Daugelis neurodegeneracinių ligų klinikinių žymenų yra nespecifiniai ir nustatomi tik progresavus ligai. Neurodegeneracinio parkinsonizmo diagnostika remiasi klinikiniais kriterijais, tačiau idiopatinės Parkinsono ligos (PL), kuri yra pati dažniausia neurodegeneracinio parkinsonizmo priežastis, klinikiniai požymiai dažnai pasireiškia ir esant kitiems parkinsonizmo sindromams. Patikimas, neinvazinis, nebrangus ir saugus diagnostinis testas PL, galbūt ir demencijų diagnostikai bei diferencinei diagnostikai yra aktualus dėl kelių pagrindinių priežasčių: skirtingų parkinsonizmo sindromų medikamentinis gydymas ir ligos prognozė labai skiriasi; tiksli diagnozė svarbi imantis neatidėliotinų priemonių užkertant kelią kai kurioms sindromams būdingoms gyvybei grėsmingoms komplikacijoms; PL ankstyvoji diagnostika ikiklinikinėje stadijoje leistų anksčiau parinkti ir pradėti patogenezinį gydymą; atsiradus efektyvios neuroprotekcijos galimybėms, atsirastų ir tam tikro amžiaus populiacijos atrankinės patikros įrankio poreikis. Disertacinio darbo tikslas buvo nustatyti transkranijinės sonografijos vertę neurodegeneracinių ekstrapiramidinės nervų sistemos ligų diagnostikai, diferencinei diagnostikai ir atrankinei patikrai. Užsienio mokslininko dalyvavimas doktorantūros procese finansuojamas Lietuvos mokslo tarybos (konkurso paraiškos Nr. VIZ-DOK-124, doktorantūros tarybos narė doc. dr. Pille Taba). / The most symptoms of neurodegenerative disorders are non-specific and come to clinical attention only when the disease has progressed. The diagnostics of neurodegenerative parkinsonism is based on clinical criteria. However, the symptoms of idiopathic Parkinson‘s disease (PD), which is the most common cause of neurodegenerative parkinsonism, are often observed in patients with other parkinsonian syndromes. A reliable, non-invasive, safe and affordable test for the diagnosis and differential diagnosis of PD and, perhaps, dementia is relevant for multiple reasons: the disease prognosis and treatment of parkinsonian syndromes differs greatly and an unbiased disease marker would facilitate the development of neuroprotective drugs; the exact diagnosis is crucial in order to take urgent measures to avoid life-threatening complications; early diagnosis of PD would enable pathogenetic treatment; with the arrival of neuroprotective options, the need for selective screening of population according to certain age and other risk factors would arise. The aim of the doctoral study was to investigate the value of transcranial sonography for the diagnosis, differential diagnosis and screening of neurodegenerative extrapyramidal disorders. Participation of the Scientist from foreign institution in the Process of Doctoral Studies is financed by the Research Council of Lithuania (Tender-based financing application No VIZ-DOK-124, the Defence Council Member Assoc. Prof. Dr. Pille Taba).

