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1
Parton, Matthew James. "Disease-modifying factors in motor neuron disease." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289882.
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Martin, Joanne Elizabeth. "Cellular pathology of the lower motor neuron in motor neuron disease." Thesis, Queen Mary, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266426.
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Williams, David Bruce. "Genetic factors in motor neuron disease." Thesis, The University of Sydney, 1989. https://hdl.handle.net/2123/26235.
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The term motor neuron disease is used by different authors to designate one or more of a wide variety of disorders whose principal common feature is dysfunction of the motor neuron (MN) or anterior horn cell (AHC). In one convention, the term motor neuron disease is used to denote all such disorders, including both infantile- and juvenile-onset forms of spinal muscular atrophy, and corticospinal degenerations in which the upper motor neuron is prominently affected. At other times the term motor neuron disease refers only to the relatively common and presumably more homogeneous condition which is idiopathic, has its onset in late adult life and is almost inevitably fatal. Often the distinction between these two uses is not clearly stated and must be inferred. In another more recent, but not yet universal convention, the term motor neuron disease designates all disorders of the anterior horn cell and associated motor system, and amyotrophic lateral sclerosis (ALS) is used to indicate the commonest disorder. This is also potentially confusing, as by definition the term ALS is the clinical presentation of a patient with combined upper and lower motor neuron signs in either or both of the bulbar and spinal regions. Therefore its use may implicitly exclude patients with the clinical features of progressive bulbar palsy (PBP) (exclusive lower motor neuron involvement in the bulbar region) or progressive muscular atrophy (PMA) (exclusive lower motor neuron involvement in the spinal region, (also called progressive spinal muscular atrophy (PSMA))). Some authors suggest that PMA has a sufficiently different clinical presentation and prognosis to define it is a different disease (Norris et al, 1978). However, there is poor correlation between the clinical and pathological features of clinically defined cases of ALS and PMA (Chou, 1978), the electrophysiological abnormalities are indistinguishable (Hansen and Ballantyne, 1978), and one clinical form may change into another (Friedman and Freedman, 1950). When patients with either pure PMA or pure PBP are examined repeatedly during the course of their illness, they are often found to develop upper motor neuron signs, so exclusive lower motor neuron syndromes confirmed at autopsy are probably quite rare (cf the Mayo Clinic patients in Juergens et al, 1980). Therefore, a reasonable inference is that ALS, PBP and PMA are clinical variants of one disease. By contrast, most authors are cautious to discuss pure upper motor neuron degeneration, or primary lateral sclerosis (PLS), as a separate entity (Stark and Moersch, 1945; Younger et al, 1988).
In this thesis, the uncapitalised phrase 'motor neuron diseases' will refer to all disorders where loss or degeneration of the AHC is the principal salient feature. The abbreviation MND/ALS will be this author's term for the idiopathic, adult-onset disease which may have the variety of clinical presentations (ALS, PBP, PMA) described above. The terms MND or ALS will be used alone when they refer to a patient or group of patients described by a specific author, so that then the reference will be to the definition utilised by that author. Clinical presentations will be called the ALS, PMA or PBP 'form' of MND/ALS.
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Sargsyan, Siranush Anna. "Microglial activationas a potential contributor to motor neuron injury in motor neuron disease." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444237.
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Bäumer, Dirk. "Functional genetic analysis of motor neuron disease." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:859016f8-5eff-4a8e-bfda-48afb8695646.
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Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the commonest motor neuron diseases of adult- and childhood onset. Alterations of the RNA binding protein TDP-43 are associated with most cases of ALS, while SMA is caused by deletion of the Survival Motor Neuron (SMN1) gene. SMN has been well characterised in its role in the assembly of the cellular machinery that carries out splicing of pre-mRNA, but is thought to have other functions in RNA metabolism unrelated to pre-mRNA splicing. It is conceivable that specific aspects of RNA handling are disrupted in both SMA and ALS. A variety of genetic, molecular and neuropathological approaches were applied to investigate a potential common pathway in these diseases. The spectrum of genetic mutations underlying motor neuron disorders were explored by screening patient DNA. Cell culture and mouse models were used to test the hypothesis that altered pre-mRNA splicing causes motor neuron death. Human neuropathological specimens were examined for changes in proteins involved in RNA metabolism. The results indicate that altered pre-mRNA splicing is a late occurrence in disease and more likely to be a consequence rather than the cause of motor neuron degeneration. However, the notion that RNA metabolism is highly relevant to motor neuron diseases was strengthened by the discovery of mutations in another RNA binding protein, FUS, in cases of ALS without TDP-43 pathology. Overall the findings highlight the need to consider disruption of mRNA transport and regulation of mRNA translation in future motor neuron disease research.
6
Long, Zhe. "Frontotemporal Dementia-Motor Neuron Disease: disease continuum or distinct entity?" Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23012.
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Frontotemporal dementia-motor neuron disease (FTD-MND) is a rare disease characterised by the simultaneous occurrence of FTD and MND. Clinical, pathological, and genetic investigations have highlighted the association between FTD and MND, but much remains unclear. The experimental studies of this thesis comprehensively and systematically investigate the natural history of cognition and behaviour in FTD-MND and explore whether FTD-MND is distinct from well-recognised FTD phenotypes using clinical, neuropsychological and multimodal neuroimaging analyses. Results arising from two separate studies (Chapters 3 and 4) reveal that the majority of FTD-MND presents with variable combinations of behaviour, language and motor deficits initially, and fulfil FTD-MND diagnosis within 24 months from symptom onset. Heterogenous deficits persist even after meeting FTD-MND diagnostic criteria. Clinical heterogeneity in FTD-MND, highlighted by using a data-driven approach, may reflect variable white matter tract involvement. Language impairment in FTD-MND is highly prevalent, and more mixed than in FTD language phenotypes. The frequency and severity of behavioural and language deficits in FTD-MND lie between that of FTD phenotypes. Over time (Chapter 5), cognition and language deficits progress more rapidly in FTD-MND than bvFTD. Progression in FTD-MND may be driven by left inferior frontal gyrus and anterior temporal lobe involvemeny. Survival in FTD-MND is much shorter than in FTD, despite a similar age at onset. Motor neuron dysfunction may be highly specific for frontotemporal lobar degeneration TAR DNA binding protein 43 kDa (FTLD-TDP, Chapter 6), but the current FTLD-TDP pathological staging scheme may not correlate with clinical progression. These findings demonstrate that FTD-MND is distinct from, rather than simply a later clinical stage of, FTD.
7
Kwok, Alice. "Unfolded protein responses in models of Motor Neuron Disease." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:2f3efba7-dce1-4521-bda6-4db8ee81094d.
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Motor neuron disorders are a heterogeneous group of diseases characterized by the selective degeneration of motor neurons leading to muscle wasting and atrophy. Amyotrophic Lateral Sclerosis (ALS) is the most common amongst these disorders and is characterized by the selective loss of both upper and lower motor neurons in the brain and spinal cord. 20% of familial cases of ALS are caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1), a ubiquitously expressed enzyme responsible for scavenging superoxide radicals. The exact mechanisms underlying mutant SOD1-mediated neurotoxicity are unknown. Misfolded mutant SOD1 accumulates in the cytosol and mitochondrial intermembrane space (IMS) indicating the involvement of unfolded protein responses in ALS pathogenesis. Unfolded protein responses (UPRs) are complex signal transduction cascades which detect perturbations in protein folding and couple them to the expression of protein quality control machinery thereby allowing individual compartments to adapt to stress. In the cytosol, this study has shown that HspB8 was upregulated by SOD1 mutants, where it induced the clearance of aggregates by macroautophagy. This is a protective mechanism, as overexpression of HspB8 suppressed mutant-SOD1 mediated toxicity. In contrast, HspB8 mutants were impaired in macroautophagy and are toxic to NSC-34 cells. The mechanisms for the IMS-UPR have not been previously identified. To address this issue, a model for the accumulation of misfolded mutant SOD1 within the IMS was created and candidate proteins involved in protein quality control within the IMS were explored at the transcriptional level and at the level of protein expression. Preliminary results revealed some possible candidates that may have a role in the adaptation to mitochondrial stress. Interestingly, increased mitophagy was also found in IMS-G93A expressing cells, advocating the central role of macroautophagy in eliminating protein aggregates and damaged mitochondria in SOD1-FALS.
