scholarly journals Age-linked suppression of lipoxin A4 mediates cognitive deficits in mice and humans

2021 ◽  
Author(s):  
Fabrício A. Pamplona ◽  
Gabriela Vitória ◽  
Felipe C. Ribeiro ◽  
Carolina A. Moraes ◽  
Pitia F. Ledur ◽  
...  
Keyword(s):  
Memory Performance ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
The Elderly ◽  
Lipid Mediator ◽  
Lipoxin A4 ◽  
Age Related ◽  
Learning Impairment ◽  
The Brain

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-β. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

scholarly journals The Impact of Bone on the Biology of Aging

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 740-740
Author(s):  
Gerard Karsenty
Keyword(s):  
Muscle Function ◽  
Male Fertility ◽  
Leydig Cells ◽  
Memory Loss ◽  
Age Related ◽  
Systematic Exploration ◽  
Biology Of Aging ◽  
The Impact ◽  
The Brain ◽  
Regulate Energy Metabolism

Abstract We hypothesized that bone may secrete hormones that regulate energy metabolism and reproduction. Testing this hypothesis revealed that the osteoblast-specific secreted protein osteocalcin is a hormone regulating glucose homeostasis and male fertility by signaling through a GPCR, Gprc6a, expressed in pancreatic β bells and Leydig cells of the testes. The systematic exploration of osteocalcin biology, revealed that it regulates an unexpectedly large spectrum of physiological functions in the brain and peripheral organs and that it has most features of an antigeromic molecule. As will be presented at the meeting, this body of work suggests that harnessing osteocalcin for therapeutic purposes may be beneficial in the treatment of age-related diseases such as depression, age-related memory loss and the decline in muscle function seen in sarcopenia.

scholarly journals Efficacy and immunogenicity of MultiTEP-based DNA vaccines targeting human α-synuclein: prelude for IND enabling studies

npj Vaccines ◽  
2022 ◽  
Vol 7 (1) ◽  
Author(s):  
Changyoun Kim ◽  
Armine Hovakimyan ◽  
Karen Zagorski ◽  
Tatevik Antonyan ◽  
Irina Petrushina ◽  
...  
Keyword(s):  
Dna Vaccines ◽  
Neurodegenerative Disorder ◽  
Neuronal Damage ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
The Elderly ◽  
Brain Regions ◽  
Dependent Manner ◽  
Lewy Neurites ◽  
The Brain

AbstractAccumulation of misfolded proteins such as amyloid-β (Aβ), tau, and α-synuclein (α-Syn) in the brain leads to synaptic dysfunction, neuronal damage, and the onset of relevant neurodegenerative disorder/s. Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are characterized by the aberrant accumulation of α-Syn intracytoplasmic Lewy body inclusions and dystrophic Lewy neurites resulting in neurodegeneration associated with inflammation. Cell to cell propagation of α-Syn aggregates is implicated in the progression of PD/DLB, and high concentrations of anti-α-Syn antibodies could inhibit/reduce the spreading of this pathological molecule in the brain. To ensure sufficient therapeutic concentrations of anti-α-Syn antibodies in the periphery and CNS, we developed four α-Syn DNA vaccines based on the universal MultiTEP platform technology designed especially for the elderly with immunosenescence. Here, we are reporting on the efficacy and immunogenicity of these vaccines targeting three B-cell epitopes of hα-Syn aa85–99 (PV-1947D), aa109–126 (PV-1948D), aa126–140 (PV-1949D) separately or simultaneously (PV-1950D) in a mouse model of synucleinopathies mimicking PD/DLB. All vaccines induced high titers of antibodies specific to hα-Syn that significantly reduced PD/DLB-like pathology in hα-Syn D line mice. The most significant reduction of the total and protein kinase resistant hα-Syn, as well as neurodegeneration, were observed in various brain regions of mice vaccinated with PV-1949D and PV-1950D in a sex-dependent manner. Based on these preclinical data, we selected the PV-1950D vaccine for future IND enabling preclinical studies and clinical development.

MR Brain Screening using Optimization Techniques – A survey

2021 ◽  
Vol 17 ◽  
Author(s):  
Chitradevi D ◽  
Prabha S.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cell Loss ◽  
Optimization Techniques ◽  
Amyloid Β Protein ◽  
The Brain ◽  
Brain Tissues

