This thesis characterises the cortical pattern of degeneration in progressive supranuclear palsy (PSP) and its consequences. Global atrophy was first examined using a recently developed staging scheme in pathologically-proven PSP cases compared with other tauopathies: gross atrophy was not observed in PSP. Quantification of regional volume loss throughout the brain was then used to determine the magnitude of more focal tissue atrophy in PSP, cortical dysfunction was investigated by measuring cerebral blood flow (CBF) changes, and several cortical cellular pathologies were analysed. Any changes observed were related to each other and clinical assessments of motor, cognitive and behavioural abnormalities. At mid-stage PSP, frontal and subcortical atrophy related to decreased CBF in the frontal cortex and cognitive decline. Parietocerebellar CBF increases were also identified (related to frontal CBF deficits) and related to motor and non-motor deficits. By end-stage PSP, focal atrophy had advanced from frontal and subcortical structures to include atrophy in the parietal lobe. Parietal lobe atrophy related to behavioural abnormalities. Histopathological analysis at end-stage revealed that the cortical atrophy and cell loss does not relate to tau deposition. The focal cortical cell loss related exclusively to motor deficits whilst the more widespread cortical tau deposition related to cognitive and behavioural impairments. Both the tau deposition and these non-motor impairments increased in severity over time. The results show that frontal atrophy and dysfunction occurs rapidly and early in PSP and relate to increasing cognitive deficits. Such deficits appear to cause compensatory CBF enhancement in parietocerebellar regions which then also undergo rapid and severe neurodegeneration. These later changes occur in concert with the more classic PSP symptoms, such as oculomotor features. Throughout the disease, the progressive increase in frontotemporal tau deposition contributes to cognitive and behavioural deficits which become most marked late in the disease. The findings strongly suggest that progressive clinical dysfunction in PSP is directly related to progressive cortical degeneration. Cortical degeneration appears to occur in two independent functional networks. Increased CBF in PSP may be a useful early indicator for future neurodegeneration, although the cellular mechanism leading to cell death requires further investigation.

The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks. The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks.

Made available in DSpace on 2016-04-27T18:12:43Z (GMT). No. of bitstreams: 1 Maria Aparecida Gomes.pdf: 648694 bytes, checksum: 3afa4cbfda448ac630c681ffe983bc75 (MD5) Previous issue date: 2010-02-05 / Centro Universitario de Caratinga / The human aging has been discussed for scholars of diverse areas and has changed its meaning throughout the time. This process can bring damages to the general functions and the health of the swallow apparatus in its clinical aspects, disturbing the quality of life. Therefore, the objective of this study was to delineate the work of speech therapy intervention with the elderly people with Supranuclear Paralysis. Method: qualitative case study, descriptive nature, with two elderly people with Supranuclear Paralysis referred to the speech clinic complaining of swallowing disorders. Eighteen care provided in homes of the patients with duration of 50 minutes each were audio recorded and transcribed in regular spelling, to make the data analysis. To these they had added registers of the daily life of the patients. Results: To be effective the speech therapy intervention involved a work of establishing possibilities of communication among the patients, therapist, their familiar, and other caregivers; to keep in contact with the patients` suffering, to create a support that allowed them to stand the new condition of life. It was possible to avoid the gastrostomy of one of the patients who has beens with the illness for ten years and of another one, that had the illness for six years, up to thirty six days before his death. Conclusion: The speech therapy intervention allowed to improve the quality of life of the two studied patients / O envelhecimento humano tem sido discutido por estudiosos de diversas áreas e vem mudando