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Over the past ten years, there has been an increasing recognition that syndromes of frontotemporal dysfunction (FTD) are a common occurrence in patients with amyotrophic lateral sclerosis (ALS). Such syndromes may be present in as many as 60% of patients with ALS. Conversely, the occurrence of motor neuron dysfunction in patients with clinically pure frontotemporal dementia is increasingly recognized. This suggests that to some extent there are overlapping syndromes in which both ALS and FTD occur within the same individual. This volume summarizes the advances in our understanding of these two disorders, as well as the potential relationship between the two. Key topics include advances in our ability to clinically describe the frontotemporal syndromes, preclinical detection, neuroimaging, and genetics. The exploding field of new markers in neuropathology is examined, as is the role of new genetic mutations in DNA/RNA transport systems. This book is the essential reference text for this topic, and will be of interest to neurologists and neurological trainees with a clinical or research interest in the FTDs or ALS, neuropsychologists, neuropathologists, and researchers.
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) are two rare but devastating neurodegenerative diseases that share pathological features and genetic factors. A central question in both diseases is the role of the RNA-binding proteins transactive response DNA-binding protein 43kDa (TDP-43) and fused in sarcoma (FUS). These proteins play a vital role in RNA regulation in all cells but in diseased neurons they alter their cellular localisation to form potentially pathogenic aggregates. This process can be linked to rare genetic mutations in the TARDBP and FUS genes, although most cases of ALS and FTD have no known genetic cause. My work uses the revolutionary technology of RNA sequencing to measure and compare gene expression and RNA splicing in different cellular and animal models of sporadic and genetic disease. Here I present the results of four studies that investigate the biology of TDP-43 and FUS, assessing both their normal cellular roles and the impact of rare disease-causing mutations. In these projects I analyse RNA sequencing data to discover novel gene expression and RNA splicing phenomena. This includes the repression of cryptic splicing by TDP-43 but not FUS, the progressive downregulation of mitochondrial and ribosomal transcripts in a mouse model of FUS ALS, a gain of splicing function by TDP-43 mutations affecting constitutive exon splicing, and widespread changes in intron retention caused by FUS knockout or aggressive FUS mutations. I also discover a novel mechanism for how FUS might regulate its own translation. This work expands on what is currently known about the roles in RNA regulation for TDP- 43 and FUS and provides new avenues for understanding both the causes and progression of ALS and FTD.
Amytrophic Lateral Sclerosis (ALS or motor neurone disease) is a progressive neurodegenerative disease that can cause profound suffering for both the patient and their family. Whilst new treatments for ALS are being developed, these are not curative and offer only the potential to slow its progression. Palliative care must therefore be integral to the clinical approach to the disease. Palliative Care in Amyotrophic Lateral Sclerosis: From diagnosis to bereavement reflects the wide scope of this care; it must cover not just the terminal phase, but support the patient and their family from the onset of the disease. Both the multidisciplinary palliative care team and the neurology team are essential in providing a high standard of care and allowing quality of life (both patient and carer) to be maintained. Clear guidelines are provided to address care throughout the disease process. Control of symptoms is covered alongside the psychosocial care of patients and their families. Case studies are used to emphasise the complexity of the care needs and involvement of the patient and family, culminating in discussion of bereavement. Different models of care are explored, and this new edition utilizes the increase in both the evidence-base and available literature on the subject. New topics discussed include complementary therapies, personal and family experiences of ALS, new genetics research, and updated guidelines for patient care, to ensure this new edition remains the essential guide to palliative care in ALS.
Though considerable amount of research, both pre-clinical and clinical, has been conducted during recent years, Amyotrophic Lateral Sclerosis (ALS) remains one of the mysterious diseases of the 21st century. Great efforts have been made to develop pathophysiological models and to clarify the underlying pathology, and with novel instruments in genetics and transgenic techniques, the aim for finding a durable cure comes into scope. On the other hand, most pharmacological trials failed to show a benefit for ALS patients. In this book, the reader will find a compilation of state-of-the-art reviews about the etiology, epidemiology, and pathophysiology of ALS, the molecular basis of disease progression and clinical manifestations, the genetics familial ALS, as well as novel diagnostic criteria in the field of electrophysiology. An overview over all relevant pharmacological trials in ALS patients is also included, while the book concludes with a discussion on current advances and future trends in ALS research.