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Stephens, Benjamin. "Pathology of spinal interneurons in motor neuron disease." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251759.
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Blackburn, Daniel J. "The role of glial cells in motor neuron disease." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531123.
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Shum, Carole Yick Lam. "Modelling motor neuron disease using induced pluripotent stem cells." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/modelling-motor-neuron-disease-using-induced-pluripotent-stem-cells(1686136a-d045-4edc-9439-1028b0ea47db).html.
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Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease. The majority of ALS cases are sporadic (SALS), but 10% of patients have a familial form of ALS (FALS). Mutations in Fused in Sarcoma (FUS) occur in approximately 4% of FALS and less than 1% of SALS. A hallmark feature of ALS is the degeneration of upper and lower motor neurons in the brain and spinal cord; however, the mechanism underlying this loss is not known. Studies of degenerative mechanisms have been impeded by the inaccessibility of human neural tissue. A possible solution is to use induced pluripotent stem cells (iPSCs) derived from patients, which may be differentiated into the cell types affected by disease. To test whether patient-specific stem cells can be used to model aspects of ALS pathogenesis, iPSC lines were generated from a patient carrying the pathogenic FUS R521C mutation. FUS iPSCs derived from patient fibroblasts and WT iPSCs derived from fibroblasts from two healthy controls were differentiated into neural progenitors and motor neurons. FUS iPSC-derived neuronal cells recapitulate key aspects of FUSassociated ALS, including mislocalisation of FUS protein, the redistribution of FUS protein into cytoplasmic stress granules, and increased apoptotic cell death. The second study uses this iPSC model to investigate the effects of mutant FUS on dendritic morphology and synaptic regulation. FUS iPSC-derived neurons display abnormal dendritic morphology, such as reduced neurite outgrowth and reduced density of dendritic protrusions. FUS iPSC-derived neurons also show differences in the localisation of synaptic proteins. This study suggests that physiological levels of mutant FUS protein affect the morphology and synaptic structure of human neurons. These studies validate the stem cell approach to disease modelling and provide support for the use of patient-specific stem cells for the study of disease mechanisms.
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Christou, Yiota Apostolou. "Generation of motor neurons from embryonic stem cells : application in studies of the motor neuron disease mechanism." Thesis, University of Sheffield, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505426.
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Embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to the proposal that in the future, the use of human embryonic stem cells or their differentiated progeny may be beneficial in regenerative medicine. In particular, a current goal in the field of clinical neurology is to use stem cells in cell-based therapies for motor neuron disease (MND) or amyotrophic lateral ~clerosis. MND is a progressive neurodegenerative disease that specifically affects upper and lower motor neurons and leads ultimately to death from respiratory failure. Stem cellderived motor neurons could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurons, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro to direct embryonic stem cells towards motor neurons. This thesis presents the work I have performed on the directed differentiation of embryonic stem cells towards motor neuron fates. I describe the various experimental approaches I took in attempts to produce motor neurons in vitro. My studies reveal that it is possible to deploy the signals used during normal development to direct the differentiation of both human and mouse embryonic stem cells into neural and neuronal cells, including motor neurons. Two major limitations precluded my analysis of pure motor neuron cultures: first, the high concentrations of the ventralising morphogen, SHH, apparently required to direct embryonic stem cells towards motor neuron fates, and second, the difficulties encountered in culturing purified motor neurons. However, using a mixed culture, I obtained evidence that motor neurons and their progenitors fail to survive in medium conditioned by mutant SOD1-G93A astrocytes.
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Cristofani, R. M. "PROTEIN MISFOLDING IN KENNEDY¿S DISEASE AND IN RELATED MOTOR NEURON DISEASES (MNDS)." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/339901.
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Motor neuron diseases, like spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are characterized by the presence of inclusions or aggregates of proteinaceous materials. In SBMA, inclusions are formed by testosterone dependent aggregates of mutant androgen receptor (AR) with an elongated polyglutamine tract (ARpolyQ), while in ALS inclusions contain several aggregated proteins including TDP43, ubiquilin, optineurin. Exceptions are familial ALS forms linked to superoxide dismutase 1 (SOD1) mutations, to mutated TDP43 and to C9ORF72 poly-dipeptides (DPRs), in which aggregates are mainly composed of mutant SOD1, mutant TDP43 or DPRs, respectively. In general, protein aggregation is due to generation of aberrant protein conformations (misfolding) combined to a failure, in neuronal cells, of the protein quality control (PQC) system, which may be insufficient to correctly remove the misfolded proteins. In other target tissue, such as the muscles, a different physiological PQC regulation may be helpful to remove misfolded proteins related to MNDs.
The PQC system requires the activities of chaperones, degradative systems ubiquitin- proteasome (UPS) and autophagy. After misfolded protein recognition by chaperones, the dynein motor complex plays a crucial role to efficiently remove these species via autophagy, transporting them to autophagosome and assisting autophagosome- lysosome fusion.
In this thesis, I have investigated the implications of protein misfolding in SBMA and in ALS. Taking advantage of a comparative analysis of misfolded proteins response in skeletal muscle and in spinal cord of SMBA mice, we proved that autophagy is dramatically perturbed in muscles. Indeed, we found the up-regulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3). In addition, the chaperon small Heat Shock Protein B8 (HSPB8) and its co-chaperone BCL2-Associated Athanogene 3 (BAG3), required for autophagy, were robustly up-regulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Interestingly, the BAG3:BAG1 ratio, increased in muscle, suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Misfolded proteins, recognized by HSPB8-BAG3 complex, are actively transport by dynein to MTOC to be inserted in autophagosome and degraded by autophagy,
Then, we analysed the role of dynein mediate transport in the autophagic removal of misfolded proteins. In immortalized motoneuronal NSC34 cells, we found that the reduction of dynein protein levels, obtained using a specific siRNA, resulted in autophagy inhibition and in unexpected testosterone dependent ARpolyQ aggregates reduction. Also, we found that pharmacological dynein inhibition, with erythro-9-(2- Hydroxy-3-nonyl) adenine hydrochloride (EHNA), in NSC34 cells expressing ARpolyQ, mutant SOD1, truncated TDP43 form or C9ORF72 DPRs, induced a great reduction of mutant protein aggregates, even in presence of an autophagy inhibitor (3-MA), but not of a proteasome inhibitor (MG132). By performing fractionation studies we found that EHNA increased the ARpolyQ levels in PBS and Triton-X100 fractions. Surprisingly, we found that ENHA effects were paralleled by an increased expression of BAG1, a co- chaperone which routes misfolded proteins to UPS, but not of BAG3 suggesting the prevalence of UPS functions. Indeed, when dynein activity was blocked, BAG3:BAG1 ratio was decreased, thus in favour of BAG1 expression, suggesting the involvement of the pro-degradative activity of BAG1 on ARpolyQ aggregates. Collectively, these data show that mutant ARpolyQ induces a potent autophagic response in muscle cells. This may be useful to evaluate the SBMA progression.
