The theoretical part of this dissertation presents a current view of functional (psychogenic) movement disorders (FMD) in the current International Classification of Diseases (ICD-10) referred to as dissociative (conversion) motor disorders, which has undergone significant development in the last two decades. It is a heterogeneous group of diseases with a tendency of becoming chronic diseases, which, in addition to motor symptoms, are manifested by a number of comorbid non-motor symptoms (fatigue, pain, anxiety, depression, cognitive difficulties, etc.). Despite the potential reversibility, these disorders still have an unfavorable prognosis and are associated with a low quality of life. Based on our current understanding, abnormalities of attentional processes are among the central phenomena of the development and maintenance of FMD. So far, only a minimum of studies has focused on attentional processes in the context of complex cognitive performance with contradictory findings. The dissertation had two goals. The first of the presented studies focused on the impact of subjectively assessed non-motor symptoms including subjective cognitive complaints and objectively assessed motor symptoms on the quality of life. The aim of the second study was to examine the cognitive profile of patients with FMD...

La maladie de Parkinson (MP) est une maladie neurodégénérative chronique qui apparait en moyenne à partir 55 ans. Sa cause reste inconnue mais son apparition et son développement sont corrélés avec la perte progressive des neurones dopaminergique de la substance noire qui innervent les ganglions de la base (GB). Jusqu'à ce jour le traitement le plus efficace est basé sur la compensation du déficit en dopamine (DA) par l'administration de son précurseur, la L-DOPA, qui est métabolisé en DA. Ce traitement améliore les symptômes moteurs de la maladie et donc la qualité de vie des patients. Néanmoins, après une certaine période des effets secondaires invalidants apparaissent, en particulier des fluctuations motrices et des mouvements anormaux involontaires appelés dyskinésies. De plus, ce traitement n'apporte pas de réponse à la progression de la dégénérescence et donc de la maladie. C'est pour ces raisons que la communauté scientifique est à la recherche d'une thérapie pharmacologique alternative à la L-DOPA, ou du moins visant à minimiser ses effets indésirables. Dans ce contexte, les récepteurs métabotropiques du glutamate, en particulier mGluR4, semblent constituer une cible privilégiée. En effet, mGluR4 est situé à des synapses des GB supposées hyperactives dans la MP, et son activation par des moyens pharmacologiques pourrait donc rétablir une activité normale grâce à son action inhibitrice sur la libération de neurotransmetteur. Nos résultats démontrent le bien-fondé de cette hypothèse sur le plan fonctionnel, en utilisant un nouvel agoniste allostérique spécifique de mGluR4, Lu AF21934. / Parkinson's disease (PD) is a progressive neurodegenerative disorder that appears around 55 years of age. The causes of PD remain unknown but its appearance and progression are correlated with the progressive loss of dopaminergic neurons of substantia nigra pars compacta innervating the basal ganglia (BG). Up to date, the most efficient treatment is based on restoring a normal level of dopamine (DA) in the brain by the administration of L-DOPA, a DA precursor that is metabolized to DA. However, at long term, L-DOPA treatment induces some side-effects, in particular the highly disabling L-DOPA-induced dyskinesia (LID). For this reason, the scientific community is searching for a pharmacological treatment alternative to L-DOPA and/or minimizing LID. In this context, metabotropic glutamate receptors, in particular mGluR4, are targets of interest. mGlu4 are localized at presynaptic terminals within BG circuitry that become hyperactive in PD. For this reason, mGluR4 has been considered a key strategic target for non-dopaminergic pharmacological treatments aimed at modulating these synapses, due to its ability to reduce neurotransmitter release. Herein we provide physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGluR4 positive allosteric modulator (PAM). By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission. In rats rendered parkinsonian, Lu AF21934 combined with sub-threshold doses of L-DOPA acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID.