This practical guide to the diagnosis of neurodegenerative diseases discusses modern molecular techniques, morphological classification, fundamentals of clinical symptomology, diagnostic pitfalls and immunostaining protocols. It is based on the proteinopathy concept of neurodegenerative disease, which has influenced classification and provides new strategies for therapy. Numerous high-quality images, including histopathology photomicrographs and neuroradiology scans, accompany the description of morphologic alterations and interpretation of immunoreactivities. Diagnostic methods and criteria are placed within recent developments in neuropathology, including the now widespread application of immunohistochemistry. To aid daily practice, the guide includes diagnostic algorithms and offers personal insights from experienced experts in the field. Special focus is given to the way brain tissue should be handled during diagnosis. This is a must-have reference for medical specialists and specialist medical trainees in the fields of pathology, neuropathology and neurology working with neuropathologic features of neurodegenerative diseases.
Book 9 focuses on a new dementia type, LATE, mistaken as Alzheimer's disease until now.LATE stands for Limbic-predominant age-related TDP-43 encephalopathy, the protein buildup responsible for this dementia. This book is organic, like the series, meaning we never consider our books as finished. Science evolves, which is why our books go through continuous updates. Since LATE is a new dementia classification, we expect continuous further information to emerge. Watch Amazon alerts for potential digital updates. We provide free digital copies on all paperback purchases, so everybody receives free updates.
Distils the most valuable discoveries in dementia research into clear, insightful chapters written by international experts.
Amyotrophic lateral sclerosis (ALS) is fatal neurodegenerative disease for which there is no cure. The only treatment available extends survival by only a matter of months. There are over 20 genes that are known to cause ALS. Over half of the ALS cases with a family history of disease (FALS) can be explained by mutations in known ALS genes with hexanucleotide repeat expansions in C9ORF72 accounting for 40% of families. However roughly 90% of cases have no family history of disease (sporadic ALS or SALS) and a much smaller proportion (10%) of these cases can be explained by mutations in known ALS genes. Understanding the genetic factors that cause ALS or influence its progression will help us understand the cellular pathways involved in disease and identify potential therapeutic targets. We used a pooled-sample sequencing approach to identify mutations in 17 ALS genes in a cohort of FALS and SALS patients to investigate the contribution of these genes to SALS, including the role of rare variants and the effect of mutations in multiple ALS genes in an individual. We identified potentially pathogenic mutations in 64.3% of familial and 27.8% of sporadic subjects. 3.8% of subjects had mutations in more than one ALS gene and these individuals on average had onset 10 years earlier than those with mutations in only one ALS gene (p=0.0046). There were no individual rare variants that were significantly associated with sporadic ALS, but rare variants in SOD1 were cumulatively more common in SALS subjects. In addition we investigated the genetic background and stability of C9ROF72 repeat expansions in ALS. The presence of a risk haplotype shared between all expansion-carriers led to the prevailing idea of a founder expansion event, however this shared haplotype also supports the hypothesis of a genetic background that is more prone to expansion. We identified a rare variant rs147599399 on this genetic background that is present in some expansion carriers and some non-expansion carriers, indicating that the expansion arose on at least two separate occasions. This raises the possibility that C9ORF72 repeat expansions in sporadic ALS could be the result of de novo expansions on the risk haplotype. Furthermore we showed that expansion carriers with rs147599399 minor allele had longer survival than expansion carriers without the SNP (p=0.00047), indicating that the genetic background surrounding the C9ORF72 influences the effects of the expansion. We performed Southern blotting to explore the size and stability of C9ORF72 repeat expansions. There was a high degree of somatic instability and instability in transmissions between families. There was no difference between expansion sizes in symptomatic and asymptomatic expansion carriers in families an there was no correlation between expansion size in any patient tissues and any clinical characteristics. These results need to be confirmed in a larger sample cohort, but suggest that expansion size alone doesn{u2019}t determine pathogenicity of C9ORF72 repeat expansions. Lastly we examined the candidate gene TREM2 as a risk factor for ALS. This gene is involved in regulation of microglial activity, which is a known component of ALS pathogenesis, and the rare variant p.R47H was recently associated with risk Alzheimer{u2019}s disease. We found that the same p.R47H variant was significantly associated with ALS in our cohort and that expression of TREM2 was increased in ALS patients and SOD1 mutant mice compared to controls. A variant in the related gene TREML4 was marginally associated with ALS, but the effect of this variant is unknown. Mutations in the TREM genes provide a genetic link between to the neuro-inflammatory component of ALS and suggest other genes involved in microglial activation are good candidates for novel variant identification.