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

There has been considerable progress in the clinical, pathological and genetic fractionation of frontotemporal lobar degeneration syndromes in recent years, driving the development of novel diagnostic criteria. However, phenotypic boundaries are not always distinct and syndromes converge with disease progression, limiting the insights available from traditional diagnostic classification. Alternative transdiagnostic approaches may provide novel insights into the neurobiological underpinnings of symptom commonalities across the frontotemporal lobar degeneration spectrum. In this thesis, I illustrate the use of transdiagnostic methods to investigate apathy and impulsivity. These two multifaceted constructs are observed across all frontotemporal lobar degeneration syndromes, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. They cause substantial patient morbidity and carer distress, often coexist and are undertreated. Using data from the Pick’s disease and Progressive supranuclear palsy Prevalence and INcidence (PiPPIN) Study, I examine the frequency, characteristics and components of apathy and impulsivity across the frontotemporal lobar degeneration spectrum. A principal component analysis of the neuropsychological data identified eight distinct components of apathy and impulsivity, separating patient ratings, carer ratings and behavioural tasks. Apathy and impulsivity measures were positively correlated, frequently loading onto the same components and providing evidence of their overlap. The data confirmed that apathy and impulsivity are common across the spectrum of frontotemporal lobar degeneration syndromes. Voxel based morphometry revealed distinct neural correlates for the components of apathy and impulsivity. Patient ratings correlated with white matter changes in the corticospinal tracts, which may reflect retained insight into their physical impairments. Carer ratings correlated with grey and white matter changes in frontostriatal, frontotemporal and brainstem systems, which have previously been implicated in motivation, arousal and goal directed behaviour. Response inhibition deficits on behavioural tasks correlated with focal frontal cortical atrophy in areas implicated in goal-directed behaviour and cognitive control. Diffusion tensor imaging was highly sensitive to the white matter changes underlying apathy and impulsivity in frontotemporal lobar degeneration syndromes. Diffusion tensor imaging findings were largely consistent with voxel-based morphometry, with carer ratings reflecting widespread changes while objective measures showed changes in focal, task-specific brain regions. White matter abnormalities often extended beyond observed grey matter changes, providing supportive evidence that white matter dysfunction represents a core pathophysiology in frontotemporal lobar degeneration. Apathy was a significant predictor of death within two and a half years from assessment, consistent with studies linking apathy to poor outcomes. The prognostic importance of apathy warrants more accurate measurement tools to facilitate clinical trials. Although causality remains unclear, the influence of apathy on survival suggests effective symptomatic treatments may also prove disease-modifying. These findings have several implications. First, clinical studies for apathy/impulsivity in frontotemporal lobar degeneration syndromes should target patients who present with these symptoms, irrespective of their diagnostic category. Second, data-driven approaches can inform the choice of assessment tools for clinical trials, and their link to neural drivers of apathy and impulsivity. Third, the components and their neural correlates provide a principled means to measure (and interpret) the effects of novel treatments in the context of frontotemporal lobar degeneration.