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Ageing
Published in Henry J. Woodford, Essential Geriatrics, 2022
Proteins can be affected by oxidation and also glycation, which is the binding of carbohydrates to form advanced glycation end-products (AGE). This can lead to reduced enzyme activity or the accumulation of protein aggregates, including amyloid plaques. Lipid peroxidation can harm bodily membranes. Nucleic acids can also be damaged. This is particularly likely to occur with mitochondrial DNA due to its proximity to free radical production and its more limited repair capacity. Damage to mitochondria can reduce energy availability within the cell. Natural repair mechanisms exist and greatly limit the damage done, but they are imperfect and are highly energy-dependent. Thus, mitochondrial damage may reduce energy availability for cellular repair, further promoting the ageing process.
Neuroimaging in Nuclear Medicine
Published in Michael Ljungberg, Handbook of Nuclear Medicine and Molecular Imaging for Physicists, 2022
Anne Larsson Strömvall, Susanna Jakobson Mo
In Alzheimer´s disease (AD), the most common form of dementia, amyloid plaques, mainly composed of clumps of β-amyloid (a part of a protein occurring in the synapse) and neurofibrillary tangles, are formed by aggregation of an intracellular protein type called tau. In AD the degenerative process causes damage to nerve-cells communicating with the neurotransmitter acetylcholine. In the brain, acetylcholine is important for cognitive functions, including memory. As the neurons die and the function in affected areas is decreased, the regional blood flow and glucose metabolism will be lower than in normally functioning areas. Typically, the parietal and temporal lobes are affected in Alzheimer´s disease, causing memory loss as well as, for example, difficulties in time and space orientation.
Dementia
Published in Sally Robinson, Priorities for Health Promotion and Public Health, 2021
Pat Chung, Trish (Patricia) Vella-Burrows
Alzheimer’s disease was named after the clinician Alois Alzheimer in 1906. It is the most common cause of dementia, accounting for 60% to 70% of all cases across the world and 50% to 75% of cases in the UK (WHO, 2019a; NICE, 2019). It is caused by a build-up of amyloid plaques. These are types of proteins that clump together between the nerve cells in the brainan increase in neurofibrillary tangles, twisted fibres, in the braina reduction of neurotransmitters, the chemicals that transmit messages between the brain cells
Antibodies to watch in 2022
Published in mAbs, 2022
Hélène Kaplon, Alicia Chenoweth, Silvia Crescioli, Janice M. Reichert
The late-stage development program for Aduhelm consisted of two Phase 3 clinical trials with identical designs conducted in patients with mild-cognitive impairment due to AD and mild AD dementia with a positive amyloid PET scan. One study (NCT02484547, 221AD302, EMERGE), initiated in September 2015, showed positive results for the 10 mg/kg dose group, specifically a reduction in the baseline- and placebo-corrected primary efficacy endpoint, Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) scores during the 78-week treatment period. CDR-SB is a dementia-staging instrument used in making or excluding a diagnosis of dementia in people with mild cognitive deficits. However, the second trial (NCT02477800, 221AD301, ENGAGE), initiated in August 2015, did not meet the primary endpoint. FDA documents indicate that, based on the data presented to them, their review team found clear exposure–efficacy and dose–response relationships for aducanumab, a consistent pharmacodynamic effect (Aβ plaque reduction) in clinical studies, and a clear relationship between Aβ plaque reduction and clinical endpoint CDR-SB for aducanumab.48 The reduction in amyloid plaque is considered a surrogate for a reduction in clinical decline. A post-approval trial must be conducted to verify that the drug provides the expected clinical benefit.49
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
Alzheimer’s disease (AD), the most common cause of dementia, is a growing health concern with huge implications for individuals and society. Current estimates suggest that 44 million people with dementia live worldwide. This number is predicted to increase more than triple by 2050 as the population ages, whereas no effective causal therapeutics are available1. The most typical clinical manifestation of AD in the elderly represents insidious and progressive problems associated with episodic memory. The distinctive features of Alzheimer’s pathology are amyloid plaques and neurofibrillary tangles. Amyloid plaques are extracellular accumulations composed of abnormally folded amyloid protein, whereas neurofibrillary tangles are intracellularly lodged paired helical filaments consisting of hyperphosphorylated tau protein. The downstream consequences of these pathological processes include neurodegeneration with synaptic and neuronal loss leading to macroscopic atrophy2.
COR388 (atuzaginstat): an investigational gingipain inhibitor for the treatment of Alzheimer disease
Published in Expert Opinion on Investigational Drugs, 2022
Marwan N. Sabbagh, Boris Decourt
Until recently, amyloid beta (Aβ) 42 was considered exclusively as a peptide that is one of the principal pathogenic drivers of clinical Alzheimer disease (AD). This hypothesis was strongly supported by the observation of accelerated accumulation of amyloid plaques in the brains of persons with specific genetic mutations. These mutations affect proteins implicated in amyloidogenesis, such as mutations of the presenilin 1 (PSEN1), PSEN2, amyloid precursor protein (APP), and Down syndrome (also known as trisomy 21) genes, and they often lead to the presenile onset of AD [1]. In these autosomal dominant mutations and trisomy 21 (APP is located on chromosome 21), Aβ is frequently overexpressed and detectable at a young age. Persons who carry these mutations express symptomatic cognitive decline by the fourth or fifth decade of life, with increased Aβ loads detectable as early as the third decade in the cerebrospinal fluid (CSF) and in positron emission tomography (PET) imaging of the brain [2]. The long-term consensus formulated in the amyloid cascade hypothesis [3] has been that Aβ overproduction is an early event in AD pathogenesis that then drives downstream pathologies, including tau neurofibrillary tangles, central inflammation, excitotoxicity, and neurochemical changes [4].