Dissertations / Theses on the topic 'Progressive neurodegenerative diseases'

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.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by movement impairment, or parkinsonism, for which there is still no cure. The manifest clinical signs result from neuronal loss of more than 60% in the substantia nigra pars compacta. Cognitive disorders and dementia in PD usually occur, thus leading to Parkinson disease with dementia (PDD). Moreover, Dementia with Lewy bodies (DLB) is also considered a neurodegenerative disease and one of the most common causes of dementia, with cognitive impairment symptoms similar to Alzheimer-type dementia, and with parkinsonism. Its onset is insidious and is characterized by a slow progression in comparison with its fast form, also known as Dementia with Lewy bodies rapidly progressive (rpDCL), which appears suddenly and progresses quickly. In these pathologies there occurs a neural degeneration not only related to the accumulation of altered proteins, but more likely as a result of multiple deleterious factors. The hypothesis of this work is that the identification of molecular changes analyzed through the application of "-omics" techniques will be useful to obtain information about a risk transcriptome/proteome in the aforementioned diseases. Thus, the main objective of the present thesis is the identification of molecular alterations underlying functional cerebral changes and anatomical modifications in different brain regions and different Braak stages of PD, as well as DCL and DCLrp, with the use of post-mortem human brain samples compared with controls, combining microarray, mRNA, protein and enzyme assays studies. The obtained results have identified molecular alterations in PD, DLB, and rpDLB of different metabolic pathways including changes in the machinery of protein synthesis, in the mitochondrial energy metabolism, in neuroinflammation, in the purine pathway, and in new signaling pathways comprising olfactory and taste receptors paths.
La enfermedad de Parkinson (EP) es una patología neurodegenerativa perteneciente al grupo de afecciones conocidas como trastornos del movimiento, o parkinsonismo, para la cual actualmente no existe cura. Los signos clínicos que manifiesta son resultado de una pérdida neuronal superior al 60% en el área cerebral más afectada, la sustancia nigra pars compacta. Asimismo, la aparición de demencia y los desórdenes cognitivos en la EP conducen a una EP con demencia. A su vez, la Demencia con cuerpos de Lewy (DCL) es también una enfermedad neurodegenerativa considerada como una de las causas más comunes de demencia, con una sintomatología de deterioro cognitivo similar a la observable en la demencia de tipo Alzheimer y con la aparición de síntomas de parkinsonismo. Su aparición es insidiosa y se caracteriza por presentar una progresión lenta, a diferencia de su forma rápida también conocida como Demencia con cuerpos de Lewy rápidamente progresiva (DCLrp), que aparece de forma súbita y evoluciona vertiginosamente. En todas estas enfermedades se produce una degeneración neural debida no únicamente a la acumulación de proteínas alteradas, sino más probablemente consecuencia de múltiples factores deletéreos convergentes. La hipótesis de este trabajo es considerar que la identificación de cambios moleculares analizados gracias a la aplicación de métodos “-ómicos” servirá para obtener información sobre un trascriptoma/proteoma de riesgo en las anteriormente citadas enfermedades. El principal objetivo abordado en la presente tesis es la identificación de las alteraciones moleculares subyacentes a los cambios cerebrales funcionales y anatómicos presentes en diferentes regiones cerebrales y en distintos estadiajes de Braak de la EP, así como en la DCL y en la DCLrp, por medio del uso de muestras de cerebro humano post-mortem comparando con controles, combinando estudios de microarrays, mRNA, proteínas y ensayos enzimáticos. Los resultados obtenidos por medio de métodos de transcriptómica con su posterior validación y ampliación a proteómica han permitido identificar alteraciones moleculares en la EP, DCL y DCLrp de distintas vías metabólicas incluyendo cambios en la maquinaria de síntesis de proteínas, en el metabolismo mitocondrial y energético, en la neuroinflamación, en la vía de las purinas y en nuevas vías de señalización comprendiendo las vías de receptores olfatorios y gustativos.

