1,721,159 research outputs found
Dementia
No full textDementia is a general term for a number of progressive, organic brain diseases affecting around half a million people in England alone. Most neurodegenerative diseases that lead to dementia are characterized by processes that result in the aberrant polymerization of proteins, and a proportion of subjects with these diseases develop dementia as a direct result of the presence of mutations or polymorphisms in genes that influence these processes. The most common cause of dementia, and the best studied, is Alzheimer’s disease. Other important causes include vascular dementia; dementia with Lewy bodies and frontotemporal dementia. Management of dementia is largely focussed on helping carers to cope with the increase in physical dependence of patients as the disease progresses or with the emergence of troublesome neuropsychiatric symptoms. Current pharmacological treatments are based on the neurochemical changes that are found in these diseases. Cholinesterase inhibitors offer some help in ameliorating the inevitable cognitive decline found in Alzheimer’s disease and may have some role in the treatment of dementia with Lewy bodies. However, the treatment of neuropsychiatric symptoms in dementia is still largely empirical and is hampered by either limited efficacy or troublesome side effects.<br/
Genotype and phenotype in Alzheimer's disease
No full textBackground: patients with Alzheimer's disease show a wide variation in clinical phenotype. Genetic research has been largely concerned with the role of mutations or common variants as risk factors for the disease. Do genetic factors also influence clinical phenotype?Aims: to examine the evidence that genetic factors influence the clinical expression of the disease in addition to influencing risk.Method: a selective review was made of the key literature.Results: mutations in three genes, coding for amyloid precursor protein, presenilin-1 and presenilin-2, and a common variation ({epsilon}4) in another gene, APOE, have been shown to lead to an earlier development of the disease. More recently, genetic association and twin studies have suggested a role for genetic factors in the development of other aspects of clinical phenotype, notably the appearance of non-cognitive symptoms.Conclusions: in Alzheimer's disease genetic variation influences a number of aspects of clinical phenotype
Dementia
No full text‘Dementia’ is an umbrella term for a number of progressive, organic brain diseases that affect approximately 850,000 people in the UK. Most neurodegenerative diseases leading to dementia are characterized by processes that result in the aberrant polymerization of proteins. A small proportion of individuals with these diseases develop dementia as a direct result of mutations or polymorphisms in genes influencing these processes. The most common cause of dementia is Alzheimer's disease. Other important causes include vascular dementia, dementia with Lewy bodies and fronto-temporal dementia. The management of dementia largely focuses on helping patients and families to cope with increasing care needs as the disease progresses, and with the emergence of troublesome neuropsychiatric symptoms. Current pharmacological treatments are based on the neurochemical changes that are found in these diseases. Cholinesterase inhibitors and N-methyl-d-aspartate receptor antagonists offer some help in ameliorating the inevitable cognitive decline found in Alzheimer's disease. However, the treatment of neuropsychiatric symptoms in dementia is still largely empirical and is hampered by either limited efficacy or troublesome adverse effects
Dementia
No full textDementia is a general term for a number of progressive, organic brain diseases affecting approximately 670,000 people in the UK. Most neurodegenerative diseases leading to dementia are characterized by processes that result in the aberrant polymerization of proteins, whereas a small proportion of individuals with these diseases develop dementia as a direct result of mutations or polymorphisms in genes influencing these processes. The most common cause of dementia, and the best studied, is Alzheimer's disease. Other important causes include vascular dementia, dementia with Lewy bodies and fronto-temporal dementia. The management of dementia largely focuses on helping carers to cope with the increase in patients' physical dependence as the disease progresses and with the emergence of troublesome neuropsychiatric symptoms. Current pharmacological treatments are based on the neurochemical changes that are found in these diseases. Cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists offer some help in ameliorating the inevitable cognitive decline found in Alzheimer's disease. However, the treatment of neuropsychiatric symptoms in dementia is still largely empirical and is hampered by either limited efficacy or troublesome adverse effects.</p
Role of infection in the pathogenesis of Alzheimer's disease: implications for treatment