seu significado ao longo do tempo. Esse processo pode trazer prejuízos às funções gerais e à saúde do aparelho de deglutição em seus aspectos clínicos, perturbando a qualidade de vida. Assim sendo, o objetivo deste estudo foi delinear o trabalho de intervenção fonoaudiológica com adultos idosos, portadores de Paralisia Supranuclear. Método: estudo de caso clínico qualitativo, de natureza descritiva, com dois idosos portadores de Paralisia Supranuclear encaminhados à clínica fonoaudiológica com queixa de distúrbios de deglutição. Dezoitos atendimentos realizados nas residências dos pacientes, com duração de 50 minutos cada, foram audiogravadas e transcritas em ortografia regular, para compor os dados de análise. A estes somaram - se registros do cotidiano dos pacientes. Resultados: Para ser efetiva a intervenção fonoaudiológica envolveu um trabalho de estabelecer possibilidades de comunicação entre os pacientes, fonoaudiólogo seus familiares e demais cuidadores; de entrar em contato com o sofrimento dos pacientes, para criar um suporte que lhes permitisse suportar a nova condição de vida. Foi possível evitar a gastrostomia de um dos pacientes que está há dez anos com a doença e de outro, que ficou seis anos com a doença, até trinta e seis dias antes de seu falecimento. Conclusão: A intervenção fonoaudiológica permitiu melhorar a qualidade de vida dos dois pacientes estudados

Background: Idiopathic parkinsonism is a neurodegenerative syndrome of unknown cause and includes Parkinson’s disease (PD) and atypical parkinsonian disorders. The atypical parkinsonian disorders are: Multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The incidence rates of these diseases in Sweden are largely unknown. The diagnosis of each disease relies mainly on clinical examination although several imaging and laboratory parameters may show changes. A diagnosis based on clinical examination is especially difficult early in the course of each disease; diagnosis is easier later on when disease-charactersistic signs have evolved and become more prominent. However, even in later stages it is not uncommon that patients are misdiagnosed. PD can be divided into subgroups based on the main clinical symptoms, i. e. tremor dominant, postural instability and gait difficulty (PIGD), and indeterminate. The PIGD subtype has worse prognosis including higher risk of dementia. The aims were to study the incidence of idiopathic parkinsonism and the different specific parkinsonian disorders in the Umeåregion and to investigate the patients early in the course of the disease with brainmagnetic resonance tomography (MRI), external anal sphincterelectromyography (EAS-EMG) and oculomotor examination. Can these methods improve the differential diagnostic work-up and/or differentiate between the subtypes of PD? Methods: We examined all patients in our catchment area (142,000 inhabitants) who were referred to us due to a suspected parkinsonian syndrome. Our clinic is the only clinic in the area receiving referrals regarding movement disorders. During the period (January 1, 2004 through April 30,2009) 190 patients fulfilled the inclusion criteria and were included in the study. Healthy volunteers served as controls.  Results: Incidence: We found the highest incidences reported in the literature: PD (22.5/100,000/year), MSA(2.4/100,000/year), and PSP (1.2/100,000/year). No CBD patients were encountered. Brain MRI: Degenerative changes were common both in controls and PD. There were no differences between the PD subtypes. EAS-EMG: Pathological changes in EAS-EMG examination were common in PD, MSA and PSP. It was not possible to separate PD, MSA and PSP by the EAS-EMG examination. Oculomotor examination: Pathological results were common in all diagnosis groups compared to controls. It was not possible to separate PD, MSA and PSP or the PD subtypes with the help of oculomotor examination. Conclusions: The incidences of idiopathic parkinsonism, PD, MSA and PSP were higher than previously reported in the literature. It is not clear weather this is due to a true higher incidence in the Umeå region or a more effective casefinding than in other studies. MRI, EAS-EMG and oculomotor examination could not contribute to the differential diagnostic work-up between PD, MSA and PSP nor differentiate between PD subtypes early in the course of the disease.