Neurodegenerative disease is an umbrella term for pathologies that primarily damage neurons. As their incidence increases with age it is becoming of a greater concern for the west, due to its aging population. Due to their chronic nature and the difficulty to create reliable and reproducible animal models of these diseases their pathophysiologies are still poorly understood. For all these reasons, a mathematical modelling approach is suggested. The methodology of the work here consisted of identifying the state of the art models that describe the healthy behaviour of cells (e.g. metabolism and ionic regulation) and adapting them for pathological environments. With these models hypotheses provided by clinicians and pathologists were tested. The work focuses on developing models of mechanisms common to neurodegenerative diseases, which include: glutamate excitotoxicity, aquaporin water kinetics, inflammatory complement lysis and acute inflammation. Glutamate excitotoxicity was modelled by creating a compartmental model of glutamate exchange between neurons and astrocytes. This model was the first model of glutamate kinetics validated in an ischaemic stroke context. The aquaporin water kinetics and complement lysis models were developed in the context of the autoimmune disease Neuromyelitis Optica. Through this project a hypothesised trigger for the pathology was confirmed. Additionally, the first model of astrocytic cytotoxic oedema due to complement lysis was developed. Finally, a preventative drug for complement lysis was simulated. Acute inflammation was explored in the context of understanding the potential of chemerin as a pro-resolving cytokine. To that effect, a model of acute inflammation was developed where pro-resolving mechanisms were included. This model was the first to attempt model the effects of an intervention in inflammation. The results indicated that there is a maximum inhibitory effect of chemerin on inflammation. Additionally, two preventive avenues for chronic inflammation were found. With this work, the first attempts of capturing relevant mechanisms of neurodegenerative diseases were presented. These models can now be further developed and adapted to other pathological environments.

Las lipofuscinosis neuronal ceroidea (LNCs) constituyen uno de los grupos de enfermedades neurodegenerativas de herencia autosómica recesiva más frecuentes en la infancia. Presentan variabilidad en la edad de inicio y comparten amplio espectro fenotípico: epilepsia, déficit visual, deterioro motor y cognitivo progresivos con fallecimiento a edad precoz. Se han identificado ocho genes responsables de las diferentes formas clínicas en la edad pediátrica (CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8 y CLN8). El análisis mutacional permite asociar el defecto genético a cada una de las formas clínicas: congénita, LNCC (CLN10); infantil, LNCI (CLN1); infantil tardía, LNCIT (CLN2); juvenil, LNCJ (CLN3); variante infantil tardía finlandesa, vLNCITFin (CLN5); variante infantil tardía juvenil precoz, vLNCITJuv (CLN6); variante infantil tardía turca, vLNCITTur (CLN7) y variante infantil tardía epilepsia del norte con retraso mental, EPMR - variante infantil tardía (CLN8). Nos proponemos, a través de los estudios realizados en los pacientes españoles con LNC, profundizar en el conocimiento de los aspectos clínicos y moleculares de este grupo de enfermedades, determinar el espectro mutacional de los genes CLN1, CLN2, CLN3, CLN5 y CLN7 y establecer una adecuada correlación genotipo-fenotipo en la población pediátrica de nuestro país. Desde el año 1974-2011 se estudiaron 6 pacientes con LNCI (5 núcleos familiares). Desde el año 1979-2011 se estudiaron 12 pacientes con LNCIT (10 núcleos familiares). Desde el año 1975-2010 se estudiaron 24 pacientes con LNCJ, divididos en 2 grupos: variante (11 pacientes) con mutaciones en el gen CLN1 y clásico (13 pacientes) con mutaciones en el gen CLN3. Se describieron 3 pacientes con vLNCITFin y uno con vLNCITTur. Se creó una base de datos clínica con 50 ítems. Para el estudio estadístico se utilizó la prueba de Kaplan-Meier. Los pacientes con LNCI, iniciaron la enfermedad entre los 8-15 meses con retraso en el