In parallel, dynein blockage perturbs autophagy and modifies the response of PQC system to misfolded protein. This results in reduced aggregation of MNDs-related misfolded proteins, a phenomenon that may occurs via an increase in their solubility and the induction of UPS functions.
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Günther, Rene, Nicole Richter, Anna Sauerbier, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Alexander Storch, and Andreas Hermann. "Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-217311.
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Background
The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.
Methods
We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.
Results
In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.
Conclusion
NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.
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Günther, Rene, Nicole Richter, Anna Sauerbier, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Alexander Storch, and Andreas Hermann. "Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases." Frontiers Research Foundation, 2016. https://tud.qucosa.de/id/qucosa%3A30109.
Full textAbstract:
Background
The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.
Methods
We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.
Results
In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.
Conclusion
NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.
15
Gopinath, Sumana. "Finding new genes causing motor neuron diseases." Thesis, The University of Sydney, 2006. http://hdl.handle.net/2123/1624.
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Abstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.
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Gopinath, Sumana. "Finding new genes causing motor neuron diseases." University of Sydney, 2006. http://hdl.handle.net/2123/1624.
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Doctor of PhilosophyAbstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.
17
Lyon, Alison Nicole. "Generation and Analysis of Motor Neuron Disease Models in Zebrafish." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861.
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Witherden, Abigail Sian. "Positional cloning of Loa, a mouse motor deficit mutation." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248151.
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Garcia-Willingham, Natasha E. "LANGUAGE DYSFUNCTION IN MOTOR NEURON DISEASE: COGNITIVE FEATURES AND SCREENING SENSITIVITY." UKnowledge, 2019. https://uknowledge.uky.edu/psychology_etds/168.
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Motor neuron disease (MND) is a set of neuromuscular diseases that affect the upper and/or lower motor neurons, resulting in progressive disability. Amyotrophic lateral sclerosis (ALS) and Primary lateral sclerosis (PLS) are two forms of MND that both involve upper motor neuron degeneration, which can also accompany extra-motor changes in cognitive, behavioral, and/or emotional functioning for some individuals. Characterization of the cognitive profile of MND is still evolving, with growing interest in cognitive subtypes. The development of cognitive screens targeted to the MND cognitive profile aim to provide efficient and accurate brief assessments. However, empirical evaluation of tailored MND cognitive screens is needed for cross-validation independent of tests’ original developers. The present study addresses the cognitive profile of MND and the utility of brief cognitive screens with a focus on impairments in the language domain. The two primary aims include: (1) comprehensive assessment and characterization of language dysfunction in MND, and (2) empirical evaluation of brief cognitive screens with regard to detecting language impairments.
Forty-one patients with MND (ALS n = 36; PLS n = 5) were administered a comprehensive language battery to classify cognitive impairment (MND/ALSci; Strong et al., 2017) in the language domain and/or verbal fluency. Patients also completed two tailored cognitive screens [ALS Cognitive Behavioral Screen (ALS-CBS), Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and one general screen (Montreal Cognitive Assessment; MoCA).
The current preliminary results suggest language dysfunction in MND is characterized by prominent difficulties with word retrieval (confrontation naming) and/or syntax comprehension. However, evidence of reduced word production resembling nonfluent/agrammatic aphasia was not found. In total, 19.5% of the sample met criteria for MND/ALSci in the language domain (n = 8, all ALS); 22.0% met criteria for MND/ALSci in the verbal fluency domain (n = 9). Patients were classified into three subgroups, those with broad language impairments (ALSci-L n = 4, 9.8%), phonemic fluency impairments (MNDci-VF n = 5, 12.2%), or both impairments (ALSci-L+VF n = 4, 9.8%). Results also revealed existing challenges in accurately classifying patients with language dysfunction using brief cognitive screens. The ECAS Language subscore offered limited classification of broad language impairments in the present MND sample (sensitivity 50%, specificity 70%). Among the broader cognitive screens, sensitivities to language impairments were: ALS-CBS (100%), ECAS ALS-Specific Score (75%), and MoCA (71%). Convergent validity was demonstrated between outcomes on the ALS-CBS and ECAS ALS-Specific Score (rФ = .59). Discriminant validity was also demonstrated between outcomes on ALS-CBS compared to the MoCA (rФ = .11).
Future research is needed to assess whether language dysfunction reflects a distinct MND cognitive phenotype(s) and potential relationships with disease prognosis. Naming and syntax comprehension may be fruitful language screening targets for future research.
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Friberg, Danielle. "Nerve lesions in pharynx - an aetiology of obstructive sleep apnoea /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2721-9.
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Bermingham, Nessan Anthony. "Genetic characterisation of the progressive motor neuron degeneration mouse 'Legs as odd angles' (Loa)." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264956.
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Mather, Mary Srikanti. "Putative protein abnormalities in amyotrophic lateral sclerosis." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239078.
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Sassi, Mohammed M. "Apolipoprotein-E genotype in major neurodegenerative diseases." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339716.
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Bros, Virginie. "In-situ characterisation of the recessive motor neuron disease protein, ALS2/ALSIN." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420377.
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Turner, Martin Robert. "Understanding pathophysiologial mechanisms in sporadic and familial cases of motor neuron disease." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417085.
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Palmieri, Arianna. "A neuropsychological and cognitive insight in amyotrophic lateral sclerosis / motor neuron disease." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425586.
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A neuropsychological and cognitive insight into motor neuron disease/amyotrophic lateral sclerosis (MND/ALS)
1) We evaluated cognitive functioning in 128 MND patients (vs 113 healthy controls), with a comprehensive neuropsychological battery. Dysfunctions were significantly present in 40% of cases (mainly for executive functioning and short-term memory); 7% of them showed clear frontal or fronto-temporal dementia (chapter 2).
2) Nine ALS patients (vs 10 healthy controls) underwent the fMRI study: significant differences were displayed in lateralized activation between patients and controls during the attentional task, both for unpleasant and for neutral word stimuli (statistically greater activation in right middle frontal gyrus for patients, greater activation for frontal, parietal and cerebellar areas in controls) and lower activation was shown in patients in the posterior cingulate during mnesic recall, for both unpleasant and neutral stimuli (chapter 3).
3) We validated an Italian version of a specific quality of life questionnaire for MND/ALS: the ALSAQ-40, psychometric reliability in terms of internal reliability, construct validity, test-retest reliability and face validity were evaluated on the basis of 76 patients’ responses. Correlation with functional and clinical measures are discussed in the text (chapter 4).
5) Similarly, we validated an Italian version of the ELQ, (a questionnaire for detecting emotional lability) on 41 MND patients and 39 respective caregivers (vs 39 healthy controls and 39 pseudo-caregivers). The lack of correlation with neuropsychological profile and correlations with psychopathological indices, both in patients and in caregivers, are described in the text (chapter 5).
5) The Rorschach test (according to Exner’s guidelines) was administred to 21 ALS patients with early onset, 21 with onset longer than two years and 21 myasthenic controls. Among the numerous findings obtained, suicidal ideation was significantly more present in the ALS group with a recent diagnosis compared to those with a more remote one (chapter 6).
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Griffiths, Lowri Ann. "Investigating the role of eEF1A2 in motor neuron degeneration." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5924.
