The aim of this study was to investigate whether exercise could improve motor behavioral deficits and alter expression of glial fibrillary acidic protein (GFAP) in dorsal striatum in a 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease (PD). To this end, animals were randomly divided into 4 groups: sham sedentary (SS, n = 7); sham trained (ST, n=8); lesioned sedentary (LS, n=8) and lesioned trained (LT, n = 8). Rats were unilaterally lesioned with 6-OHDA (10 μg/3 μg) injected into the left medial forebrain bundle and sham groups were only injected with vehicle solution. The treadmill training protocol consisted of running with progressive increase in velocity, 5 days/week, during 4 weeks. Behavioral tasks were applied to asses the motor abilities of all animals prior to 6-OHDA injection and at 8th and 29th days post-injection. The tyrosine hydroxylase (TH - in substantia nigra pars compacta) and GFAP (in dorsal striatum) immunostaining was evaluated by semiquantitative analysis of the intensity (optical density - OD). The 6-OHDA lesion decreased the OD of TH and increased the OD of GFAP. In addition, the 6-OHDA lesion increased the number of ipsilateral rotations induced by methylphenidate (40 mg/kg, i.p., 30 min) and caused motor behavioral deficits. On the other hand, the treadmill training resulted in an increase in maximal exercise capacity in both trained groups (ST and LT). The training was able to reduce the number of ipsilateral rotations and ameliorated the motor behavioral deficits on 8th and 29th days postlesion. Interestingly, the exercise led to a significant increase in OD of GFAP in the LT group while there was no such effect in ST group. Our results indicate that treadmill training can improve motor behavioral deficits and suggest that the effects of exercise may be directly or, indirectly, mediated by astrocytes, as an increase in GFAP was observed in the dorsal striatum. Nevertheless, these are the first data showing an increase in GFAP expression post-exercise in this model and further research is needed to determine the precise action of exercise on astrocytes in Parkinson’s disease.

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.

La maladie de Parkinson (MP) est caractérisée par une perte dopaminergique dans le striatum, structure sous-corticale impliquée dans le contrôle moteur, la mémoire et les comportements émotionnels. Les interneurones cholinergiques (ChIs) striataux jouent un rôle clef dans cette réorganisation pathologique du striatum en modulant l’activité des neurones de projection striataux (MSNs). Ce travail vise à étudier l’implication des ChIs et des récepteurs muscariniques (mAChRs) dans les mécanismes qui sous-tendent l’expression des déficits moteurs, cognitifs et émotionnels dans différents modèles de la MP chez la souris. L’inhibition optogénétique des ChIs réduit les déficits moteurs (akinésie, asymétrie posturale, déficit sensori-moteur). Les enregistrements électrophysiologiques montrent que l’inhibition des ChIs réduit l’excitabilité des MSNs et rétablit l’équilibre d’activité des deux voies de sortie striatale. Ces effets antiparkinsoniens sont reproduits par le blocage pharmacologique striatal des mAChRs M1 et M4. Ils sont dus à une action préférentielle de l’ACh sur les mAChRs au niveau des MSNs à l’origine de la voie striatonigrale puisqu’ils disparaissent chez des souris invalidées pour les récepteurs M4 exprimés dans ces neurones. La photoinhibition des ChIs réduit les déficits mnésiques et l’anxiété. L’antagoniste des mAChRs M1 réduit l’anxiété mais est inefficace sur les déficits mnésiques, suggérant que d’autres récepteurs cholinergiques striataux puissent être engagés dans les fonctions mnésiques. L’ensemble de nos résultats apporte un éclairage nouveau sur l’implication des ChIs striataux dans le fonctionnement physiologique et pathologique du striatum. / Parkinson’s disease (PD) is characterized by a dopamiergic loss into the striatum, a subcortical structure involved in motor control, memory and emotional behaviors. Striatal cholinergic interneurons (ChIs) play a key role in this pathological reorganization of the striatal circuitry by modulating striatal projection neurons (MSNs). This study aims to investigate the involvement of ChIs and muscarinic receptors (mAChRs) in the mechanisms underlying the expression of motor, cognitive and emotional deficits observed in different models of PD in mice. ChIs optogenetic inhibition reduced motor deficits (akinesia, postural asymmetry, sensorimotor deficit). Electrophysiological recordings show that ChIs photoinhibition reduces MSNs excitability and restores the balance between the two striatal output pathways. These antiparkinsonian effects are reproduced by pharmacological intrastriatal blockade of M1 and M4 mAChRs. They are due to a preferential action of ACh on mAChRs expressed on striatonigral MSNs since the deficits disappear in mutant mice that lack M4 mAChRs only in these neurons. ChIs photoinhibition also reduces memory deficits and anxiety. M1 mAChRs antagonist reduces anxiety but is inefficient on memory deficits, suggesting that other cholinergic receptors might be involved in striatal memory functions. Overall, these results give new insights on the role of cholinergic interneurons in the normal and pathological functioning of the striatum.

