This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. ...Five researchers presented their results related to infection and Alzheimer's disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the
bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fülöp described the role of AD-associated amyloid beta (Aβ) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD-associated Aβ and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Aβ deposition via formation of non-toxic, soluble Aβ/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Aβ. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the "amyloid cascade hypothesis," which so far has been quite unsuccessful, to a new "infection hypothesis," or perhaps more broadly, "innate immune system dysregulation hypothesis," which may well permit and lead to the discovery of new treatments for AD patients.
What if there’s no such thing as “aging”? Cohen, Alan A.; Legault, Véronique; Fülöp, Tamàs
Mechanisms of ageing and development,
December 2020, 2020-12-00, 20201201, Letnik:
192
Journal Article
Recenzirano
Odprti dostop
•Our mental categories tend to correspond to our linguistic categories.•We argue there is no biological phenomenon that corresponds to the word “aging”.•We show how the concept of “aging” misleads us ...from asking the right questions.•We lay out a path for aging research without the concept of “aging” itself.•We advocate gradual abandonment of the word “aging” in scientific contexts.
Are diseases caused by aging? What are the mechanisms of aging? Do all species age? These hotly debated questions revolve around a unitary definition of aging. Because we use the word “aging” so frequently, both colloquially and scientifically, we rarely pause to consider whether this word maps to an underlying biological phenomenon, or whether it is simply a grab-bag of diverse phenomena linked more by our mental associations than by any underlying biology. Here, we consider how the presence of the colloquial word “aging” generates a cognitive bias towards supposing there is a unitary biological phenomenon. We ask what kind of evidence would support or refute that idea, and subsequently show clear evidence at multiple levels that aging is not a unitary phenomenon. In particular, the known aging pathways lead to heterogeneous outputs, not a single coordinated phenomenon. From levels ranging from cellular/molecular to clinical to demographic to evolutionary, we show how the supposition that aging is a unitary phenomenon can mislead and distract us from asking the best questions. For major sub-disciplines of aging biology, we show how going beyond the notion of unitary aging can hone the paradigm and help advance the pace of discovery.
Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the main actors of this inflammation is monocytes, with the switch in their phenotypes and irregularities ...in their cytokine production. Objective: This study was aimed to investigate the nutraceutical potential of extra virgin olive oil (EVOO) on the inflammatory status of monocytes in participants showing different levels of cardiovascular risk. Methods: 43 participants 65–85 years old were recruited including 14 healthy, 12 dyslipidemic patients with hypercholesterolemia recently diagnosed, and 17 post-infarct patients. Participants from all groups were supplemented with EVOO (25 mL/day) for 6 months. IL-1β, IL-6, IL-10, TNF-α cytokine production, and monocyte phenotypes were investigated both at quiescent and at stimulated state by flow cytometry. Results: At the baseline (pre-intervention), dyslipidemic patients, compared to healthy and post-infarct participants, showed monocytes in an inflammatory state characterized by a significantly weaker IL-10 production. Our results do not show a significant modulation of the phenotype or IL-10, IL-6, and TNF-α production following a 6-month EVOO intake whether at quiescence or under stimulation. However, IL-1β is significantly increased by the intervention of EVOO in post-infarct patients. Paradoxically after the 6-month intervention, monocytes from dyslipidemic patients showed a significantly decreased secretion of IL-1β under LPS stimulation despite the increase observed at basal state. Conclusion: Our results show that 6-month EVOO intervention did not induce a monocyte phenotypic change or that this intervention significantly modifies cytokine production.
Anti-Viral Properties of Amyloid-β Peptides Bourgade, Karine; Dupuis, Gilles; Frost, Eric H ...
Journal of Alzheimer's disease,
10/2016, Letnik:
54, Številka:
3
Journal Article
Recenzirano
Amyloid-β (Aβ) peptides generated by the amyloidogenic pathway of amyloid-β protein precursor processing contribute significantly to neurodegeneration characteristic of Alzheimer's disease (AD). The ...involvement of Aβ peptides in the etiology of AD remains a subject of debate. Data published in the last 6 years by three different groups have added a new twist by revealing that Aβ peptides could act as antimicrobial peptides (AMP) in in vitro assays against some common and clinically relevant microorganisms, inhibit replication of seasonal and pandemic strains of influenza A and HSV-1 virus. These observations are of significance with respect to the notion that pathogens may be important contributors to the development of AD, particularly in the case of herpes simplex virus (HSV) infection, which often resides in the same cerebral sites where AD arises. Here, we review the data that support the interpretation that Aβ peptides behave as AMP, with an emphasis on studies concerning HSV-1 and a putative molecular mechanism that suggests that interactions between Aβ peptides and the HSV-1 fusogenic protein gB lead to impairment of HSV-1 infectivity by preventing the virus from fusing with the plasma membrane. A number of avenues for future research are suggested.
