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Neurodegenerative diseases are closely related to inflammatory and autoimmune events, suggesting that the dysregulation of the immune system is a key pathological factor. Both multiple sclerosis (MS) and Alzheimer's disease (AD) are characterized by infiltrating immune cells, activated microglia, astrocyte proliferation, and neuronal damage. Moreover, MS and AD share a common pro-inflammatory signature, characterized by peripheral leukocyte activation and transmigration to the central nervous system (CNS). MS and AD are both characterized by the accumulation of activated neutrophils in the blood, leading to progressive impairment of the blood–brain barrier. Having migrated to the CNS during the early phases of MS and AD, neutrophils promote local inflammation that contributes to pathogenesis and clinical progression. The role of circulating T cells in MS is well-established, whereas the contribution of adaptive immunity to AD pathogenesis and progression is a more recent discovery. Even so, blocking the transmigration of T cells to the CNS can benefit both MS and AD patients, suggesting that common adaptive immunity mechanisms play a detrimental role in each disease. There is also growing evidence that regulatory T cells are beneficial during the initial stages of MS and AD, supporting the link between the modulatory immune compartments and these neurodegenerative disorders. The number of resting regulatory T cells declines in both diseases, indicating a common pathogenic mechanism involving the dysregulation of these cells, although their precise role in the control of neuroinflammation remains unclear. The modulation of leukocyte functions can benefit MS patients, so more insight into the role of peripheral immune cells may reveal new targets for pharmacological intervention in other neuroinflammatory and neurodegenerative diseases, including AD.

Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer’s disease (AD). However, the underlying pathogenetic mechanisms are still much disputed. Several endogenous neurotoxic ligands, including Aβs, and/or p-Tau-es activate innate immunity-related danger-sensing/pattern recognition receptors (PPRs) thereby advancing AD’s neuroinflammation and progression. The major PRR families involved include scavenger, Toll-like, NOD-like, AIM2-like, RIG-like, and CLEC-2 receptors, plus the calcium-sensing receptor (CaSR). This quite intricate picture stresses the need to identify the pathogenetically topmost Aβ-activated PRR, whose signaling would trigger AD’s three main drivers and their intra-brain spread. In theory, the candidate might belong to any PRR family. However, results of preclinical studies using in vitro nontumorigenic human cortical neurons and astrocytes and in vivo AD-model animals have started converging on the CaSR as the pathogenetically upmost PRR candidate. In fact, the CaSR binds both Ca2+ and Aβs and promotes the spread of both Ca2+ dyshomeostasis and AD’s three main drivers, causing a progressive neurons’ death. Since CaSR’s negative allosteric modulators block all these effects, CaSR’s candidacy for topmost pathogenetic PRR has assumed a growing therapeutic potential worth clinical testing.

AbstractWe developed a novel interpretable biological heart age estimation model using cardiovascular magnetic resonance radiomics measures of ventricular shape and myocardial character. We included 29,996 UK Biobank participants without cardiovascular disease. Images were segmented using an automated analysis pipeline. We extracted 254 radiomics features from the left ventricle, right ventricle, and myocardium of each study. We then used Bayesian ridge regression with tenfold cross-validation to develop a heart age estimation model using the radiomics features as the model input and chronological age as the model output. We examined associations of radiomics features with heart age in men and women, observing sex-differential patterns. We subtracted actual age from model estimated heart age to calculate a “heart age delta”, which we considered as a measure of heart aging. We performed a phenome-wide association study of 701 exposures with heart age delta. The strongest correlates of heart aging were measures of obesity, adverse serum lipid markers, hypertension, diabetes, heart rate, income, multimorbidity, musculoskeletal health, and respiratory health. This technique provides a new method for phenotypic assessment relating to cardiovascular aging; further studies are required to assess whether it provides incremental risk information over current approaches.