Tyrimo objektas: sergančiųjų Parkinsono liga savarankiškumas, pusiausvyra, ėjimas, kvėpavimas, ištvermė. Darbo tikslas: palyginti sergančiųjų Parkinsono liga funkcinę būklę, taikant ritmišką stimuliaciją garsu ir diferencinę treniruotę kineziterapijos metu. Uždaviniai: 1) įvertinti stimuliacijos garsu poveikį sergančiųjų Parkinsono liga funkcinei būklei; 2) įvertinti diferencinės treniruotės poveikį sergančiųjų Parkinsono liga funkcinei būklei; 3) palyginti skirtingų kineziterapijos metodikų poveikį sergančiųjų Parkinsono liga funkcinei būklei. Tyrimo metodika: 23 asmenys, sergantys Parkinsono liga, atsitiktinai suskirstyti į dvi grupes: pirmoje grupėje 11, o antroje 12 tiriamųjų. Pirmos grupės tiriamiesiems kineziterapijos metu buvo taikytas diferencinės treniruotės metodas, o antrosios – ritmiškos stimuliacijos garsu metodas. Kvėpavimo funkcija vertinta spirometrijos metodu, ištvermė - 6 minučių ėjimo testu, ėjimas - matuojant žingsnio ilgį, ėjimo greitį ir žingsnio trukmę, pusiausvyra - Fulertono pusiausvyros testu, savarankiškumas - Fizinės veiklos testu. Tyrimo rezultatai ir išvados: 1. Kineziterapijos metu taikant ritmiškos stimuliacijos garsu metodą, statistiškai reikšmingai (p<0,05) pagerėjo sergančiųjų Parkinsono liga funkcinė būklė: padidėjo forsuota gyvybinė plaučių talpa, forsuotas iškvėpimo tūris per pirmą sekundę, savarankiškumas, žingsnio ilgis, ėjimo greitis ir pagerėjo pusiausvyra. 2. Diferencinės treniruotės metodas statistiškai reikšmingai (p<0,05)... [toliau žr. visą tekstą] / Research object: physical performance, balance, gait, endurance and respiratory function in individuals with Parkinson’s disease. The aim of this paper is to compare an effect of rhythmic auditory stimulation and differential training on functional state in individuals with Parkinson’s disease. Objectives: 1) to evaluate an effect of rhythmic auditory stimulation on functional state in individuals with Parkinson’s disease; 2) to evaluate an effect of differential training on functional state in individuals with Parkinson’s disease; 3) to compare an effect of different physical therapy methods on functional state in individuals with Parkinson’s disease. Research methods: 23 individuals with Parkinson’s disease were divided into two groups: 11 patients in one group and 12 in another group. During the physical therapy one group of patients had differential training practice, and another group – rhythmic auditory stimulation practice. Patient’s respiratory function was evaluated using spyromethry method, endurance – 6-minute walk test, gait – measuring step length, walking velocity, and step time, balance – Fullerton Balance Scale, physical performance – Physical Performance Test. Conclusion: 1. Rhythmic auditory stimulation significantly (p<0,05) improved functional state in individuals with Parkinson’s disease: forced vital capacity, forced expiratory volume in one second, physical performance, step length, walking velocity, balance. 2. Differential training significantly (p<0... [to full text]

Pharmacotherapy for Parkinson’s disease (PD) is based on levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies. To evaluate the impact of levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma levodopa levels was found in all patients, irrespective of treatment regimen. The impact of levodopa pharmacokinetics was further studied in a crossover trial comparing sustained-release tablets and continuous daytime intestinal infusion. Infusion produced significantly decreased variability in plasma levels of levodopa, resulting in significantly normalised motor function. A permanent system for long-term levodopa infusion has been developed and 28 patients have been followed for 87 patient-years. Motor response was generally preserved during the long-term observation period, implying that there is no development of tolerance to infusion therapy. Levodopa tablets are normally used in multiples of 50 or 100 mg, thus a rough estimate of individual dosage. A new concept for individualising levodopa/carbidopa doses with microtablets of 5/1.25 mg is under development. An electronic drug-dispensing device for administering the microtablets was tested on patients with PD. All were able to handle the dispenser and most were interested in future use of the concept. Self-assessment of symptoms is accurate in PD, but traditional paper diaries are associated with low compliance. A wireless electronic diary was compared with a corresponding paper diary. The time-stamped and thus completely reliable patient compliance was 88% with the electronic diary. To conclude, pharmacokinetics of levodopa is the major determinant for motor fluctuations in PD. Every effort to individualise dosage and to smooth out the fluctuations in levodopa concentrations should be made, e.g. by means of microtablets or enteral infusion. Electronic patient diaries for real-time data capture are suitable for PD studies.