Bakgrund: Unified Parkinson’s Disease Rating Scale är ett bedömningsinstrument som är frekvent använt, både i Sverige och internationellt, inom vården för personer med Parkinsons sjukdom. Under 2001 granskades och reviderades instrumentet vilket resulterade i en ny version benämnt Movement Disorder Society Unified Disease Rating Scale. Del III av MDSUPDRS syftar till att undersöka motoriska symtom och anses viktiga i bland annat fysioterapeuters utredning och som utvärdering efter behandling. I dagsläget saknas en svensk validerad översättning av del III. Syfte: Syftet med detta arbete var att översätta del III av bedömningsinstrumentet MDSUPDRS från engelska till svenska och därefter undersöka innehållsvaliditet för den svenska versionen. Metod: Översättningen skedde genom forward translation, backward translation samt analys av innehållsvaliditet genom Content Validity Index (CVI). Översättningen undersöktes med hjälp av fem forskningspersoner, sakkunniga inom området. Validitet analyserades under två skattningsomgångar utifrån följande CVI-delar med tillhörande referensvärden: I-CVI (0,80), S-CVI/AVE (0,90) och S-CVI/UA (0,80). Resultat: Efter två omgångar skattade samtliga forskningspersoner 20 av 24 frågor som relevanta med ett I-CVI-värde på 1,0. Resterande fyra frågor uppnådde ett I-CVI-värde på 0,80. Värdena för S-CVI/AVE och S-CVI/UA var 0,97 respektive 0,83, vilket innebar att dessa översteg de uppsatta referensvärdena. Skalan kan därmed i sin helhet ses som valid, då samtliga CVI-värden uppnådde de uppsatta referensvärdena. Slutsats: Den översatta versionen kan i sin helhet betraktas som valid. / Background: The Unified Parkinson’s Disease Rating Scale is a frequently used assessment tool world wide in clinics in care of people with Parkinson’s disease. In 2001, the assessment tool were reviewed and revised, which was titled Movement Disorder Society Unified Parkinson’s Disease Rating Scale. Part III of MDS-UPDRS aims to investigate motor symptoms and is considered important in, among other things, physiotherapists' investigation, and as evaluation after treatment. Currently, a Swedish validated translation of Part III is lacking. Aim: The aim of this study is to translate part III of MDS-UPDRS from english to swedish, and then analyze content validity for the swedish version. Method: The translation was done with the use of forward translation, backward translation and the content validity was analyzed with Content Validity Index (CVI). The translation were analyzed in two rounds, with help by five individual proficient to the area. The content validity were set by following domains and reference values: I-CVI (0,80), S-CVI/AVE (0,90) and SCVI/UA (0,80). Results: After two rounds, 20 questions out of 24 reached an I-CVI of 1,0. The remaining four questions reached an I-CVI of 0,80. The values of S-CVI/AVE and S-CVI/UA were 0,97 and 0,83 which meant that it exceeded the set reference values. The integer scale can be considered valid based on the reference values on S-CVI/AVE and S-CVI/UA. Conclusion: The integer translated version of MDS-UPDRS part III can be considered valid.

