Early detection of dementia with fMRI
Why we are interested: The incidence of dementia is on the rise, with Alzheimer’s disease (AD) being the most common cause. Early detection of brain changes associated with dementia would provide the opportunity for early interventions to slow or disrupt the disease process. Previous work has indicated that changes in functional connectivity between certain brain regions are apparent via MRI in high-risk populations relative to healthy populations, even before the onset of cognitive symptoms. However, prior to this study, it wasn’t clear whether these changes could be used at the level of the individual to predict future dementia risk.
What this study showed: This nested case-control study employed functional MRI scans during a resting state (rs-fMRI) along with computer modeling to map effective connectivity in 103 dementia cases (22 individuals with prevalent dementia and 81 who later developed dementia over the 9-year follow-up) and 1,030 matched controls. The researchers focused their investigations on the brain’s default-mode network (DMN), a network of brain areas thought to be particularly susceptible to AD pathology, and identified 15 connectivity parameters which could be used to predict future dementia. Use of effective connectivity maps in the DMN was found to be superior to other prognostication models (e.g., volumes of brain regions associated with AD, cognitive scores) in predicting future dementia incidence, with an area under the receiver operator characteristic (AUROC) of 0.82, indicating performance well above chance (which would correspond to an AUROC of 0.5). This work suggests that using rs-fMRI to determine effective connectivity could become a tool for identifying signatures of dementia risk early in the course of disease, prior to cognitive symptoms.
doi: 10.1038/s44220-024-00259-5
Pentadecanoic acid demonstrates potential as a geroprotective molecule
Why we are interested: The identification of molecules with anti-aging and disease-preventing effects has obvious value for the pursuit of longer, healthier lives while also offering insights into the cellular mechanisms that underlie aging and disease. This study investigated how pentadecanoic acid (C15:0), an essential saturated fatty acid found in milk fat, compared with more established geroprotective molecules in combating cellular processes related to aging and chronic disease development.
What this study showed: This study utilized Eurofins BioMAP Diversity PLUS assay system to test C15:0 and more established longevity molecules (rapamycin, metformin, and acarbose, all discussed with Rich Miller in episode #281) in 12 human cell-based systems (a total of 148 assays) to characterize their effects on various cellular activities related to inflammation, fibrosis, immune function, and other processes related to aging and chronic disease. Each compound was assessed at various doses to assess dose-response relationships.
Results showed that C15:0 and rapamycin performed comparably in promoting positive, dose-dependent, clinically relevant effects across the activities tested, with C15:0 showing significant effects for 36 activities in 10 of 12 cell systems and rapamycin showing significant effects in 32 activities in 12 of 12 cell systems. Both compounds outperformed metformin (17 activities) and acarbose (5 activities). C15:0 and rapamycin, both of which inhibit mTOR, were found to share many cellular processes, overlapping in 24 significant activities including reductions in markers of chronic inflammation, cell proliferation, autoimmune activity, fibrosis, and others. These results indicate that C15:0 can counteract cellular processes related to aging and disease to a comparable degree as rapamycin, suggesting that C15:0 may therefore have positive effects on longevity, though follow-up animal studies are required in order to test net effects on lifespan.
doi: 10.3390/nu15214607
Enzymes from gut bacteria used to generate ABO-universal blood
Why we are interested: Blood transfusions save millions of lives every year, but matching the ABO blood groups of donor red blood cells (RBCs) and recipients is critical to avoid a systemic immune response by the recipient against the donor blood. ABO blood groups differ on the antigens found on their exterior, and the recipient immune system recognizes and attacks RBCs with foreign antigens. Blood types A and B have additional antigens in comparison to type O, which, because of the absence of these other antigens, can therefore be used universally in a medical emergency when a patient’s blood type is unknown.
What this study showed: Enzymes can be used to convert group A and/or group B RBCs to the ABO-universal group O blood type by degrading the additional antigens. This type of enzymatically processed blood is called ECO blood. Early trials of enzymatic production of ECO blood had problems with unexplained reactions with recipient plasma, now thought to be caused by extended antigens that were not degraded in this initial process. This study reports the discovery of enzymes sourced from bacteria found in the human gut, Akkermansia muciniphila, to remove the extended antigens found on type A and type B RBCs. This strain of bacteria exclusively degrades intestinal mucins, a family of heavily glycosylated proteins, as energy sources, and since intestinal mucins have the same ABO antigens on their surfaces, enzymes found within Akkermansia would likely be able to degrade antigens found on the surface of RBCs – a hypothesis put to the test by this study.