Las mutaciones en el gen LRRK2, en especial la G2019S, parecen ser una causa relativamente frecuente de enfermedad de Parkinson (EP).Mutaciones en este gen se detectan en el 5-6% de los casos con EP familiar y en el 1-2 % de los casos esporádicos de diferentes poblaciones occidentales. La mutación R1441G del gen LRRK2 también es una causa frecuente de parkinsonismo en el País Vasco. Las hipótesis del presente trabajo son: 1) En Cataluña las mutaciones G2019S y R1441G del gen LRRK2 son causa de parkinsonismo tanto familiar como esporádico, 2) Las manifestaciones clínicas motoras y no motoras del parkinsonismo asociado a mutaciones en el gen LRRK2 son heterogéneas, y 3) El sustrato neuropatológico del parkinsonismo asociado a mutaciones en el gen LRRK2 es heterogéneo y determina el fenotipo clínico. En relación a estas hipótesis, los objetivos son: 1) Determinar la frecuencia de las mutaciones G2019S y R1441G del gen LRRK2 en pacientes con diagnóstico clínico de EP en un hospital terciario de Barcelona, 2) Definir el fenotipo clínico de los pacientes con EP portadores de una mutación en el gen LRRK2, y 3) Determinar la presencia de las mutaciones G2019S y R1441G del gen LRRK2 en cerebros diagnosticados de EP, de parkinsonimo degenerativo, o de degeneración lobar frontotemporal, y estudiar las características clínicas y patológicas de los casos portadores de una mutación en este gen. Los resultados y conclusiones son: 1) La frecuencia de mutaciones en el gen LRRK2 en pacientes con EP que atienden a una consulta especializada en un hospital terciario de Barcelona es del 5,3%, siendo la mutación G2019S la más frecuente (el 4,3% de los pacientes son portadores). La mutación R1441G es más infrecuente (0,7%). 2) Las mutaciones en el gen LRRK2 son más frecuentes en casos familiares de EP (un 9,6% de los casos son portadores) que en casos esporádicos (un 3,4% son portadores). Hasta en un 43,7% de los pacientes con mutaciones en el gen LRRK2 no existen antecedentes familiares de parkinsonismo. 3) Las características clínicas de los síntomas motores y no motores del parkinsonismo asociado a mutaciones en el gen LRRK2 es indistinguible de los observados en la EP clásica. 4) Las alteraciones neuropatológicas del parkinsonismo asociado a la mutación G2019S del gen LRRK2 son heterogéneas. Si bien el sustrato neuropatológico más frecuente es la patología tipo Lewy, describimos un caso que confirma que uno de los fenotipos neuropatológicos asociados a la mutación G2019S es la degeneración nigral inespecífica sin inclusiones distintivas. 5) No hemos detectado mutaciones en el gen LRRK2 en cerebros asociados a otro tipo de enfermedad neurodegenerativa diferente a la EP, como la demencia por cuerpos de Lewy, la parálisis supranuclear progresiva o la atrofia multisistémica. Su existencia habría que considerarla probablemente excepcional o coincidental. / LRRK2 G2019S mutation is a frequent cause of Parkinson’s disease (PD). This mutation is present in 5-6% of familial PD cases and 1-2 % of sporadic PD patients. LRRK2 R1441G is frequent in PD patients from the Basque country. We hypothesize that 1) In Catalonia, the G2019S and R1441G mutations are frequent in patients with familial as well as sporadic parkinsonism. 2) Clinical features in LRRK2-related parkinsonism are heterogeneous 3) The neuropathological substrate of LRRK2-related parkinsonism is pleomorphic and determines the clinical phenotype. We aim to assess 1) The frequency of the G2019S and R1441G mutations in patients with a clinical diagnosis of PD in Barcelona 2) The clinical phenotype of PD patients carrying a LRRK2 mutation, and 3) The presence of LRRK2 G2019S and R1441G mutations in brains diagnosed of PD, other neurodegenerative parkinsonism, as well as frontotemporal lobar degeneration, and assess the clinical and neuropathological features of those cases carrying a LRRK2 mutation. Results and conclusions: 1) LRRK2 mutations are frequent in PD patients from Barcelona (5.3% of them). The G2019S mutation is more frequent (4.3%) than the R1441G mutation (0.7%). 2) LRRK2 mutations are more frequent in familial PD cases (9.6% of them) than in sporadic cases (3.4%). Family history of parkinsonism is absent in up to 43.7% of patients with LRRK2 mutations. 3) Clinical features of motor and non-motor symptoms of LRRK2-related parkinsonism is indistinguishable from those of classical PD. 4) The neuropathological phenotype of LRRK2 G2019S-related parkinsonism is heterogeneous. Although the most frequent neuropathological substrate is Lewy boby type pathology, we describe a patient with non-specific nigral degeneration and the G2019S mutation. 5) We have not been able to identify LRRK2 mutations in brains of a neurodegenerative disease other than PD (e.g Lewy bodies dementia, Progressive supranuclear palsy or Multiple system atrophy). Presence of LRRK2 mutations in these neurodegenerative diseases would be exceptional or coincidental.