Background: Alzheimer’s disease (AD) is associated with Dementia, and it is also a memory syndrome in the brain. It affects the brain tissues and causes major changes in day-to-day activities. Aging is a major cause of Alzheimer's disease. AD is characterized by two pathological hallmarks as, Amyloid β protein and neurofibrillary tangles of hyperphosphorylated tau protein. The imaging hallmarks for Alzheimer’s disease are namely, swelling, shrinkage of brain tissues due to cell loss, and atrophy in the brain due to protein dissemination. Based on the survey, 60% to 80% of dementia patients belong to Alzheimer’s disease. Introduction: AD is now becoming an increasing and important brain disease. The goal of AD pathology is to cause changes/damage in brain tissues. Alzheimer's disease is thought to begin 20 years or more before symptoms appear, with tiny changes in the brain that are undetectable to the person affected. The changes in a person's brain after a few years are noticeable through symptoms such as language difficulties and memory loss. Neurons in different parts of the brain have detected symptoms such as cognitive impairments and learning disabilities. In this case, neuroimaging tools are necessary to identify the development of pathology which relates to the clinical symptoms. Methods: Several approaches have been tried during the last two decades for brain screening to analyse AD with the process of pre-processing, segmentation and classification. Different individual such as Grey Wolf optimization, Lion Optimization, Ant Lion Optimization and so on. Similarly, hybrid optimization techniques are also attempted to segment the brain sub-regions which helps in identifying the bio-markers to analyse AD. Conclusion: This study discusses a review of neuroimaging technologies for diagnosing Alzheimer's disease, as well as the discovery of hallmarks for the disease and the methodologies for finding hallmarks from brain images to evaluate AD. According to the literature review, most of the techniques predicted higher accuracy (more than 90%), which is beneficial for assessing and screening neurodegenerative illness, particularly Alzheimer's disease.

Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

2021 ◽  
pp. 1-14
Author(s):  
Andrew L. Zhou ◽  
Nidhi Sharda ◽  
Vidur V. Sarma ◽  
Kristen M. Ahlschwede ◽  
Geoffry L. Curran ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Single Photon ◽  
Photon Emission ◽  
Amyloid Β ◽  
Emission Computed Tomography ◽  
Systemic Injection ◽  
Age Related ◽  
Age Dependent ◽  
Plasma Pharmacokinetics ◽  
The Brain

Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

COGNITIVE AGING AND COGNITIVE RESERVE: POINT OF CONTACT

2020 ◽  
pp. 256-264
Author(s):  
В. С. Мякотных ◽  
А. П. Сиденкова ◽  
Е. С. Остапчук ◽  
И. А. Кулакова ◽  
Н. А. Белых ◽  
...  
Keyword(s):  
Cognitive Aging ◽  
Cognitive Reserve ◽  
Cognitive Disorders ◽  
The Elderly ◽  
Educational Process ◽  
Special Role ◽  
Age Related ◽  
The Central Nervous System ◽  
The One

Высокий риск когнитивных расстройств у лиц пожилого и старческого возраста заставляет, с одной стороны, искать их причины, с другой - возможности профилактики. В связи с этим в последние годы получило распространение понятие когнитивного резерва, подразумевающего совокупность количественных параметров головного мозга и его способности сохранять высокую функциональную активность в процессе старения и на фоне связанной с возрастом патологии головного мозга. Представленный в статье материал на основе обзора научной литературы освещает два основных момента, касающихся возможности сохранения когнитивного резерва, - гендерный и образовательный факторы. Указывается на разные возможности женщин и мужчин, связанные со структурными и функциональными особенностями ЦНС у представителей разного пола, и на особую роль поддерживаемого в течение всей жизни образовательного процесса. Обозначена авторская позиция о необходимости разделения понятий образования и образованности, то есть уровня общей культуры и создания удобного инструмента для определения последнего. Это, в свою очередь, помогло бы в разработке модели когнитивного резерва, нацеленной на предотвращение трансформации физиологического когнитивного старения в патологическое. The high risk of cognitive disorders in the elderly and senile age makes, on the one hand, to look for their causes, on the other - the possibility of prevention. In this regard, in recent years, the concept of cognitive reserve has become widespread, implying a set of quantitative parameters of the brain and its ability to maintain high functional activity in the process of aging and against the background of age-related brain pathology. The material presented in the article on the basis of the review of scientific literature highlights two main points concerning the possibility of preserving the cognitive reserve-gender and educational factors. It is pointed to the different opportunities of women and men associated with the structural and functional characteristics of the Central nervous system in representatives of different sexes and the special role of the educational process supported throughout life. The author’s position on the need to separate the concepts of education and the level of General culture, and the creation of a convenient tool for determining the latter is indicated. This, in turn, would help in the development of a cognitive reserve model aimed at preventing the transformation of physiological cognitive aging into pathological aging.