Full textAbstract:
Abnormal expression of the eukaryotic translation elongation factor 1A (eEF1A) has been implicated in disease states such as motor neuron degeneration and cancer. Two variants of eEF1A are found in mammals, named eEF1A1 and eEF1A2. These two variants are encoded by different genes, produce proteins which are 92% identical but have very different patterns of expression. eEF1A1 is almost ubiquitously expressed while eEF1A2 is expressed only in specialised cell types such as motor neurons and muscle. A spontaneous mutation in eEF1A2 results in the wasted mouse phenotype which shows similar characteristics in the mouse to those seen in human motor neuron degeneration. This mutation has been shown to be a 15.8kb deletion resulting in the complete loss of the promoter region and first non coding exon of eEF1A2 which completely abolishes protein expression. The main aim of this project was to further investigate the role of eEF1A2 in motor neuron degeneration. Firstly, although the wasted phenotype is considered to be caused by a recessive mutation, I established a cohort of aged heterozygote mice to evaluate whether any changes are seen later in life that might model late onset motor neuron degeneration. A combination of behavioural tests and pathology was used to compare wild type and heterozygous mice up to 21 months of age. Whilst results indicate that there is no significant difference between ageing heterozygotes and wildtype controls, there is an indication that female heterozygote mice perform slightly worse that wildtype controls on the rotarod (a behavioural test for motor function). Secondly, I aimed to investigate the primary cause of the wasted pathology by generating transgenic wasted mice expressing neuronal eEF1A2 only. This would complement previous experiments in the lab which studied transgenic wasted mice expressing eEF1A2 in muscle only. Unfortunately the expression of eEF1A2 in the transgenic animals was not neuronal specific. However a transgenic line with expression of eEF1A2 in neurons and skeletal muscle but not cardiac muscle has been generated which clearly warrants further investigation. Thirdly, I wished to assess whether eEF1A2 has any role in human motor neuron degeneration. To achieve this, eEF1A2 expression was investigated in spinal cords from human motor neuron disease (MND) patients. Preliminary data suggests that motor neurons from some MND patients express significantly less eEF1A2 than motor neurons of control samples. Further work is required to confirm these findings. Finally, I investigated the individual roles of eEF1A1 and eEF1A2 in the heat shock response. I used RNAi to ablate each variant separately in cells and subsequently measured the ability of each variant individually to mount a heat shock response. Results indicate a clear role for eEF1A1 but not eEF1A2 in the induction of heat shock. This may explain in part why motor neurons exhibit a poor heat shock response as they express eEF1A2 and not eEF1A1. These experiments shed light on our understanding of the role of eEF1A2 in motor neuron degeneration and uncover many new avenues of future investigation.
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Wagner, Justin. "Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34124.
Full textAbstract:
Lower motor neuron diseases and peripheral neuropathies are two groups of diseases that include multiple rare disorders where many causes are unknown and definitive treatments are unavailable. Understanding the molecular etiology of these genetic diseases provides an opportunity for rapid diagnosis, preconception genetic counseling and, in a subset, direction for the development of future treatment options. The recent introduction of whole exome sequencing (WES) marks a new era in Mendelian genetic disease research as the majority of the coding region of the genome can be sequenced in a timely and cost-effective manner. In this study, WES was used to investigate the molecular etiology of a cohort of 37 patients presenting with lower motor neuron disease or peripheral neuropathy. A molecular diagnosis was determined for seven patients informing the diagnostic utility of WES. Novel phenotypes were found for three genes originally associated with a different disorder. Finally, the foundation has been laid, through the use of functional studies and large scale data-sharing, to identify novel disease-causing genes for lower motor neuron disease and peripheral neuropathy.
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Couillard-Despres, Sebastien. "Transgenic mouse models to study the role of neurofilaments in motor neuron disease." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37882.
Full textAbstract:
Neurofilaments are the major type of intermediate filaments found in the adult nervous system of mammalians. Abnormalities of the neurofilament network constitute a common finding of many neurological disorders. For instance depositions of neurofilament aggregates in the perikarya and axons of motor neurons are observed in most amyotrophic lateral sclerosis (ALS) cases, sporadic and familial. The impact of such accumulation of neurofilaments on the course of motor neuron disease remains to be fully elucidated.In order to investigate the role of neurofilaments in motor neuron disease, transgenic mice expressing a mutant form of the Cu,Zn superoxide dismutase (SOD1) were used as an animal model of familial ALS. Increasing the perikaryal neurofilament content in these mutant SOD1 mice slowed down the motor neuron disease progression and increased their life span by up to 65%. To date, this approach constitutes the most efficient way to increase the life span of mutant SOD1 mice. Moreover, increasing the axonal neurofilament content in mutant SOD1 mice by human neurofilament-light subunit (hNF-L) overexpression demonstrated that axonal neurofilaments do not constitute an exacerbating factor in the neurodegeneration caused by mutant SOD1.
The pathogenicity of human neurofilament-heavy (hNF-H) proteins expressed in transgenic mice was also investigated. Two alleles of the NF-H gene are present in the normal human population. Expression of both alleles in transgenic mice provoked motor neuron dysfunction. The adverse property of NF-H overexpression is the result of an improper stoichiometry between the NF-L and the NF-H subunits. Restoration of an adequate stoichiometry, via the co-expression of NF-L and NF-H subunits, rescued mice from the motor neuron dysfunction. Finally, expression of the allele called NFH43, bearing less phosphorylation sites than the other allele called NFH44, was shown to be more pathogenic in transgenic mice.
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Larivière, Roxanne. "Transgenic approach to study the role of intermediate filaments in motor neuron disease." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84279.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Many reports lead to the hypothesis that a high axonal neurofilament burden and a large axonal caliber account for the selective vulnerability of motor neurons affected in ALS (Kawamura et al., 1981; Sobue et al., 1981; 1987). Transgenic mice expressing a mutant form of SOD1-linked to familial ALS and having one disrupted allele for each neurofilament gene were generated to address this issue. Despite a 40% reduction in neurofilament content and a decrease of large axonal caliber from 5--9 mum to 1--5 mum, these mice did not show an extended life span, nor did they display an alleviated loss of motor axons. These results do not support the idea that high neurofilament content and large axonal caliber are responsible for the selective vulnerability of motor neurons in ALS.Peripherin, a type III intermediate filament (IF) protein is also expressed in spinal motor neurons, and is present together with neurofilaments in axonal spheroids of ALS patients, suggesting that this protein could be involved in the pathogenesis of ALS. Moreover, mice overexpressing a peripherin transgene develop a late-onset motor neuron death characterized by the presence of IF inclusion bodies (Beaulieu et al., 1999a). In a first attempt to clarify the role of peripherin in ALS, peripherin knockout mice were generated. Peripherin null mice were viable, reproduce normally and did not exhibit overt phenotype. However, they did show a 34% reduction in the number of L5 unmyelinated sensory fibers demonstrating a requirement of peripherin for the proper development of a subset of sensory neurons.
Finally, in order to investigate whether peripherin contributes to the pathogenesis of ALS, mutant SOD1 mice were generated in a peripherin overexpressing background and a peripherin depleted background. Unexpectedly, upregulation or suppression of peripherin expression had no effect on disease onset, mortality and motor neuron loss in mutant SOD1 mice. Taken together, these results provide compelling evidence that peripherin is not a key contributor of motor neuron degeneration associated with toxicity of mutant SOD1.
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Nicholson, Sharon Joycelyn. "Mapping of Loa : a mouse motor deficit gene." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344089.
