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Emerging Role Norepinephrine In Cognitive

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Emerging Role Norepinephrine In Cognitive Question: Discuss About The Emerging Role Norepinephrine In Cognitive.   Answer: Introduction Alzheimer’s disease is the most common type of brain dementia that causes in ageing and that causes cognitive damage. Initially the Alzheimer’s disease may notice only a mild confusion or difficulties in remembering. Management is distinctively different from that of some common forms of dementia. The AD subspecialists are able to distinguish the steps of the cognitive decline by recognizing the histopathological features of the brain.   Pathophysiology  The defined histopathological feature defining AD are the extracellular amyloid plaques and the presence of the intracellular neurofibrillary tangles. Recently the recognized histopathologic feature included synaptic degradation, aneuploidy and the hippocampal neuronal loss. The diagnosis of the AD is associated with the tallying of the plaques and the tangles with the histopathologic diagnostic standards. Some of the early symptoms of the disease is short term memory loss with confusion with space and time, impairment of the judgment, difficulty in planning, disturbances in the personality and hence social withdrawal and some neurologic difficulties such as impairment of speech, sensory problems, or problems related to expression of thoughts. The progression of the Alzheimer’s disease takes place slowly in five stages- the preclinical stages, the mild cognitive impairment (MCI), moderate dementia due to AD, and severe dementia. Stages Of AD The preclinical stage- AD develops long before the manifestation of the symptoms. In the preclinical stage there would be no symptoms. This stage can last for years and may for even decades. Although no symptoms can be observed but the new imaging techniques can identify the deposits of the amyloid beta proteins in the brain cells. The preclinical AD begins at the entorhinal cortex, that connects the hippocampus which is responsible for the formation of the memory (Morrison & Lyketsos, 2005). Several studies have shown that neuronal loss may begin earlier than the onset of the clinical symptoms. With the atrophy of the brain, the cerebrospinal fluid fills in the space previously filled by the neurons. Mild cognitive impairment (MCI) is a special type of memory loss that does not necessarily impair the daily functioning of the person but can cause short term memory loss. In mild to moderate AD, the patients face more loss in memory (such as challenges in recalling the names or confusion regarding a particular place), reduction in the ability to process the complex thoughts (such as difficulties in calculation or preparing a meal) and in some cases mild personality or change in the mood. In this stage the brain atropy spreads to the other parts of the cerebral cortex (Jacobs et al., 2012). The severe AD is characterized by the total memory loss, severe cognitive impairment, blurred speech, severe behavioral symptoms (Morrison & Lyketsos, 2005). The parts of the brain that are responsible for the control of the speech, reasoning and processing of the conscious thoughts are gradually affected. With time and severity of the condition there occurs more neuronal loss leading to the memory loss, seizures, weight loss, incontinence, non-recognition of the peers and the loved ones.   Degenerative Processes Occurring In Alzheimer’s Disease AD is featured by 3 neuropathologic hall marks, such as the extracellular plaques consisting of the β-amyloid proteins or the plaques, the neurofibrillary tangles (NFTs) and degeneration of the neuronal cells (Morrison & Lyketsos, 2005). As stated by Swerdlow, (2007) neurofibrillary plaques are present in other forms of dementia but in AD the NFTs and the plaques are localized within some particular regions of the brain that is associated with the clinical symptoms. According to the researches the Beta amyloid plaques plays the crucial role in the progression of the AD. Amyloid Plaque Hypothesis Amyloid plaques are lumps of insoluble proteins that are generated by the normal cleavage of the amyloid precursor proteins (APP). The APP is normally cleaved by the secretase family of enzymes. In AD the γ-secretase cleaves the peptide at a wrong site resulting in the 42 amino acid peptide known as amyloid beta that is not soluble and are capable of forming clumps. Jacobs et al., (2012) have stated that three genes have been found to be linked with the pathogenesis of the AD, the APP, PS1 [presenilin 1], and PS2, located in the chromosome 21, has been found to be linked with the formation of the amyloid plaques. Interestingly it has been found that people suffering from Down’s syndrome possess these 21-3 copies of the chromosome (Morrison & Lyketsos, 2005). This results in the death of the neuronal cells. After the formation of the plaque occurs the hyper-phosphorylation of the tau proteins. Another important pathology related to AD is the loss of the cholinergic neurons.  PS1 and the PS2 are the genes that codes for the catalytic subunit of γ-secretase. In the histological staining of the human brain neurofibrillary tangles are seen. As opposed by Nelson et al., (2012), the NFTs and no the amyloid-b plaques correlates with the degree of cognitive impairment in the AD. Other clinic-pathological studies have discovered that it is not the density and but the extent of the NFTs linked with the ante-mortem cognitive status.  