Cognition in Ageing

2018 ◽  
pp. 118-133 ◽  
Author(s):  
Susmita Halder ◽  
Akash Kumar Mahato
Keyword(s):  
Cognitive Functions ◽  
The Elderly ◽  
Daily Functioning ◽  
Cognitive Changes ◽  
Geriatric Population ◽  
Medical Issues ◽  
Age Related ◽  
Growing Age ◽  
The Common ◽  
The Brain

This chapter focuses on cognitive functions and impairment in the elderly; its implications in daily functioning with inputs on differences in the existing literature. The chapter further focuses on the diagnostic and assessment issues and intervention strategies. Ageing is an inevitable phase of life and encompasses changes in physical, psychological and social realms of an individual. Concern with the dwindling health and presence of any medical issues make the geriatric population prone to develop mental health conditions. Poor memory and reduced functional ability is one of the common complaints from older adults coming to psychiatric or neurology clinics. Cognitive functions have been well documented regarding their role in daily functioning of an individual. With growing age of the brain; while some cognitive functions do slow down; some of the functions do evolve better with experience. In this context, it is important to differentiate between normal age related cognitive changes and symptoms of any degenerative disease.

scholarly journals Low Protein Diet Induces Memory Loss and Anxiety Like Behavior via Decreases of Neurotransmitters in Aged Male Mice (P14-028-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Hideaki Sato ◽  
Masako Tsukamoto-Yasui ◽  
Satoko Ueno ◽  
Keiko Matsunaga ◽  
Akihiko Kitamura
Keyword(s):  
Cerebral Cortex ◽  
Memory Loss ◽  
The Elderly ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Avoidance Task ◽  
Maze Task ◽  
Low Protein ◽  
Plus Maze ◽  
The Brain

Abstract Objectives Increase of elderly people, dementia and cognitive decline has been already one of the social problems all over the world. There are a lot of risk factors including dietary composition. Several studies have reported the importance of protein for maintaining brain functions in the elderly, but the details are not well understood. To clarify the relationship between protein intake and brain function in the elderly, we evaluated the effect of low protein diet on cognitive function and psychiatric symptoms in aged mice. Methods Male mice at 60 weeks of age were fed a control diet (NPD; casein 20%) or a low protein diet (LPD; casein 5%). To evaluate neurobehavioral abnormality, we performed the elevated plus maze task (Day 64) and Passive avoidance task (conditioning: Day 66, evaluation: Day 67). Cerebral cortex tissues and plasma were measured for free amino acid concentration by LC-MSMS method, and monoamine concentration in cerebral cortex was measured by HPLC method. Results In the Passive avoidance task, LPD group decreased the time to keep staying in the light box and the rate of individuals entering the dark box during the test period. In the elevated plus maze task, LPD group significantly increased in the number of entry and staying times in open arm. In addition, total travel distance was significantly increased. Moreover, LPD decreased the concentration of not only amino acid in plasma and cerebral cortex but also neurotransmitter such as Glutamate, GABA, Aspartate, Glycine, Dopamine, Norepinephrine, Serotonin. Conclusions We found that long-term intake of low-protein diet occurred memory loss and anxiety like behavior in elderly mice. Intracerebral neurotransmitters are mainly synthesized from amino acids, which is transferred from blood, within the brain. Therefore, behavioral change observed in LPD group might be induced by the decrease of neurotransmitters in the brain. Funding Sources Ajinomoto Co., Inc.

scholarly journals Entorhinal cortex tau, amyloid-β, cortical thickness and memory performance in non-demented subjects

Brain ◽  
2019 ◽  
Vol 142 (4) ◽  
pp. 1148-1160 ◽  
Author(s):  
David S Knopman ◽  
Emily S Lundt ◽  
Terry M Therneau ◽  
Prashanthi Vemuri ◽  
Val J Lowe ◽  
...  
Keyword(s):  
Entorhinal Cortex ◽  
Cortical Thickness ◽  
Memory Performance ◽  
Verbal Learning ◽  
Amyloid Β ◽  
Gradient Boosting ◽  
Amyloid Pet ◽  
Delayed Recall ◽  
Age Related ◽  
Z Scores

AbstractAs more biomarkers for Alzheimer’s disease and age-related brain conditions become available, more sophisticated analytic approaches are needed to take full advantage of the information they convey. Most work has been done using categorical approaches but the joint relationships of tau PET, amyloid PET and cortical thickness in their continuous distributions to cognition have been under-explored. We evaluated non-demented subjects over age 50 years in the Mayo Clinic Study of Aging, 2037 of whom had undergone 3 T MRI scan, 985 amyloid PET scan with 11C-Pittsburgh compound B (PIB) and MRI, and 577 PIB-PET, 18F-AV1451 flortaucipir PET and MRI. Participants received a nine-test cognitive battery. Three test scores (logical memory delayed recall, visual reproduction delayed recall and auditory verbal learning test delayed recall) were used to generate a memory composite z-score. We used Gradient Boosting Machine models to analyse the relationship between regional cortical thickness, flortaucipir PET signal, PIB-PET signal and memory z-scores. Age, education, sex and number of test exposures were included in the model as covariates. In this population-based study of non-demented subjects, most of the associations between biomarkers and memory z-scores accrued after 70 years of age. Entorhinal cortex exhibited the strongest associations between biomarkers and memory z-scores. Other temporal regions showed similar but attenuated associations, and non-temporal regions had negligible associations between memory z-scores and biomarkers. Entorhinal flortaucipir PET signal, PIB-PET signal and entorhinal cortical thickness were independently and additively associated with declining memory z-scores. In contrast to global PIB-PET signal where only very high amyloid-β levels were associated low memory z-scores, entorhinal flortaucipir PET signal just above background levels was associated with low memory z-scores. The lowest memory z-scores occurred with the confluence of elevated entorhinal flortaucipir PET signal and lower entorhinal cortical thickness.