desarrollo motor y marcha inestable. La epilepsia puede aparecer en cualquier momento. La LNCI se caracteriza por un severo y progresivo curso clínico y en nuestra población, la mutación V181M en el gen CLN1 está asociada con el fenotipo más severo de la enfermedad. La LNCIT se inició entre los 18 meses y los 3.7 años con retraso del lenguaje y convulsiones febriles simples seguidas de epilepsia. El trastorno de aprendizaje y la ataxia ocurrieron a los 4 años. La regresión clínica se inició con una pérdida de las frases, seguido de pérdida de la deambulación. Todos los pacientes desarrollaron epilepsia mioclónica continua. La LNCIT presenta un curso clínico muy homogéneo y se demuestra heterogeneidad genética en nuestra población. La forma variante de LNCJ se inició con retraso / regresión del lenguaje y dificultades de aprendizaje mientras que la forma clásica se inició con déficit visual. La regresión clínica se inició con una pérdida de las frases seguida por una pérdida de la deambulación durante la adolescencia en el grupo variante y durante la edad adulta el grupo clásico. El curso clínico es más severo y progresivo en pacientes con mutaciones en el gen CLN1 que en el gen CLN3. La mutación V181L en el gen CLN1 fue identificada en homocigosis en 9 pacientes pertenecientes a 4 familias consanguíneas, no relacionadas, todas de etnia gitana. Se considera la posibilidad de realizar un diagnóstico precoz de LNCJ en base a la sintomatología inicial y la edad de inicio. El índice de progresión de la enfermedad orienta hacia los fenotipos causados por mutaciones en los genes CLN1 / CLN3 y el diagnóstico definitivo deberá confirmarse mediante el análisis mutacional de dichos genes. Se ha elaborado un protocolo diagnóstico que permite realizar estudios de correlación genotipo-fenotipo y amplía el espectro clínico-mutacional en la población española afectada de lipofuscinosis neuronal ceroidea.
Neuronal ceroid lipofuscinosis (NCLs) is one of the most common groups of progressive neurodegenerative diseases in childhood. Eight disease genes causing NCL in childhood have been identified: CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, and CLN8. The main objective was to assess the natural history of the disease and to establish phenotype/genotype correlations in Spanish patients with NCL. Infantile neuronal ceroid lipofuscinosis (INCL) is caused by mutations in the CLN1/PPT gene. The age at disease onset in six Spanish patients with INCL ranged from 8 to 15 months. Delayed motor skills and ataxia were the initial symptoms. The V181M mutation in the CLN1 gene was found in homozygosis which is associated with the most severe INCL phenotype. Late infantile neuronal ceroid lipofuscinosis (LINCL) is caused by mutations in the CLN2. The clinical outcome in 12 Spanish patients reported the age at onset of clinical symptoms ranged from 18 months to 3.7 years, and they included delayed speech and simple febrile seizures followed by epilepsy. Clinical regression was initiated by loss of sentences followed by loss of walking ability. The clinical progression of LINCL was relatively homogeneous and genetic heterogeneity was demonstrated in the 10 families studied. Juvenile neuronal ceroid lipofuscinosis (JNCL) is usually caused by a 1.02-kb deletion in the CLN3 gene and mutations in the CLN1 gene may be associated with a variant form of JNCL (vJNCL). To assess the natural history of the disease, 24 Spanish patients with JNCL were studied. Patients were classified into the groups of vJNCL with mutations in the CLN1 gene (n= 11) and classic JNCL (cJNCL) with mutations in the CLN3 gene (n=13). Patients with vJNCL showed a more severe and progressive clinical course than those with cJNCL. The rate of disease progression may be useful to diagnose vJNCL or cJNCL, which should be confirmed by molecular studies in CLN1/CLN3 genes. Three unrelated patients with Finnish variant late infantile (CLN5) and another patient with Turkish variant late infantile (CLN7) were described. The diagnostic algorithm is a useful tool for the diagnosis of the patients with NCL and the correlation genotype-phenotype studies in Spain.

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.

