Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2016-10-13T17:13:38Z No. of bitstreams: 2 Dissertação Victor de Melo Caixeta - 2015.pdf: 2750656 bytes, checksum: c7c2c97e0c6537b3d17aa54409152ad3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2016-10-14T20:03:21Z (GMT) No. of bitstreams: 2 Dissertação Victor de Melo Caixeta - 2015.pdf: 2750656 bytes, checksum: c7c2c97e0c6537b3d17aa54409152ad3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-10-14T20:03:21Z (GMT). No. of bitstreams: 2 Dissertação Victor de Melo Caixeta - 2015.pdf: 2750656 bytes, checksum: c7c2c97e0c6537b3d17aa54409152ad3 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-10-15 / Background: Corticobasal Degeneration (CBD) is an rare and heterogeneous disease in its presentations, representing an great diagnostic challenge. There aren´t, in Brasil, large CBD case series, and there aren´t many in the world as well. Its cognitive and behavioural aspects have received little (despite growing) attention. Objectives: To describe sociodemographic, clinic, neuropsychiatric, neuropathological, and neuroradiologic aspects in a large brazilian DCB case series. To perform a literature review on CBD, with special focus on cognitive and behavioural aspects. Methods: 70 patients data was collected, with CBD diagnosis according to the Cambridge criteria modified by Bak and Hodges (2011). The patients underwent clinical, neuropsychiatric, neuroradiologic (structural and functional) and pathologic (in six cases) retrospective analysis. There were studied clinical, sociodemographic, neuropsychiatric, neuroanatomic variables and family history. Results and Discussion: The mean age at onset was 62.8 years (sd=9,5), and both sexes were equally affected (52,9% male). Hemispheric asymmetry was present in 97% of cases, and the left brain hemisphere was the most affected (68,2% of cases). The most frequent initial presentation was “psychiatric” (with changes in behaviour and/or mood), present in 68,1% of cases, followed by motor-extrapyramidal presentation (54.3%). In the course of the disease, the predominant clinical form (phenotype) was the extrapyramidal-motor with 61.4% of cases, followed by "psychiatric" with 51.4%. There were five cases with presentation of Posterior Cortical Atrophy (PCA) In 37.7% there were not found classic CBD syndromes (e.g., alien hand syndrome). We found 18.7% of cases with family DCB, with four families presenting a phenotype not yet described, of CBD with NPH (Normal Pressure Hydrocephalus). We also observed cognitive and functional impairments in the evaluated scales (MMSE, Pfeffer and CDR), and frequent medical and psychiatric comorbidities, especially diabetes mellitus (23.5%), hypothyroidism (22.1%) and Bipolar Spectrum Disorders (46, 4%), the last two significantly more frequent in the sample. There were six cases of rapidly progressive DCB and six confirmed by autopsy CBD cases in the sample. Conclusion: We observed, in agreement with the literature, a wide variety of CBD presentations, including new and little described phenotypes (NPH and PCA). In the characterization of the sample, we observed a great prevalence and importance of cognitive, affective and behavioural presentations. / Introdução: A Degeneração Corticobasal (DCB), é uma doença rara e heterogênea em suas apresentações, representando um grande desafio diagnóstico. Não há descrições de grandes amostras de DCB no Brasil, e poucas no mundo. Seus aspectos cognitivos e comportamentais têm recebido pouca (apesar de crescente) atenção. Objetivos: Descrever aspectos sociodemográficos, clínicos, neuropsiquiátricos, neuropatológicos e de