OBJECTIVES: As part of the multinational Burden of Lung Disease (BOLD) survey, this study investigated the flavonoid content and agreement levels of foods included in BOLD's food frequency questionnaire (FFQ), using four international flavonoid composition tables. METHODS: The USDA (American), BioActive Substances in Food Information System (eBASIS; European), Indian Food Composition (IFCT), and Phenol-Explorer (European) Tables were selected for their comparable data on five subclasses of flavonoids (flavan-3-ols, flavanones, flavones, flavonols, and isoflavones). Flavonoid estimates were derived for all foods available in each table (n = 117 USDA; n = 77 eBASIS; n = 69 IFCT; n = 90 Phenol-Explorer), and comparisons were carried out for foods common between tables. Percentage differences of flavonoid content were calculated, and intra-class correlation coefficients (ICCs; 95% confidence intervals [95%CI]) estimated. ICC reliability was categorized as low (0.90). RESULTS: Compared to the USDA Table, total flavonoid content was overestimated by 181.5%, 14.1%, and 26.5%, in the eBASIS, IFCT, and Phenol-Explorer tables, respectively. Compared to Phenol-Explorer, total flavonoid content was overestimated by 53.0% in eBASIS and by 29.6% in IFCT. The reliability for total flavonoid content between the USDA and Phenol-Explorer tables was moderate (ICC 0.51; 95% CI 0.33, 0.65), low between Phenol-Explorer and eBASIS (ICC 0.27; 95% CI 0.02, 0.49), and low between Phenol-Explorer and IFCT (ICC 0.22, 95%CI −0.07, 0.48). There was good-to-excellent reliability between USDA and Phenol-Explorer for flavanones and flavones (ICC 0.93; 95%CI 0.82, 0.98; and ICC 0.86; 95%CI 0.73, 0.93, respectively). Phenol-Explorer and IFCT showed good reliability for flavanone and flavanol subclasses. ICCs for other subclasses was low across tables. CONCLUSIONS: Flavonoid estimates varied considerably across international tables. These differences should be taken into consideration when deriving flavonoid content in population-based surveys. FUNDING SOURCES: MAA is funded by the European Union's Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie Grant Agreement). The UK's Medical Research Council (MR/R011192/1) funds the BOLD stud.

Recent evidence suggests that shorter telomere length (TL) is associated with neuro degenerative diseases and aging related outcomes. The causal association between TL and brain characteristics represented by image derived phenotypes (IDPs) from different magnetic resonance imaging (MRI) modalities remains unclear. Here, we use two-sample Mendelian randomization (MR) to systematically assess the causal relationships between TL and 3,935 brain IDPs. Overall, the MR results suggested that TL was causally associated with 193 IDPs with majority representing diffusion metrics in white matter tracts. 68 IDPs were negatively associated with TL indicating that longer TL causes decreasing in these IDPs, while the other 125 were associated positively (longer TL leads to increased IDPs measures). Among them, ten IDPs have been previously reported as informative biomarkers to estimate brain age. However, the effect direction between TL and IDPs did not reflect the observed direction between aging and IDPs: longer TL was associated with decreases in fractional anisotropy and increases in axial, radial and mean diffusivity. For instance, TL was positively associated with radial diffusivity in the left perihippocampal cingulum tract and with mean diffusivity in right perihippocampal cingulum tract. Our results revealed a causal role of TL on white matter integrity which makes it a valuable factor to be considered when brain age is estimated and investigated.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer with an overall 5-year survival rate of less than 9%. The high aggressiveness of PDAC is linked to the presence of a subpopulation of cancer cells with a greater tumorigenic capacity, generically called cancer stem cells (CSCs). CSCs present a heterogeneous metabolic profile that might be supported by an adaptation of mitochondrial function; however, the role of this organelle in the development and maintenance of CSCs remains controversial. To determine the role of mitochondria in CSCs over longer periods, which may reflect more accurately their quiescent state, we studied the mitochondrial physiology in CSCs at short-, medium-, and long-term culture periods. We found that CSCs show a significant increase in mitochondrial mass, more mitochondrial fusion, and higher mRNA expression of genes involved in mitochondrial biogenesis than parental cells. These changes are accompanied by a regulation of the activities of OXPHOS complexes II and IV. Furthermore, the protein OPA1, which is involved in mitochondrial dynamics, is overexpressed in CSCs and modulates the tumorsphere formation. Our findings indicate that CSCs undergo mitochondrial remodeling during the stemness acquisition process, which could be exploited as a promising therapeutic target against pancreatic CSCs.