RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1ß- and RNA-dependent co-activator of osteoclast gene expression.

The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1ß with the NCoR/HDAC3 complex, resulting in the activation of PGC1ß and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis.

A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. It has been difficult to find safe ways to steer the targeting of natural regulatory antigen. Here, we show that the administration of exogenous mouse major histocompatibility complex class II protein bounding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen-specific TCR through a positively charged tag. This leads to expanding a VISTA-positive nonconventional regulatory T cells, resulting in a potent dominant suppressive effect and protection against arthritis in mice. The therapeutic effect is dominant and tissue specific as the suppression can be transferred with regulatory T cells, which downregulate various autoimmune arthritis models including antibody-induced arthritis. Thus, the tolerogenic approach described here may be a promising dominant antigen-specific therapy for rheumatoid arthritis, and in principle, for autoimmune diseases in general.

White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

Differential atrophy along the longitudinal hippocampal axis in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the hippocampus. Since hippocampal studies have highlighted a differential subregional regulation along its longitudinal axis, a more detailed analysis addressing subregional changes along the longitudinal hippocampal axis has the potential to provide new relevant biomarkers. This study included structural brain MRI data of 583 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cognitively normal (CN) subjects, mild cognitively impaired (MCI) subjects and AD patients were conveniently selected considering the age and sex match between clinical groups. Structural MRI acquisitions were pre-processed and analysed with a new longitudinal axis segmentation method, dividing the hippocampus in three subdivisions (anterior, intermediate, and posterior). When normalizing the volume of hippocampal sub-divisions to total hippocampus, the posterior hippocampus negatively correlates with age only in CN subjects (r = -.31). The longitudinal ratio of hippocampal atrophy (anterior sub-division divided by the posterior one) shows a significant increase with age only in CN (r = .25). Overall, in AD, the posterior hippocampus is predominantly atrophied early on. Consequently, the anterior/posterior hippocampal ratio is an AD differentiating metric at early disease stages with potential for diagnostic and prognostic applications.

Interleukin 33 supports squamous cell carcinoma growth via a dual effect on tumour proliferation, migration and invasion, and T cell activation.

Interleukin (IL)-33 is an important cytokine in the tumour microenvironment; it is known to promote the growth and metastasis of solid cancers, such as gastric, colorectal, ovarian and breast cancer. Our group demonstrated that the IL-33/ST2 pathway enhances the development of squamous cell carcinoma (SCC). Conversely, other researchers have reported that IL-33 inhibits tumour progression. In addition, the crosstalk between IL-33, cancer cells and immune cells in SCC remains unknown. The aim of this study was to investigate the effect of IL-33 on the biology of head and neck SCC lines and to evaluate the impact of IL-33 neutralisation on the T cell response in a preclinical model of SCC. First, we identified epithelial and peritumoural cells as a major local source of IL-33 in human SCC samples. Next, in vitro experiments demonstrated that the addition of IL-33 significantly increased the proliferative index, motility and invasiveness of SCC-25 cells, and downregulated MYC gene expression in SCC cell lines. Finally, IL-33 blockade significantly delayed SCC growth and led to a marked decrease in the severity of skin lesions. Importantly, anti-IL-33 monoclonal antibody therapy increase the percentage of CD4+IFNγ+ T cells and decreased CD4+ and CD8+ T cells secreting IL-4 in tumour-draining lymph nodes. Together, these data suggest that the IL-33/ST2 pathway may be involved in the crosstalk between the tumour and immune cells by modulating the phenotype of head and neck SCC and T cell activity. IL-33 neutralisation may offer a novel therapeutic strategy for SCC.

Combining Advanced Analytical Methodologies to Uncover Suspect PFAS and Fluorinated Pharmaceutical Contributions to Extractable Organic Fluorine in Human Serum (Tromsø Study).

A growing number of studies have reported that routinely monitored per- and polyfluoroalkyl substances (PFAS) are not sufficient to explain the extractable organic fluorine (EOF) measured in human blood. In this study, we address this gap by screening pooled human serum collected over 3 decades (1986-2015) in Tromsø (Norway) for >5000 PFAS and >300 fluorinated pharmaceuticals. We combined multiple analytical techniques (direct infusion Fourier transform ion cyclotron resonance mass spectrometry, liquid chromatography-Orbitrap-high-resolution mass spectrometry, and total oxidizable precursors assay) in a three-step suspect screening process which aimed at unequivocal suspect identification. This approach uncovered the presence of one PFAS and eight fluorinated pharmaceuticals (including some metabolites) in human serum. While the PFAS suspect only accounted for 2-4% of the EOF, fluorinated pharmaceuticals accounted for 0-63% of the EOF, and their contribution increased in recent years. Although fluorinated pharmaceuticals often contain only 1-3 fluorine atoms, our results indicate that they can contribute significantly to the EOF. Indeed, the contribution from fluorinated pharmaceuticals allowed us to close the organofluorine mass balance in pooled serum from 2015, indicating a good understanding of organofluorine compounds in humans. However, a portion of the EOF in human serum from 1986 and 2007 still remained unexplained.