Only social feedback reduces age-related prospective memory deficits in “Virtual Week”

2014 ◽  
Vol 26 (5) ◽  
pp. 759-767 ◽  
Author(s):  
Agnieszka Niedźwieńska ◽  
Peter G. Rendell ◽  
Krystian Barzykowski ◽  
Alicja Leszczyńska
Keyword(s):  
Older Adults ◽  
Prospective Memory ◽  
Independent Living ◽  
Memory Performance ◽  
The Elderly ◽  
Control Group ◽  
Social Feedback ◽  
Feedback Group ◽  
Age Related ◽  
Memory For Intentions

ABSTRACTBackground:Prospective memory, or remembering to do things in the future, is crucial for independent living in old age. Although there is evidence of substantial age-related deficits in memory for intentions, older adults have demonstrated the ability to compensate for their deficits in everyday life. The present study investigated feedback as a strategy for facilitating prospective memory in the elderly.Method:Young and older adults played a computer-based task, Virtual Week, in which they had to remember to carry out life-like intentions. After each virtual day, specific feedback on prospective memory performance was automatically provided on the computer screen that participants either proceeded through by themselves (non-social feedback) or were taken through by an experimenter (social feedback). The control group received no feedback.Results:We found that, compared with no-feedback group, only social feedback substantially reduced the age-related deficit in prospective memory. Older adults significantly benefited from feedback provided by the experimenter on the tasks of intermediate difficulty. Unexpectedly, prospective memory with non-social feedback was not only worse than with social feedback, but it was not any better than without any feedback at all.Conclusions:The results extended previous findings on the effectiveness of feedback in improving the memory performance of older adults to include memory for intentions. Despite the feedback meeting the critical recommendations of being specific, objective, and well-targeted, it was ineffective when the feedback displayed on the computer was not introduced by the experimenter. This has implications for computerized training tasks where automated feedback is considered crucial.

scholarly journals Neural pattern similarity differentially affects memory performance of younger and older adults: Age differences in neural similarity and memory

2019 ◽  
Author(s):  
Verena R. Sommer ◽  
Yana Fandakova ◽  
Thomas H. Grandy ◽  
Yee Lee Shing ◽  
Markus Werkle-Bergner ◽  
...  
Keyword(s):  
Older Adults ◽  
Young Adults ◽  
Memory Performance ◽  
Activity Patterns ◽  
Quality Of Information ◽  
Neural Representations ◽  
Age Related ◽  
Pattern Similarity ◽  
The Brain

AbstractAge-related memory decline is associated with changes in neural functioning but little is known about how aging affects the quality of information representation in the brain. Whereas a long-standing hypothesis of the aging literature links cognitive impairments to less distinct neural representations in old age, memory studies have shown that high similarity between activity patterns benefits memory performance for the respective stimuli. Here, we addressed this apparent conflict by investigating between-item representational similarity in 50 younger (19–27 years old) and 63 older (63–75 years old) human adults (male and female) who studied scene-word associations using a mnemonic imagery strategy while electroencephalography was recorded. We compared the similarity of spatiotemporal frequency patterns elicited during encoding of items with different subsequent memory fate. Compared to younger adults, older adults’ memory representations were more similar to each other but items that elicited the most similar activity patterns early in the encoding trial were those that were best remembered by older adults. In contrast, young adults’ memory performance benefited from decreased similarity between earlier and later periods in the encoding trials, which might reflect their better success in forming unique memorable mental images of the joint picture–word pair. Our results advance the understanding of the representational properties that give rise to memory quality as well as how these properties change in the course of aging.Significance statementDeclining memory abilities are one of the most evident limitations for humans when growing older. Despite recent advances of our understanding of how the brain represents and stores information in distributed activation patterns, little is known about how the quality of information representation changes during aging and thus affects memory performance. We investigated how the similarity between neural representations relates to subsequent memory quality in younger and older adults. We present novel evidence that the interaction of pattern similarity and memory performance differs between age groups: Older adults benefited from increased similarity during early encoding whereas young adults benefited from decreased similarity between early and later encoding. These results provide insights into the nature of memory and age-related memory deficits.

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