents the development and evaluation of IT-based methods and systems for supporting assessment of symptoms and enabling remote monitoring of Parkinson‟s disease (PD) patients. PD is a common neurological disorder associated with impaired body movements. Its clinical management regarding treatment outcomes and follow-up of patients is complex. In order to reveal the full extent of a patient‟s condition, there is a need for repeated and time-stamped assessments related to both patient‟s perception towards common symptoms and motor function. In this thesis, data from a mobile device test battery, collected during a three year clinical study, was used for the development and evaluation of methods. The data was gathered from a series of tests, consisting of selfassessments and motor tests (tapping and spiral drawing). These tests were carried out repeatedly in a telemedicine setting during week-long test periods. One objective was to develop a computer method that would process tracedspiral drawings and generate a score representing PD-related drawing impairments. The data processing part consisted of using the discrete wavelet transform and principal component analysis. When this computer method was evaluated against human clinical ratings, the results showed that it could perform quantitative assessments of drawing impairment in spirals comparatively well. As a part of this objective, a review of systems and methods for detecting the handwriting and drawing impairment using touch screens was performed. The review showed that measures concerning forces, accelerations, and radial displacements were the most important ones in detecting fine motor movement anomalies. Another objective of this thesis work was to design and evaluate an information system for delivering assessment support information to the treating clinical staff for monitoring PD symptoms in their patients. The system consisted of a patient node for data collection based on the mobile device test battery, a service node for data storage and processing, and a web application for data presentation. A system module was designed for compiling the test battery time series into summary scores on a test period level. The web application allowed adequate graphic feedback of the summary scores to the treating clinical staff. The evaluation results for this integrated system indicate that it can be used as a tool for frequent PD symptom assessments in home environments.

[pt] Embora o envelhecimento normal tenha como consequência o acúmulo de cobre, ferro e zinco no cérebro, isso se torna mais relevante na neurodegeneração. Há muito tempo que o dobramento defeituoso de proteínas tem sido associado ao desenvolvimento de algumas doenças degenerativas, chamadas de agregopatias. A ligação a metais geralmente é um fator promotor da agregação de tais proteínas, bem como do estresse oxidativo generalizado quando metais redox-ativos estão envolvidos. Neste sentido, o uso de terapias que têm como alvo a desomeostase metálica tem sido motivo de intensa pesquisa nos últimos anos. Os compostos atenuadores da interação metal-proteína (MPACs, Metal-Protein Attenuating Compounds) são quelantes moderados que visam interromper interações metal-proteína anormais específicas. Nosso grupo de pesquisa já estabeleceu que a classe química das N-acilidrazonas compõe um conjunto de MPACs verdadeiramente promissores para o manejo bioinorgânico de agregopatias exacerbadas por metais. Nosso composto-líder, INHHQ, entretanto, não apresenta parâmetros farmacocinéticos ideais, o que pode constituir um obstáculo em seu caminho para se tornar um fármaco comercial. O presente trabalho consiste no estudo de cinquenta e cinco N-acilidrazonas de estrutura relacionada (INHHQ mais cinquenta e quatro análogos) e na seleção dos melhores candidatos como quelantes moderados, chamados MPACs, no contexto de agregopatias humanas importantes. Os compostos foram projetados por meio de mudanças racionalmente efetuadas na estrutura do INHHQ, que podem reduzir sua taxa de hidrólise, melhorar sua solubilidade em meio aquoso e ajustar sua afinidade de coordenação por cobre. Inicialmente, foram realizadas análises farmacológicas in silico para determinar algumas características dos compostos que são relevantes no desenvolvimento de um novo fármaco. Os valores de referência para permeação da barreira hematoencefálica, em conjunto com a solubilidade em água, foram limitantes para selecionar compostos para a próxima etapa. As hidrazonas com melhor perspectiva farmacológica teórica foram sintetizadas (9 compostos mais INHHQ) e caracterizadas minuciosamente, tanto em solução quanto no estado sólido. Além disso, seus perfis de resistência à hidrólise foram determinados e, quando possível, também seus coeficientes de partição experimental octanol/água. Um total de oito hidrazonas foram selecionadas para as etapas seguintes. Estes compostos foram então novamente avaliados in silico, desta vez com relação ao seu potencial tóxico teórico, o que demonstrou que a presença da porção orto-piridina derivada do aldeído leva a uma moderada toxicidade. Isso foi provado experimentalmente por meio de ensaios de sobrevivência em células H4 de neuroglioma humano. Ademais, a inibição de agregação proteica em um modelo celular de sinucleinopatia foi avaliada para todas os oito compostos selecionados. A N-acilidrazona 1d, contendo o grupamento 1-metilimidazol, superou as expectativas, sendo não só o análogo mais estável e menos tóxico, mas também o que mais interferiu no padrão de inclusões de proteína no modelo celular avaliado, tornando-as menos compactas e, portanto, mais acessíveis para serem clivadas por proteinase-K. Além disso, este composto se liga seletivamente a formas