neuroimagem em uma grande série de casos brasileiros com DCB. Realizar uma revisão da literatura sobre a DCB, com especial enfoque em aspectos cognitivos e comportamentais. Metodologia: Foram colhidos dados de 70 pacientes com DCB de acordo com critérios de Cambridge modificados por Bak e Hodges (2011). Os pacientes foram submetidos à avaliação retrospectiva clínica e neuropsiquiátrica, de neuroimagem estrutural e funcional e seis pacientes ao exame neuropatológico. Foram estudadas variáveis sociodemográficas, clínicas, neuropsiquiátricas, neuroanatômicas, e antecedentes familiares. Resultados e Discussão: A idade média de início dos sintomas foi de 62,8 anos (dp=9,5), sendo os dois sexos igualmente afetados (52,9% masculino). Assimetria hemisférica esteve presente em 97% dos casos e o hemisfério esquerdo foi o mais acometido (68,2% dos casos). A apresentação inicial mais freqüente foi a “psiquiátrica” (com alterações do comportamento e/ou humor), presente em 68,1% dos casos, seguida da apresentação motora-extrapiramidal (54,3%). No decorrer da doença, a forma clínica (fenótipo) predominante foi a motora-extrapiramidal, com 61,4% dos casos, seguida da “psiquiátrica”, com 51,4%. Houve cinco casos com apresentação de Atrofia Cortical Posterior (ACP). Em 37,7% não ocorreram achados clássicos da DCB (por exemplo, síndrome da mão estrangeira). Encontramos 18,7% de casos com DCB familiar, com quatro famílias apresentando um fenótipo ainda não descrito, de DCB com HPN (Hidrocefalia de Pressão Normal). Observamos também prejuízos cognitivos e funcionais nas escalas avaliadas (MEEM, Pfeffer e CDR), e comorbidades clínicas e psiquiátricas frequentes, em especial Diabetes Mellitus (23,5%), hipotireoidismo (22,1%) e Transtornos do Espectro Bipolar (46,4%), os dois últimos com frequência na amostra significativamente maior que na população. Houve seis casos de DCB rapidamente progressiva e seis casos confirmados por necropsia na amostra. Conclusão: Observamos, em consenso com a literatura, uma grande variedade de apresentações da DCB, inclusive com formas novas e pouco descritas (HPN e ACP). Na caracterização da amostra, percebemos grande frequência e importância das apresentações comportamentais, afetivas e cognitivas.

Submitted by JÚLIO HEBER SILVA (julioheber@yahoo.com.br) on 2016-12-12T17:52:54Z No. of bitstreams: 2 Dissertação - George Martins Ney da Silva Júnior - 2015.pdf: 2151149 bytes, checksum: 266f50dd135504e70740809576b490bf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2016-12-13T19:31:57Z (GMT) No. of bitstreams: 2 Dissertação - George Martins Ney da Silva Júnior - 2015.pdf: 2151149 bytes, checksum: 266f50dd135504e70740809576b490bf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-12-13T19:31:57Z (GMT). No. of bitstreams: 2 Dissertação - George Martins Ney da Silva Júnior - 2015.pdf: 2151149 bytes, checksum: 266f50dd135504e70740809576b490bf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-08-04 / Background: this study aimed to contribute to the knowledge of the interrelation of two morbid conditions that affect the autonomy and independence of the elderly: Bipolar disorder (BD) and the dementias. Methods: the medical records were reviewed to meet criteria at the same time for BD and dementia, resulting in a database of 130 cases (n = 130). Their demographics characteristics were described, as well as the frequencies of the diagnoses of dementia subtypes, their correlations with the age of dementia, the age of initiation of BD, its clinical forms and psychopathologic presentation. It was also studied the impact when the DSM4-TR diagnostic criteria was shifted to the Akiskal