INTRODUCCIÓN: La parálisis supranuclear progresiva (PSP) se caracteriza por el depósito anormal de proteína tau hiperfosforilada en ganglios basales y tronco cerebral. Su etiología es desconocida y el único factor de riesgo genético conocido es su asociación con el haplotipo H1, que engloba un conjunto de polimorfismos en la región 17q21 incluyendo el gen tau y genes flanqueantes. Este haplotipo podría actuar modulando la expresión o el "splicing" de tau, pero existen otros genes candidatos importantes para la función neuronal o relacionados con la función de tau como saitohin, NIK y CRHR1 en esta región, o kinasas implicadas en la fosforilación de tau como GSK-3beta, en otras regiones. OBJETIVOS: Investigar el efecto de polimorfismos y mutaciones de los genes saitohin, CRHR1, región 3'-UTR de tau y GSK-3β sobre el riesgo de desarrollar PSP, y analizar la expresión de CRHR1 en el cerebro de pacientes fallecidos con PSP.METODOLOGÍA: Pacientes con criterios de PSP probable y controles sanos reclutados por la Unidad de Trastornos del Movimiento del Hospital Clínic. Se secuenció la región 3'UTR de tau, diseñando primers específicos, y la región codificante de saitohin en 3 PSP y se genotipó el polimorfismo Q7R en 57 PSP y 83 controles usando métodos previamente descritos. Se secuenció la región codificante de NIK en 3 PSP con métodos previamente descritos y se genotipó el polimorfismo 2839G/C en 40 PSP y 35 controles mediante el enzima de restricción HphI. Se cuantificó la expresión génica de CRHR1 en globus pallidus con PCR a tiempo real en 12 PSP, 10 Alzheimer, 5 pacientes con enfermedad cerebrovascular y 6 controles. Se secuenció la región codificante de CRHR1 en 2 PSP y se genotipó el polimorfismo -16C/T en 40 PSP y 51 controles mediante SSCP. Se genotipó el polimorfismo -50T/C de GSK-3beta en 93 PSP y 125 controles. Los análisis estadísticos se hicieron con el programa SPSS 11.5, usando el test chi-cuadrado para comparar las frecuencias genotípicas y alélicas y el test de Kruskal-Wallis para la comparación de los niveles de expresión génica.RESULTADOS: No se hallaron mutaciones en la región 3'-UTR de tau ni en la región codificante de los genes saitohin, NIK y CRHR1. El genotipo QQ de saitohin fue más frecuente en PSP que en controles (91.2% vs 47%) y cosegregaba con el genotipo CC del polimorfismo G(-221)C del promotor de tau. No se hallaron diferencias entre PSP y controles en la frecuencia genotípica del polimorfismo de NIK. La expresión de mRNA de CRHR1 en globus pallidus fue similar en PSP y el resto de sujetos. El genotipo CC del polimorfismo de CRHR1 fue más frecuente en PSP que en controles (80% vs 53%). El genotipo CC del polimorfismo-50 T/C de GSK-3-betafue algo menos frecuente (p=0.048) y el alelo T más frecuente (p=0.033) en PSP que en controles, y no se detectó interacción con el haplotipo H1/H1.CONCLUSIONES: Nuestros resultados no apoyan que la región 3'UTR de tau presente variantes génicas que puedan explicar el riesgo proporcionado por el haplotipo H1 para sufrir PSP. El genotipo QQ de saitohin y el genotipo CC del polimorfismo de CRHR1 están asociados a PSP en nuestra población y forman parte del haplotipo H1. El gen NIK no está incluído en el haplotipo H1 y no incrementa el riesgo de PSP. La ausencia de mutaciones y de alteración en la expresión génica en ganglios basales no apoya un papel funcional del gen CRHR1 en la PSP. El alelo T del polimorfismo -50T/C GSK-3β está sobrerepresentado en PSP y podría ser un factor de riesgo adicional independiente del haplotipo H1; alternativamente, el genotipo CC podría ser un factor protector. / Progressive supranuclear palsy (PSP) is characterised by abnormal deposition of hyperphosphorylated tau protein in basal ganglia and brainstem. The only known genetic risk factor is the H1 haplotype in the tau gene region, but there are other candidate genes related to tau or neuronal function like saitohin, NIK and CRHR1 in this region or tau-kinases like GSK-3beta in other regions. The aim of this work was to analyse variations of these genes and CRHR1 brain expression in PSP. Patients and controls were recruited by the Hospital Clínic Movement Disorders Unit. Sequencing of tau-3'UTR region and coding region of saitohin were performed in 3 PSP patients, and the Q7R saitohin polymorphism was genotyped in 57 PSP and 83 controls. The coding region of NIK was sequenced in 3 PSP and the 2839G/C polymorphism was genotyped in 40 PSP and 35 controls. CRHR1 gene expression was quantified in globus pallidus using real-time PCR in 12 PSP, 10 Alzheimer, 5 stroke patients and 6 controls. The coding region of CRHR1 was sequenced in 2 PSP and the -16C/T polymorphism was genotyped in 40 PSP and 51 controls. The GSK-3beta -50T/C polymorphism was genotyped in 83 PSP and 125 controls. Genotype and allelic frequencies were compared using the chi-square test and gene expression levels with the Kruskal-Wallis test. No mutations were found. The saitohin QQ genotype and the CRHR1 CC genotype were more frequent in PSP than in controls (91.2% vs 47%; 80% vs 53%), and the NIK genotype frequencies were similar. CRHR1 mRNA expression in globus pallidus was similar in PSP and the rest of subjects. The T allele of the GSK-3polymorphism was more frequent in PSP than in controls (p=0.033), and no interaction was detected with the H1/H1 haplotype. Our results do not support a role of tau-3'UTR and CRHR1 in PSP. The saitohin and CRHR1 polymorphisms are associated with PSP in the context of the H1 haplotype. The NIK gene is not included in the H1 haplotype and does not increase the risk of PSP. GSK-3β genetic variations could be an additional genetic risk factor indepedent of the H1 haplotype.

