A Hypothesis About Alzheimer’s Disease, Its Cause and …
T1 - The cholinergic hypothesis of neuropsychiatric symptoms in Alzheimer's disease
Alzheimer's disease - Wikipedia
The hallmarks of Alzheimer’s disease involve a loss of neurons, the shrinkage of large cortical neurons and synapses in the brain over a period of time. The result is an eventual degeneration in the cingulate gyrus, temporal and parietal lobes, the frontal cortex, brainstem nuclei and locus coruleus. In addition, the disease is characterized amyloid plaques and neurofibrillary tangles concentrated in vulnerable areas in the brain and are visible under a microscope. The plaques are made up fibrous proteins known as β-amyloid, diffuse plaques (poorly defined amyloids) and burnt-out plaques containing an isolated amyloid core. These plaques form clumps in the cortex and are hypothesized to result in a cascade of events leading to cell dysfunction and necrosis. (Yaari, 2007) Even with increasing evidence to suggest this, it is not a view supported by all. (Hardy, 1991). Neurofibrillary tangles are associated with tau, a microtubule protein that has become hyperphosphorylated and clustered together with others of its kind. Though these plaques and tangles are not only seen Alzheimer’s sufferers, those who do suffer from the disease exhibit a much larger prevalence of them than one who does not suffer from it. (Bouras, 1994).
N2 - A variety of neuropsychiatric symptoms occur in Alzheimer's disease (AD) including agitation, psychosis, depression, apathy, disinhibition, anxiety, purposeless behavior, and disorders of sleep and appetite. Neuropsychiatric symptoms have been related to cholinergic deficiency and improve after treatment with cholinomimetic agents. Cholinergic drugs are unique among psychotropic agents in exerting disease-specific and broad-spectrum effects. These observations provide the basis for the cholinergic hypothesis of the neuropsychiatric symptoms of AD, suggesting that the cholinergic deficit of AD contributes to the neuropsychiatric symptoms of AD and that cholinomimetic therapy ameliorates the behavioral disturbances accompanying AD.
Alzheimer disease, Alzheimer's: ..
AB - The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.
Scientific evidence collected over the past four decades suggests that a loss of cholinergic innervation in the cerebral cortex of patients with Alzheimer's disease (AD) is an early pathogenic event correlated with cognitive impairment. This evidence led to the formulation of the "cholinergic hypothesis of AD" and the development of cholinesterase inhibitor therapies. Although approved only as symptomatic therapies, recent studies suggest that long-term use of these drugs may also have disease-modifying benefits. A Cholinergic System Workgroup reassessed the role of the cholinergic system on AD pathogenesis in light of recent data, including neuroimaging data charting the progression of neurodegeneration in the cholinergic system and suggesting that cholinergic therapy may slow brain atrophy. Other pathways that contribute to cholinergic synaptic loss and their effect on cognitive impairment in AD were also reviewed. These studies indicate that the cholinergic system is one of several interacting systems failures that contribute to AD pathogenesis.
Alzheimer's disease (AD), also referred to simply as Alzheimer's, ..
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the " hypothesis" and suggests that AD begins as a deficiency in the production of the . The medications that treat acetylcholine deficiency have served to only treat symptoms of the disease and have neither halted nor reversed it. The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholingeric effects have been proposed to initiate large-scale aggregation leading to generalized neuroinflammation.
Research after 2000 includes hypotheses centered on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions are lightheartedly described as "ba-ptist" and "tau-ist" viewpoints in scientific publications by Alzheimer's disease researchers. "Tau-ists" believe that the abnormalities initiate the disease cascade, while "ba-ptists" believe that deposits are the causative factor in the disease. The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss; however, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.
The MEND™ protocol for Alzheimer’s disease: …
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Treatment of Alzheimer's Disease: The Legacy of the Cholinergic Hypothesis, Neuroplasticity, and Future Directions
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Treatment of Alzheimer’s Disease: The Legacy of the Cholinergic Hypothesis, Neuroplasticity, and Future Directions
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Pathogenesis of Alzheimer's disease--beyond the cholinergic hypothesis: discussion paper ..
The Cholinergic Hypothesis of Neuropsychiatric Symptoms …
AB - Alzheimer's disease (AD) is a highly complex neurodegenerative disorder of the aged that has multiple factors which contribute to its etiology in terms of initiation and progression. This review summarizes these diverse aspects of this form of dementia. Several hypotheses, often with overlapping features, have been formulated to explain this debilitating condition. Perhaps the best-known hypothesis to explain AD is that which involves the role of the accumulation of amyloid-β peptide in the brain. Other theories that have been invoked to explain AD and summarized in this review include the cholinergic hypothesis, the role of neuroinflammation, the calcium hypothesis, the insulin resistance hypothesis, and the association of AD with peroxidation of brain lipids. In addition to summarizing each of the theories that have been used to explain the structural neural changes and the pathophysiology of AD, the potential role of melatonin in influencing each of the theoretical processes involved is discussed. Melatonin is an endogenously produced and multifunctioning molecule that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD. Production of this indoleamine diminishes with increasing age, coincident with the onset of AD. In addition to its potent antioxidant and anti-inflammatory activities, melatonin has a multitude of other functions that could assist in explaining each of the hypotheses summarized above. The intent of this review is to stimulate interest in melatonin as a potentially useful agent in attenuating and/or delaying AD.
The Cholinergic Hypothesis of Neuropsychiatric Symptoms in ..
One of the older theories, the cholinergic hypothesis states that Alzheimer’s associated brain tissue degradation is a result of the deficiency in the neurotransmitter acetylcholine. Research now shows that there isn’t a causational relationship acetylcholine levels and the onset of Alzheimer’s disease. It is shown, however, that lower levels of acetylcholine are present in patients with the disease and this may be due to brain tissue damage. In the recent past, the neurotransmitter has been proposed to be a potential causal agent in the formation of aggregates and neuroinflammation. (Shen, 2004)
The Cholinergic Hypothesis of Neuropsychiatric ..
The biochemistry or course of actions that results in Alzheimer’s disease is not yet definite. Many hypotheses have been established over the years in order to explain the phenomenon. Of all of the existing theories, three have gained ample recognition and support in comparison to the rest. Before examining the theories below, it is important to note that there is no causational link clearly identified in the literature. The three most popular hypotheses include: Amyloid Hypothesis, Cholinergic hypothesis and Tau hypothesis.
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