scholarly journals Chronic colitis exacerbates NLRP3-dependent neuroinflammation and cognitive impairment in middle-aged brain

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiao-fei He ◽  
Li-li Li ◽  
Wen-biao Xian ◽  
Ming-yue Li ◽  
Li-ying Zhang ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Nlrp3 Inflammasome ◽  
Lymphatic Vessels ◽  
Neuronal Loss ◽  
Amyloid Plaque ◽  
The Elderly ◽  
Age Related ◽  
Bowel Diseases ◽  
Brain Degeneration

Abstract Background Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome has been implicated in neuroinflammation. Therefore, we examined if the NLRP3 inflammasome contributes to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD. Methods Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. Colitis induction was confirmed by histopathology. Exploratory behavior was examined in the open field, associative memory by the novel-object recognition and Morris water maze tests, glymphatic clearance by in vivo two-photon imaging, and neuroinflammation by immunofluorescence and western blotting detection of inflammatory markers. Results Administration of DSS induced colitis, impaired spatial and recognition memory, activated microglia, and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in the cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely, NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS. Conclusions Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

scholarly journals Chronic Colitis Exacerbates Nlrp3-dependent Neuroinflammation and Cognitive Impairment in Middle-aged Brain

2021 ◽  
Author(s):  
Xiao-fei He ◽  
Li-li Li ◽  
Wen-biao Xian ◽  
Ming-yue Li ◽  
Li-ying Zhang ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Spatial Cognition ◽  
Nlrp3 Inflammasome ◽  
Lymphatic Vessels ◽  
Neuronal Loss ◽  
Amyloid Plaque ◽  
The Elderly ◽  
Age Related ◽  
Bowel Diseases

Abstract Background: Neuroinflammation is a major driver of age-related brain degeneration and concomitant functional impairment. In patients with Alzheimer’s disease, the most common form of age-related dementia, factors that enhance neuroinflammation may exacerbate disease progression, in part by impairing the glymphatic system responsible for clearance of pathogenic beta-amyloid. Inflammatory bowel diseases (IBDs) induce neuroinflammation and exacerbate cognitive impairment in the elderly. The NACHT-LRR and pyrin (PYD) domain-containing protein 3 (NLRP3) inflammasome have been implicated in neuroinflammation. We therefore examined if the NLRP3 inflammasome contributed to glymphatic dysfunction and cognitive impairment in an aging mouse model of IBD.Methods: Sixteen-month-old C57BL/6J and NLRP3 knockout (KO) mice received 1% wt/vol dextran sodium sulfate (DSS) in drinking water to model IBD. The Morris water maze was used to examine spatial cognition, in vivo two-photon imaging to examine glymphatic clearance, and immunofluorescence staining and western blotting to detect markers of neuroinflammation. Results: Administration of DSS induced colitis, impaired spatial cognition, activated microglia and increased A1-like astrocyte numbers. In addition, DSS treatment impaired glymphatic clearance, aggravated amyloid plaque accumulation, and induced neuronal loss in cortex and hippocampus. These neurodegenerative responses were associated with increased NLRP3 inflammasome expression and accumulation of gut-derived T lymphocytes along meningeal lymphatic vessels. Conversely NLRP3 depletion protected against cognitive dysfunction, neuroinflammation, and neurological damage induced by DSS.Conclusions: Colitis can exacerbate age-related neuropathology, while suppression of NLRP3 inflammasome activity may protect against these deleterious effects of colitis.

scholarly journals Improving Dignity of Care in Community-Dwelling Elderly Patients with Cognitive Decline and Their Caregivers. The Role of Dignity Therapy

2020 ◽  
Vol 10 (12) ◽  
pp. 178
Author(s):  
Heifa Ounalli ◽  
David Mamo ◽  
Ines Testoni ◽  
Martino Belvederi Murri ◽  
Rosangela Caruso ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Early Stage ◽  
Psychosocial Interventions ◽  
The Elderly ◽  
Community Dwelling ◽  
Anticipatory Grief ◽  
Dignity Therapy ◽  
Existential Distress ◽  
Age Related

Demographic changes have placed age-related mental health disorders at the forefront of public health challenges over the next three decades worldwide. Within the context of cognitive impairment and neurocognitive disorders among elderly people, the fragmentation of the self is associated with existential suffering, loss of meaning and dignity for the patient, as well as with a significant burden for the caregiver. Psychosocial interventions are part of a person-centered approach to cognitive impairment (including early stage dementia and dementia). Dignity therapy (DT) is a therapeutic intervention that has been shown to be effective in reducing existential distress, mood, and anxiety symptoms and improving dignity in persons with cancer and other terminal conditions in palliative care settings. The aims of this paper were: (i) To briefly summarize key issues and challenges related to care in gerontology considering specifically frail elderly/elderly with cognitive decline and their caregivers; and (ii) to provide a narrative review of the recent knowledge and evidence on DT in the elderly population with cognitive impairment. We searched the electronic data base (CINAHL, SCOPUS, PSycInfo, and PubMed studies) for studies regarding the application of DT in the elderly. Additionally, given the caregiver’s role as a custodian of diachronic unity of the cared-for and the need to help caregivers to cope with their own existential distress and anticipatory grief, we also propose a DT-dyadic approach addressing the needs of the family as a whole.