No description available.

PhD / People with a chronic illness, such as Parkinson’s disease, often live in the community for many years while the illness becomes progressively more debilitating. Little is known about how such people control the impact the disease has upon their various roles in life. This study employed naturalistic qualitative research methods to investigate how people with Parkinson’s disease and their partners continue to actively participate as members of their social community. Using in-depth semi-structured, focused interviews, participants with Parkinson’s disease and their partners were asked to name and describe roles that occupied their daily activity. They were asked about their most significant occupational roles, what they did in these roles, the knowledge or strategies they employed to deal with barriers to occupational role performance, and the personal meaning such roles held. Four basic themes evolved from the data: the impact of the disease on occupational role performance, or ‘doing’, secondary personal limitations to occupational role performance, secondary social limitations to occupational role performance and cumulative barriers to occupational role performance. Loss of control over choice and manner of engagement in occupational roles was a significant element of all four themes. Sense of self and sense of social fit were identified as major elements that informed participants’ perceptions of control. Participants described a range of diverse responses that they used to actively restore personal control of occupational performance in the face of degenerative illness. Learning new coping styles appeared to be underpinned by a personal set of rules or ‘blueprint’, despite professional input. This blueprint was actualised through a problem identification, problem solving and active engagement cycle that was termed a cycle of control. A conceptual model of a cycle of control was proposed as the final stage of the research. The model represented a way of describing how participants acted to restore a sense of personal control once a specific barrier to occupational role performance had been perceived. The findings of this study support the notion that people with chronic illness, such as Parkinson’s disease, are active and knowledgeable participants in health care, and have occupational histories and experiences that they harness when dealing with barriers to performance. Moreover, the findings demonstrate that people with chronic illness work in tandem with significant role partners to constantly maintain the valued partnership in meaningful occupational roles as the disease progresses. A greater understanding of how people with chronic illness and their partners strive to maintain a sense of personal control can enable occupational therapists to work effectively as ancillary partners in care. A greater understanding of the way in which role partners work together to maintain occupational integrity in their lives would be central to assessment and intervention for community programs for people with chronic illness.

PhD / When modeling a system as complex as the brain, considerable simplifications are inevitable. The nature of these simplifications depends on the available experimental evidence, and the desired form of model predictions. A focus on the former often inspires models of networks of individual neurons, since properties of single cells are more easily measured than those of entire populations. However, if the goal is to describe the processes responsible for the electroencephalogram (EEG), such models can become unmanageable due to the large numbers of neurons involved. Mean-field models in which assemblies of neurons are represented by their average properties allow activity underlying the EEG to be captured in a tractable manner. The starting point of the results presented here is a recent physiologically-based mean-field model of the corticothalamic system, which includes populations of excitatory and inhibitory cortical neurons, and an excitatory population representing the thalamic relay nuclei, reciprocally connected with the cortex and the inhibitory thalamic reticular nucleus. The average firing rates of these populations depend nonlinearly on their membrane potentials, which are determined by afferent inputs after axonal propagation and dendritic and synaptic delays. It has been found that neuronal activity spreads in an approximately wavelike fashion across the cortex, which is modeled as a two-dimensional surface. On the basis of the literature, the EEG signal is assumed to be roughly proportional to the activity of cortical excitatory neurons, allowing physiological parameters to be extracted by inverse modeling of empirical EEG spectra. One objective of the present work is to characterize the statistical distributions of fitted model parameters in the healthy population. Variability of model parameters within and between individuals is assessed over time scales of minutes to more than a year, and compared with the variability of classical quantitative EEG (qEEG) parameters. These parameters are generally not normally distributed, and transformations toward the normal distribution are often used to facilitate statistical analysis. However, no single optimal transformation exists to render data distributions approximately normal. A uniformly