agregadas da proteína (alfa)-Syn, conforme comprovado por meio de experimentos de RMN-STD. Uma série de caracterizações biofísicas in vitro adicionais por RMN foram realizadas com o propósito de avaliar a capacidade de 1d de competir com monômeros de proteína (alfa-sinucleína) pela ligação de íons cobre(I) e cobre(II), que são centrais na patologia da doença de Parkinson. Uma desejada preferência por cobre(I) foi observada. A constante de afinidade aparente desta N-acilidrazona por cobre(II) foi determinada através de cálculos baseados no método de Job e encontra-se na ordem de 5,66. Devido aos promissores resultados apresentados pelo grupo de hidrazonas derivadas do 1-metilimidazol-2-carboxaldeído, quatro compostos da classe foram parte de um pedido de patente depositado junto ao Instituto Nacional da Propriedade Industrial (INPI), que inclui uma estrutura Markush mais genérica. Além disto, os compostos foram avaliados qualitativamente frente a um modelo de formação de grânulos de estresse (SGs, Stress Granules), para se obter uma perspectiva do efeito dessas N-acilidrazonas sobre essas importantes inclusões. Nesse âmbito, três dos quatro ligantes contendo 1-metilimidazol em sua estrutura apresentaram, mais uma vez, resultados encorajadores, evitando completamente a formação de SGs a uma concentração de 100 (micro)mol L-1. Finalmente, embora as agregopatias exacerbadas por metais apresentem certas características em comum, como por exemplo proteínas que são propensas a se agregar após a interação com íons metálicos, essas doenças são multifatoriais, e pode-se esperar que N-acilidrazonas estruturalmente diferentes tenham atividades distintas em modelos experimentais de diversas patologias. Neste sentido, embora hidrazonas derivadas de piridina-2-carboxaldeído não tenham mostrado resultados significativos na agregação da proteína α-sinucleína, elas atuam como agentes protetores de peptídeos com relação aos efeitos deletérios da oxidação catalisada por cobre em um fragmento mutante da proteína priônica humana. Através da coleta de todos esses dados teóricos, químicos, espectroscópicos e biológicos, foi estabelecida uma relação qualitativa entre estrutura e atividade, a fim de determinar a influência de cada característica estrutural no desempenho de uma hidrazona como MPAC. Acredita-se que o presente trabalho possa constituir uma contribuição significativa para o campo de estudo em questão, abrindo novas perspectivas para o desenvolvimento de compostos atenuadores da interação metal-proteína para a terapia de agregopatias exacerbadas por metais. / [en] Although normal aging results in an accumulation of copper, iron and zinc in the brain, this becomes more relevant in neurodegeneration. Protein misfolding has long been linked with the development of some degenerative diseases, called aggregopathies. Metal binding is generally a factor for promoting the aggregation of such proteins, as well as generalized oxidative stress when redox-active metals are involved. In this sense, the use of therapies that target metal dyshomeostasis has been the subject of intense research in recent years. Our research group has already established that N-acylhydrazones compose a set of truly encouraging agents for the bioinorganic management of metal-enhanced aggregopathies. Our lead compound, INHHQ, however, does not present ideal pharmacokinetic parameters, which might constitute an obstacle in its path towards becoming a commercial drug. The present work consists of the study of fifty-five N-acylhydrazones of related structure (INHHQ plus fifty-four analogues) and in the selection of the best candidates as moderate chelators, Metal-Protein Attenuating Compounds (MPACs), in the context of important human aggregopathies. The ligands were designed through rationally thought changes in INHHQ s structure. Initially, in silico analyses were conducted. Blood-brain barrier crossing reference values, together with water solubility, were limiting features to select compounds for the next step. The hydrazones with the best theoretical pharmacological prospect (9 compounds plus INHHQ) were synthesized and thoroughly characterized, both in solution and in the solid state. Moreover, their hydrolysis resistance profiles were determined and, when possible, also their experimental octanol/water partition coefficient. A total of eight hydrazones were selected for the next phases, in which their effect on the survival of H4 cells and their ability of inhibiting protein aggregation in a cellular model of synucleinopathy were evaluated. 1-methylimidazole-containing N-acylhydrazone 1d excelled the expectations, being not only the most stable and least toxic analogue, but the one which interfered the most with protein inclusion patterns in the evaluated model, making them less compact. Furthermore, this compound binds selectively to aggregated forms of the (alpha)-Syn protein, as proven through STD experiments. A series of additional in vitro biophysical characterizations by NMR were carried out with the purpose of evaluating the ability of 1d to compete with monomers of (alpha)-Syn for the binding of copper(I) and copper(II) ions, which are central to Parkinson s disease pathology. A desired preference for copper(I) was observed. The apparent affinity constant of this N-acylhydrazone for copper(II) was determined through calculations based on the Job method and is in the order of 5.66. A qualitative structure-activity relationship was established for the synthesized compounds. We believe that the present work may constitute a significant contribution to the field of study in question, opening new perspectives for the development of MPACs for the therapy of metal-enhanced aggregopathies.