criteria for BD. Results: in the sample, the predominant dementia age range was senile dementia (senile: 85.71%; presenile: 14.29%) and the most common dementia subtypes were Corticobasal degeneration (CBD: 24.62%) and the Fronto-Temporal Lobar Degeneration (FTLD: 19.23%). The age of initiation of BD starting 35 years old or over amounted to 74.78% (between 10 and 34 years: 25.22%; between 35 and 59 years: 36.52%; and ≥ 60 years: 38.26%), with the following clinical forms of BD present in the sample: BD1: 71.54%, BD2: 20.77%; and Cyclothymia: 7.69%. The psychopathologic clinical presentation of BD prevalent in the sample was Mixed Episodes (38.46%), followed by Mania (33.07%), Hypomania with major depression (20.77%) and Hypomania without major depression (7.7%). When applied diagnostic criteria of Akiskal, the clinical form of BD prevalent in the sample remained the BD1 (46.92%), followed by the BD6 (34.62%) and the BD2 (18.46%). Conclusions: the results showed that the CBD and FTLD were the most common dementia in comorbidity with BD. And that the BD, in such cases, was predominantly late (≥ 35 years) or very late (≥ 60 years) and in its most severe form (BD1), with the most common psychopathologic syndrome of Mixed State or Mania, suggesting that the CBD and FTLD should be actively searched in the follow-up of these cases. DCB and DLFT in comorbidity to BD offer a privileged field of research for the pathophysiology of dementia and TB itself. / Introdução: O presente estudo teve como objetivo contribuir para o conhecimento da inter-relação de duas condições mórbidas que afetam a autonomia e a independência dos idosos: o Transtorno Bipolar (TB) e as demências. Métodos: Foram revistos os prontuários que preenchiam critérios concomitantemente para TB e demência, resultando num banco de dados de 130 casos. Foram descritas as suas caraterísticas sociodemográficas, as frequências dos diagnósticos dos subtipos de demência e suas correlações com: a faixa etária da demência; a faixa etária de início do TB, suas formas clínicas e apresentação psicopatológica. Foi também estudado se a mudança de critérios diagnósticos do DSM4-TR para os de Akiskal impactaria nos resultados. Resultados: Na amostra (n=130), a faixa etária predominante da demência foi a senil (senil: 85,71%; pré-senil:14,29%) e os tipos de demência mais frequentes foram a Degeneração Corticobasal (DCB: 24,62%) e a Degeneração Lobar Fronto-Temporal (DLFT: 19,23%). A faixa etária de início do TB acima dos 35 anos ocorreu em 74,78% (entre 10 e 34 anos: 25,22%; entre 35 e 59 anos: 36,52%; e≥60 anos: 38,26%), com as seguintes formas clínicas de TB presentes na amostra: TB1: 71,54%, TB2: 20,77% e Ciclotimia: 7,69%. A configuração psicopatológica de apresentação clínica do TB predominante na amostra foi a de Episódios Mistos (38,46%), seguida por Mania (33,07%), Hipomania com Depressão Maior (20,77%) e Hipomania sem Depressão Maior (7,7%). Quando aplicados os critérios diagnósticos de Akiskal, a forma clínica de TB predominante na amostra permaneceu o TB1 (46,92%), seguido pelo TB6 (34,62%) e o TB2 (18,46%). Conclusões: Os resultados mostraram que a DCB e a DLFT foram as demências mais frequentes em comorbidade com o TB. E que o TB, nesses casos, foi predominantemente de início tardio (≥35 anos) ou muito tardio (≥60 anos) e em sua forma mais grave (TB1), tendo como síndrome psicopatológica mais frequente o Episódio Misto ou a Mania, sugerindo que a DCB e a DLFT sejam pesquisadas ativamente ao longo de seu seguimento. DCB e DLFT comórbidas ao TB oferecem um campo privilegiado de pesquisas para a fisiopatologia das demências e do próprio TB.

