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      Exploring Methylene Blue and Its Derivatives in Alzheimer's Treatment: A Comprehensive Review of Randomized Control Trials


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          Methylene blue (MB) and its compounds are investigated for their potential benefits in the management of Alzheimer's disease (AD). AD is a widely seen neuropathological disorder characterized by the gradual decline of cognitive abilities, ultimately leading to the development of severe dementia. It is anticipated that there will be a significant increase in the prevalence of AD due to the aging population. Histopathologically, AD is distinguished by the presence of intracellular tangles of neurofibrillary tissues (NFTs) and extracellular amyloid plaques within the brain. MB is a thiophenazine dye with FDA approval for treating several illnesses. Its ease in crossing the blood-brain barrier and potential therapeutic use in central nervous system diseases have increased interest in its application for treating AD. The literature review includes randomized clinical trials investigating MB's potential benefits in treating AD. The findings of the studies indicate that the administration of MB has demonstrated enhancements in cognitive function, reductions in the accumulation of plaques containing beta-amyloid, improvements in memory and cognitive function in animal subjects, and possesses antioxidant properties that can mitigate oxidative stress and inflammation within the brain. This review evaluates the modern and latest research on the application of MB for treating AD.

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          Neuropathological stageing of Alzheimer-related changes

          Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.
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            Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study.

            Similar to most chronic diseases, Alzheimer's disease (AD) develops slowly from a preclinical phase into a fully expressed clinical syndrome. We aimed to use longitudinal data to calculate the rates of amyloid β (Aβ) deposition, cerebral atrophy, and cognitive decline. In this prospective cohort study, healthy controls, patients with mild cognitive impairment (MCI), and patients with AD were assessed at enrolment and every 18 months. At every visit, participants underwent neuropsychological examination, MRI, and a carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET scan. We included participants with three or more (11)C-PiB PET follow-up assessments. Aβ burden was expressed as (11)C-PiB standardised uptake value ratio (SUVR) with the cerebellar cortex as reference region. An SUVR of 1·5 was used to discriminate high from low Aβ burdens. The slope of the regression plots over 3-5 years was used to estimate rates of change for Aβ deposition, MRI volumetrics, and cognition. We included those participants with a positive rate of Aβ deposition to calculate the trajectory of each variable over time. 200 participants (145 healthy controls, 36 participants with MCI, and 19 participants with AD) were assessed at enrolment and every 18 months for a mean follow-up of 3·8 (95% CI CI 3·6-3·9) years. At baseline, significantly higher Aβ burdens were noted in patients with AD (2·27, SD 0·43) and those with MCI (1·94, 0·64) than in healthy controls (1·38, 0·39). At follow-up, 163 (82%) of the 200 participants showed positive rates of Aβ accumulation. Aβ deposition was estimated to take 19·2 (95% CI 16·8-22·5) years in an almost linear fashion-with a mean increase of 0·043 (95% CI 0·037-0·049) SUVR per year-to go from the threshold of (11)C-PiB positivity (1·5 SUVR) to the levels observed in AD. It was estimated to take 12·0 (95% CI 10·1-14·9) years from the levels observed in healthy controls with low Aβ deposition (1·2 [SD 0·1] SUVR) to the threshold of (11)C-PiB positivity. As AD progressed, the rate of Aβ deposition slowed towards a plateau. Our projections suggest a prolonged preclinical phase of AD in which Aβ deposition reaches our threshold of positivity at 17·0 (95% CI 14·9-19·9) years, hippocampal atrophy at 4·2 (3·6-5·1) years, and memory impairment at 3·3 (2·5-4·5) years before the onset of dementia (clinical dementia rating score 1). Aβ deposition is slow and protracted, likely to extend for more than two decades. Such predictions of the rate of preclinical changes and the onset of the clinical phase of AD will facilitate the design and timing of therapeutic interventions aimed at modifying the course of this illness. Science and Industry Endowment Fund (Australia), The Commonwealth Scientific and Industrial Research Organisation (Australia), The National Health and Medical Research Council of Australia Program and Project Grants, the Austin Hospital Medical Research Foundation, Victorian State Government, The Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

              Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.

                Author and article information

                Cureus (Palo Alto (CA) )
                9 October 2023
                October 2023
                : 15
                : 10
                : e46732
                [1 ] Geriatrics, College of Human Medicine, Michigan State University, East Lansing, USA
                [2 ] Internal Medicine, White River Health, Batesville, USA
                [3 ] Internal Medicine, Michigan State University, East Lansing, USA
                [4 ] Internal Medicine, College of Human Medicine, Michigan State University, East Lansing, USA
                [5 ] Nephrology, Harlem Hospital Center, Columbia University, New York, USA
                [6 ] Family Medicine, College of Human Medicine, Michigan State University, East Lansing, USA
                Author notes
                Muhammad Usman Hashmi muh.haashmi@ 123456gmail.com
                Copyright © 2023, Hashmi et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                : 9 October 2023
                Family/General Practice
                Internal Medicine

                primary senile degenerative dementia,alzheimer’s dementia,amyloid-β,white matter,synaptic plasticity,methylene blue,hippocampal fibres,hippocampal ca1,axonal degeneration,alzheimer disease


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