Background: In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design: A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion: We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD.

No description available.

Background/Aims: The diagnostic value of olfactory testing for the discrimination of tremor-dominant Parkinson’s disease (PD) from other tremor disorders remains enigmatic. We evaluated whether olfactory testing can accurately detect PD in tremor patients. Methods: A retrospective analysis of 299 consecutive subjects referred for the differential diagnosis of a tremor disorder was done. Olfactory testing was performed using ‘Sniffin’ Sticks’, resulting in a composite TDI score of odor threshold (T), discrimination (D), and identification (I). Receiver operating curve (ROC) plots were used to calculate sensitivity/specificity for the detection of PD. Results: Of all subjects, 167 (55.9%) had PD and 85 (28.4%) had essential tremor (ET). The mean TDI score in PD was significantly reduced compared to those in ET and other tremor disorders with no differences between ET and other tremor disorders. ROC analysis revealed strong correlations of TDI scores with PD [area under the curve: 0.85 (95% CI: 0.80–0.89); p < 0.001]. The highest Youden index was observed for a TDI score <25 (Youden index: 0.58). Using this cutoff score and that generated from normative data of healthy controls, the TDI score provided high sensitivity (negative predictive value) and specificity (positive predictive value) of approximately 80% for detecting PD. Conclusion: Olfactory testing is a useful, easily applied and inexpensive diagnostic test which is helpful to detect PD among tremor patients.

Background: Epidemiological data on the prevalence of Parkinson’s disease (PD) in Germany are limited. The aims of this study were to estimate the age- and gender-specific prevalence of PD in Germany as well as the severity and illness duration. Summary: A systematic literature search was performed in 5 different databases. European studies were included if they reported age- and gender-specific numbers of prevalence rates of PD. Meta-analytic approaches were applied to derive age- and gender-specific pooled prevalence estimates. Data of 4 German outpatient samples were incorporated to calculate the proportion of patients with PD in Germany grouped by Hoehn and Yahr (HY) stages and disease duration. In the German population, 178,169 cases of PD were estimated (prevalence: 217.22/100,000). The estimated relative illness duration was 40% with less than 5 years, 31% with 5–9 years, and 29% with more than 9 years. The proportions for different HY stages were estimated at 13% (I), 30% (II), 35% (III), 17% (IV), and 4% (V), respectively. Key Message: We provide an up-to-date estimation of age and gender-specific as well as severity-based prevalence figures for PD in Germany. Further community studies are needed to estimate population-based severity distributions and distributions of non-motor symptoms in PD.