This thesis provides new insights about how the brain controls skilled movements, through the study of limb apraxia in two major neurological disorders: Stroke and Corticobasal Syndrome (CBS). Limb apraxia is a cognitive-motor deficit characterized by impairment in the performance of skilled movement. The Conceptual-Production systems model, used as framework in this thesis, proposes that skilled movement is under the control of three systems: a sensory/perceptual system, a conceptual system and a production system. Deficits in any of these systems produce limb apraxia, and depending on which system is affected, a distinct pattern of apraxia emerges. This information processing approach was used to evaluate performance levels, study brain asymmetries and discern patterns of deficits in each population. In addition, longitudinal assessments in sample subsets revealed patterns of recovery after stroke and of progression in CBS. The first study examined acute-subacute and chronic stroke patients with left (LHD) and right hemisphere damage (RHD) for their ability to pantomime and imitate transitive and intransitive gestures. The results indicated that LHD and acute-subacute were more severely impaired. Concurrent deficits in pantomime and imitation were most common, especially after LHD. Since acute-subacute patients were more severely impaired, in the absence of any therapies, it is likely that some degree of recovery occurs over time. The second study study examined longitudinal recovery in a series of transitive gestures tasks among stroke patients and indicated that patients significantly recovered in all tasks, except in Action Identification, a conceptual apraxia task which probes knowledge of actions. Finally, two comparative studies were conducted in CBS, a neurodegenerative disorder in which apraxia is common, making this one of the first studies that evaluated patient performance on a complete limb apraxia battery. The first study found that patients were often impaired on all gesture production tasks, while conceptual knowledge of gestures and tools was usually preserved. A case series constituted the second study, which documented the progression of apraxia in CBS demonstrating that, while deficits in gesture production usually are present at first examination, deficits in conceptual knowledge are infrequent and in many cases do not develop at all. Study limitations were discussed and it was suggested that future research should expand on our findings for recovery in stroke and progression in CBS.

This thesis provides new insights about how the brain controls skilled movements, through the study of limb apraxia in two major neurological disorders: Stroke and Corticobasal Syndrome (CBS). Limb apraxia is a cognitive-motor deficit characterized by impairment in the performance of skilled movement. The Conceptual-Production systems model, used as framework in this thesis, proposes that skilled movement is under the control of three systems: a sensory/perceptual system, a conceptual system and a production system. Deficits in any of these systems produce limb apraxia, and depending on which system is affected, a distinct pattern of apraxia emerges. This information processing approach was used to evaluate performance levels, study brain asymmetries and discern patterns of deficits in each population. In addition, longitudinal assessments in sample subsets revealed patterns of recovery after stroke and of progression in CBS. The first study examined acute-subacute and chronic stroke patients with left (LHD) and right hemisphere damage (RHD) for their ability to pantomime and imitate transitive and intransitive gestures. The results indicated that LHD and acute-subacute were more severely impaired. Concurrent deficits in pantomime and imitation were most common, especially after LHD. Since acute-subacute patients were more severely impaired, in the absence of any therapies, it is likely that some degree of recovery occurs over time. The second study study examined longitudinal recovery in a series of transitive gestures tasks among stroke patients and indicated that patients significantly recovered in all tasks, except in Action Identification, a conceptual apraxia task which probes knowledge of actions. Finally, two comparative studies were conducted in CBS, a neurodegenerative disorder in which apraxia is common, making this one of the first studies that evaluated patient performance on a complete limb apraxia battery. The first study found that patients were often impaired on all gesture production tasks, while conceptual knowledge of gestures and tools was usually preserved. A case series constituted the second study, which documented the progression of apraxia in CBS demonstrating that, while deficits in gesture production usually are present at first examination, deficits in conceptual knowledge are infrequent and in many cases do not develop at all. Study limitations were discussed and it was suggested that future research should expand on our findings for recovery in stroke and progression in CBS.

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.