Bakgrund: Virtual Reality (VR) är en teknik som skapar en simulerad miljö där användaren kan uppleva en virtuell värld. Effekten av VR-träning på gång och balansförmågan hos personer med Parkinsons sjukdom (PS) är ännu oklar trots flera systematiska studier. Sammanfattning av befintlig evidens kan ge en överblick samt kartlägga den kliniska nyttan av VR. Syfte: Syftet är att genomföra en översiktsstudie av systematiska litteraturstudier för att utvärdera behandlingseffekten av VR-träning jämfört med traditionell träning på gång- och balansförmåga hos personer med PS. Metod: Systematiska litteraturstudier i databaserna PubMed, CINAHL samt PEDro som publicerats mellan åren 2019-2022 har granskats. Kvalitetsgranskning utfördes med AMSTAR 2 och en narrativ syntes användes för att sammanfatta de rapporterade fynden av gång- och balansförmåga. Utfallsmåtten som använts är statisk och dynamisk balans samt gångparametrar. Resultat: Av totalt 298 systematiska litteraturstudier inkluderades sju studier med 128 randomiserade kontrollerade studier (4736 deltagare) som uppfyllde kriterier. Enligt AMSTAR 2 graderades fyra studier till kritiskt låg kvalitet. I fem av sju systematiska litteraturstudier rapporterades förbättrad statisk balans (MD=1.13-2.69 SMD=0.22-0.26) för gruppen med VR-träning jämfört med kontrollgrupp. I tre av sex studier rapporterades förbättring (MD –1.55 till -2.86) på dynamisk balans. Temporala gångparametrar rapporterade ingen skillnad mellan VR träning och kontrollgrupp. Spatiala gångparametrarna rapporterade blandade resultat. Slutsats: Studierna bedömdes övergripande ha låg metodologisk kvalitet. Resultaten visade att VR-träning kunde förbättra balansförmågan när det gäller statisk balans, men det fanns varierande resultat när det gällde dynamisk balans jämfört med kontrollgrupp. Ingen skillnad rapporterades mellan grupperna gällande temporala gångparametrar. Varierande resultat visades för spatiala gångparametrar. Ytterligare högkvalitativa systematiska översikter eftersträvas för att kunna dra mer tillförlitliga slutsatser. / Background: Virtual Reality (VR) is a technology that creates a simulated environment where the user can experience a virtual world. The effect of VR training on gait and balance ability in people with Parkinson's disease (PS) remain unclear despite several systematic reviews. Summary of existing evidence can provide an overview of the current state of research and facilitate the mapping of the clinical benefit of VR. Aim: The aim is to conduct an overview of systematic reviews on gait and balance ability in people with PD using VR in comparison with traditional training. Method: A systematic search was performed including systematic reviews from PubMed, CINAHL and PEDro and published 2019-2022. Quality assessment was performed using AMSTAR 2.A narrative synthesis was conducted to synthesize the reported findings of gait and balance ability from the systematic reviews. The outcome measures used in this overview was staticand dynamic balance and gait parameters. Results: Of a total of 298 studies, seven systematic reviews with 128 randomized clinical trials (4736 participants) were included. Four studies had critically low quality after quality assessment. Static balance was improved (MD=1.13-2.69 SMD=0.22-0.26) in five of seven reviews with VR training compared to control group. Three of six reviews reported an improvement in dynamic balance (MD –1.55 till -2.86) with VR training. Temporal gait parameters reported no difference between VR training and control group. The spatial gait parameters reported mixed results among the systematic reviews. Conclusions: The included systematic reviews, in general, had low methodological quality. VR training were demonstrated to improve static balance but varied results regarding dynamic balance. Mixed findings were found regarding the spatial and temporal gait parameters. High-quality systematic reviews are warranted to general VR effect on gait and balance.Keyword: Balance, Gait, Overview, Parkinson´s disease, Virtual Reality

Bakgrund Mer än tio miljoner människor i världen lever med Parkinsons sjukdom, och prevalensen ökar med en åldrande befolkning. Parkinsons sjukdom är en kronisk neurologisk sjukdom som medför en mängd funktionsnedsättande symtom, både motoriska och icke-motoriska, vilka har stor påverkan på en persons dagliga liv. Den medicinska behandling som finns kan endast lindra symtom delvis och därför finns det ett behov av komplementära behandlingar, exempelvis musikterapi, som kan lindra symtom hos personer med Parkinsons sjukdom. Syfte Syftet med denna litteraturstudie är att belysa musikterapi i form av sång som symtomlindrande omvårdnadshandling vid Parkinsons sjukdom. Metod Studiedesignen är en icke-systematisk litteraturöversikt. Totalt 15 vetenskapliga artiklar inkluderades, däribland 13 kvantitativa och 2 kvalitativa. Resultatet sammanställdes i form av en integrerad analys. Resultat Två huvudkategorier, motoriska och icke-motoriska symtom, samt sex underkategorier till dessa identifierades i studien. Resultatet visade positiva effekter av sångterapi på såväl motoriska som icke-motoriska symtom. Förbättringar av motoriska symtom gällde framför allt kommunikations- och talförmåga. En viss förbättring av sväljförmåga och gångförmåga observerades dock.  