This diploma thesis focuses on the automated diagnosis of hypokinetic dysarthria in the multilingual speech corpus, which is a motor speech disorder that occurs in patients with neurodegenerative diseases such as Parkinson’s disease. The automatic speech recognition approach to diagnosis is based on the acoustic analysis of speech and subsequent use of mathematical models. The popularity of this method is on the rise due to its objectivity and the possibility of working simultaneously on different languages. The aim of this work is to find out which acoustic parameters have high discriminative power and are universal for multiple languages. To achieve this, a statistical analysis of parameterized speech tasks and subsequent modelling by machine learning methods was used. The analyses were performed for Czech, American English, Hungarian and all languages together. It was found that only some parameters enable the diagnosis of the hypokinetic disorder and are, at the same time, universal for multiple languages. The relF2SD parameter shows the best results, followed by the NST parameter. When classifying speakers of all the languages together, the model achieves accuracy of 59 % and sensitivity of 72 %.

Si les neurosciences connaissent d’importants progrès dans l’imagerie et le génotypage, le phénotypage repose encore largement sur des échelles visuelles. Le phénotype chez l’homme repose principalement sur son style perceptivo-moteur qui donne une empreinte à la marche, la posture, l’équilibre, l’habilité des membres supérieurs, les mouvements oculaires etc. La marche, fonction complexe et fondamentale de l’être humain, implique l’ensemble du système musculo-squelettique, le système nerveux central et périphérique ainsi que les organes sensoriels. Elle est le produit d’un patron de marche automatique et inconscient modulé par le tronc cérébral, les noyaux gris centraux et par des retours sensitifs (visuels, proprioceptives, vestibulaires et épicritiques). Enfin, la marche est aussi sous contrôle volontaire. Le phénotypage quantitatif de la marche suppose la construction préalable de bases de données de signaux de marche d’un nombre élevé (centaines) de sujets et de patients. Ceci peut être mené à bien grâce à des outils de mesure simples d’utilisation et adaptés à la pratique médicale de routine. Il existe plusieurs moyens pour phénotyper la marche mais le capteur inertiel, en raison de son prix, de sa souplesse d’utilisation et de l’accès aux données brutes est un outil particulièrement adapté pour l’étude de la marche en consultation de routine. Les capteurs inertiels permettent le calcul de nombreux paramètres. L’exercice de marche de 10 m aller/retour à vitesse de confort départ arrêté donne accès aux différentes phases de la marche (initiation, croisière, demi-tour) dans des conditions de consultation de routine. Ainsi, l’objectif de ce travail est d’approcher les mécanismes d’adaptation des personnes à des perturbations à différents niveaux anatomiques des structures impliquées dans la marche. Nous abordons cette question par un phénotypage quantitatif à partir du signal de capteurs inertiels recueilli sur des patients au cours d’un exercice de marche de 10 m aller/retour en consultation clinique de routine. Nous avons étudié successivement la marche de patients atteints d’arthrose du membre inférieur comme modèle d’adaptation de la marche à la douleur, puis la marche dans la maladie de Parkinson comme modèle d’atteinte du système de la mise en place des procédures motrices, enfin, la locomotion des patients hémiparétiques à la suite d’un accident vasculaire cérébral hémisphérique comme modèle d’atteinte de la commande volontaire. Nous montrons que la douleur dans l’arthrose du membre inférieur mène à une rigidification globale de la cinématique corporelle. Cette rigidification est prépondérante sur le membre atteint. Elle traduit la perte des synergies musculaires par la mise en place de boucle-réflexe anti-douleur. Nous démontrons que ces modifications sont corrélées à la sévérité clinique de l’arthrose. Pour analyser la régularité de la marche dans la maladie de Parkinson indépendamment des variabilités