Isolation and characterisation of Leishmania (Leishmania) infantum from cutaneous leishmaniasis patients in northeast Brazil.

BACKGROUND: In Brazil, Leishmania (Leishmania) infantum is a widely distributed protozoan parasite. The human leishmaniasis caused by this species is often associated with visceral form. Tegumentary leishmaniasis (TL) cases due to L. (L.) infantum in the country are considered rare but may be underestimated. Although probably uncommon, these cases represent a new challenge to the prevention and control of leishmaniasis. OBJECTIVES: Here, we describe two distinct cases of TL with atypical clinical presentations caused by L. (L.) infantum. METHODS AND FINDINGS: Parasites were isolated from cutaneous lesions of the two patients and typed as L. (L.) infantum after sequencing of the ribosomal DNA internal transcribed spacer. The dermotropic L. (L.) infantum isolates were compared in terms of growth culture patterns, metacyclogenesis and in vitro infectivity in macrophages. MAIN CONCLUSIONS: This study addresses the emergence of L. (L.) infantum as a causative agent of cutaneous disease in a visceral leishmaniasis hotspot located in northeast Brazil. The data presented provides novel information about the presence of dermotropic L. (L.) infantum in the country and demonstrates the infectivity potential of theses isolates.

De Novo Human Angiotensin-Converting Enzyme 2 Decoy NL-CVX1 Protects Mice From Severe Disease After Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.

Effects of Mannosylerythritol-Lipids-B on Cutibacterium acnes ATCC 6919.

Mannosylerythritol-lipids-B (MEL-B) are microbial-produced glycolipids with skincare properties, notably moisturizing, antimelanogenic, antimicrobial, and antiaging. Thus, there is a potential use of MEL-B in a formulation for treating acne-prone skin. This study investigated the antimicrobial effect of MEL-B against the Gram-positive bacteria Cutibacterium acnes. The broth macro dilution method was used to evaluate the growth of C. acnes (3-4 CFU/mL), in the absence (positive control) or presence of MEL-B (128, 192, 256, and 512 µg/mL). Additionally, the leakage of genetic materials was used to determine the potential drug-induced membrane disruption of glycolipids. The amount of DNA and RNA release was quantified spectrophotometrically at 260 nm. Macro dilution technique and membrane integrity experiments showed that MEL-B does not have antimicrobial activity against C. acnes. Indeed, MEL-B assisted C. acnes growth. Ultimately, MEL-B has been reported as a remarkably active compound for skincare formulations; however, preliminarily, it should be avoided for acneic skin.

FOXO1 represses PPARα-Mediated induction of FGF21 gene expression.

Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARα and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARα. Here we show that FoxO1 represses PPARα-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARα target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARα and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARα-interacting protein that antagonizes PPARα activity on the FGF21 promoter. Because other PPARα target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARα-dependent manner.

Regeneration of starfish radial nerve cord restores animal mobility and unveils a new coelomocyte population.

The potential to regenerate a damaged body part is expressed to a different extent in animals. Echinoderms, in particular starfish, are known for their outstanding regenerating potential. Differently, humans have restricted abilities to restore organ systems being dependent on limited sources of stem cells. In particular, the potential to regenerate the central nervous system is extremely limited, explaining the lack of natural mechanisms that could overcome the development of neurodegenerative diseases and the occurrence of trauma. Therefore, understanding the molecular and cellular mechanisms of regeneration in starfish could help the development of new therapeutic approaches in humans. In this study, we tackle the problem of starfish central nervous system regeneration by examining the external and internal anatomical and behavioral traits, the dynamics of coelomocyte populations, and neuronal tissue architecture after radial nerve cord (RNC) partial ablation. We noticed that the removal of part of RNC generated several anatomic anomalies and induced behavioral modifications (injured arm could not be used anymore to lead the starfish movement). Those alterations seem to be related to defense mechanisms and protection of the wound. In particular, histology showed that tissue patterns during regeneration resemble those described in holothurians and in starfish arm tip regeneration. Flow cytometry coupled with imaging flow cytometry unveiled a new coelomocyte population during the late phase of the regeneration process. Morphotypes of these and previously characterized coelomocyte populations were described based on IFC data. Further studies of this new coelomocyte population might provide insights on their involvement in radial nerve cord regeneration.

Perceived stress modulates the activity between the amygdala and the cortex.