Le rôle que pourrait jouer l’interaction des systèmes cholinergiques (ACh) et dopaminergiques (DA) semble crucial dans la physiopathologie de certaines maladies neurodégénératives, en particulier dans la démence à corps de Lewy (DCL). Ce travail de thèse se propose de valider un protocole d’imagerie moléculaire en tomographie d’émission monophotonique, consistant en un marquage de l’ACh et de la DA chez un même individu, afin de pouvoir étudier in vivo les interactions ACh/DA.Après avoir mis au point chez des sujets âgés et des patients atteints de maladie d’Alzheimer une méthode d’imagerie cérébrale quantitative des neurones ACh utilisant un radioligand sélectif du transporteur vésiculaire de l’ACh, le [123I]-IBVM, et basée sur une modélisation pharmacocinétique, nous avons montré le potentiel de cette méthode à mettre en évidence une atteinte différentielle des circuits ACh dans la Paralysie Supranucléaire Progressive et l’Atrophie Multisystématisée. Dans la dernière partie de ce travail de thèse, nous avons pour la première fois réalisé un double marquage des systèmes ACh et DA dans la DCL, en utilisant, en plus du [123I]-IBVM, un radioligand sélectif du transporteur de la dopamine et validé en routine clinique, le [123I]-FP-CIT. En parallèle, une étude comportementale évaluant la présence d’hallucinations, de fluctuations cognitives, d’altérations des rythmes circadiens ainsi qu’un bilan des performances neuropsychologiques, ont été menés. Cette étude est actuellement en cours de réalisation. Les tous premiers résultats montrent l’existence de liens cohérents entre les données d’imagerie moléculaire et les données cliniques
The question of how acetylcholine (ACh) and dopamine (DA) could be involved together in the pathophysiology of some neurodegenerative disorders is essential, particularly in dementia with Lewy bodies (DLB). The present study aims at assessing an in vivo molecular imaging method of both ACh and DA brain systems using single photon emission computed tomography. In the first part of the present study, a method based on pharmacokinetic analysis making it possible to quantify ACh neurons in vivo, using [123I]-IBVM, a specific radioligand of vesicular acetylcholine transporter, was developed and validated in healthy subjects and Alzheimer’s disease patients. Then, we showed the ability of our method to demonstrate a differential alteration of ACh pathways in Progressive Supranuclear Palsy and Multiple System Atrophy patients. In the last part of this study, we imaged for the first time both ACh and DA systems in DLB patients, using not only [123I]-IBVM, but also [123I]-FP-CIT, a specific radioligand of dopamine transporter. Concomitantly, a behavioral exploration of hallucinations, fluctuating cognition and disturbances of circadian rhythms was achieved in these patients, as well as a neuropsychological examination. This study is currently in progress. The first results show consistent links between imaging and clinical data

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.

There is a need for sensitive measures of disease progression in multiple sclerosis (MS) to monitor treatment effects and understand disease evolution. MRI measures of brain atrophy have been proposed for this purpose. This thesis investigates a number of measurement techniques to assess their relative ability to monitor disease progression in clinically isolated syndromes (CIS) and early relapsing remitting MS (RRMS). Presented, is work demonstrating that measurement techniques and MR acquisitions can be optimised to give small but significant improvements in measurement sensitivity and precision, which provided greater statistical power. Direct comparison of numerous techniques demonstrated significant differences between them. Atrophy measurements from SIENA and the BBSI (registration-based techniques) were significantly more precise than segmentation and subtraction of brain volumes, although larger percentage losses were observed in grey matter fraction. Ventricular enlargement (VE) gave similar statistical power and these techniques were robust and reliable; scan-rescan measurement error was <0.01% of brain volume for BBSI and SIENA and <0.04ml for VE. Annual atrophy rates (using SIENA) were -0.78% in RRMS and -0.52% in CIS patients who progressed to MS, which were significantly greater than the rate observed in controls (-0.07%). Sample size calculations for future trials of disease-modifying treatments in RRMS, using brain atrophy as an outcome measure, are described. For SIENA, the BBSI and VE respectively, an estimated 123, 157 and 140 patients per treatment arm respectively would be required to show a 30% slowing of atrophy rate over two years. In CIS subjects brain atrophy rate was a significant prognostic factor, independent of T2 MRI lesions at baseline, for development of MS by five year follow-up. It was also the most significant MR predictor of disability in RRMS subjects. Cognitive assessment of RRMS patients at five year follow-up is described, and brain atrophy rate was a significant predictor of overall cognitive performance, and more specifically, of performance in tests of memory. The work in this thesis has identified methods for sensitively measuring progressive brain atrophy in MS. It has shown that brain atrophy changes in early MS are related to early clinical evolution, providing complementary information to clinical assessment that could be utilised to monitor disease progression.