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Watermeyer, Tamlyn Julie. "Emotional processing and social cognition in Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND)." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/emotional-processing-and-social-cognition-in-amyotrophic-lateral-sclerosis-als--motor-neuron-disease-mnd(e3552e39-2127-40a8-8035-357b66edd75d).html.
Full textAbstract:
Amyotrophic Lateral Sclerosis (ALS) is a debilitating and life–limiting neurodegenerative disorder that causes progressive muscle atrophy and spasticity. A small proportion of ALS patients experience co–morbid Frontotemporal Dementia (FTD). Milder cognitive–behavioural changes have been noted in ALS patients without dementia. In these patients, deficits in executive functioning, language, memory and behaviour have been documented. Recently, changes to emotional processing and social cognition (EMOSOC) in ALS have also been reported, albeit with inconsistent findings. The primary aims of the current thesis were i) to delineate the nature and extent of changes in EMOSOC in ALS and ii) to determine the relationship between such changes and interindividual differences in mood, behaviour, personality, empathy and ALS–related executive dysfunction. The results of the study indicate a profile of predominant executive dysfunction, with relative sparing of EMOSOC in non–demented ALS patients. However, the ALS patients did show impaired performance on a task requiring the attribution of thoughts and feelings to characters from cartoons and vignettes. ALS patients’ performance on EMOSOC tasks was predicted by their performance on tests of executive function, above and beyond mood, behaviour, personality and empathy variables. As a secondary aim, the impact of patients’ cognitive and behavioural changes on ALS caregivers’ outcomes (mood, perceived strain, burden and marital satisfaction) were examined. The data indicated patients’ behavioural dysfunction and functional impairment as key predictors of caregivers’ outcomes. Exploratory analyses revealed differences between patients’ and caregivers’ perceptions of patients’ personality, empathy and behaviour; these differences were associated with caregiver outcomes. In summary, the current thesis characterises the profile of EMOSOC changes in non–demented ALS and highlights the role of ALS–related executive dysfunction in these changes. It also assesses the relative impact of patients’ disease, cognitive and behavioural changes on ALS caregivers.
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Richardson, Katie. "The investigation of oxidative damage to nucleic acids during ageing and motor neuron disease." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/5720/.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder, characterised by the degeneration of upper and lower motor neurons. Multiple mechanisms have been associated with ALS pathology, however the precise molecular events leading to selective motor neuron degeneration have yet to be understood. Prominent neuronal RNA oxidation has been reported during ageing and presymptomatic stage of ALS, with specific transcripts selectively modified during disease, which may contribute towards selective cellular degeneration. Gene expression changes using microarray technology has been widely used to investigate pathways underlying ageing and neurodegenerative disease. The aim of our study was to investigate the gene expression profile of an oxidised fraction of RNA extracted from the anterior spinal cord of normal mice aged six, twelve, and eighteen months. In data presented here, we identify specific classes of genes to be enriched within the oxidised fraction at each age. Furthermore, genes previously linked to the pathogenesis of ALS and normal ageing, such as those involved in RNA processing and transcriptional regulation, are identified as being differentially oxidised in the anterior spinal cord. The presence and distribution of oxidative damage to nucleic acids within an in vivo model of familial ALS and age-matched controls is demonstrated. The predominance of cytoplasmic 8-hydroxyguanosine reactivity within motor neurons supports previous data of RNA susceptibility to oxidative modification in neurodegenerative disease. Investigation of RNA oxidation in an in vitro model of fALS harbouring G93A and H48Q human SOD1 mutations identified prominent levels of RNA oxidation in comparison to controls, which correlated with a reduction in human SOD1 protein expression within these cells. Subsequent work demonstrated the G93A mutation to be the most susceptible to oxidative stress related cellular decline, in terms of mitochondrial bioenergetics, mitochondrial morphology, and cell viability. The heterogeneity of various SOD1 mutations on cellular function is demonstrated.
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Sandoe, Jackson L. "Developing Human Stem Cell Derived Motor Neuron Models of Amyotrophic Lateral Sclerosis." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070028.
Full textAbstract:
Human neurodegenerative disorders are among the most difficult to study. In particular, the inability to readily obtain the faulty cell types most relevant to these diseases has impeded progress for decades. Amyotrophic lateral sclerosis is a late onset neurodegenerative disease in which the upper and lower motor neurons degenerate, leading to paralysis and eventually death. Recent advances in pluripotent stem cell technology now grant access to significant quantities of disease pertinent neurons both with and without predisposing mutations. The two studies described in this thesis demonstrate the feasibility of using MNs, generated from pluripotent stem cell lines harboring known ALS mutations, to establish in-vitro models of the disease. Specifically, we first used gene targeting to establish genetically controlled systems, able to identify causal relationships between a familial ALS mutation and in vitro phenotypes. Next, using transcriptional profiling, we identified novel pathways altered by the mutation and demonstrated functional consequences of these pathways' misregulation. Furthermore, by monitoring the physiology of the pluripotent stem cell derived MNs, we discovered an increased firing rate in the mutant MNs, and identified an FDA-approved drug, retigabine, capable of rescuing this defect. Lastly, to aid in the discovery of additional therapeutic compounds, we combined gene targeting, transcriptional profiling, and a fluorescent reporter human embryonic stem cell line to establish a well-controlled in vitro system capable of identifying genetic modifiers of the phenotypes described herein.
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Valdmanis, Paul Nils. "Genetic analysis of amyotrophic lateral sclerosis and other motor neuron disorders." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111916.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease which results from the degeneration of upper and lower motor neurons in the brainstem, spinal cord and motor cortex. Tragically there is no treatment to prevent ALS. The drug Riluzole acts to delay progression, but only by a month or so in this disease that has a survival length of three to five years. The identification of genes that are mutated in patients with ALS would help devise novel therapeutic strategies as much remains to be discovered about the genetics of ALS. Familial forms of the disease account for only 5-10% of patients. Among these familial cases, about 15-20% are caused by mutations in the zinc/copper superoxide dismutase gene, but the genetic basis of the remaining familial cases and the many sporadic cases continues to be largely unknown.Altogether, the results presented in this thesis came from the use of several strategies to establish the genetic cause of ALS and the related motor neuron disorders like hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). A concerted and collaborative effort was put forth to identify the gene causative for ALS3 on chromosome 18. In addition, a recently reported locus has been confirmed on chromosome 9p for patients that present both ALS and frontotemporal dementia. The major finding involves the discovery of eight mutations in the TARDBP gene in nine patients with sporadic and familial ALS. Furthermore, a large association study evaluated the role of common polymorphisms in the paraoxonase gene cluster in susceptibility to the development of ALS. In the analysis of upper motor neuron diseases, mutations in a novel gene, KIAA0196, were identified for the HSP locus SPG8 on chromosome 8. Finally, the first locus for PLS was discovered on the p-arm of chromosome 4 following genome scan analysis of a large Quebec family with PLS.
These genetic discoveries all contributed novel advances to the field of motor neuron disorders. As more is elucidated regarding the biochemical function of these the proteins encoded by these genes, a more comprehensive picture of ALS and other motor neuron disorders will hopefully emerge.
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Fong, Chung-yan Gardian. "A study of motor neuron disease in the community and in a large multigenerational kindred." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37602263.
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Fong, Chung-yan Gardian, and 方頌恩. "A study of motor neuron disease in the community and in a large multigenerational kindred." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37602263.
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Yazdani, Armin A. "The Smn-Independent Beneficial Effects of Trichostatin A on an Intermediate Mouse Model of Spinal Muscular Atrophy." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30703.
Full textAbstract:
Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.