La maladie de Parkinson (MP) se caractérise par une dégénérescence progressive et irréversible des neurones dopaminergiques de la substance noire induisant une perte de dopamine (DA) dans les structures cibles. Lorsque cette perte DA se situe entre 60 % et 80 %, les patients présentent des symptômes moteurs (rigidité, tremblement, akinésie) et non-moteurs très variés (dépression, anxiété, apathie). Ces derniers apparaissent avant et/ou en même temps que les symptômes moteurs. La dopathérapie permet de contrecarrer certains symptômes, mais tous ne sont pas sensibles à cette médication. Parallèlement à la dégénérescence DA, le système sérotoninergique (5-HT) serait aussi altéré de façon précoce dans la maladie. Cette dégénérescence est liée par l’expression de symptômes moteurs et non-moteurs. Néanmoins, aucun lien causal n’a été mis en évidence entre cette lésion 5-HT et la symptomatologie parkinsonienne. Ainsi, il était primordial de déterminer le rôle de la 5-HT dans 1) l’expression des troubles moteurs et non-moteurs 2) dans la réponse au traitement sérotoninergique et dopaminergique. Nous avons utilisé un nouveau modèle animal primate ayant une lésion 5-HT (via la MDMA) puis une lésion DA (via le MPTP). Ce modèle nous permet de mettre en évidence l’impact d’une lésion 5-HT précoce dans la symptomatologie. Des approches comportementales, pharmacologiques, d’imagerie et de neuroanatomie ont été utilisées. La lésion 5-HT a induit un trouble anxieux chez les animaux lésés à la MDMA, qui ne sont pas contrecarrer avec un traitement sérotoninergique (antidépresseur). Cette lésion a également induit une sévérité et une progression plus rapide des symptômes moteurs induits par la lésion DA / Parkinson’s disease (PD) is characterized by a progressive and irreversible degeneration of dopaminergic (DA) neurons localized in the substantia nigra, leading to a loss of dopamine within the target structures. When the loss of DA reaches 60 to 80 %, PD patients develop a wide range of motor (rigidity, tremor, akinesia fro example) and non-motor (depression, anxiety, apathy for example) symptoms. Dopatherapy allows the reduction of symptoms expression. But some motor and non-motor symptoms are not counteracted by those DA drugs. In addition to DA degeneration, patients present an early serotonergic (5-HT) lesion. This lesion is linked to the severity of some motor and non-motor symptoms. However, there is no causal link established between 5-HT lesion and parkinsonian symptoms. Therefore, it was essential to determine the role of 5-HT 1) in the expression of motor and non-motor symptoms 2) and in the response of DA and 5-HT treatments. For that, we used a new monkey model of PD, exhibiting a 5-HT lesion (with MDMA ‘”ecstasy”)) followed by a DA lesion (with MPTP). This model allowed us to evaluate the impact of an early 5-HT lesion on parkinsonian symptoms. We used different approaches: PET imaging, pharmacology, behavioral and neuroanatomy. The MDMA-driven early 5-HT lesion induced an anxious-like behavior on MDMA treatedmonkeys. This behavioral modification was not counteracted by 5-HT drugs (antidepressant). This MDMA lesion has also increased the severity and the progression of parkinsonian symptoms induced by DA lesion with MPTP

Hintergrund: Die Parkinson-Krankheit (PK) ist häufig durch Demenz und Depression gekennzeichnet, die den Krankheitsverlauf erschweren und das Risiko einer Pflegebedürftigkeit zusätzlich erhöhen können. Über die genauen Zusammenhänge zwischen PK und diesen Komplikationen liegen für Ambulanzpatienten jedoch bislang keine Zahlen vor. Patienten und Methode: Bundesweit wurden 1449 Patienten mit PK von 315 niedergelassenen Fachärzten untersucht. Neben dem neurologischen Zustand und der Pflegebedürftigkeit wurden auch demenzielle Syndrome nach DSM-IV-Kritierien sowie Depressionen mit der Montgomery-Asberg Depression Rating Scale (MADRS) dokumentiert. Ergebnisse: Insgesamt 18,3% der Patienten waren pflegebedürftig, hiervon hatten 51,9% und 43,2% die Pflegestufen I und II. Auch nach Kontrolle des PK-Schweregrads hatten Patienten mit Depression (OR=2,8, 95%-KI:1,8–4,3), Demenz (OR=2,7; 95%-KI:1,8–4,1) bzw. mit beiden Störungen (OR=3,9, 95%-KI:2,5–6,0) ein höheres Risiko für Pflegebedürftigkeit als Patienten ohne diese Störungen. Patienten ≥76 Jahre hatten ein 4fach höheres Risiko für eine Pflegestufe als Patienten ≤65 Jahre (OR=3,5, 95%-KI:2,3–5,5). Über die Altersgruppen hinweg nahm das Risiko, pflegebedürftig zu werden, bei depressiven Patienten am stärksten zu (von 11,9% auf 42,0%). Schlussfolgerung: Das Risiko für eine Pflegebedürftigkeit ist bei Demenz und Depression stark erhöht. Die Daten legen insbesondere für die Depression als Einzelkomplikation eine vergleichbar hohe Krankheitslast nahe wie für die Demenz. / Background: Parkinson’s disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. Patients and methods: A nationwide sample of outpatients (n=1,449) was examined by office-based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8–4.3), dementia (OR=2.7; 95% CI 1.8–4.1) or both (OR=3.9; 95% CI 2.5–60,0) were at higher risk for CD than patients without dementia or depression. Patients aged ≥76 years were fourfold more likely to be care dependent than patients aged ≤65 years (OR=3.5; 95% CI 2.3–5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). Conclusion: The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia.