It has been found that the NFTs in the temporal lobe is associated with low episodic memory.  The NFTs are generated from the destruction of the neuronal microtubules caused by the alteration of the support proteins tau (Swerdlow, 2007). In general the microtubules are the main components of the neuronal cells as they help in the transmission of the neuronal messages. In AD the phosphorylation of the tau proteins occur destroying the bonds of the microtubules and disrupting their normal structure. Neuropathological survey and in vivo studies have shown linkage between the tau pathology and the cognitive impairment. However it is also related to the pathophysiology of the amyloid plaques and neuronal loss. The growing evidences have suggested that along with the accumulation of the fibrillar amyloid-β peptides, the tau proteins also form aggregates (Bejanin et al., 2013). The spatial distribution of the Tau protein has been associated with the cognition. Reactive Oxygen Species Lushchak, (2014), have emphasized on the oxidative stress hypothesis behind the progression of AD. The Aβ protein causes the lipid peroxidation in the neurons generating reactive oxygen species that reacts with the other macromolecules for achieving a stable conformation. The reactive oxygen species forms a molecular bond throwing a high energy electron (Lushchak, 2014). This reactive thrown of molecule (free radical) damages the neuronal cells. It affects the macromolecules such as the nucleic acids, carbohydrates, proteins and the lipids (Morrison & Lyketsos, 2005). Due to the high consumption rate of the brain, and high lipid content and paucity of the antioxidant enzymes, the brain experiences high oxidative stress. High rate of oxidative stress have been found to play a main role in the progression of the AD. According to Revel et al., (2015), the mitochondrial derived ROS are involved with the initial development of the amyloid plaques in AD along with the alterations in the glutathione (GSH), glutathione peroxidase (GPx) and the malondialdehyde (MDA) levels. The presence of these biomarkers are involved in the protection against the ROS attacks on the lipids (Bejanin et al., 2013). Presence of the MDA reflects the radical attacks on the lipids due to the lipid peroxidation. In a cross sectional study by Gustaw?Rothenberg, Kowalczuk & Stryjecka?Zimmer, (2010) patients suffering with mild cognitive impairment has found to possess higher levels of MDA.   Neurotransmitter Deficiencies In AD the portions of the brain where the serotonin, acetyl choline and norepinephrine are prominent are changed impacting a large area of the cerebral cortex.  Serotonin is normally considered to be effective in treating depression and anxiety. The serotonin receptors are altered in case of AD that affects the cognitive function of the patients. Depression has been fpund to be one of the common comorbities in AD. The reduction in the levels of the norepinephrine in case of AD can be linked with the psychology symptoms observed in AD ( agitation, psychosis, memory loss). Vazey & Aston-Jones, 2012) have stated the emerging role of the norepinephrine in the cognitive dysfunction in AD due to the loss of the locus coeruleus norepinephrine (LC-NE) neurons (Vazey & Aston-Jones, 2012). LC is the sole source of the NE throughout the cerebral cortex and are highly involve in the cognitive functions. The Glutamatergic Theory Glutamate is an important excitatory neurotransmitter of the brain and has been found to be in 66% of the brain synapses. The glutamatergic neurons are also important because they form projections in other areas of the brain influencing the cognitive status (Swerdlow, 2007). Normally three types of postsynaptic glutamate receptors, are associated with cognition but in case of the AD pathology only one type of glutamate receptors are associated (Mlyniec, 2015). It has been found that there is a low activation of the -methyl-D-aspartate (NMDA) receptor in the AD brains, which results in a low level of neurotransmission in the brain. The low regulation of the glutamate NMDA receptor causes a vicious cycle of neuronal damage, where the continuous activation of the receptor causes a huge influx of the calcium that affects the normal signal transduction in brain  (Swerdlow, 2007). It has been noticed that this results in an increased production of the APP, that is again linked with a higher rate of plaque formation and hyperphotophosphorylation of the tau proteins in brain (Mohsenzadegan & Mirshafiey, 2012). The Chronic Inflammation In The Brain The NFTs, amyloid β plaques and the damaged nerve cells results develops inflammatory response as a natural response to any kind of cell damage (Heneka et al., 2012).  The microglia of the brain during an AD pathogenesis, releases cytotoxic molecules like the pro-inflammatory cytokines, reactive oxygen species, complement proteins and the reactive oxygen species (Swerdlow, 2007). This kind of a response to the cellular damage causes harm than protection. Programmed cell death of the neurons can be initiated by the cytokines causing damage to the myelin sheath. The increased inflammatory response augments the prostaglandin levels produced by the cyclogenases COX-1 and COX-2 in a brain with AD (Heneka et al., 2012). Effect Of Cholesterol Recent researches have been found that the cholesterol levels are involved in the pathogenesis of the AD. Since brain contains the highest amount of the cholesterol reserve. The increase in the cholesterol levels helps in the production of the Aβ. As stated by Wood et al., (2014) vascular dementia is a common feature that coexist in AD patients. A study was conducted that reports that there is a strong association between the high density lipoprotein cholesterol and the amount of NFTs and plaques in the cerebral cortex (Nelson et al., 2012). Diagnosis AD can be measured to some extent by the reflexes of the person, the muscle tone and the strength, sensory function, balance and coordination. Blood tests can be useful to rule out the other causes of confusion and memory loss.  