inter-individuelles du patron de marche nous avons développé un outil de visualisation de l’exercice de marche. La maladie de Parkinson affecte en particulier la régularité de la marche. Notre travail apporte la preuve que cette irrégularité est corrélée à la sévérité des symptômes chez les patients atteints de la maladie de Parkinson. Nous montrons enfin qu’une lésion du cortex dans l’accident vasculaire hémisphérique provoque un changement de stratégie dans le demi-tour. Comme d’autres, nous faisons l’hypothèse que les stratégies de demi-tours sont en partie stockées dans le cortex frontal et que les hémisphères droit et gauche ne jouent pas un rôle symétrique. Nous montrons que le choix de stratégie de demi-tour est corrélé avec la survenue de chutes à 6 mois et pourrait constituer un nouvel élément pour orienter la rééducation. (...) / In the field of neurosciences, significant improvement has been made in the last decades in imaging and genotyping. However, phenotyping remains stagnant at the state of visual observation or visual grading scales. The human phenotype is made up of locomotion (gait, posture and displacement of daily living), upper-limb fine and rough movements, eye movements, language, cognition and complex social behaviors. Gait is a central function in humans, implying volitional, emotional and automatic processes. It involves the whole musculoskeletal system as well as the central and the peripheral nervous system including sensory organs. Building a gait phenotyping system implies setting up a database of gait signals of many (hundreds) of subjects and patients. This goal can be achieved with user-friendly devices deployed in routine medical practice. For instance, inertial measurement units (IMUs) are a valid tool to measure spatio-temporal gait parameters and are adapted to routine medical use. The 10-meter walking test forward and back at self-selected walking speed is adapted to routine testing at the doctor’s office. It allows for measuring gait initiation, gait cruise, gait termination and a 180° turn. In that context, beyond technical challenges, the aim of this work was to address the question How does the central nervous system adapt to an external alteration on various levels in the command chain of gait? To answer this question, we studied sequentially the IMU signal of gait spatio-temporal kinematics in lower-limb osteoarthritis as a model of gait affected by pain, in Parkinson disease as a model of a lesion of the central nervous system muscle tone regulator and finally, in post-hemispheric stroke as a model of lesions of brain structures responsible for volitional locomotion. Secondary clinical questions were How can the severity of a disease be objectively graded with gait kinematics? and How can locomotion kinematics participate in the fall risk prediction in frail populations? In osteoarthritis, we showed that pain in lower-limb osteoarthritis led to a global stiffness of the body during locomotion. This stiffness was preponderant on the affected limbs and led to the loss of muscular synergies by the establishment of anti-pain reflexes as a reaction to pain. This change was correlated with the severity of lower-limb osteoarthritis. In Parkinson disease, to analyze gait regularity independently from inter-individual gait signature, we constructed a novel gait visualization tool and show that a lesion of the muscle tone regulator in Parkinson disease affects gait regularity. This regularity was associated with disease symptoms. Finally, in stroke, we showed that a lesion in the cortex implied a change in the 180° turning stepping, a volitional task. In line with other authors, we hypothesized that locomotion patterns could be generated in the frontal cortex and that the right and left frontal cortex did not have a symmetric role. We showed specific stepping patterns associated more with risk of fall, which could constitute a new argument to orientate rehabilitation. Altogether then, this work suggests that simple measuring hardware (here IMUs), with appropriate signal processing, allowed for decomposing and quantifying complex behavioral tasks (here locomotion) in daily hospital settings.