As discussed in my discussion with Colleen Cutcliffe in episode #283, Akkermansia is notoriously difficult to culture, as it requires an anaerobic environment. However, once the enzymes were extracted and purified, the conversion of type A and type B RBCs to type O was performed in 30 minutes at room temperature, conditions that suggest clinical feasibility. The enzymes were removed post-treatment to avoid any adverse carryover effects. The degradation of A, B, and extended antigens greatly reduced the number of incompatible O plasmas, although more optimization is required to reduce incompatibilities further. This work offers a way forward for the production of ABO-universal blood, a potential solution during blood shortages.
doi: 10.1038/s41564-024-01663-4
An immunotherapy target to reduce T cell exhaustion in cancer
Why we are interested: As detailed in past podcast episodes, the development of immune checkpoint inhibitors has constituted a major advance in immunotherapy treatment of many cancers. Cancer cells often evade destruction by the body’s immune system by activating immune checkpoints which inhibit T cell responses. Immune checkpoint inhibitors block these inhibitory signals, thus allowing T cells to kill tumor cells. However, chronic T cell activation can lead to a physiologic state called “T cell exhaustion,” in which T cells are no longer able to kill cancer cells. Enhancing the effectiveness of checkpoint inhibitor therapy therefore depends on gaining a better understanding of the processes that control T cell exhaustion.
What this study showed: This study characterized a connection between the sympathetic stress response, tissue innervation, and CD8+ T cell exhaustion. Catecholamines (noradrenaline and adrenaline, also called norepinephrine and epinephrine) are released by the activation of sympathetic (i.e., “fight or flight”) nerves and activate β-adrenergic receptors, such as ADRB1. Not surprisingly, the chronic stress of malignant disease is associated with increased levels of catecholamines.
The authors showed that terminally exhausted CD8+ T cells exhibit increased expression of ADRB1, and in some disease models, these T cells were positioned closer to sympathetic nerves than their non-exhausted counterparts. However, the deletion of Adrb1 (the gene encoding the ADRB1 receptor) promoted the maintenance of progenitor T cells (stem-like T cells) and impaired migration toward sympathetic nerves. Similarly, the use of β-blockers selective for ADRB1 promoted T cell effector function and reduced T cell exhaustion. Tumor-infiltrating lymphocytes (TILs) showed high expression of Adrb1 in mouse models of colon cancer and immune checkpoint blockade (ICB)-responsive melanoma. Blockade of ADRB1 signaling in combination with ICB provided synergistic benefits, and the investigators observed smaller tumors and increased cytokine production by CD8+ T cells. In other words, blockade of ADRB1 improved T cells’ ability to fight cancer cells, as predicted by the mechanistic experiments demonstrating reduced T cell exhaustion.
This study proposes that ADRB1 is a new immune checkpoint that is expressed by exhausted T cells. The adrenergic signaling via ADRB1 of a chronic stress response contributes to the terminal differentiation of exhausted T cells. Targeting adrenergic receptors in combination with ICB may be effective in promoting anti-tumor T cell responses and reducing T cell exhaustion.
doi: 10.1038/s41586-023-06568-6
Intragastric expandable oral capsules for weight loss, phase 3 trial
Why we are interested: Obesity remains a major global health concern and raises one’s risk of many chronic diseases including type 2 diabetes, metabolic disease, cardiovascular disease, and cancer. The development of novel, effective treatment options has the potential to improve the quality and length of countless lives, as well as to advance our understanding of the pathogenesis of obesity and the physiological mechanisms underlying appetite and satiation.
What the study showed: This phase 3, double-blind randomized trial was based on the premise that satiety can be induced if a substantial volume of the stomach is full, regardless of whether the fullness results from caloric food or a non-caloric substance. Participants with BMIs between 24-40 kg/m2 across six Chinese hospitals were randomized to treatment with either placebo capsules (n=137) or expandable oral capsules (carboxymethylcellulose cross-linked with citric acid) which absorb water, forming a gel that expands to occupy approximately one-quarter of the stomach volume (n=140). Four capsules were taken with water every day before lunch and dinner for 24 weeks, and at the end of the trial, mean weight change among all participants randomized to the expandable capsules was –4.9%±5.4% and –1.9%±4.5% among those randomized to placebo (P<0.001). When analysis was restricted to those who completed the full treatment protocol, mean body weight change at week 24 was –6.1%±5.4% for the expandable capsule group (n=111) and −2.5%±4.5% for the placebo group (n=103), again demonstrating superior weight loss among the treatment group.
Mild gastrointestinal discomfort was the most common adverse event reported in both groups and did not differ significantly between treatments (25% in the expandable capsule group versus 21.9% in the placebo group). The gel used in this study is pH-sensitive, which enables it to degrade in the colon where the released water is reabsorbed and the hydrogel is expelled in feces. Of note, this gel is similar to the FDA-approved hydrogel Plenity, which has also been shown in a six-month trial to improve weight loss relative to placebo.
doi: 10.1111/dom.15418
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