Made available in DSpace on 2015-12-06T23:06:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2005 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Introdução: A diferenciação clínica dos parkinsonismos atípicos, incluindo a paralisia supranuclear progressiva (PSP) e a atrofia de múltiplos sistemas (AMS) em relação ao parkinsonismo idiopático ou doença de Parkinson (DP) nem sempre é possível. O objetivo deste trabalho é o de avaliar a importância da Ressonância Magnética (RM) na diferenciação entre as síndromes parkinsonianas atípicas e a doença de Parkinson e avaliar os principais achados nas síndromes parkinsonianas atípicas. Material e métodos: Foram avaliados vinte pacientes com parkinsonismo, segundo critérios atuais de diagnóstico, sendo seis pacientes com AMS (idade média de 57,5 anos) e cinco pacientes com PSP (idade média de 69,4 anos) e nove pacientes com DP (idade média de 58,2 anos). Todos os pacientes foram submetidos à RM de 1.5 Tesla, segundo protocolo pré-estabelecido, incluindo análise de alterações morfológicas e de sinal, bem como medidas através de aquisições volumétricas tridimensionais. Foram avaliados: presença ou não do halo putaminal e do sinal periaquedutal, dilatação do 111 ventrículo, diâmetro antero-posterior do mesencéfalo, espessura da lâmina quadrigêmea, medida dos ângulos interpedunculares, volumetrias do tronco cerebral e cerebelo e medidas volumétricas e lineares dos núcleos caudado e putâmen Resultados: Nos pacientes com PSP a presença da dilatação do 111 ventrículo (presente em 100 por cento dos casos) associada à diminuição do diâmetro antero- posterior do mesencéfalo (média de 13,28 mm) e a diminuição da espessura da lâmina quadrigêmea (média de 2,86 mm) pode auxiliar na diferenciação da PSP com a DP e AMS. Na AMS a diminuição do volume putaminal (pvol=0,36) associada à presença do halo putaminal (presente em 100 por cento dos casos) podem auxiliar na diferenciação entre a AMS e a DP Conclusão: A associação dos achados semiológicos e protocolos de RM específicos para os parkinsonismos atípicos pode aumentar a acurácia diagnóstica nos casos duvidosos. Porém a RM permanece apenas como método auxiliar no diagnóstico, não substituindo o diagnóstico clínico e anatomopatológico destas doenças. / Background: Clinical differentiation of atypical parkinsonism, which includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA), in relation to the idiophatic parkinsonism or Parkinson´s disease (PD) is often difficult.The objective of this study is to differentiate atypical parkinsonism syndromes in relation to Parkinson´s disease through magnetic resonance imaging (MRI) and to evaluate its principal findings through this screening Methods: We studied 20 consecutive patients who fulfilled the diagnostic criteria for one of the following disease: PD, MSA, PSP. Five patients of these patients fulfilled the National Institute of Neurological Disorders and Stroke and Society for PSP (NINDS-SPSP) criteria for probable PSP. Six patients fulfilled the MSA criteria (possible and probable) according to Gilman and cols. There were nine patients with the clinical diagnosis of Parkinson disease, defined according to the United Kingdon PD Brain Bank criteria. The mean age and disease duration was not different between the groups at the time of MRI imaging. All these patients were submitted to MRI (1.5 T) screening according to pre-established ruling measures for atypical parkinsonism. These measures include dilatation of the third ventricle, midbrain diameter on axial scans, quadrigeminal plate thickness, presence of putaminal hyperintensity, volumetry of brainstem and cerebellum, volumetry of caudate and putamen, linear measurements of caudate and putamen and interpeduncular