Braun imaging techniques such as the MRI, computerized tomography (PET), testing of the cerebrospinal fluid, positron emission tomography (Frisoni et al., 2013). Treatments  There is no such treatment to treat the condition but the treatment lies in slowering down the progression of the disease. Some medicines like donepezil, galantamine, rivastigine and tacrine can be useful in AD diseases. These medications work by inhibiting the enzyme acetylcholinesterase that is responsible for the breaking down of acetyl choline. Cholinesterase inhibitors can also be used as the therapy (Salomone et al., 2012). Memantidine can be used in case of severe AD. Antidepressant medications can be provided for controlling the behavioral symptoms (McKhann et al., 2012). Anti-anxiety medications such as Clonazepam and Lorazepam can be used.  Researchers are turning out to be more medically relevant such as measuring the outcome such as the functional decline i.e the ability to perform the daily activities. Jacobs et al., (2012) have stated that the loss of the ADLs in AD is a predictor of institutionalization. The ideal treatment of AD in elderly people involves cognitive behavioral therapy, constructive activity for the AD patients, helping out the patients to accomplish their daily chores. Social inclusion of these people is necessary to improve their quality of living.   Conclusion In conclusion it can be said that the evolving pathophysiology of the AD can pave the way for the future of the therapeutics. The amyloid plaques and the neurofibrillary tangles are the probable hallmarks of AD. The future treatment strategies would probably focus on the multiple mechanism in AD. A large number of factors such as the oxidative stress , cholesterol, loss of cholinergic neurons, accumulation of the amyloid and the tau proteins and chronic inflammatory response can cause the formation of the plaques and the tangles in the brain. Although caring for a person with AD can be challenging but a pinch of love and care can help in reshaping the life of these people. Coping and support, calm and a quite environment helps to control the behavioral problems in the AD patient.   References Bejanin, A., Schonhaut, D. R., La Joie, R., Kramer, J. Healthcare., Baker, S. L., Sosa, N., … & O’neil, J. P. (2017). Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain, 140(12), 3286-3300. Frisoni, G. B., Fox, N. C., Jack Jr, C. R., Scheltens, P., & Thompson, P. M. (2010). The clinical use of structural MRI in Alzheimer disease. Nature Reviews Neurology, 6(2), 67. Gustaw?Rothenberg, K., Kowalczuk, K., & Stryjecka?Zimmer, M. (2010). Lipids’ peroxidation markers in Alzheimer’s disease and vascular dementia. Geriatrics & gerontology international, 10(2), 161-166. Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., … & Herrup, K. (2015). Neuroinflammation in Alzheimer’s disease. The Lancet Neurology, 14(4), 388-405. Jacobs, H. I., Van Boxtel, M. P., Jolles, J., Verhey, F. R., & Uylings, H. B. (2012). Parietal cortex matters in Alzheimer’s disease: an overview of structural, functional and metabolic findings. Neuroscience & Biobehavioral Reviews, 36(1), 297-309. Lushchak, V. I. (2014). Free radicals, reactive oxygen species, oxidative stress and its classification. Chemico-biological interactions, 224, 164-175. McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Kawas, C. H., … & Mohs, R. C. (2011). The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia: the journal of the Alzheimer’s Association, 7(3), 263-269. Mlyniec, K. (2015). Zinc in the glutamatergic theory of depression. Current neuropharmacology, 13(4), 505-513. Mohsenzadegan, M., & Mirshafiey, A. (2012). The immunopathogenic role of reactive oxygen species in Alzheimer disease. Iranian Journal of Allergy, Asthma and Immunology, 11(3), 203. Morrison, A. S., & Lyketsos, C. (2005). The pathophysiology of alzheimer disease and directions in treatment. Adv Stud Nurs, 3(8), 256-270. Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., … & Duyckaerts, C. (2012). Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. Journal of Neuropathology & Experimental Neurology, 71(5), 362-381. Revel, F., Gilbert, T., Roche, S., Drai, J., Blond, E., Ecochard, R., & Bonnefoy, M. (2015). Influence of oxidative stress biomarkers on cognitive decline. Journal of Alzheimer’s Disease, 45(2), 553-560. Salomone, S., Caraci, F., Leggio, G. M., Fedotova, J., & Drago, F. (2012). New pharmacological strategies for treatment of Alzheimer’s disease: focus on disease modifying drugs. British journal of clinical pharmacology, 73(4), 504-517. Swerdlow, R. H. (2007). Pathogenesis of Alzheimer’s disease. Clinical Interventions in Aging, 2(3), 347–359. Vazey, E. M., & Aston-Jones, G. (2012). The emerging role of norepinephrine in cognitive dysfunctions of Parkinson’s disease. Frontiers in Behavioral Neuroscience, 6, 48. Wood, W. G., Li, L., Müller, W. E., & Eckert, G. P. (2014). Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. Journal of neurochemistry, 129(4), 559-572.

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