applicable solution that not only yields data following the normal distribution as closely as possible, but also increases test-retest reliability, is described in Chapter 2. Specialized versions of this transformation have been known for some time in the statistical literature, but it has not previously found its way to the empirical sciences. Chapter 3 contains the study of intra-individual and inter-individual variability in model parameters, also providing a comparison of test-retest reliability with that of commonly used EEG spectral measures such as band powers and the frequency of the alpha peak. It is found that the combined model parameters provide a reliable characterization of an individual's EEG spectrum, where some parameters are more informative than others. Classical quantitative EEG measures are found to be somewhat more reproducible than model parameters. However, the latter have the advantage of providing direct connections with the underlying physiology. In addition, model parameters are complementary to classical measures in that they capture more information about spectral structure. Another conclusion from this work was that a few minutes of alert eyes-closed EEG already contain most of the individual variability likely to occur in this state on the scale of years. In Chapter 4, age trends in model parameters are investigated for a large sample of healthy subjects aged 6-86 years. Sex differences in parameter distributions and trends are considered in three age ranges, and related to the relevant literature. We also look at changes in inter-individual variance across age, and find that subjects are in many respects maximally different around adolescence. This study forms the basis for prospective comparisons with age trends in evoked response potentials (ERPs) and alpha peak morphology, besides providing a standard for the assessment of clinical data. It is the first study to report physiologically-based parameters for such a large sample of EEG data. The second main thrust of this work is toward incorporating the thalamocortical system and the basal ganglia in a unified framework. The basal ganglia are a group of gray matter structures reciprocally connected with the thalamus and cortex, both significantly influencing, and influenced by, their activity. Abnormalities in the basal ganglia are associated with various disorders, including schizophrenia, Huntington's disease, and Parkinson's disease. A model of the basal ganglia-thalamocortical system is presented in Chapter 5, and used to investigate changes in average firing rates often measured in parkinsonian patients and animal models of Parkinson's disease. Modeling results support the hypothesis that two pathways through the basal ganglia (the so-called direct and indirect pathways) are differentially affected by the dopamine depletion that is the hallmark of Parkinson's disease. However, alterations in other components of the system are also suggested by matching model predictions to experimental data. The dynamics of the model are explored in detail in Chapter 6. Electrophysiological aspects of Parkinson's disease include frequency reduction of the alpha peak, increased relative power at lower frequencies, and abnormal synchronized fluctuations in firing rates. It is shown that the same parameter variations that reproduce realistic changes in mean firing rates can also account for EEG frequency reduction by increasing the strength of the indirect pathway, which exerts an inhibitory effect on the cortex. Furthermore, even more strongly connected subcircuits in the indirect pathway can sustain limit cycle oscillations around 5 Hz, in accord with oscillations at this frequency often observed in tremulous patients. Additionally, oscillations around 20 Hz that are normally present in corticothalamic circuits can spread to the basal ganglia when both corticothalamic and indirect circuits have large gains. The model also accounts for changes in the responsiveness of the components of the basal ganglia-thalamocortical system, and increased synchronization upon dopamine depletion, which plausibly reflect the loss of specificity of neuronal signaling pathways in the parkinsonian basal ganglia. Thus, a parsimonious explanation is provided for many electrophysiological correlates of Parkinson's disease using a single set of parameter changes with respect to the healthy state. Overall, we conclude that mean-field models of brain electrophysiology possess a versatility that allows them to be usefully applied in a variety of scenarios. Such models allow information about underlying physiology to be extracted from the experimental EEG, complementing traditional measures that may be more statistically robust but do not provide a direct link with physiology. Furthermore, there is ample opportunity for future developments, extending the basic model to encompass different neuronal systems, connections, and mechanisms. The basal ganglia are an important addition, not only leading to unified explanations for many hitherto disparate phenomena, but also contributing to the validation of this form of modeling.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Nöroloji Anabilim Dalı, 2004. / Bibliyografya var.

Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2008.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dalı, 2007. / Kaynakça var.