No full textWhile our understanding of the neuropathology of Alzheimer's disease continues to grow, its pathogenesis remains a subject of intense debate. Genetic mutations contribute to a minority of early-onset autosomal dominant cases, but most cases are of either late-onset familial or sporadic form. CNS infections, most notably herpes simplex virus type 1, Chlamydophila pneumoniae and several types of spirochetes, have been previously suggested as possible aetiological agents in the development of sporadic Alzheimer's disease but with little consistent evidence. However, peripheral infections may have a role to play in accelerating neurodegeneration in Alzheimer's disease by activating already primed microglial cells within the CNS. Potential pharmacological interventions could aim at modification of this peripheral inflammatory response through targeting various agents involved in this inflammatory pathway. However, benefit could also be gained clinically through the meticulous detection, treatment and prevention of infections in individuals either alone or in combination with anti-inflammatory therapy
The Cromwellian 'Other House' and the search for a settlement, 1656-1659
Full text linkThis thesis seeks to illuminate a blind spot in the scholarship of the later Cromwellian Protectorate by focusing on an intriguing innovation in the parliamentary constitution of 1657 – the creation of an upper chamber or "Other House". The Other House may have filled the void left vacant by the defunct House of Lords, but it did not necessarily mean that the Protectorate was backsliding its way towards the ancient constitution of King, Lords and Commons. Although many aspects of ceremony and procedure remained exactly the same as its predecessor, its functions were reformulated and its membership was significantly different. The life peers nominated by Oliver Cromwell to sit there were politically, religiously, socially and geographically diverse. Yet, Cromwell's attempt to nominate a chamber that would please all sides ultimately ended up pleasing nobody; instead of bringing definition to the constitutional arrangement, his choices simply muddied the waters further. The resulting mood was one of apathy among civilian Cromwellian MPs in the second session of the second Protectorate Parliament towards both the Other House and the settlement as a whole. More importantly, the Other House was never a bulwark for the military Cromwellians; it did not institutionalise the army's position within the constitution. Although this posed no immediate problem under the Protectorate of Oliver Cromwell, it came to the fore following the succession of his conservative-minded son Richard. When the Commons and Protector united behind an anti-military programme in April 1659, the military Cromwellians found themselves outnumbered and outmanoeuvred in the Other House. Unable to protect their interests by constitutional means, the military men turned to their ultimate source of strength – the army. In forcing the Protector to dissolve Parliament, they undermined completely the constitutional arrangement and effectively sealed the end of the Protectorate regime
Microglial priming in neurodegenerative disease
No full textUnder physiological conditions, the number and function of microglia-the resident macrophages of the CNS-is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state-a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration<br/
Inflammation and dementia: Using rheumatoid arthritis as a model to develop treatments?
No full textDementia is a major international public health problem which looks set to grow as the ageing population increases. Despite large amounts of investment there has been relatively little progress in developing new therapies to combat this. There is a growing body of evidence that both local and systemic inflammation are important in dementia; with cerebral inflammation occurring secondarily to beta-amyloid plaques, raised levels of serum inflammatory molecules and cytokines being present in Alzheimer's disease patients and systemic inflammation being associated with cerebral microvasculature disease in vascular dementia. Observational studies had suggested that non-steroidal anti-inflammatory drugs may reduce the risk of dementia, but subsequent interventional studies have been disappointing. More recently some observational studies have suggested a protective effect from conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS) and tumour necrosis factor inhibiting (TNFi) biological therapies. Treatments for inflammatory rheumatic diseases have previously been repurposed and used successfully in other diseases, such as TNFi for inflammatory bowel disease. There are also studies looking at the use of csDMARDs such as methotrexate to improve outcomes after cardiovascular events. Ongoing interventional trials are currently looking at whether therapies designed to treat inflammatory and autoimmune diseases have the potential to be used to treat dementia.</p
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