Bakgrund: Parkinsons sjukdom är en kronisk progredierande neurodegenerativ sjukdom och är den näst största i dess slag. Sjukdomen kan ge uttryck i både motoriska och icke-motoriska symtom. Genom sjukdomsförloppet genomgår personen olika faser som medför förlust av både mentala och kroppsliga funktioner. Förlusten av funktionerna ger en generellt sämre livskvalitet än hos andra personer. Syfte: Syftet med litteraturöversikten var att belysa symtomens påverkan på livskvaliteten hos personer med Parkinsons sjukdom. Metod: En allmän litteraturstudie baserad på tio kvalitativa studier. Resultat: Resultatet visar på att personer som lever med Parkinsons sjukdom har en komplex livssituation. De fysiska symtom som sjukdomen kännetecknas av ger svårigheter i vardagen. Resultatet visar också att den psykiska hälsan blir väsentligt påverkad i samband med detta. En följd av de fysiska och psykiska symtomen kan leda till social isolering, och tillsammans kan dessa skapa en kedjereaktion som leder till en försämrad livskvalitet. Slutsats och förslag på forskning: De motoriska symtomen är det mest påfrestande med att leva med Parkinsons sjukdom och bidrar starkt till en minskad livskvalitet. Därför behövs vidare omvårdnadsforskning för personer med Parkinsons sjukdom samt vilka omvårdnadsåtgärder som skulle kunna leda till förbättrad livskvalitet. / Background: Parkinson's disease is a chronic progressive neurodegenerative disease and is the second largest of its kind. The disease expresses both motor and non-motor symptoms. Through the course of the disease, the person undergoes different phases that cause loss of both mental and physical functions. The loss of functions gives a generally poorer quality of life than other people. Aim: The aim of the literature review was to highlight the effects of the symptoms on quality of life for people with Parkinson's disease. Method: A general literature study based on ten qualitative studies. Result: The result shows that people who are living with Parkinson's disease, lives in a complex life situation. The physical symptoms that the disease is characterized by creates difficulties in everyday life. The result also shows that mental health is significantly affected in this regard. A consequence of the physical and mental symptoms can lead to social isolation, and together they can create a chain reaction that leads to a deteriorating quality of life. Conclusion and Suggestions for Research: The motor symptoms are the most profound of living with Parkinson's disease and contribute significantly to a reduced quality of life. Therefore, nursing research is needed for people with Parkinson's disease as well as nursing measures that could lead to improved quality of life.

Background The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. Methods We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. Results In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. Conclusion NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

Background The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. Methods We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. Results In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. Conclusion NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