Corticobasal Syndrome (CBS) is a rare movement and cognitive disorder. There is significant heterogeneity observed in it clinical presentation, neuroimaging, pathology and genetics. Understanding this heterogeneity is a priority and may help to shed light on underlying pathogenic mechanisms. We first demonstrated that truncating mutations in the progranulin gene (PGRN) can cause familial CBS associated with frontotemporal lobar degeneration (FTLD)-ubiquitin pathology. This study identified a mutation in PGRN (Intervening Sequence 7+1 guanine > adenine [IVS7+1G>A]) that segregated with CBS in a family. The mutation was predicted to result in a shortened messenger RNA (mRNA) sequence and the absence of the mutant PGRN allele was confirmed in the reverse transcriptase-polymerase chain reaction (RT-PCR) product, which supported the model of haploinsufficiency for PGRN-linked disease. In a second familial study, clinical, radiological, genetic, and pathological studies were performed to contrast clinical features of the affected members. Sequencing PGRN revealed a novel, heterozygous cytosine-adenine dinucleotide deletion in exon 11 (g.2988_2989delCA, P439_R440fsX6). The proband`s clinical diagnosis was frontotemporal dementia and parkinsonism (FTDP). The proband’s brother with the same mutation presented initially as a progressive non-fluent aphasia (PNFA), and later evolved into a CBS. Pathological analysis revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/ TAR DNA-binding protein 43 (TDP43) positive pathology. The next studies shift away from pathogenic mechanisms to focus on brain-behavioural correlations and phenotypic heterogeneity in a prospective sample of 31 CBS cases. We provide the first direct correlative analysis between the severity of ideomotor apraxia, a common sign in CBS, and cerebral SPECT perfusion imaging. Reductions in perfusion within the left inferior parietal lobule (t=5.7, p=0.03, Family-Wise Error [FWE] corrected), including the left angular gyrus (t=5.7, p=0.02, FWE corrected), were associated with more severe ideomotor apraxia. We stratified the sample into CBS presenting with early motor features (CBS-M; n=9) or early dementia (CBS-D; n=22), which identified that CBS-M were more likely to have cortical sensory loss than CBS-D (p=0.005). In contrast, the presence of aphasia was found to be more common and severe in CBS-D compared to CBS-M (p=0.02). CBS-M patients had significantly reduced perfusion in the right supplementary and premotor areas compared to CBS-D (p<0.05).

Corticobasal Syndrome (CBS) is a rare movement and cognitive disorder. There is significant heterogeneity observed in it clinical presentation, neuroimaging, pathology and genetics. Understanding this heterogeneity is a priority and may help to shed light on underlying pathogenic mechanisms. We first demonstrated that truncating mutations in the progranulin gene (PGRN) can cause familial CBS associated with frontotemporal lobar degeneration (FTLD)-ubiquitin pathology. This study identified a mutation in PGRN (Intervening Sequence 7+1 guanine > adenine [IVS7+1G>A]) that segregated with CBS in a family. The mutation was predicted to result in a shortened messenger RNA (mRNA) sequence and the absence of the mutant PGRN allele was confirmed in the reverse transcriptase-polymerase chain reaction (RT-PCR) product, which supported the model of haploinsufficiency for PGRN-linked disease. In a second familial study, clinical, radiological, genetic, and pathological studies were performed to contrast clinical features of the affected members. Sequencing PGRN revealed a novel, heterozygous cytosine-adenine dinucleotide deletion in exon 11 (g.2988_2989delCA, P439_R440fsX6). The proband`s clinical diagnosis was frontotemporal dementia and parkinsonism (FTDP). The proband’s brother with the same mutation presented initially as a progressive non-fluent aphasia (PNFA), and later evolved into a CBS. Pathological analysis revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/ TAR DNA-binding protein 43 (TDP43) positive pathology. The next studies shift away from pathogenic mechanisms to focus on brain-behavioural correlations and phenotypic heterogeneity in a prospective sample of 31 CBS cases. We provide the first direct correlative analysis between the severity of ideomotor apraxia, a common sign in CBS, and cerebral SPECT perfusion imaging. Reductions in perfusion within the left inferior parietal lobule (t=5.7, p=0.03, Family-Wise Error [FWE] corrected), including the left angular gyrus (t=5.7, p=0.02, FWE corrected), were associated with more severe ideomotor apraxia. We stratified the sample into CBS presenting with early motor features (CBS-M; n=9) or early dementia (CBS-D; n=22), which identified that CBS-M were more likely to have cortical sensory loss than CBS-D (p=0.005). In contrast, the presence of aphasia was found to be more common and severe in CBS-D compared to CBS-M (p=0.02). CBS-M patients had significantly reduced perfusion in the right supplementary and premotor areas compared to CBS-D (p<0.05).