The dementias are persistent or progressive disorders affecting more than one cognitive domain that interfere with an individual’s ability to function at work or home, and represent a decline from a previous level of function. In this thesis I consider the neurophysiology of dementia at a number of levels. I investigate the ways in which the connectivity and function of the brain predisposes to the specific focal patterns of neurodegeneration seen in the various dementias. I aim to identify the mesoscopic changes that occur in individuals with neurodegeneration and how these relate to their cognitive difficulties. I show how, by assessing patients in whom there is focal disruption of brain networks and observing the outcomes in comparison to controls, I can gain insight into the mechanisms by which the normal brain makes predictions and processes language. In Chapter 1, I set the scene for the focussed experimental investigations of model diseases by beginning with an introductory, clinically-focussed review that sets out the features, aetiology, management, epidemiology and prognosis of the dementias. This places these model diseases in the context of the broader clinical challenge posed by the dementias. In Chapter 2, I turn to ‘prototypical’ model diseases that represent neurodegenerative tauopathies with predominantly cortical (Alzheimer’s disease, AD) and subcortical (Progressive Supranuclear Palsy, PSP) disease burdens. I investigate the neurophysiological causes and consequences of Tau accumulation by combining graph theoretical analyses of resting state functional MR imaging and in vivo ‘Tau’ PET imaging using the ligand AV-1451. By relating Tau distribution to the functional connectome I provide in vivo evidence consistent with ‘prion-like’ trans-neuronal spread of Tau in AD but not PSP. This provides important validation of disease modification strategies that aim to halt or slow down the progression of AD by sequestration of pathological Tau in the synapse. In contrast, I demonstrate associations consistent with regional vulnerability to Tau accumulation due to metabolic demand and a lack of trophic support in PSP but not AD. With a cross-sectional approach, using Tau burden as a surrogate marker of disease severity, I then go on to show how the changes in functional connectivity that occur as disease progresses account for the contrasting cognitive phenotypes in AD and PSP. In advancing AD, functional connectivity across the whole brain becomes increasingly random and disorganised, accounting for symptomatology across multiple cognitive domains. In advancing PSP, by contrast, disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer passed through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Together, this resulted in increasingly modular processing with inter-network communication taking less direct paths, accounting for the bradyphrenia characteristic of the ‘subcortical dementias’. From chapter 3 onwards, I turn to the in-depth study of a model disease called non-fluent variant Primary Progressive Aphasia (nfvPPA). This disease has a clear clinical phenotype of speech apraxia and agrammatism, associated with a focal pattern of mild atrophy in frontal lobes. Importantly, general cognition is usually well preserved until late disease. In chapter 3 itself, I relate an experiment in which patients with nfvPPA and matched controls performed a receptive language task while having their brain activity recorded with magnetoencephalography. I manipulated expectations and sensory detail to explore the role of top-down frontal contributions to predictive processes in speech perception. I demonstrate that frontal neurodegeneration led to inflexible and excessively precise predictions, and that fronto-temporal interactions play a causal role in reconciling prior predictions with degraded sensory signals. The discussion here concentrates on the insights provided by neurodegenerative disease into the normal function of the brain in processing language. Overall, I demonstrate that higher level frontal mechanisms for cognitive and behavioural flexibility make a critical functional contribution to the hierarchical generative models underlying speech perception In chapter 4, I precisely define the sequence processing and statistical learning abilities of patients with nfvPPA in comparison to patients with non-fluent aphasia due to stroke and neurological controls. I do this by exposing participants to a novel, mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships, and then assessing the degree of implicit rule learning. I demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently in health and disease. In chapter 5, I summarise the synergies between the experimental