scholarly journals Arrhythmia susceptibility in senescent rat hearts

2014 ◽  
Vol 87 (1) ◽  
Author(s):  
Stefano Rossi ◽  
Silvana Baruffi ◽  
Domenico Corradi ◽  
Sergio Callegari ◽  
Ezio Musso ◽  
...  
Keyword(s):  
Cardiac Electrophysiology ◽  
The Elderly ◽  
Detailed Knowledge ◽  
Activation Patterns ◽  
Electrophysiological Properties ◽  
Age Related ◽  
Rat Hearts ◽  
Arrhythmogenic Substrate ◽  
Ventricular Activation

Cardiovascular disease increases with age as well as alterations of cardiac electrophysiological properties, but a detailed knowledge about changes in cardiac electrophysiology relevant to arrhythmogenesis in the elderly is relatively lacking. The aim of this study was to determine specific age-related changes in electrophysiological properties of the ventricles which can be related to a structural-functional arrhythmogenic substrate. Multiple epicardial electrograms were recorded on the ventricular surface of in vivo control and aged rats, while arrhythmia vulnerability was investigated by premature stimulation protocols. Single or multiple ectopic beats and sustained ventricular arrhythmias were frequently induced in aged but not in control hearts. Abnormal ventricular activation patterns during sinus rhythm and unchanged conduction velocity during point stimulation in aged hearts suggest the occurrence of impaired impulse conduction through the distal Purkinje system that might create a potential reentry substrate.

scholarly journals Cerebral Microinfarcts: A Systematic Review of Neuropathological Studies

2012 ◽  
Vol 32 (3) ◽  
pp. 425-436 ◽  
Author(s):  
Manon Brundel ◽  
Jeroen de Bresser ◽  
Jeroen J van Dillen ◽  
L Jaap Kappelle ◽  
Geert Jan Biessels
Keyword(s):  
Cognitive Impairment ◽  
High Resolution ◽  
Neuronal Loss ◽  
Weighted Average ◽  
Vascular Cognitive Impairment ◽  
Brain Regions ◽  
Older Individuals ◽  
High Resolution Mri ◽  
Magnetic Resonance Imaging Mri

Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.

scholarly journals Arginine behaviour after arginine or citrulline administration in older subjects

2015 ◽  
Vol 115 (3) ◽  
pp. 399-404 ◽  
Author(s):  
C. Moinard ◽  
J. Maccario ◽  
S. Walrand ◽  
V. Lasserre ◽  
J. Marc ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
The Elderly ◽  
Volume Of Distribution ◽  
Elderly Subjects ◽  
Healthy Elderly ◽  
Age Related ◽  
Loading Tests ◽  
Kinetics Of ◽  
Healthy Elderly Subjects

AbstractArginine (ARG) and its precursor citrulline (CIT) are popular dietary supplements, especially for the elderly. However, age-related reductions in lean body mass and alterations in organ functions could change their bioavailability. Pharmacokinetics and tolerance to amino acid (AA) loads are poorly documented in elderly subjects. The objective here was to characterise the plasma kinetics of CIT and ARG in a single-dosing study design. Eight fasting elderly men underwent two separate isomolar oral loading tests (10 g of CIT or 9·94 g of ARG). Blood was withdrawn over an 8-h period to measure plasma AA concentrations. Only CIT, ornithine and ARG plasma concentrations were changed. Volume of distribution was not dependent on AA administered. Conversely, parameters related to ARG kinetics were strongly dependent on AA administered: after ARG load, elimination was higher (ARG>CIT; P=0·041) and admission period+time at peak concentration was lower (ARG<CIT; P=0·033), and the combination of both phenomena results in a marked increase in ARG availability when CIT was administered (ARG<CIT; P=0·033) compared with ARG administration itself. In conclusion, a single CIT administration in the elderly is safe and well tolerated, and CIT proves to be a better in vivo ARG precursor than ARG itself in healthy elderly subjects.

scholarly journals T2 heterogeneity as an in vivo marker of microstructural integrity in medial temporal lobe subfields in ageing and mild cognitive impairment