angle. All data were compared to previous published findings obtained from PD patients. Results: PSP patients presented dilatation of third ventricle (100%), lower midbrain diameter (mean 13,28 mm) and thinning of the quadrigeminal plate (mean 2,86 mm) in comparison with MSA and PD. MSA patients presented hyperintensive putaminal rim (100%) and lower putaminal volumetry in comparison with PD. This findings appears to be the most important in the difference of this diseases. Conclusions: Association of semiological findings and specific MRI ruling measures for atypical parkinsonism can increase the diagnostic accuracy; however, the gold standard still continues to be the anatomopathologic evaluation of the brain. / BV UNIFESP: Teses e dissertações

nÃo hà / Este trabalho consiste de dois estudos: o primeiro estudo avalia o papel da morfometria por ressonÃncia magnÃtica (RM) no diagnÃstico diferencial das sÃndromes parkinsonianas; o segundo avalia as alteraÃÃes do sono nessas sÃndromes e suas relaÃÃes com alteraÃÃes estruturais na RM. Nas fases iniciais da doenÃa o diagnÃstico diferencial entre as sÃndromes parkinsonianas pode ser de difÃcil realizaÃÃo. As medidas por RM podem contribuir para o diagnÃstico diferencial entre a doenÃa Parkinson (DP), paralisia supranuclear progressiva (PSP) e atrofia de mÃltiplos sistemas (AMS). O objetivo do primeiro estudo foi avaliar o valor diagnÃstico das alteraÃÃes anatÃmicas estruturais identificadas pela RM no diagnÃstico diferencial dessas sÃndromes. Foram estudados 21 casos com DP, 11 casos com atrofia de mÃltiplos sistemas forma cerebelar (AMS-c), 8 casos de atrofia de mÃltiplos sistemas forma parkinsoniana (AMS-p) e 20 com PSP. A Ãrea sagital mediana do mesencÃfalo (Ams), Ãrea sagital mediana da ponte (Apn), largura mÃdia do pedÃnculo cerebelar mÃdio (PCM) e pedÃnculo cerebelar superior (PCS) foram medidas pela RM. ComparaÃÃes mÃltiplas foram realizadas entre a PD, AMS-c, AMS-p e PSP. A morfometria da Apn, PCM e PCS apresentaram diferenÃas entre os casos com diferentes diagnÃsticos. A Ams e a morfometria do PCS foram as medidas mais preditivas para o diagnÃstico de PSP, de tal forma que uma Ãrea do mesencÃfalo < 105 mm2 e a medida do PCS < 3 mm mostraram uma grande probabilidade para este diagnÃstico (sensibilidade de 95,0 e 80,0%, respectivamente). Nos casos de AMS-c, a morfometria da Apn < 315mm2 apresentou boa especificidade e valor preditivo positivo para o diagnÃstico (93,8% e 72,7%, respectivamente). Em conclusÃo, demonstramos que dimensÃes e valores de cortes obtidos a partir de exames de RM podem diferenciar entre PD, PSP e AMS-c, com boa sensibilidade, especificidade e precisÃo. Na segunda etapa desse trabalho, foram avaliados e comparados os distÃrbios do sono em pacientes com DP, AMS e PSP e as possÃveis associaÃÃes com a morfometria por RM do encÃfalo em 16 casos de DP, 13 AMS, 14 PSP e 12 controles. Os distÃrbios do sono foram avaliados pela escala de SonolÃncia de Epworth, Ãndice de Qualidade do sono de Pittsburgh (IQSP), escala de pernas inquietas e questionÃrio de Berlim. A Apn e Ams e largura do PCS e do PCM foram medidas pela RM. A mà qualidade do sono, o risco da sÃndrome da apnÃia obstrutiva do sono (SAOS) e sÃndrome das pernas inquietas (SPI) foi detectado em todos os grupos. Pacientes com AMS apresentaram maior risco de SAOS e menor nÃmero de casos com SPI. Nos casos de AMS, uma correlaÃÃo entre os escores do IQSP e o estÃgio do Hoehn & Yahr foi observada (p<0,05). Na PSP, a SPI foi freqÃente (57%) e relacionou-se com a menor duraÃÃo e pior eficiÃncia do sono. Na DP, sonolÃncia diurna excessiva relacionou-se com a atrofia do PCM (p=0,01). Em conclusÃo, o alto risco de SAOS foi comum e proeminente nos casos de AMS. SPI foi mais freqÃente na