Vad gäller icke-motoriska symtom så framkom ett flertal positiva effekter på psykisk, social och existentiell hälsa/livskvalitet; sångterapi visade sig kunna förbättra humör och minska depressiva symtom, oro/ångest, stress och apati. Dessutom hittades förbättringar vad gäller förmågan och viljan att socialisera sig med andra. Slutsats Resultatet av denna studie visar att sångterapi kan ha en symtomlindrande funktion i omvårdnaden av personer med Parkinsons sjukdom vad gäller såväl motoriska som icke-motoriska symtom. De huvudsakliga symtomlindrande effekterna av sångterapi gällde tal och kommunikation samt psykisk, social och existentiell hälsa/ livskvalitet. Dock behövs mer omfattande studier inom området, särskilt RCT-studier. / Background More than ten million people around the world are living with Parkinson’s disease, and the prevalence is increasing with an ageing population. Parkinson’s disease is a chronic neurological disease that entails a variety of functional impairments. the symptoms are motor as well as non-motor, all of which have a large impact on a person’s daily life. The existing medical treatment can relieve symptoms only partly; on account of this there is a need of complementary treatments, for example music therapy, for added symptom relief. Aim The aim of this literature review is to illustrate music therapy by singing as a symptom relieving nursing act. Method The study design is a non-systematic literature review. A total of 15 scientific articles were included, 13 quantitative studies and 2 qualitative studies. The result was compiled in the form of an integrative analysis. Results Two main categories, motor, and non-motor symptoms, and six subcategories were identified. Results of this study shows positive effects of singing therapy on motor and non-motor symptoms.  Improvements of motor symptoms mainly concerned communication and speech abilities. Some improvement of swallowing abilities and gait function could be observed.  Regarding non-motor symptoms several positive effects were displayed for mental, social, and existential health/quality of life; singing therapy improved temper and reduced depressive symptoms, anxiety, stress, and apathy. Improvements regarding the ability and will to socialize with other people were also found. Conclusions This study shows that singing therapy could have a symptom relieving function in nursing care for individuals with Parkinson´s disease, for both motor and non-motor symptoms. The main symptom relieving effects concerned communication and speech abilities and mental, social, and existential health/quality of life. However, there is a need for further studies, especially randomized controlled studies.

Hintergrund: Das idiopathische Parkinsonsyndrom (IPS) ist eine progrediente neurodegenerative Erkrankung. Sie ist charakterisiert durch Hypokinese, Tremor und Rigor. Außerdem treten zahlreiche sogenannte nicht - motorische Symptome (NMS), wie z.B Schlafstörungen oder Geruchsminderung, auf. Neben dieser somatischen Problematik sind die Patient*innen durch die chronische Erkrankung psychisch belastet. Häufige Komorbiditäten sind Depression und Angststörungen. Hier zeigt die aktuelle Literatur eine Unterversorgung in Diagnostik und Therapie. Eine besondere Form der Angst ist Progredienzangst, also der Angst vor dem Fortschreiten der Erkrankung. Es ist bekannt, dass Patient*innen mit IPS häufig unter dieser Angstform leiden. Wie und wovon die PA bei IPS beeinflusst wird und welche Verbindungen es zu NMS und Hoffnung gibt, wurde bisher nicht untersucht. Um eine Therapie der PA für IPS Patient*innen zu entwickeln, sollten diese Faktoren untersucht werden. Methoden: Es wurden Patient*innen mit IPS in der neurologischen Ambulanz des Universitätsklinikums Dresden befragt. Der Fragebogenkatalog umfasste den Progredienzangstfragebogen in Kurzform (PA-KF), den Herth Hope Index (HHI), die Hospitality Anxiety and Depression Scale (HADS), das Distress-Thermometer (DT) sowie ein selbstentwickelten Fragebogen zu psychosozialen Belastungsfaktoren. Außerdem wurden klinische Daten (Krankheitsdauer, Stadium, Komorbiditäten) und die nicht - motorischen Symptome (NMS) anhand des NMS-Questionnaire erhoben. Es folgte die statische Auswertung und der Gruppenvergleich zwischen Patient*innen mit und ohne überschwelliger PA. Um Einflussfaktoren für die PA zu ermitteln, wurde eine multivariate logistische Regressionsanalyse durchgeführt. Der Zusammenhang der PA und NMS wurde mittels Korrelationsanalyse dargestellt