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

Background Corticobasal syndrome is associated with cerebral protein aggregates composed of 4-repeat (~50% of cases) or mixed 3-repeat/4-repeat tau isoforms (~25% of cases) or nontauopathies (~25% of cases). Objectives The aim of this single-center study was to investigate the diagnostic value of the tau PET-ligand [18F]PI-2620 in patients with corticobasal syndrome. Methods Forty-five patients (71.5 ± 7.6 years) with corticobasal syndrome and 14 age-matched healthy controls underwent [18F]PI-2620-PET. Beta-amyloid status was determined by cerebral β-amyloid PET and/or CSF analysis. Subcortical and cortical [18F]PI-2620 binding was quantitatively and visually compared between β-amyloid-positive and -negative patients and controls. Regional [18F]PI-2620 binding was correlated with clinical and demographic data. Results Twenty-four percent (11 of 45) were β-amyloid-positive. Significantly elevated [18F]PI-2620 distribution volume ratios were observed in both β-amyloid-positive and β-amyloid-negative patients versus controls in the dorsolateral prefrontal cortex and basal ganglia. Cortical [18F]PI-2620 PET positivity was distinctly higher in β-amyloid-positive compared with β-amyloid-negative patients with pronounced involvement of the dorsolateral prefrontal cortex. Semiquantitative analysis of [18F]PI-2620 PET revealed a sensitivity of 91% for β-amyloid-positive and of 65% for β-amyloid-negative cases, which is in excellent agreement with prior clinicopathological data. Regardless of β-amyloid status, hemispheric lateralization of [18F]PI-2620 signal reflected contralateral predominance of clinical disease severity. Conclusions Our data indicate a value of [18F]PI-2620 for evaluating corticobasal syndrome, providing quantitatively and regionally distinct signals in β-amyloid-positive as well as β-amyloid-negative corticobasal syndrome. In corticobasal syndrome, [18F]PI-2620 may potentially serve for a differential diagnosis and for monitoring disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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No. of bitstreams: 2 Dissertacao Lorena Dias Resende - 2013.pdf: 1401725 bytes, checksum: b4f101e9ff3343d1112e15b4cb3e94f5 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-10-01 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Introduction: Gait apraxia is characterized by a deficiency in the integration of the sensorial, motor and cerebellar functions necessary for gait. The patients with this compromise have difficulty initiating and there is a congelation of the gait, mainly when turning ove their own axle. It is frequently associated with an emotional instability, a urinary bladder dysfunction and behavioral abnormalities. It is generally observed in gait disturbances high level cortical functions, but its relationship to disease progression and cognitive function is unknown. Objectives: To evaluate the gait apraxia in patients with dementia, its prevalence and association with other types of apraxia as well as observing what phase of the disease in which it appears. Methods: Gait apraxia has been researched in a universe of patients with dementia consecutively assisted in the HC-UFG Neurodementia Ambulatory. The instruments used were the Mini-Mental State Examination and Clinical Dementia Rating Scale (CDR) to evaluate the cognitive functions, Pfeffer's Questionnaire for the functional evaluation of the activities of the daily life, the Scale of Berg's Functional Balance (BERG) and the Timed Up and Go Test (TUG) for the balance mensuration, besides the evaluation of the gait and the posture of the trunk (AWS). Results: A total of fifteen patients, a sample 160, with gait apraxia were included in the study and all had some other associated apraxia. The prevalence of patients with dementia and apraxia of gait was 9,37%. Regarding the CDR showed that 33,3% of patients were mild stage of the disease, 46,7% in the moderate and 20% in the severe. In Pfeffer Questionnaire patients had an average of 19,6±1,40. There balance