2020 ◽  
Author(s):  
Alfie R. Wearn ◽  
Volkan Nurdal ◽  
Esther Saunders-Jennings ◽  
Michael J. Knight ◽  
Christopher R. Madan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Learning Task ◽  
Quantitative Mri ◽  
Associate Learning ◽  
Age Related ◽  
Brain Changes

ABSTRACTA better understanding of early brain changes that precede loss of independence in diseases like Alzheimer’s disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n=49) compared to healthy older controls (n=99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in the entorhinal cortex also predicted cognitive decline over a year in people with MCI, where measures of volume or T2 in any other subfield or whole hippocampus could not. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative disease.

scholarly journals The role of high cholesterol in age-related COVID19 lethality

2020 ◽  
Author(s):  
Hao Wang ◽  
Zixuan Yuan ◽  
Mahmud Arif Pavel ◽  
Robert Hobson ◽  
Scott B. Hansen
Keyword(s):  
Viral Entry ◽  
Super Resolution ◽  
The Elderly ◽  
High Cholesterol ◽  
Entry Site ◽  
Age Related ◽  
Entry Points ◽  
Resolution Imaging ◽  
Tissue Cholesterol

ABSTRACTCoronavirus disease 2019 (COVID19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originating in Wuhan, China in 2019. The disease is notably severe in elderly and those with underlying chronic conditions. A molecular mechanism that explains why the elderly are vulnerable and why children are resistant is largely unknown. Here we show loading cells with cholesterol from blood serum using the cholesterol transport protein apolipoprotein E (apoE) enhances the entry of pseudotyped SARS-CoV-2 and the infectivity of the virion. Super resolution imaging of the SARS-CoV-2 entry point with high cholesterol shows almost twice the total number of endocytic entry points. Cholesterol concomitantly traffics angiotensinogen converting enzyme (ACE2) to the endocytic entry site where SARS-CoV-2 presumably docks to efficiently exploit entry into the cell. Furthermore, in cells producing virus, cholesterol optimally positions furin for priming SARS-CoV-2, producing a more infectious virion with improved binding to the ACE2 receptor. In vivo, age and high fat diet induces cholesterol loading by up to 40% and trafficking of ACE2 to endocytic entry sites in lung tissue from mice. We propose a component of COVID19 severity based on tissue cholesterol level and the sensitivity of ACE2 and furin to cholesterol. Molecules that reduce cholesterol or disrupt ACE2 localization with viral entry points or furin localization in the producer cells, may reduce the severity of COVID19 in obese patients.

scholarly journals Immunosenescence of Polymorphonuclear Neutrophils

2010 ◽  
Vol 10 ◽  
pp. 145-160 ◽  
Author(s):  
Inga Wessels ◽  
Judith Jansen ◽  
Lothar Rink ◽  
Peter Uciechowski
Keyword(s):  
Molecular Mechanisms ◽  
Adaptive Immune System ◽  
The Elderly ◽  
Polymorphonuclear Neutrophils ◽  
Traditional Role ◽  
Functional Changes ◽  
The Public ◽  
Age Related

All immune cells are affected by aging, contributing to the high susceptibility to infections and increased mortality observed in the elderly. The effect of aging on cells of the adaptive immune system is well documented. In contrast, knowledge concerning age-related defects of polymorphonuclear neutrophils (PMN) is limited. During the past decade, it has become evident that in addition to their traditional role as phagocytes, neutrophils are able to secrete a wide array of immunomodulating molecules. Their importance is underlined by the finding that genetic defects that lead to neutropenia increase susceptibility to infections. Whereas there is consistence about the constant circulating number of PMN throughout aging, the abilities of tissue infiltration, phagocytosis, and oxidative burst of PMN from aged donors are discussed controversially. Furthermore, there are numerous discrepancies betweenin vivoandin vitroresults, as well as between results for murine and human PMN. Most of the reported functional changes can be explained by defective signaling pathways, but further research is required to get a detailed insight into the underlying molecular mechanisms. This could form the basis for drug development in order to prevent or treat age-related diseases, and thus to unburden the public health systems.

In vivo evidence of an age-related increase in ATP cost of contraction in the plantar flexor muscles

2013 ◽  
Vol 126 (8) ◽  
pp. 581-592 ◽  
Author(s):  
Gwenael Layec ◽  
Joel D. Trinity ◽  
Corey R. Hart ◽  
Seong-Eun Kim ◽  
Henderik Jonathan Groot ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Capacity ◽  
The Elderly ◽  
Plantar Flexor ◽  
Age Related ◽  
Flexor Muscles ◽  
Response To Exercise ◽  
Plantar Flexor Muscles ◽  
Related Increase

The present study reveals that impaired skeletal muscle efficiency potentially contributes to the age-related decline in exercise capacity and may explain the altered haemodynamic response to exercise in the elderly.

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