chapters, and explain how I have applied a systems identification framework to a diverse set of experimental methods, with the common goal of defining the physiology of dementia. I then return to the results of chapter 3 with a clinical focus to explain how inflexible predictions can account for subjective speech comprehension difficulties, auditory processing abnormalities and (in synthesis with chapter 4) receptive agrammatism in nfvPPA. Overall, this body of work has contributed to knowledge in several ways. It has achieved its tripartite aims by: 1) Providing in vivo evidence consistent with theoretical models of trans-neuronal Tau spread (chapter 2), and a comprehensive clinical account of the previously poorly-understood receptive symptomatology of nfvPPA (chapter 5), thus demonstrating that systems neuroscience can provide a translational bridge between the molecular biology of dementia and clinical trials of therapies and medications. In this way, I begin to disentangle the network-level causes of neurodegeneration from its consequences. 2) Providing evidence for a causal role for fronto-temporal interactions in language processing (chapter 3), and demonstrating domain separation of statistical learning between linguistic and non-linguistic sequences (chapter 4), thus demonstrating that studies of patients with neurodegenerative disease can further our understanding of normative brain function. 3) Successfully integrating neuropsychology, behavioural psychophysics, functional MRI, structural MRI, magnetoencephalography and computational modelling to provide comprehensive research training, as the platform for a future research programme in the physiology of dementia.

La thèse s'intéresse à l'apprentissage statistique de modèles digitaux de progression des maladies neurodégénératives, en particulier la maladie d'Alzheimer. Ces modèles ont pour but de reconstruire la dynamique complexe et hétérogène de l'évolution de la structure, des fonctions et des facultés cognitives du cerveau, à un niveau moyenne mais également à l'échelle individuelle. Pour répondre à cet objectif, la thèse considère un modèle génératif à effets mixtes qui, à partir de données longitudinales, c'est à dire des observations répétées pour chaque patient, et éventuellement multimodales, recombine les trajectoires spatiotemporelles individuelles en un scénario moyen de progression de la maladie, estimant conjointement la variabilité de cette progression caractéristique. Cette variabilité est le résultat du non alignement temporel (en terme de vitesse de progression et âge de début de la maladie) et d'une variabilité spatiale qui prend la forme d'une modification de la séquence d'événements qui interviennent durant l'apparition et la progression de la maladie. Les différentes parties de la thèse forment une suite logique, depuis la problématique médicale, en passant par la description du modèle statistique associée, l'application de celui-ci pour la description de l'évolution de la maladie d'Alzheimer, et, enfin, le développement d'outils numériques à destination du corps médical pour tirer pleinement parti des méthodes présentées
This thesis focuses on the statistical learning of digital models of neurodegenerative disease progression, especially Alzheimer's disease. It aims at reconstructing the complex and heterogeneous dynamic of evolution of the structure, the functions and the cognitive abilities of the brain, at both an average and individual level. To do so, we consider a mixed-effects model that, based on longitudinal data, namely repeated observations per subjects that present multiple modalities, in parallel recombines the individual spatiotemporal trajectories into a group-average scenario of change, and, estimates the variability of this characteristic progression which characterizes the individual trajectories. This variability results from a temporal un-alignment (in term of pace of progression and age at disease onset) along with a spatial variability that takes the form of a modification in the sequence of events that appear during the course of the disease. The different parts of the thesis are ordered in a coherent sequence: from the medical problematic, followed by the statistical model introduced to tackle the aforementioned challenge and its application to the description of the course of Alzheimer's disease, and, finally, numerical tools developed to make the previous model available to the medical community