Ergebnisse: Insgesamt wurden 105 Patient*innen, 37 Frauen und 68 Männer in die Studie eingeschlossen. Das mittlere Alter lag bei 66 Jahren. Die meisten der Patient*innen (59%) befanden sich im Stadium Hoehn & Yahr 2&3. Die Auswertung der Fragebögen zeigte eine hohe psychische Belastung der Patient*innen. Mehr als ein Viertel (27%) der Patient*innen zeigte eine überschwellige PA (Summenwert im PA-KF ≥34). Sie gaben eine hohe Gesamtbelastung (DT-Thermometerwert) an. Die Patient*innen mit überschwelliger PA zeigte signifikant höhere Werte für Angst und Depression (HADS) und signifikant niedrigere Werte für Hoffnung (HHI). Diese Gruppe gibt signifikant mehr nicht - motorische Symptome (NMS) an. Die Anzahl der NMS korreliert mit der PA. Die Regressionsanalyse konnte fehlende Unterstützung durch die Familie, emotionale Probleme und Unsicherheit bzgl. Verlauf und Therapie, sowie wenig Hoffnung als Einflussfaktoren für die PA identifizieren. Schlussfolgerung: Die PA ist ein häufiges Symptom bei IPS. PA sollte im klinischen Alltag präsent sein und aufgrund der Häufigkeit und der klinischen Relevanz sollte ein Screening routinemäßig durchgeführt werden. Eine spezifische Therapie für die PA muss noch entwickelt werden. Ein möglicher Baustein könnte hier die Stärkung der Hoffnung durch Aufzeigen eines Therapiepfades sein.:Inhaltsverzeichnis 1 Einleitung 1 1.1 Das idiopathische Parkinsonsyndrom 1 1.2 Epidemiologie des IPS 2 1.3 Pathophysiologie des IPS 2 1.4 Symptome 3 1.4.1 Motorische Symptome 3 1.4.2 Nicht - motorische Symptome 4 1.5 Stadieneinteilung 5 1.6 Diagnose und Differentialdiagnosen 6 1.7 Therapie 9 1.7.1 Pharmakologische Therapie 9 1.7.2 Tiefe Hirnstimulation (THS) 11 1.7.3 Behandlung nicht - motorischer Symptome 11 1.7.4 Supportive Therapie 11 1.8 Beeinträchtigung der Lebensqualität durch nicht - motorische Symptome 12 1.9 Psychische Belastung bei IPS 12 1.9.1 Depression bei IPS (IPS-D) 12 1.9.2 Ängste bei IPS 13 1.9.3 Progredienzangst (PA) 14 2 Ziel der Arbeit und Hypothesen 16 2.1 Forschungsfragen 16 2.2 Hypothesen 16 3 Methoden 17 3.1 Ein- und Ausschlusskriterien 17 3.2 Erhebungsinstrumente 17 3.3 Datenverarbeitung 19 3.3.1 t-Test für unabhängige Stichproben 19 3.3.2 Mann-Whitney-U Test 20 3.3.3 Chi-Quadrat-Test 20 3.3.4 Multiple lineare Regressionsanalyse 20 4 Ergebnisse 22 4.1 Stichprobenbeschreibung 22 4.2 Auswertungen der psychologischen Testung und Gruppenvergleiche 26 4.2.1 Progredienzangst-Fragebogen-Kurzform 26 4.2.2 Distress-Thermometer (DT) 28 4.2.3 Ergebnisse der Problemliste 28 4.2.4 Herth Hope Index (HHI) 29 4.2.5 Hospitality Anxiety and Depression Scale (HADS) 30 4.2.6 PD-NMS-Questionnaire 31 4.2.7 Fragebogen zur psychosozialen Belastung und Bewältigungsstrategien 32 4.3 Lineare Regressionsanalyse 40 4.4 Korrelationsanalyse 44 5 Diskussion 45 5.1 Stichprobenzusammensetzung 45 5.2 Progredienzangst und Besonderheiten im Zusammenhang mit klinisch-demographischen Daten 47 5.3 Die Progredienzangst ist assoziiert mit Depression und Angst 50 5.4 Wenig Hoffnung verstärkt die Progredienzangst 51 5.5 Die Progredienzangst korreliert mit der Anzahl der Nicht - motorischen Symptome 52 5.6 Bedeutung für die klinische Arbeit 52 6 Ausblick für Folgestudien 54 7 Limitationen 54 8 Schlussfolgerung 55 9 Zusammenfassung 56 10 Summary 58 11 Danksagung 59 12 Tabellen- und Abbildungsverzeichnis 60 13 Abkürzungsverzeichnis 60 14 Literaturverzeichnis 62 15 Anhang 85 15.1 Fragebögen 85 15.2 Erfassung klinischer Daten 98 15.3 Einverständniserklärung und Teilnehmer*innen Information 103 15.4 Erklärung zur Eröffnung des Promotionsverfahrens und Einhaltung gesetzlicher Vorgaben 109 / Background: The Parkinson's disease is a progressive neurodegenerative disorder. It is characterized by lack of movement, tremor, and rigor. Moreover, there are numerous non-motor symptoms (NMS), such as sleeping disorders or loss of smell. In addition to these somatic problems, patients are psychologically burdened by the chronic disease. Common comorbidities are depression and anxiety disorders. The current literature shows a undertreatment in standards of diagnosis and therapy. A special form of anxiety is progression anxiety, the fear of the progression of the disease. It is known that patients with IPS suffer from this kind of anxiety. How and by what PA is affected in IPS and what the links are to NMS and hope is little studied. In order to develop and establish a therapy for PA in IPS patients, these parameters should be analyzed. Methods: Patients with IPS in the neurological outpatient clinic of the University Hospital Dresden were interviewed. The questionnaire catalog included the Progression Anxiety Questionnaire in Short Form (PA-KF), the Herth Hope Index (HHI), the Hospitality Anxiety and Depression Scale (HADS), the Distress-Thermometer (DT), and a self-developed questionnaire on psychosocial stress factors. Clinical data (disease duration, stage, comorbidities) and