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Åkerblom, Ylva. "Experiences of pain and associations between pain, disease severity and individual quality of life in people with motor neuron diseases." Licentiate thesis, Uppsala universitet, Institutionen för neurovetenskap, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-396033.
Full textAbstract:
Many people with the incurable and often times fatal motor neuron diseases have pain, but there is lack of knowledge about people’s experiences of living with pain. Further, the correlation between pain and their quality of life is not well understood, and previous studies have not used individual quality of life, namely that people with their own words express what quality of life is. The aim of these studies was to explore the experiences of pain and the association between pain and quality of life in people with MND. Methods: Study I was explorative about the individual experience of pain, while study II was correlational between pain, pain severity, disease severity and IQOL. Study I was qualitative, whereas study II used both qualitative and quantitative analysis. Results and conclusions: People with motor neuron diseases experienced pain to have multiple characteristics and impact. However, the results emphasise that the individual experienced some pain characteristics as difficult and that pain could worsen functions that were already affected by the disease. The experience was also that it could be challenging to manage pain. However, the symptom of pain could pass unnoticed in contacts with healthcare professionals (study I). The three most important areas for individual quality of life in both participants with and without pain were: Social relations, followed by Activities for amusement and relaxations, and Being in the outdoor environment. Individual quality of life was noticed to be good regardless of pain. Pain and pain severity were not found to be associated with satisfaction of individual quality of life in patients with motor neuron diseases, neither was disease severity. The results support previous findings, that strong associations between symptoms of MND and IQoL are not obvious. However, this does not infer that pain in people with MNDs should be neglected and undertreated. On the contrary, it seems to be important for healthcare to pay more attention to pain in people with motor neuron diseases and that pain continuously is measured, individually treated and followed. Regardless of whether persons with MND have pain or not, the results point to the importance of healthcare professionals providing support to not only the patient but also the patient’s family and friends, as well as assisting in various forms of relaxing activities and possibility of being in the outdoor environment.
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Brown-Wright, Sian Heledd. "Investigating metabotropic glutamate receptor 5 (mGlu5) as a novel therapeutic target in motor neuron disease (MND)." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/22583/.
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Oosthuizen, Imke. "Message banking : comparing perceptions of persons with motor neuron disease significant others and speech language pathologists." Diss., University of Pretoria, 2015. http://hdl.handle.net/2263/53453.
Full textAbstract:
Facing the reality of a diagnosis of Motor Neuron Disease (MND) and preparing for the
possibility of losing one s ability to speak is extremely challenging. The aim of this study
was to determine and compare the perceptions of ten persons with MND (PMNDs), 11
significant others (SOs) and 17 speech-language pathologists (SLPs) about message
banking, a process where messages are pre-recorded so as to use them in a speechgenerating
device. A quantitative, non-experimental, multi-group, posttest-only survey
design was used. The 38 participants listened to a short presentation of what message
banking entails and how it is done and then individually completed a questionnaire
about their perceptions. Data was compared between the three participant groups to
investigate the similarities and differences between them. Results indicated that most
PMNDs and SOs reported they had never heard of AAC or message banking. SLPs knew
only a little about AAC. Only 43% of SLPs were currently using AAC strategies for
PMNDs. AAC methods that were most recommended for PMNDs were gestures, letter
boards or communication boards. Participants agreed most with the statement that
message banking was a good idea for PMNDs in general, although only 80% of PMNDs
and 36% of SOs showed an interest in doing message banking for themselves or their
loved one with MND. SLPs showed 100% interest in doing message banking with their
patients with MND. PMNDs ranked messages important for message banking in
descending order namely: social closeness, needs and wants, social etiquette and
sharing information. SOs mostly agreed but thought that messages about needs and
wants were more important to bank than were messages about social closeness. The
SOs also thought that sharing information was more important than social etiquette,
which was different to what PMNDs thought. In conclusion, all participants confirmed
an awareness of AAC and message banking, although participants perception about
AAC and message banking differed somewhat. They also had slightly differing views
about the categories of messages that were important to bank during message banking.Dissertation (MA)--University of Pretoria, 2015.
Centre for Augmentative and Alternative Communication (CAAC)
MA
Unrestricted
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Stevens, James Clement. "An investigation of the behaviour of superoxide dismutase 1 in in-vitro models of motor neuron disease." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/17316/.
Full textAbstract:
Motor neuron disease is an incurable neurodegenerative condition. A proportion of motor neuron disease is inherited in autosomal dominant manner, of which approximately 10% is due to mutations in the enzyme superoxide dismutase 1 (SOD1). The mechanism by which mutant SOD1 selectively kills motor neurons is not understood. Motor neuron disease due to mutant SOD1 has been modelled by the SOD1 transgenic mouse which possesses a SOD^{G93A} transgene array. This mouse develops progressive motor neuron loss, resulting in premature death. The Legs at odd angles (Loa) mouse, which has a missense mutation in the gene encoding cytoplasmic dunein, develops progressive – wild-type, Loa/+, SOD1 ^{G93A} and Loa/SOD1^{G93A}. Surprisingly, Loa/SOD1^{G93A} mice survive significantly longer than their SOD1^{G93A} littermates, thus the presence of a mutation in dynein reduces the toxic effect of mutant SOD1. To gain further understanding of how mutant SOD1 kills motor neurons, the behaviour of mutant SOD1 between neurons of these genotypes was compared. Differences in behaviour of mutant SOD1 between these genotypes may correlate with the observed differences in survival and thereby suggest toxic mechanisms. Methods of tagging SOD1 for live cell imaging were assessed and strategies of transfecting cultured motor neurons with tagged SOD1 evaluated. Lentiviral vectors were used to transduce cultured motor neurons with tagged SOD1. Methods of assessing anterograde axonal transport were evaluated. The localisation and movement characteristics of wild-type and mutant SOD1 were evaluated in wild-type motor neurons. No statistically significant differences were found. The localisation and movement characteristics of mutant SOD1 was evaluated in motor neurons of genotypes wild-type, Loa/+, SOD1^{G93A} and Loa/ SOD1^{G93A}. No statistically significant differences were found. Thus the behaviour of the toxic moiety, mutant SOD1, was not demonstrated to be different between neurons with different survival characteristics.
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Parry, Katherine Elizabeth. "Investigation of the interactions of DVAP-33A, the orthologue of human VAPB." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5538.
Full textAbstract:
Amyotrophic Lateral Sclerosis is the most common type of motor neuron disease, characterized by progressive degeneration of the upper and lower motor neurons. Sufferers present with symptoms of muscle weakness and this quickly develops on to paralysis and finally death due to respiratory failure within 5 years of disease onset. Although the majority of cases are sporadic, about 10% are familial and it is hoped that through the investigation of these few cases a greater understanding of the disease process, the reasons for its delayed onset and vulnerability of motor neurons will be achieved. Recently a novel mutation linked to ALS was discovered in an evolutionary conserved protein named Vesicle associated membrane protein (VAMP) associated protein B (VAPB). VAPB is an integral type II membrane protein localised at the Endoplasmic Reticulum and thought to have a role in protein transport. The orthologue in Drosophila has been shown to be involved in the homeostatic regulation of bouton formation at the Neuromuscular Junction through an association with the microtubule network. To elucidate the mechanism through which this protein causes ALS, Pennetta et al have created a Drosophila model of the disease by expressing the mutated orthologue in the fly. To complement this model, I have undertaken a number of biochemical experiments to look for potential interactors of the VAP proteins. The yeast two hybrid system utilises the yeast GAL4 transcriptional activator to indicate a protein interaction within a yeast cell and can be used to test a cDNA library for interactors. Through this technique a number of interesting binding partners have been found that may play crucial roles in the progression of the disease.