DP e na PSP. Nos casos com PSP, a SPI associou-se com uma reduÃÃo da eficiÃncia e duraÃÃo do sono; e nos pacientes com DP e sonolÃncia excessiva diurna apresentaram maior atrofia do PCM (DP com sonolÃncia excessiva diurna PCM= 16,08Â0,93; DP sem sonolÃncia excessiva diurna PCM =17,82 0,80 p=0,01), sugerindo degeneraÃÃo de estruturas do tronco cerebral nesses pacientes. / We describe two studies, as follows: one concerns the role of cerebral morphometry as evaluated by magnetic resonance imaging (MRI) in the differential diagnosis of the parkinsonian syndromes; the other is about sleep alterations and the relationship with MRI changes in these syndromes. MRI measures can be useful for differential diagnosis between Parkinson disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). The aim of this study was to evaluate the diagnostic value of structural anatomic changes identified by MRI in the differential diagnosis of these syndromes. We studied 21 cases with PD, 11 with MSA-c, 8 with MSA-p, 20 with PSP and 12 controls. Midbrain area (Ams), Pons area (Apn), middle cerebellar peduncle (MCP) and superior cerebellar peduncle (SCP) width were measured using MRI. Multiple comparisons were made between PD, MSA-p, MSA-c and PSP and we show that Apn, MCP and SCP width morphometry dimensions have clear cut differences in these syndromes. The Ams and SCP were the most predictive measures of PSP. A Midbrain area below 105 mm2 and SCP less than 3 mm showed a major probability for this diagnosis (sensitivity of 95.0 and 80.0%, respectively). For the group of MSA-c patients, an Apn area below 315mm2 showed good specificity and positive predictive value (93.8% and 72.7%, respectively). In conclusion, we demonstrate that dimensions and cut off values obtained from routine MRI can differentiate between PD, PSP and MSA-c with good sensitivity, specificity and accuracy. Despite common reports in PD, in other parkinsonian syndromes, sleep disturbances have been less frequently described. We compare sleep disturbances in patients with PD, MSA and PSP and analyze associations with brain MRI morphometry. This was a cross-sectional study of 16 PD cases, 13 MSA and 14 PSP. Sleep disturbances were evaluated by Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI), Restless Legs Scale and Berlin questionnaire. Apn, Ams, MCP width, and SCP width were measured using MRI. Poor quality sleep, risk of obstructive sleep apnea (OSA) and restless legs syndrome (RLS) were detected in all groups. Patients with MSA showed higher risk of OSA and less frequent RLS. In MSA, a correlation between PSQI scores and Hoehn and Yahr stage was observed (p<0.05). In PSP, RLS was frequent (57%) and related with reduced sleep duration and efficiency. In PD, excessive daytime sleepiness was related to atrophy of the MCP (p= 0.01). High risk of OSA was common and prominent in MSA cases. RLS was more frequent in PD and PSP, and in PSP, was associated with reduced sleep efficiency and sleep duration. In conclusion, the morphometric analysis of PD patients with excessive daytime sleepiness showed more atrophy of MCP (PD with excessive daytime sleepiness MCP= 16.08Â0.93; PD without excessive daytime sleepiness MCP=17.82Â0.80 p= 0.01) suggesting widespread degeneration of brainstem sleep structures on the basis of sleep abnormalities in these patients.

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVIII

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13220号 / 論医博第2167号 / 新制||医||1033(附属図書館) / (主査)教授 高橋 淳, 教授 宮本 享, 教授 伊佐 正 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP). Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities. Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.). Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.