non-motor symptoms (NMS) were also collected using the NMS-Questionnaire. Static evaluation and group comparison between patients* with and without suprathreshold PA followed. Multivariate logistic regression analysis was performed to identify factors influencing PA. The correlation of PA and NMS was shown by means of correlation analysis. Results A total of 105 patients were included in the study, 37 women and 68 men. The mean age was 66 years. Most of the patients (59%) were in the Hoehn & Yahr 2&3 stage. The evaluation of the questionnaires showed a clear psychological burden of the patients. A quarter (27%) of the patient*s showed suprathreshold PA (sum score in PA-KF ≥34). They reported a high total burden (DT thermometer score). The patients* with suprathreshold PA showed significantly higher scores for anxiety and depression (HADS) and significantly lower scores for hope (HHI). This group reports significantly more non-motor symptoms (NMS). The number of NMS correlates with PA. Regression analysis identified lack of family support, emotional problems and uncertainty about course and treatment, and low hope as predictors of PA. Conclusion: PA is a common concomitant of IPS. This issue should be present in clinical practice and screening should be routinely performed. A specific therapy for PA should be developed. A possible approach could be hope enhancement.:Inhaltsverzeichnis 1 Einleitung 1 1.1 Das idiopathische Parkinsonsyndrom 1 1.2 Epidemiologie des IPS 2 1.3 Pathophysiologie des IPS 2 1.4 Symptome 3 1.4.1 Motorische Symptome 3 1.4.2 Nicht - motorische Symptome 4 1.5 Stadieneinteilung 5 1.6 Diagnose und Differentialdiagnosen 6 1.7 Therapie 9 1.7.1 Pharmakologische Therapie 9 1.7.2 Tiefe Hirnstimulation (THS) 11 1.7.3 Behandlung nicht - motorischer Symptome 11 1.7.4 Supportive Therapie 11 1.8 Beeinträchtigung der Lebensqualität durch nicht - motorische Symptome 12 1.9 Psychische Belastung bei IPS 12 1.9.1 Depression bei IPS (IPS-D) 12 1.9.2 Ängste bei IPS 13 1.9.3 Progredienzangst (PA) 14 2 Ziel der Arbeit und Hypothesen 16 2.1 Forschungsfragen 16 2.2 Hypothesen 16 3 Methoden 17 3.1 Ein- und Ausschlusskriterien 17 3.2 Erhebungsinstrumente 17 3.3 Datenverarbeitung 19 3.3.1 t-Test für unabhängige Stichproben 19 3.3.2 Mann-Whitney-U Test 20 3.3.3 Chi-Quadrat-Test 20 3.3.4 Multiple lineare Regressionsanalyse 20 4 Ergebnisse 22 4.1 Stichprobenbeschreibung 22 4.2 Auswertungen der psychologischen Testung und Gruppenvergleiche 26 4.2.1 Progredienzangst-Fragebogen-Kurzform 26 4.2.2 Distress-Thermometer (DT) 28 4.2.3 Ergebnisse der Problemliste 28 4.2.4 Herth Hope Index (HHI) 29 4.2.5 Hospitality Anxiety and Depression Scale (HADS) 30 4.2.6 PD-NMS-Questionnaire 31 4.2.7 Fragebogen zur psychosozialen Belastung und Bewältigungsstrategien 32 4.3 Lineare Regressionsanalyse 40 4.4 Korrelationsanalyse 44 5 Diskussion 45 5.1 Stichprobenzusammensetzung 45 5.2 Progredienzangst und Besonderheiten im Zusammenhang mit klinisch-demographischen Daten 47 5.3 Die Progredienzangst ist assoziiert mit Depression und Angst 50 5.4 Wenig Hoffnung verstärkt die Progredienzangst 51 5.5 Die Progredienzangst korreliert mit der Anzahl der Nicht - motorischen Symptome 52 5.6 Bedeutung für die klinische Arbeit 52 6 Ausblick für Folgestudien 54 7 Limitationen 54 8 Schlussfolgerung 55 9 Zusammenfassung 56 10 Summary 58 11 Danksagung 59 12 Tabellen- und Abbildungsverzeichnis 60 13 Abkürzungsverzeichnis 60 14 Literaturverzeichnis 62 15 Anhang 85 15.1 Fragebögen 85 15.2 Erfassung klinischer Daten 98 15.3 Einverständniserklärung und Teilnehmer*innen Information 103 15.4 Erklärung zur Eröffnung des Promotionsverfahrens und Einhaltung gesetzlicher Vorgaben 109

ZIEL Als Ursache für die sporadische Creutzfeldt-Jakob Krankheit wird eine spontane Konfigurationsänderung des Prionproteins diskutiert. Die Annahme der Beeinflussung fehlgefaltete Proteinketten, welche bei neurodegenerativen Erkrankungen wie der Alzheimer Demenz oder Parkinson vorliegen, auf die Entwicklung einer zweiten Proteinfehlfaltung stellen eine mögliche Verbindung zwischen dem Auftreten neurodegenerativer Erkrankungen und Prionerkrankungen her. Das Ziel dieser retrospektiven Untersuchung ist es, die klinischen und diagnostischen Eigenschaften von sCJD-Patienten mit Morbus Parkinson oder Demenz in der Familienanamnese zu analysieren um die Diagnostik verbessern zu können. METHODEN Für die vorliegende Arbeit wurde ein Kollektiv aus 133 Patienten mit sicherer oder wahrscheinliche sCJD mit bekannter Ausprägung am Codon-129 rekrutiert. Bei den Geschwistern, den Eltern oder den Großeltern mütterlicher- oder väterlicherseits lag ein Parkinsonsyndrom oder eine dementielle Erkrankung vor. Gegenüber gestellt wurde diesem eine Kontrollgruppe nach Zuordnung nach Geschlecht, Alter (+/- 5 Jahre) sowie PRnP-Codon 129-Genotyp. Der Schwerpunkt der Arbeit liegt auf der klinischen Symptomatik, den Liquorparametern und den Ergebnissen