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.

The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology. This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease. A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD. Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity. LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion. In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

Hyperfosforylering av biomarkörproteinet Tau förekommer i flera neurodegenerativa sjukdomar som kallas Taupathies. Proteinets huvudfunktion i människokroppen är att modulera flexibilitet och stabilitet för axonal-mikrotubulin. I Taupathies utlöser hyperfosforyleringen av Tau instabilitet och neurodegenerationen. I dagens läge kan hyperfosforylering av treonin 217 (P217) endast mätas i hjärnan. I den här studien undersöks hyperfosforyleringen av treonin 217 (P217). I syfte att se om nivåerna av P217 är mätbara i cerebrospinalvätska (CSV) och i blodet. Samt för att evaluera hur nivåer av P217 förändras i olika Taupathies, genom att testa hjärnprover från friska kontroller och olika Taupathies. Studien görs för att öka kunskapen om effekten av hyperfosforylering av treonin 217 i Taupathies och för att bidra med en ny provtagningsmetod för P217. Simoa HD-1 Analyzer var instrumentet som användes för analyserna av P217. Det är ett instrument som kan upptäcka onormala nivåer av biomarkörer genom kvantifiering, med hjälp av antikroppar och ett enzym. Enzymet kallas Streptavidin β-galaktosidas och omvandlar en befintlig P217-molekyl i proven till en fluorescerande produkt. Genom Simoa HD-1 Analyzer utvecklades en ultrasensitiv analys med antikropparna P217 och Tau 12, som kunde upptäcka mycket låga nivåer av P217 i hjärnan, CSF och i blod. Förändring av P217-nivåer hittades även i olika Taupathies. De Taupathies med de högsta nivåerna av P217 var Progressiv supranukleär pares, Corticobasal degeneration och Globular glial Taupathies. / Hyperphosphorylation of the biomarker protein Tau occurs in many neurodegenerative diseases called Taupathies. The proteins main function in the human body is to modulate flexibility and stability for axonal microtubules. In Taupathies the hyperphosphorylation of the Tau triggers instability and neurodegeneration. Nowdays hyperphoshorylation on threonine 217 (P217) can only be measured in the brain. In this study the hyperphoshorylation on the phosphorylation site of threonine 217 (P217) is examined. In aim to see if levels of P217 is measurable in cerebrospinal fluid (CSF) and in blood. As well to evaluate how P217 variate in different Taupathies, through the use of brain samples from healthy controls and different Taupathies. The study is made for the purpose of enhancing the pure knowledge about the effect of hyperphosphorylation on threonine 217 in Taupathies and to contribute with a new sampling method for P217. Simoa HD-1 Analyzer was the key instrument of the analyses of P217. It’s an instrument which can detect abnormal levels of biomarkers through quantification, with help of antibodies and an enzyme. The enzyme is called Streptavidin β-galactosidase and converts an existing P217 molecule in the samples to a fluoresce product. Through the use of Simoa HD-1 Analyzer an ultrasensitive assay with antibodies P217 and Tau 12 was developed which could detect very low levels of P217 in brain, CSF and in blood. Variation of P217 levels was also found in different Taupathies. The Taupathies with the highest levels of P217 was Progressive supranuclear palsy, Corticobasal Degeneration and Globular glial Taupathies.

In dieser Arbeit kann gezeigt warden, dass mit der kortiko-muskulären und intermuskulären Frequenzanalyse distinkte Koheränzmuster bei verschiedenen Bewegungsstörungen (kortikaler Myoklonus, Extremitätendystonie, Myoklonus bei kortikobasaler Degeneration) identifiziert werden können. Ferner konnte gezeigt werden, dass das retikulospinale System mit der intermuskulären Frequenzanalyse untersucht werden kann, was neue Perspektiven bei der Untersuchung subkortikaler Abschnitte des motorischen Systems ermöglicht. / It can be shown in this work that distinct patterns of cortico-muscular and/or intermuscular coherence can be identfied in a variety of movement disorders (cortical myoclonus, limb dystonia, myoclonus of CBD). Additionally, it could be demonstrated that the assessment of the reticulospinal system is feasible by using intermuscular frequency analysis of homologous muscles, which might open up a new line of research of subcortical drives within the motor system.