Hintergrund: Die Parkinson-Krankheit (PK) ist häufig durch Demenz und Depression gekennzeichnet, die den Krankheitsverlauf erschweren und das Risiko einer Pflegebedürftigkeit zusätzlich erhöhen können. Über die genauen Zusammenhänge zwischen PK und diesen Komplikationen liegen für Ambulanzpatienten jedoch bislang keine Zahlen vor. Patienten und Methode: Bundesweit wurden 1449 Patienten mit PK von 315 niedergelassenen Fachärzten untersucht. Neben dem neurologischen Zustand und der Pflegebedürftigkeit wurden auch demenzielle Syndrome nach DSM-IV-Kritierien sowie Depressionen mit der Montgomery-Asberg Depression Rating Scale (MADRS) dokumentiert. Ergebnisse: Insgesamt 18,3% der Patienten waren pflegebedürftig, hiervon hatten 51,9% und 43,2% die Pflegestufen I und II. Auch nach Kontrolle des PK-Schweregrads hatten Patienten mit Depression (OR=2,8, 95%-KI:1,8–4,3), Demenz (OR=2,7; 95%-KI:1,8–4,1) bzw. mit beiden Störungen (OR=3,9, 95%-KI:2,5–6,0) ein höheres Risiko für Pflegebedürftigkeit als Patienten ohne diese Störungen. Patienten ≥76 Jahre hatten ein 4fach höheres Risiko für eine Pflegestufe als Patienten ≤65 Jahre (OR=3,5, 95%-KI:2,3–5,5). Über die Altersgruppen hinweg nahm das Risiko, pflegebedürftig zu werden, bei depressiven Patienten am stärksten zu (von 11,9% auf 42,0%). Schlussfolgerung: Das Risiko für eine Pflegebedürftigkeit ist bei Demenz und Depression stark erhöht. Die Daten legen insbesondere für die Depression als Einzelkomplikation eine vergleichbar hohe Krankheitslast nahe wie für die Demenz. / Background: Parkinson’s disease (PD) is frequently accompanied by dementia or depression which can aggravate the clinical picture of the disease and increase the risk of care dependency (CD). Little is known about the associations between PD, these neuropsychiatric comorbidities and CD in outpatients. Patients and methods: A nationwide sample of outpatients (n=1,449) was examined by office-based neurologists (n=315) comprising the documentation of the general, neurological status and the degree of CD. The dementia status was clinically rated according to the established DSM-IV criteria. Depression was screened with the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Overall, 18.3% of all patients were care dependent. Even after adjustment for PD severity, patients with depression (OR=2.8; 95% CI 1.8–4.3), dementia (OR=2.7; 95% CI 1.8–4.1) or both (OR=3.9; 95% CI 2.5–60,0) were at higher risk for CD than patients without dementia or depression. Patients aged ≥76 years were fourfold more likely to be care dependent than patients aged ≤65 years (OR=3.5; 95% CI 2.3–5.5). Across all age groups, patients with depression featured the highest increments (from 11.9 to 42.0%). Conclusion: The risk for CD is substantially elevated in outpatients with PD when further neuropsychiatric symptoms are present. The data suggest that depression contributes equally to disability as does dementia.

En plus de leurs difficultés motrices bien documentées, les personnes atteintes de la maladie de Parkinson présentent un large éventail de symptômes non moteurs. Ces symptômes non moteurs comprennent des difficultés perceptives, telles que la détection du contraste, la perception du mouvement et les réductions du champ visuel, ainsi que des difficultés cognitives, incluant des déficits de l'attention, du traitement visuospatial et de mémoire. Ces symptômes non moteurs demeurent sous-étudiés et peu compris, et ce, malgré le fait qu’ils jouent un grand rôle dans la qualité de vie des personnes avec la maladie de Parkinson ainsi que dans leur profil clinique. Dresser un profil des atteintes visuo-perceptives dès les premiers stades de la maladie est donc d’une grande importance. Pour ce faire, nous avons testé 14 adultes âgés et 10 adultes avec la maladie de Parkinson sur différents tests mesurant la perception et les capacités cognitives. Nous avons obtenu quelques évidences démontrant des atteintes au niveau de la cognition, mais aucune en lien avec la visuo-perception. De plus, nos résultats quelque peu contradictoires ne nous permettent pas d’infirmer ou confirmer la présence d’interactions entre la visuo-perception et la cognition dans les premiers stades de la maladie de Parkinson. / In addition to their well-documented motor difficulties, individuals afflicted with Parkinson's disease manifest a broad spectrum of non-motor symptoms. These non-motor symptoms encompass perceptual challenges, such as contrast detection, motion perception, and reductions in visual field, alongside cognitive impairments, including deficits in attention, visuospatial processing, and memory. Despite playing a significant role in the quality of life and clinical profile of Parkinson's disease patients, these non-motor symptoms remain insufficiently explored and understood, particularly visuo-perceptual impairments. Profiling visuo-perceptual impairments in the early stages of the disease holds considerable importance. To address this, we assessed 14 elderly adults and 10 adults diagnosed with Parkinson's disease using various tests measuring perception and cognitive abilities. While we obtained some evidence indicating cognitive impairments, none were linked to visuo-perception. Moreover, our somewhat contradictory findings do not allow us to definitively confirm or refute the presence of interactions between visuo-perception and cognition in the early stages of Parkinson's disease.