Alzheimer's disease (AD) is the most prevalent form of age-associated dementia. Cholesterol dysregulation is linked with AD onset. Besides age, the most important risk factor associated with AD is the inheritance of the epsilon-4 allele of apolipoprotein E, a cholesterol transporter. In addition, while hypercholesterolemia has been shown to be an independent risk factor for AD, the nature of the cholesterol-AD link is still not clear. This gap in our understanding is partly due to a lack of knowledge about cholesterol metabolism in the central nervous system (CNS). The low-density lipoprotein receptor (LDLR) is the main receptor of apoE and a central regulator of serum cholesterol levels. Therefore, we sought to characterize the potential participation of LDLR in AD pathogenesis and/or progression. Previous reports with similar aims came to contradictory conclusions. Such studies assessed potential changes in AD in the absence of LDLR by utilizing the LDLR-/- mouse model and crossing it to AD mouse models. Initially we evaluated LDLR-/- mice as a suitable model to study AD. We found that LDLR-/- mice overexpressed a functional splice-variant of LDLR, LDLRDelta4. Moreover, its protein localized in similar regions as the LDLR did in control mice. Finally, we determined that LDLRDelta4 bound apoE, which underscores the impact of the isoform's function in the CNS. We then focused on characterizing changes to LDLR in AD models. We found that APP overexpression in cells increased LDLR mRNA and protein. APP overexpression and Abeta treatment shifted LDLR localization. An AD mouse model showed increased LDLR in hippocampus. Conversely, LDLR levels were decreased in APP-/- mice. Finally, we found that microtubules were affected in cells overexpressing APP. In conclusion, the data presented argue for the importance of LDLR-mediated regulation of cholesterol during AD progression. Also, LDLR may participate in the initial pathogenic insults leading to amyloid deposition, which make it a potential therapeutic target to treat AD. Finally, we propose that APP/Abeta overexpression disrupts microtubule formation; this alteration affects protein trafficking. One of the proteins affected is LDLR, the repercussions of which may ultimately result in cholesterol dysregulation.

Les symptômes psychoaffectifs anxieux et dépressifs infra-cliniques sont fréquents chez les personnes âgées et sont associés à un risque accru de développer une démence et de progresser d’un stade prédémentiel à un stade démentiel. Cependant, ils pourraient également être des symptômes associés à une démence, et pourraient constituer une manifestation clinique de la pathologie sous-jacente. L’objectif de cette thèse était de contribuer à une meilleure compréhension des liens entre symptômes anxieux et dépressifs et les modifications cognitives et cérébrales structurales, fonctionnelles et moléculaires typiques de la maladie d’Alzheimer (MA), à la fois dans le vieillissement normal et au cours de cette pathologie. Nos résultats montrent que des symptômes anxieux élevés sont associés à un volume de substance grise plus bas chez les sujets âgés cognitivement sains, et ce uniquement chez les femmes. Cette même association est présente chez les sujets Subjective Cognitive Decline (SCD) recrutés dans la population générale, et montre une vulnérabilité accrue aux maladies neurodégénératives liées à l’âge, telles que les démences. Chez les SCD ayant consulté pour leur déclin cognitif subjectif, des symptômes dépressifs élevés sont associés à une charge amyloïde plus importante dans le cerveau, et donc à un risque accru de développer une MA, tandis que chez les sujets Mild Cognitive Impairment (MCI) et MA amyloïde positifs, ils sont liés à une meilleure cognition et conscience de ses propres troubles. Les symptômes psychoaffectifs semblent donc avoir un rôle évolutif au cours du passage du vieillissement normal au vieillissement pathologique, d’abord manifestation d’une vulnérabilité cérébrale, puis manifestation d’une pathologie sous-jacente et d’un risque de développement de MA, ils sont au contraire un marqueur de préservation chez les patients présentant un déclin cognitif (MCI et MA)
Subclinical psychoaffective symptoms of anxiety and depression are common in the elderly and are associated with an increased risk of developing dementia and progressing from a pre-dementia stage to a dementia stage. However, they could also be symptoms associated with dementia and could be a clinical manifestation of the underlying pathology. The aim of this thesis was to contribute towards a better understanding of the links between anxiety and depressive symptoms and Alzheimer's disease (AD) hallmarks, including cognitive, structural, functional and molecular modifications, both in normal aging and during the course of this pathology. Our results show that higher anxiety symptoms are associated with lower grey matter volume in cognitively healthy elderly subjects, but only in women. This same association is present in all Subjective