Einleitung: Tiermodelle spielen für die Aufklärung pathophysiologischer Mechanismen und die Entwicklung erfolgsversprechender Therapieoptionen zentralnervöser Bewegungsstörungen eine unverzichtbare Rolle. Die Identifizierung von Gendefekten für die Parkinson-Krankheit und Dystonien ermöglichte die Generierung von Tiermodellen mit einer hohen „construct validity“. Weibliche transgene Thy1-aSyn Mäuse sowie DYT1 Knock-in (KI) Mäuse zeigen jedoch keine motorischen Störungen. In der vorliegenden Arbeit sollten zur Aufdeckung sensomotorischer Beeinträchtigungen, die bei Parkinson- und Dystoniepatienten beobachtet werden, detaillierte Untersuchungen des Verhaltens an diesen beiden Mausmodellen durchgeführt werden. Zielstellung: Zunächst sollte ein sensitiver Verhaltenstest konstruiert und entwickelt werden, bei dem sich ändernde sensorische Stimuli während der Ausübung der motorischen Aufgabe impliziert werden. Bei der Etablierung dieses sogenannten „adaptiven rotierenden Balkentests“ (ARB-Test) sollte auch der Einfluss des genetischen Hintergrunds bei Wildtyp-Mäusen evaluiert werden. Daraufhin sollte überprüft werden, ob dieser Test den Endophänotyp der weiblichen Thy1-aSyn Mäuse aufdecken kann. In dem DYT1 KI Mausmodell sollte der Frage nachgegangen werden, ob die Tiere Verhaltensdefizite in spezifischen Tests zeigen, die sensomotorische Verschaltungen untersuchen. Material und Methoden: Die mRNA-Expression von α-Synuclein in der Substantia nigra bei männlichen und weiblichen Thy1-aSyn Mäusen wurde mithilfe der quantitativen Echtzeit-PCR (qPCR) ermittelt. Im Anschluss an die Entwicklung des neuen Verhaltensapparates für den ARB-Test wurden Thy1-aSyn Tiere beider Geschlechter in diesem Versuch getestet und ihre Leistung den Ergebnissen auf etablierten motorischen Verhaltenstests („challenging beam test“, „pole test“) gegenübergestellt. Um den Einfluss des Hintergrundstammes auf das Verhalten der Tiere auf dem ARB-Test zu untersuchen, wurden Wildtypen der reinen C57BL/6J-Linie sowie Hybrid-Tiere des Stammes C57Bl/6J × DBA2 (BDF1) allen drei o. g. Versuchen unterzogen. Bei den Mäusen des DYT1 KI Modells wurde der „adhesive removal test“ und der ARB-Test zur Analyse der Sensomotorik durchgeführt. Im Vergleich dazu wurden vielfältige Verhaltensparameter in einer Reihe vorwiegend motorischer (Offenfeld-Test, „challenging beam test“, „pole test“, Zylinder-Test, Block-Test, Nestbau-Test) und kognitiver („y-maze test“) Verhaltenstests ausgewertet. Ergebnisse: Bei den weiblichen Thy1-aSyn Mäusen wurde eine geringere Expression des Transgens im Vergleich zu den männlichen Tieren festgestellt. Der neue ARB-Test wurde erfolgreich etabliert und konnte signifikante Verhaltensdefizite der weiblichen und männlichen Mutanten des Parkinson-Modells im Vergleich zu den Kontrolltieren aufdecken. Der genetische Hintergrund beeinflusste die Leistung der Wildtypen auf diesem Balkentest. Während die DYT1 KI Tiere in den rein motorischen und kognitiven Versuchen keine Beeinträchtigungen des Verhaltens zeigten, konnten der „adhesive removal test“ sowie der neue ARB-Test signifikante sensomotorische Defizite der KI Mäuse im Unterschied zu den Wildtypen zum Vorschein bringen. Schlussfolgerung: Im Thy1-aSyn Mausmodell konnte die Bedeutung der sensomotorischen Integration für die Ausprägung motorischer Defizite sowie für eine mögliche Kompensation solcher motorischen Beeinträchtigungen demonstriert werden. Hierfür hat sich der neu entwickelte, sensitive ARB-Test als geeignet herausgestellt. Die Aufdeckung von Beeinträchtigungen der Sensomotorik spricht auch bei den DYT1 KI Tieren für den Einfluss einer gestörten sensomotorischen Integration bei der Ausprägung der Symptomatik. Damit eignet sich dieses Mausmodell für die Untersuchung weiterer Parameter, die Auswirkungen auf die Aufdeckung des Phänotyps und die Penetranz der Erkrankung haben sowie um die zugrunde liegenden pathophysiologischen Mechanismen zu erforschen.