aus bildgebenden Verfahren wie Elektroenzephalographie, zerebraler Computertomographie und Magnetresonanztomographie. ERGEBNISSE Erstes neurologisches Symptom waren zerebelläre Störungen (Ataxie), psychiatrische und visuelle Störungen, während eine dementielle Entwicklung erst im Verlauf hinzutrat. Beim Fortschreiten der Erkrankung wurden Pyramidenbahnzeichen häufiger und extrapyramidale Störungen deutlich seltener diagnostiziert. Insgesamt fiel vom klinischen Erscheinungsbild häufiger die Gruppe FA-Parkinson auf (beispielsweise häufiges Vorkommen von Antriebsstörungen), während FA-Demenz meist der Kontrollgruppe glich. Mit dem Nachweis von PSWC im EEG in 53 % bei FA-Demenz und 61 % bei FA-Parkinson übertrifft die Sensitivität der EEG-Untersuchung nicht die für die sCJD geltende von 64 % (Steinhoff et al. 2004). Mit einem Nachweis der Proteine 14-3-3 im Liquor in 96 % (FA-Demenz) und 100 % (FA-Parkinson) ergibt sich eine ebenso hohe Sensitivität wie für die sCJD bereits postuliert (94 %, Zerr et al. 2000a). Auch die Sensitivität der NSE ist bei den Patienten dieser Arbeit sehr hoch, während der Liquormarker S100b-Protein bei FA-Parkinson-Patienten deutlich seltener den cut-off-Wert erreicht. Ein CJD-typischer MRT-Befund (hyperintense Basalganglien oder kortikale Signalsteigerung) wurde nur in 52 % bei FA-Demenz und bei 49 % bei FA-Parkinson festgestellt. SCHLUSSFOLGERUNG Schließlich lässt sich festhalten, dass bei diesen Patienten nicht vorwiegend eine Demenz wegweisend zur Diagnose ist, sondern auf das Vorliegen zerebellärer oder psychiatrischer Symptome geachtet werden muss. In der Diagnostik kommt dem EEG mit einer hohen Sensitivität eine große Bedeutung zu, während die MRTUntersuchung weniger wegweisend ist. Bei Morbus Parkinson in der Familie unterstützt die Liquoruntersuchung die Diagnostik nicht so stark, während gerade pathologische Werte des Tau-Proteins und des Amyloid-ß 1-42 bei Patienten mit Demenz in der Familie auf eine sCJD hindeuten.

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-28T19:17:34Z No. of bitstreams: 1 André Tiago Rossito Goes.pdf: 1301552 bytes, checksum: 403860d83984ea13e8f76afe4c562b26 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-28T19:18:09Z (GMT) No. of bitstreams: 1 André Tiago Rossito Goes.pdf: 1301552 bytes, checksum: 403860d83984ea13e8f76afe4c562b26 (MD5) / Made available in DSpace on 2018-09-28T19:18:09Z (GMT). No. of bitstreams: 1 André Tiago Rossito Goes.pdf: 1301552 bytes, checksum: 403860d83984ea13e8f76afe4c562b26 (MD5) Previous issue date: 2018 / A doença de Parkinson (DP) é caracterizada por uma degeneração progressiva dos neurônios dopaminérgicos do sistema nigroestriatal e depleção de dopamina (DA) no corpo estriado. A crisina tem demonstrado ser uma abordagem não farmacológica promissora para reduzir o risco de doenças neurodegenerativas. Este estudo investigou o potencial efeito neuroprotetor da crisina em um modelo animal de DP induzida por 6-hidroxidopamina (6-OHDA) em camundongos. O presente estudo demonstrou que uma dose de crisina (10mg/kg/dia p.o.) durate 28 dias foi eficaz em modular as seguintes alterações resultantes da exposição à 6-OHDA: atenuar à alteração no comportamento tipo-depressivo (teste de suspensão de cauda) e disfunções locomotoras (teste de rota-rod e teste do cilindro), proteger contra o estresse oxidativo (GPx, GSH, GST, GH), reduzir os níveis de citocinas pró-inflamatórias (TNF-α, IFN-γ, IL-1β, IL-2 e IL-6), bem como atenuou a redução dos níveis de DA, DOPAC e HVA. Além disso, preveniu a redução de neurônios TH+ causados pela exposição a 6-OHDA, além de elevar os níveis BDNF, GDNF e NGF no estriado de camundongos. Estes resultados reforçam que um dos efeitos neuroproterores induzidos pela crisina na DP, são decorrentes dos efeitos antioxidante, anti-inflamatório e modulador de neurotrofinas. Portanto, o presente estudosugere que a crisina atenua os declínios cognitivos e motores, depressão, estresse oxidativo e neuroinflamação induzidas pela 6-OHDA suportando a hipótese de que a crisina pode ser usado como um tratamento coadjuvante ao tratamente farmacológico atual para reduzir os sinais da DP. / Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons of the nigrostriatal system and dopamine depletion (DA) in the striatum. Chrysin has been shown to be a promising non-pharmacological approach to reducing the risk of neurodegenerative diseases. This study investigated the potential neuroprotective effect of chrysin in an animal model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a dose of chrysin (10 mg / kg / day po) for 28 days was effective in modulating the following changes resulting from exposure to 6-OHDA: attenuating the change in type-depressive behavior (tail suspension test) (GPx, GSH, GST, GH), reduce levels of proinflammatory cytokines (TNF-α, IFN-γ, IL-1β) , IL-2 and IL-6), as well as attenuated the reduction of AD, DOPAC and HVA levels. In addition, it prevented the reduction of TH + neurons caused by exposure to 6-OHDA, in addition to raising the BDNF, GDNF and NGF levels in the striatum of mice. These results reinforce that one of the neuroproteror effects induced by chrysin in PD is due to the antioxidant, anti-inflammatory and modulating effects of neurotrophins. Therefore, the present study suggests that chrysin attenuates the 6-OHDA-induced cognitive and motor declines, depression, oxidative stress and neuroinflammation by supporting the hypothesis that chrysin may be used as a adjuvant treatment to the current pharmacological treatment to reduce the signs of PD