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Scaber, Jakub. "The pathophysiological role of TDP-43 in amyotrophic lateral sclerosis due to C9orf72 mutations." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:c5dd8dcf-c3e0-4ff7-ba9d-bfd3cb9914e8.
Full textAbstract:
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition that affects corticospinal and spinal motor neurons and leads to death within 30 months of symptom onset in half of all cases. It remains incurable and treatment is supportive. The genetic and molecular understanding of ALS has gone through a rapid expansion in recent years, notably with the discoveries of TDP-43, a heterogeneous ribonucleoprotein as a major component of neuronal inclusions in ALS, as well as the discovery of the C9orf72 hexanucleotide expansion as the most common genetic cause of this disease. This first part of this thesis addresses the question of which of the various pathological hallmarks of the C9orf72 Hexanucleotide Repeat Expansion (HRE) in autopsy material correlates best with the clinical presentation. The main finding is that TDP-43 distribution, rather than C9orf72 RNA foci or dipeptide aggregation in the brain, corresponds best with the areas relevant to the clinical subtype of ALS-FTD. Subsequently the role of TDP-43 was investigated in induced pluripotent stem cell derived motor neurons, and no evidence of the hallmarks of TDP-43 dysfunction, were seen in this model of the disease. No mislocalisation is found on immunofluorescence, and biochemical analysis shows no differences in insoluble species between the patient and control cell lines. In the final section, RNA sequencing was used to study the transcriptome of a BAC transgenic mouse carrying a human M337V transgene expressed at low levels, to identify early presymptomatic differences in gene expression. Interestingly, no changes were found in genes known to be associated with ALS through mutations, and the constitutive nuclear functions of TDP-43 in the regulation of splicing was maintained, prior to the emergence of a clinical phenotype in the mouse. This favours a gain of function mechanism for TDP-43 mutations in ALS.
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Iwagaki, Noboru. "Modulation of mammalian spinal motor networks by group I metabotropic glutamate receptors : implications for locomotor control and the motor neuron disease amyotrophic lateral sclerosis." Thesis, University of St Andrews, 2012. http://hdl.handle.net/10023/3023.
Full textAbstract:
The present study examined the role of group I metabotropic glutamate receptors (mGluRs) in mammalian spinal motor networks and investigated the potential role of mGluRs in the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS). Group I mGluR activation was found to modulate locomotor-related activity recorded from ventral roots of in vitro mouse spinal cord preparations. Activation of group I mGluRs led to an increase in the frequency of locomotor-related bursts and a decrease in their amplitude. The cellular mechanisms underlying group I mGluR-mediated modulation were investigated using whole-cell patch-clamp recordings from spinal neurons. Recordings from motoneurons revealed a wide range of effects, some of which were expected to increase motoneuron excitability, such as membrane depolarisation and hyperpolarisation of action potential thresholds. However, the net modulatory effect of group I mGluR activation was a reduction in motoneuron excitability, likely reflecting a reduction in the density of fast inactivating Na+ currents. The activation of group I mGluRs also reduced excitatory synaptic input to motoneurons, suggesting that modulation of motoneuron properties and synaptic transmission both contribute to group I mGluR-mediated reductions in locomotor motoneuron output. Recordings from spinal interneurons revealed a smaller range of modulatory effects for group I mGluRs. The clearest effect on interneurons, membrane depolarisation, may underlie group I mGluR-mediated increases in the frequency of locomotor activity. Finally, the potential role of group I mGluRs in the pathogenesis of ALS was investigated using a mouse model of the disease. Although no major perturbations in group I mGluR-mediated modulation were demonstrated in ALS affected spinal cords, there appeared to be a difference in the intrinsic excitability of spinal interneurons between wild type and ALS affected animals. Together these data highlight group I mGluRs as important sources of neuromodulation within the spinal cord and potential targets for the treatment of ALS.
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CICARDI, MARIA ELENA. "ROLE OF THE PROTEIN QUALITY CONTOL SYSTEM IN MOTOR NEURON DISEASES: THE CASE OF MUSCLE CELLS." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/585905.
Full textAbstract:
Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), are characterized by the progressive loss of motor neurons, and patients die for respiratory failure after the paralysis of voluntary muscle. Muscle system is, thus, highly affected but it is still unclear whether they play a role in disease onset or if they are a secondary target of toxicity. In my PhD period, I analyzed the behaviour in muscle cells of misfolded protein causing neurodegenerative diseases. I found that misfolded protein aggregates also in muscle cells. As a second step I studied the activation of the protein quality control system and its role at basal level in presence of misfolded proteins. I found that autophagy and proteasome are differently involved in the degradation of misfolded proteins in both muscle and motor neurons. Nevertheless, increasing the degradation of misfolded proteins by overexpressing key molecular chaperone or treating cells with autophagy inhibitors rescue the formation of aggregates in both models of disease.
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Rajagopalan, Venkateswaran. "Evaluation of Upper Motor Neuron Pathology in Amyotrophic Lateral Sclerosis by MRI: Towards Identifying Noninvasive Biomarkers of the Disease." Cleveland State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=csu1288020485.
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Gladman, Jordan Tanin. "Investigating the pre-mRNA splicing of the Survival Motor Neuron genes to model the Spinal Muscular Atrophy disease phenotype." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1281365393.
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FALZONE, YURI MATTEO. "Peripheral Nervous System Involvement in Amyotrophic Lateral Sclerosis: from diagnosis to disease understanding and development of novel biomarkers." Doctoral thesis, Università Vita-Salute San Raffaele, 2022. http://hdl.handle.net/20.500.11768/128353.