Alzheimer disease (AD) is the most prevalent form of dementia although the underlying cause(s) remains unknown at this time. However, neuroinflammation is believed to play an important role and ...suspected contributing immune parameters can be revealed in studies comparing patients at the stage of amnestic mild cognitive impairment (aMCI) to healthy age-matched individuals. A network of immune regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) maintains immune homeostasis but there are very few data on the role of these cells in AD. Here, we investigated the presence of these cells in the blood of subjects with aMCI and mild AD (mAD) in comparison with healthy age-matched controls. We also quantitated several pro- and anti-inflammatory cytokines in sera which can influence the development and activation of these cells. We found significantly higher levels of MDSCs and Tregs in aMCI but not in mAD patients, as well as higher serum IL-1β levels. Stratifying the subjects based on CMV serostatus that is known to influence multiple immune parameters showed an absence of differences between aMCI subjects compared to mAD patients and healthy controls. We suggest that the increase in MDSCs and Tregs number in aMCI subjects may have a beneficial role in modulating inflammatory processes. However, this protective mechanism may have failed in mAD patients, allowing progression of the disease. This working hypothesis obviously requires testing in future studies.
Background
Accumulating evidence points to the superiority of the MoCA over the MMSE as a cognitive screening tool. To facilitate the transition from the MMSE to the MoCA in clinical and research ...settings, authors have developed MMSE‐MoCA conversion tables. However, it is unknown whether a conversion table generated from Alzheimer's disease (AD) patients would apply to patients with other dementia subtypes like vascular dementia or frontotemporal dementia. Furthermore, the reliability and accuracy of MMSE‐MoCA conversion tables has not been properly evaluated.
Method
We retrospectively examined the MMSE‐MoCA relationship in a large multicenter sample gathered from 3 Memory Clinics in Quebec, Canada (1492 patients). We produced an MMSE‐MoCA conversion table using the equi‐percentile method with log‐linear smoothing. We then cross‐validated our conversion table with the ADNI dataset (1202 patients) and evaluated its accuracy for future predictions.
Results
The MMSE‐MoCA conversion table is consistent with previously published tables and has an intra‐class correlation of 0.633 with the ADNI sample. However, we found that the MMSE‐MoCA relationship is significantly modified by diagnosis (P < .01), with dementia subtypes associated with a dysexecutive syndrome showing a trend towards higher MMSE than other dementia syndromes for a given MoCA score. The large width of 95% confidence interval (CI) for a new prediction suggests questionable reliability for clinical use.
Conclusion
In this study, we validated a conversion table between MMSE and MoCA using a large multicenter sample. Our results suggest caution in interpreting the tables in heterogeneous clinical populations, as the MMSE‐MoCA relationship may be different across dementia subtypes.
Electronic cigarettes (e-cigarettes) for smoking cessation remain controversial.
To evaluate e-cigarettes with individual counseling for smoking cessation.
A randomized clinical trial enrolled adults ...motivated to quit smoking from November 2016 to September 2019 at 17 Canadian sites (801 individuals screened; 274 ineligible and 151 declined). Manufacturing delays resulted in early termination (376/486 participants, 77% of target). Outcomes through 24 weeks (March 2020) are reported.
Randomization to nicotine e-cigarettes (n = 128), nonnicotine e-cigarettes (n = 127), or no e-cigarettes (n = 121) for 12 weeks. All groups received individual counseling.
The primary end point was point prevalence abstinence (7-day recall, biochemically validated using expired carbon monoxide) at 12 weeks, changed from 52 weeks following early termination. Participants missing data were assumed to be smoking. The 7 secondary end points, examined at multiple follow-ups, were point prevalence abstinence at other follow-ups, continuous abstinence, daily cigarette consumption change, serious adverse events, adverse events, dropouts due to adverse effects, and treatment adherence.