Made available in DSpace on 2016-04-27T18:12:26Z (GMT). No. of bitstreams: 1 Renata Darc Scarpel.pdf: 904396 bytes, checksum: a071a505fbab67d471b86f396da27f5c (MD5) Previous issue date: 2007-10-09 / Universidade do Estado da Bahia / Introduction: Parkinson disease (PD) is classified as a progressive neurodegenerative disorder. By the progress of the disease, it promotes several speech and voice alterations, that can have repercussions in the life quality of patients. Considering it, this study tried to relate speech and voice to life quality of patients with PD. Aim: to correlate speech and voice parameters to Voice Handicap Index (VHI), according to different stages of Hoehn & Yahr (HY) scale. Approach: 56 individuals were selected between August and December of 2006. The assessments from these patients were analyzed and then submitted to voice recording in order to characterize the speech and voice alterations. VHI questionnaire was also applied to verify vocal disability occurrence, based on HY stages. Results: the outcomes of speech and voice parameters and the VHI ones, from the 56 individuals placed between level 2,0 and 4,0 of the mentioned scale, were correlated. It was found that speech and voice parameters which significantly worsened according to the stages were the followings: monopitch, monoloudness, little intra-oral air pressure for consonants, speech velocity, prolonged intervals and imprecise articulation. VHI outcomes experienced vocal disadvantage in all stages, being stage 2,0 the less compromised one followed by 3,0, 2,5, and 4,0. Regarding speech and voice parameters and VHI outcomes, the functional domain was the most compromised, correlated to vocal, prosodic and articulatory aspects. Conclusion: It was concluded from the findings that speech and voice was damaged accordingly to the disease evolution in the parameters related to monopitch, monoloudness, prosody and articulation. It was noticed, from the VHI answers, that individuals felt vocal disadvantages since the start of the disease. The functional domain was the most compromised, emotional being the least one / Introdução: a doença de Parkinson é classificada como uma patologia neurodegenerativa progressiva, de etiologia desconhecida. Com a sua evolução ocorrem alterações na fonoarticulação, que podem repercutir na qualidade de vida dos pacientes. Diante disso, a presente pesquisa buscou relacionar a fonoarticulação à qualidade de vida de pacientes com DP. Objetivo: correlacionar, segundo os estágios da escala Hoehn & Yahr, os parâmetros fonoarticulatórios com o questionário de desvantagem vocal Voice Handicap Index (VHI). Método: foram selecionados 56 sujeitos que compareceram a um centro de referência em atenção à saúde do idoso entre agosto e dezembro de 2006. Os prontuários desses pacientes foram analisados e os mesmos submetidos à gravação de voz, para a caracterização da fonoarticulação. Também foi aplicado o questionário VHI, para a verificação da ocorrência de desvantagem vocal de acordo com os estágios da Hoehn & Yahr. Resultados: correlacionou-se os achados dos parâmetros fonoarticulatórios aos achados do VHI dos 56 sujeitos que estavam entre os estágios 2,0 e 4,0 da referida escala. Encontrou-se que os parâmetros fonoarticulatórios que sofreram piora significativa de acordo com os estágios foram: monofrequência, monoloudness, consoantes com pouca pressão intra-oral, velocidade de fala, intervalos prolongados e imprecisão articulatória. Quanto às respostas do VHI em todos os estágios houve desvantagem vocal sendo que no estágio 2,0 o comprometimento foi menor, seguido pelos 3,0, 2,5 e 4,0. Quanto aos parâmetros fonoarticulatórios e os resultados do VHI, o domínio funcional foi o mais comprometido, correlacionado aos aspectos vocais, prosódicos e articulatório. Conclusão:diante destes achados conclue-se que a fonoarticulação sofreu prejuízo de acordo com a evolução da doença nos parâmetros ligados a entonação (monofrequência e monoloudness), prosódia e articulação. Com as respostas do VHI constata-se que os sujeitos percebem desvantagem vocal desde o início da doença. O domínio funcional foi o mais comprometido, seguido do orgânico. O menos comprometido foi o domínio emocional

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