and coordination deficit in all patients, since the scores of the tests BERG and TUG showed inferior results. On the scale of BERG total score obtained average 11,07±8,06 and varying between 2 and 24 points. The TUG test was performed above 20 seconds for all the patients. In AWS the average score was 14,0±6,88 ranging between 7 and 27 points. The correlation between AWS and scale BERG was significant (p=0,001). Apraxia dynamics (90,9%), ideatory (72,2%) and kinetic members (63,6%) were more frequent among patients. Forms of dementia who had gait apraxia were corticobasal degeneration (53,3%), frontotemporal dementia (13,3%), Alzheimer's disease (6,6%), dementia with chronic subdural hematoma (6,6%), normal pressure hydrocephalus (6,6%), dementia in Parkinson's disease (6,6%) and multiple system atrophy (6,6%). Conclusion: Gait apraxia is little prevalent in the universe of dementia and it is always associated with corticcortical dementia. Other forms of apraxia frequently follow gait apraxia. The corticobasal degeneration is the type of dementia most associated with the gait apraxia. / Introdução: Apraxia da marcha é caracterizada por deficiência na integração das funções sensoriais, motoras e cerebelares necessárias para a deambulação. Os pacientes com este comprometimento têm dificuldade em iniciar a marcha e há um congelamento desta, principalmente ao girar sobre o próprio eixo. É freqüentemente associada a uma instabilidade emocional, disfunção da bexiga e anormalidades comportamentais. É geralmente observada em distúrbios da marcha de alto nível das funções corticais, mas sua relação com aprogressão da doença e função cognitiva é desconhecida. Objetivos: Avaliar a apraxia da marcha em pacientes com demência, sua prevalência e associação com outras formas de apraxia, bem como observar em que fase da doença mais aparece. Métodos: Foi pesquisada a apraxia de marcha em um universo de pacientes com demência consecutivamente atendidos no ambulatório de neurodemência do HC-UFG, entre 2012 e 2013. Os instrumentos utilizados foram o Mini-Exame do Estado Mental e a Escala Clínica de Demência (CDR) para se avaliar o grau da demência, o questionário de Pfeffer para avaliação funcional das atividades instrumentais de vida diária, a Escala de Equilíbrio Funcional de Berg (BERG) e o Timed Up and Go Test (TUG) para a mensuração do equilíbrio; além da avaliação qualitativa da marcha e avaliação postural do tronco (AWS). Resultados: Um total de quinze pacientes, de uma amostra de 160, que apresentavam apraxia da marcha foi incluído no estudo e todos apresentaram alguma outra apraxia associada. A prevalência de pacientes com demência e apraxia da marcha foi de 9,37%. Em relação ao CDR observou-se que 33,3% dos pacientes estavam em estágio leve da doença, 46,7% no moderado e 20% no grave. No questionário de Pfeffer os pacientes obtiveram média de 19,6±1,40. Houve déficit de equilíbrio e coordenação em todos os pacientes, uma vez que a pontuação dos testes de BERG e TUG apresentaram resultados inferiores. Na escala de BERG a pontuação total obteve média de 11,07±8,06 e variação entre 2 e 24 pontos. O teste de TUG foi realizado com tempo acima de 20 segundos por todos os pacientes. Na AWS a média de pontuação foi de 14,00±6,88 variando entre 7 e 27 pontos. Houve correlação significativa entre AWS e a escala de BERG. A apraxia dinâmica (90,9%), ideatória (72,2%) e cinética de membros (63,6%) foram as mais frequentes entre os pacientes. As formas de demência que apresentaram apraxia da marcha foram: degeneração córtico-basal (53,3%), demência fronto-temporal (13,3%), doença de Alzheimer (6,6%), demência por hematoma sub-dural crônico (6,6%), hidrocefalia de pressão normal (6,6%), demência na doença de Parkinson (6,6%) e atrofia de múltiplos sistemas (6,6%). Conclusão: A apraxia de marcha é pouco prevalente no universo das demências e mostrou-se associada a demências córtico-subcorticais. Outras formas de apraxia frequentemente acompanham a apraxia de marcha. Degeneração córtico-basal é a forma de demência mais associada à apraxia de marcha.