Cognitive Decline (SCD) participants recruited from the general population, and shows an increased vulnerability to age-related neurodegenerative diseases such as dementia. In Subjective Cognitive Decline (SCD) subjects, high depressive symptoms are associated with greater amyloid load in the brain, and thus an increased risk of developing AD, while in amyloid-positive Mild Cognitive Impairment (MCI) and AD subjects, they are related to better cognition and awareness of their cognitive deficits. Psychoaffective symptoms thus seem to have an evolving role during the transition from normal aging to pathological aging; they first manifest a brain vulnerability, then an underlying pathology and a risk of developing AD, and then are a marker of preservation in patients with cognitive decline (MCI and AD)

The Hippo pathway is a cell signaling pathway involved in organ size regulation and tumorigenesis in mammals. This pathway regulates the activity of Yes-associated protein (YAP), a transcriptional coactivator which binds to the transcription factor TEAD to promote expression of genes controlling growth and proliferation of tissues, as well as inhibition of apoptosis. The Hippo pathway has recently been implicated as a pathogenic mechanism in neurodegenerative disorders. Specifically, mammalian sterile 20 (Ste20)-like kinase 1 (MST1), a protein kinase in the Hippo pathway, has been found to promote neuronal death under conditions of oxidative stress. Moreover, homozygous deletion of MST1 in a mouse model of Amyotrophic Lateral Sclerosis (ALS) significantly delayed onset of neurodegenerative symptoms. We examined the expression levels of key Hippo pathway components in cortex, lumbar spinal cord, and gastrocnemius muscle samples of male and female G39A SOD1 mice using western blots. Our results revealed a significant increase in phosphorylated MST1 (pMST1) in lumbar spinal cord of presymptomatic transgenic animals, and found this increase to be sex and gene copy number dependent. These results suggest that the Hippo pathway is dysregulated in the SOD1 mouse model and that MST1 may play a critical role in pathogenesis and disease progression in ALS.

The onset of a progressive, fatal illness such as Motor Neuron Disease (MND) inevitably results in physical and communication disabilities that impinge on the individuals’ ability to remain functionally independent. The loss of speech as a result of dysarthria, a motor speech disorder, is one of the most profound changes that the person with MND will experience. The decline in the individuals’ speech intelligibility, that negatively influences communication effectiveness, implies that in 80% of cases alternative and augmentative communication (AAC) strategies are required to support the daily communication needs of individuals with MND. The dyadic nature of chronic illness implies that multiple aspects of one of the most important adult relationships, marriage, will be affected. Roles and responsibilities performed by each member of the couple will continually change as the disease progresses. The emotional trauma of adjusting to the unavoidable alteration in their relationship elicits strong emotions such as guilt, anger and frustration. Communication is one of the most constructive ways of dealing with these emotions. The ability of spouses to convey their innermost thoughts, feelings and intimacy through communicative interaction is vitally important in marital communication. The aim of this study was to compare how persons with MND and their spouses perceive changes in their marital communication in relation to the deteriorating speech of persons with MND. Fourteen couples divided into two participant groups, persons with MND and spouses, participated in this non-experimental correlational research study. Data was collected during three visits at six-monthly intervals over a 12 month period. At each of these visits both participant groups completed a variety of objective and subjective measures, of which twenty percent were interrated by independent raters. Results confirmed the inevitable decline in speech intelligibility of persons with MND across the disease progression. The persons with MND did not report a change in their perception of marital communication although their spouses indicated a statistically significant decrease between the first and last visits. Interestingly, there was no statistically significant relationship between the deteriorating speech of persons with MND and the couples’ perception of marital communication, confirming that marital communication was not influenced by decreased speech intelligibility.
Thesis (PhD)--University of Pretoria, 2010.
Centre for Augmentative and Alternative Communication (CAAC)
unrestricted