Among 376 randomized participants (mean age, 52 years; 178 women 47%), 299 (80%) and 278 (74%) self-reported smoking status at 12 and 24 weeks, respectively. Point prevalence abstinence was significantly greater for nicotine e-cigarettes plus counseling vs counseling alone at 12 weeks (21.9% vs 9.1%; risk difference RD, 12.8 95% CI, 4.0 to 21.6) but not 24 weeks (17.2% vs 9.9%; RD, 7.3 95% CI, -1.2 to 15.7). Point prevalence abstinence for nonnicotine e-cigarettes plus counseling was not significantly different from counseling alone at 12 weeks (17.3% vs 9.1%; RD, 8.2 95% CI, -0.1 to 16.6), but was significantly greater at 24 weeks (20.5% vs 9.9%; RD, 10.6 95% CI, 1.8 to 19.4). Adverse events were common (nicotine e-cigarette with counseling: 120 94%; nonnicotine e-cigarette with counseling: 118 93%; counseling only: 88 73%), with the most common being cough (64%) and dry mouth (53%).
Among adults motivated to quit smoking, nicotine e-cigarettes plus counseling vs counseling alone significantly increased point prevalence abstinence at 12 weeks. However, the difference was no longer significant at 24 weeks, and trial interpretation is limited by early termination and inconsistent findings for nicotine and nonnicotine e-cigarettes, suggesting further research is needed.
ClinicalTrials.gov Identifier: NCT02417467.
Polyethylene glycol (PEG)-coated nanopharmaceuticals can cause mild to severe hypersensitivity reactions (HSRs), which can occasionally be life threatening or even lethal. The phenomenon represents ...an unsolved immune barrier to the use of these drugs, yet its mechanism is poorly understood. This study showed that a single i.v. injection in pigs of a low dose of PEGylated liposomes (Doxebo) induced a massive rise of anti-PEG IgM in blood, peaking at days 7–9 and declining over 6 weeks. Bolus injections of PEG-liposomes during seroconversion resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2–3 min, although similar treatments of naı̈ve animals led to only mild hemodynamic disturbance. Parallel measurement of pulmonary arterial pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement activation, respectively, showed a concordant rise of the two variables within 3 min and a decline within 15 min, suggesting a causal relationship between complement activation and pulmonary hypertension. We also observed a rapid decline of anti-PEG IgM in the blood within minutes, increased binding of PEGylated liposomes to IgM + B cells in the spleen of immunized animals compared to control, and increased C3 conversion by PEGylated liposomes in the serum of immunized pigs. These observations taken together suggest rapid binding of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock and accelerated blood clearance of liposome–IgM complexes. These data suggest that complement activation plays a causal role in severe HSRs to PEGylated nanomedicines and that pigs can be used as a hazard identification model to assess the risk of HSRs in preclinical safety studies.
We describe a network-based method to obtain a subset of representative variables from clinical data of subjects of the second Singapore Longitudinal Aging Study (SLAS-2), while preserving to a good ...extent the predictive performance of the full set with regards to a multi-faceted index of successful aging, SAGE. To examine differences in predictive performance of high-degree nodes ("hubs") and high-centrality ones ("cores"), we implement four subsetting strategies (two degree-based, two centrality-based) and obtain four surrogate sets of variables, which we use as input features for machine learning models to predict the SAGE index of subjects. All four models have variables belonging to the physical, cardiovascular, cognitive and immunological domains among their fifteen most important predictors. A fifth domain (leisure-time activities, LTA) is also present in some form. From a comparison of the surrogate sets' size and predictive performance, a centrality-based approach (selection of the most central variable-nodes within each cluster) yielded the smallest-sized surrogate set, while having high prediction accuracy (measured by its model's area-under-curve, AUC) in comparison to its analogous degree-based strategy (selection of the highest-degree nodes per cluster). Inclusion of the next most-central variables yielded negligible changes in predictive performance while more than doubling the surrogate set size. The centrality-based approach thus yields a surrogate set which offers a good balance between number of variables and prediction performance, and can act as a representative subset of the SLAS-2 clinical dataset.
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