Full textAbstract:
The mainstay of Amyotrophic lateral sclerosis (ALS) diagnosis is the clinical evaluation, and it can be challenging when its first manifestations overlap with those of ALS mimic disorders (ALSmd). The lack of specific diagnostic test prevents an early diagnosis. The definition of prognosis in ALS is hampered by the heterogeneity of its clinical features, with variability in survival being the most salient feature. Therefore, wet biomarkers are needed to aid clinical decision, track disease progression, and better define disease trajectories. Recent advances highlighted neurofilaments as the most promising biomarkers for ALS. In the first part of our results, we assessed serum phosphorylated neurofilament heavy chain (pNfH) in a large ALS cohort (n=219). pNfH was an independent predictor of survival for ALS and its concentration was heterogenous across the ALS phenotypes, patients with fast disease progression and a predominant upper motor neuron burden showed the highest serum concentration. Subsequently, we performed gene expression and pathways analyses, on 8 motor nerve biopsies of patients with ALS and compared with 7 motor neuropathies as controls, identifying Ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) as a potential candidate biomarker for ALS. Therefore, we tested UCHL1 in an independent large ALS and control cohorts to assess its diagnostic and prognostic performances. At the same time, we also tested serum Neurofilament light chain (NfL) and Glial fibrillary acidic protein (GFAP). In our analysis, UCHL1 resulted not promising as diagnostic biomarkers, conversely, it was an independent prognostic factor, proving itself helpful in the stratification of survival for patients with lower NfL levels. NfL consistently reached the best diagnostic performance for ALS showing almost optimal performance in discriminating ALS from healthy controls and other neurodegenerative diseases. Conversely, the diagnostic yield in distinguishing ALS from ALSmd was lower with specificity decreasing to 78.0%. As similarly observed for the pNfH, NfL concentrations were heterogenous across the ALS phenotypes and higher concentrations were detected in patients with a fast disease progression and a predominant upper motor neuron burden. Serum GFAP, a known marker of astrogliosis, differs among cognitive phenotypes, namely ALS with concomitant cognitive impairment or FTD had higher levels compared with ALS with normal cognition. Therefore, GFAP might be instrumental in tracking the occurrence of cognitive decline in ALS.La diagnosi della Sclerosi Laterale Amiotrofica (SLA) è principalmente basata sulla valutazione clinica e può essere talvolta problematica soprattutto quando le manifestazioni cliniche sono sovrapponibili a quelle di malattie neurologiche che possono mimare la SLA. L’assenza di test diagnostici specifici limitano la possibilità di formulare la diagnosi in fase precoce di malattia. La definizione della prognosi dei malati di SLA è limitata dall’eterogeneità fenotipica della malattia e dalla sua intrinseca variabilità inter-individuale. Alla luce di tali considerazioni, eventuali biomarcatori potrebbero essere utili nel guidare decisioni diagnostiche, terapeutiche e di valutazione prognostica. Recenti evidenze di letteratura hanno individuato i neurofilamenti a catena leggera e pesante (NfL e pNfH) come i due più promettenti biomarcatori per la SLA. Nella prima parte del nostro studio, abbiamo valutato la concentrazione sierica dei pNfH in una numerosa cohorte di pazienti affetti da SLA (n=219). I nostri risultati evidenziano che in analisi multivariata i pNfH sono risultati fattori indipendenti nel predizione della sopravvivenza dei pazienti. Inoltre, la concentrazione dei pNfH è risultata eterogenea nella popolazione SLA; i valori più elevati sono stati riscontrati nei pazienti con prevalente interessamento del I neurone di moto e concomitante elevata velocità di progressione di malattia. In seguito, abbiamo effettuato un’analisi di espressione genica e sequenziale analisi di pathways su 8 nervi motori ottenuti da pazienti SLA e 7 da pazienti con neuropatia motoria considerati come controlli. Da tale analisi abbiamo indentificato UCHL1 come una proteina potenzialmente promettente come biomarcatore per la SLA. Abbiamo analizzato i valori plasmatici di tale proteina esplorandone le potenzialità diagnostiche e prognostiche, in parallelo abbiamo misurato anche i valori plasmatici di NfL, GFAP e tTAU in coorte di pazienti SLA (n=143) e di controllo. Nel nostro studio UCHL1 non si è confermato un promettente biomarcatore per la diagnosti di SLA, tuttavia è risultato essere un fattore determinante per la definizione prognostica dei pazienti stratificando ulteriormente la prognosi dei pazienti SLA con bassi valori plasmatici di NfL. Dalle nostre analisi si conferma che NfL come i migliori biomarcatori diagnostici sia per discriminare i pazienti SLA dai controlli sani (HC) e da pazienti affetti da altre malattie neurodegenerative (DEG). Tuttavia, la performance diagnostica degli NfL nel distinguere le SLA dalle patologie SLA mimic è sensibilmente ridotta con una sensibilità del 78%. Come osservato per i pNfH, anche i livelli di NfL sono più elevati in pazienti con prevalente interessamento del I neurone di moto e concomitante elevata velocità di progressione di malattia. I livelli plasmatici di GFAP riflettono i diversi gradi di interessamento cognitivo nei pazienti affetti da SLA, infatti pazienti SLA con concomitante demenza fronto-temporale o interessamento cognitivo presentavano più elevati valori di GFAP rispetto a pazienti SLA con selettivo interessamento motorio. Alla luce di questi dati GFAP potrebbe essere un biomarcatore utile per tracciare il declino cognitivo dei pazienti con SLA.
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Grasso, Irene. "Psychological and neuropsychological advances in Motor neuron diseases: Amyotrophic lateral sclerosis and X-linked spinal-bulbar muscular atrophy." Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3424187.
Full textAbstract:
Motor neuron disease (MND) is a heterogeneous family of neurodegenerative diseases, rare, characterized by an early involvement of motor neurons and can be hereditary or sporadic, including Amyotrophic lateral sclerosis (ALS) and X-linked spinal-bulbar muscular atrophy (SBMA).
Three studies will be briefly presented below, with the aim of developing an understanding of psychological and neuropsychological aspects in these diseases.
In Chapter 3 is presented a retrospective study with the aim to verify whether the presence of cognitive impairment in ALS patients (according to the classification proposed by Phukan et al., 2012) may have an impact on the degree of disease progression in terms of motor decline. Up to date, in literature the debate about the influence of cognitive impairment on survival in ALS patients is still ongoing and results are conflicting. In summary, after 6 or 12 months follow up we observed the same degree of disease progression both in patients with presence or absence of cognitive impairment.
In Chapter 4 it is presented a pilot study with the aim to investigate the applicability and efficacy of a hypnotic treatment on the physical and psychological well-being perceived by ALS patients, considering also the indirect effect on the well-being on caregivers. ALS implies an inevitable and devastating psychological impact and this study represent, even if at a preliminary level, the first application of a protocol of psychological intervention with evidence of efficacy in ALS patients.
In Chapter 6, it is presented a study with the aim to investigate the neuropsychological and psychological profile in patients with SBMA, poorly characterized in the recent literature. In summary, in contrast with the previous literature, executive functioning seems to be apparently preserved in patients with SBMA; nevertheless patients seem to have a specific dysfunction on the cognitive component of the Theory of Mind (ToM), while the affective component seems to be preserved.La Malattia del motoneurone (MND) è una famiglia eterogenea di malattie neurodegenerative, rare, caratterizzate da un precoce coinvolgimento dei motoneuroni e possono essere ereditarie o sporadiche, e includono tra le altre la Sclerosi laterale amiotrofica (SLA) e l'Atrofia muscolare spinobulbare (SBMA). Sono stati condotti tre studi, brevemente presentati di seguito, con l'obiettivo di sviluppare la comprensione degli aspetti psicologici e neuropsicologici nelle suddette malattie. Nel Capitolo 3 viene presentato uno studio retrospettivo con l'obiettivo di verificare se la presenza di deficit cognitivo in pazienti affetti da SLA (in accordo con la classificazione proposta da Phukan et al., 2012) possa avere un impatto sul grado di progressione di malattia in termini di declino motorio, ambito nel quale i dati presenti in letteratura sono contrastanti. In sintesi, a distanza di 6 o 12 mesi dal baseline si osserva lo stesso grado di progressione di malattia sia in presenza sia in assenza del deficit cognitivo. Nel Capitolo 4 viene presentato uno studio pilota con l'obiettivo di indagare l'applicabilità e l'efficacia di un trattamento ipnotico sul benessere psicologico e fisico percepito dai pazienti, valutando inoltre l'effetto indiretto sul benessere dei familiari. Nonostante la SLA implichi un inevitabile e devastante impatto psicologico il presente studio rappresenterebbe, anche se a un livello preliminare, la prima applicazione di un protocollo di intervento psicologico con prove di efficacia in pazienti affetti da SLA. Nel Capitolo 6 viene presentato uno studio con l'obiettivo di indagare il profilo neuropsicologico e psicologico nei pazienti affetti da SBMA, ad oggi poco investigato con riferimento alla recente letteratura. In sintesi, a differenza degli studi presenti in letteratura, il funzionamento esecutivo sembra essere apparentemente preservato nei pazienti affetti da SBMA; ciononostante i pazienti sembrano avere una specifica disfunzione a carico della componente cognitiva della Teoria della Mente (ToM), mentre risulta preservata la componente affettiva.