The significant link between stress and psychiatric disorders has prompted research on stress's impact on the brain. Interestingly, previous studies on healthy subjects have demonstrated an association between perceived stress and amygdala volume, although the mechanisms by which perceived stress can affect brain function remain unknown. To better understand what this association entails at a functional level, herein, we explore the association of perceived stress, measured by the PSS10 questionnaire, with disseminated functional connectivity between brain areas. Using resting-state fMRI from 252 healthy subjects spanning a broad age range, we performed both a seed-based amygdala connectivity analysis (static connectivity, with spatial resolution but no temporal definition) and a whole-brain data-driven approach to detect altered patterns of phase interactions between brain areas (dynamic connectivity with spatiotemporal information). Results show that increased perceived stress is directly associated with increased amygdala connectivity with frontal cortical regions, which is driven by a reduced occurrence of an activity pattern where the signals in the amygdala and the hippocampus evolve in opposite directions with respect to the rest of the brain. Overall, these results not only reinforce the pathological effect of in-phase synchronicity between subcortical and cortical brain areas but also demonstrate the protective effect of counterbalanced (i.e., phase-shifted) activity between brain subsystems, which are otherwise missed with correlation-based functional connectivity analysis.

Effect of kombucha intake on the gut microbiota and obesity-related comorbidities: A systematic review.

Kombucha is a fermented nonalcoholic tea-based beverage produced through a symbiotic culture of bacteria and yeasts. In vitro studies have demonstrated antimicrobial, antioxidant, antiproliferative, and anti-carcinogenic properties of kombucha. However, no systematic reviews have evaluated the effects of kombucha in vivo. Thus, we aimed to evaluate the evidence that exists so far about kombucha consumption on comorbidities associated with obesity as well as on the gut microbiota. The search was conducted in accordance with PRISMA and the protocol was registered in PROSPERO (registration number: CRD42020158917). The MEDLINE/PubMed, Web of Science, LILACS, SciELO, Scopus, and Science Direct databases were used in the search considering the following terms: "kombucha" OR "kombucha tea" OR "kombucha teas" OR "tea, kombucha" OR "teas, kombucha" NOT "review." Fifteen studies were included in this review. The results suggest that kombucha consumption attenuates oxidative stress and inflammation, improves the liver detoxification process, and reduces intestinal dysbiosis. There is evidence that kombucha consumption is beneficial for the control and treatment of obesity and associated comorbidities, as well as for the modulation of the gut microbiota in vivo.

Talaromyces marneffei isolated from nasal swabs in Portugal.

Mycobiota are essential to the health of any living being, creating a balanced and complex interaction between bacteria, the immune system, and the tissue cells of the host. Talaromyces marneffei (also known as Penicillium marneffei) is a dimorphic fungus, endemic in South Asia, which often causes a life-threatening systemic fungal infection (called penicilliosis), particularly in immunocompromised hosts. Nasal swabs from 73 healthy volunteers were analysed to characterize their mycobiota, through its cultural characteristics, morphology, and molecular methods (PCR). All volunteers were also asked to answer to an anonymous questionnaire. Three women were positive (and asymptomatic) for T. marneffei. One of them was reported to have lupus. This study contributes to improving our knowledge about human normal mycobiota, identifying mycotic agents that may cause complicated systemic infections (as T. marneffei), especially in immunosuppressed patients, as well as other possible risk factors of exposure or prognosis.

• Talaromyces marneffei is a zoonotic fungus that may be responsible for life-threatening systemic infections in immune-comprised patients. • Talaromyces marneffei was identified in nasal swabs from asymptomatic volunteers. • This suggests that this fungus may be part of the nasal normal mycobiota of some humans.

Fluorine Mass Balance, including Total Fluorine, Extractable Organic Fluorine, Oxidizable Precursors, and Target Per- and Polyfluoroalkyl Substances, in Pooled Human Serum from the Tromsø Population in 1986, 2007, and 2015.

Of the thousands of per- and polyfluoroalkyl substances (PFAS) known to exist, only a small fraction (≤1%) are commonly monitored in humans. This discrepancy has led to concerns that human exposure may be underestimated. Here, we address this problem by applying a comprehensive fluorine mass balance (FMB) approach, including total fluorine (TF), extractable organic fluorine (EOF), total oxidizable precursors (TOP), and selected target PFAS, to human serum samples collected over a period of 28 years (1986, 2007, and 2015) in Tromsø, Norway. While concentrations of TF did not change between sampling years, EOF was significantly higher in 1986 compared to 2007 and 2015. The ∑12PFAS concentrations were highest in 2007 compared to 1986 and 2015, and unidentified EOF (UEOF) decreased from 1986 (46%) to 2007 (10%) and then increased in 2015 (37%). While TF and EOF were not influenced by sex, women had higher UEOF compared to men, opposite to target PFAS. This is the first FMB in human serum to include TOP, and it suggests that precursors with >4 perfluorinated carbon atoms make a minor contribution to EOF (0-4%). Additional tools are therefore needed to identify substances contributing to the UEOF in human serum.

Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses.

Invariant natural killer T (iNKT) cells serve as early rapid responders in the innate immune response to self-derived autoantigens and pathogen-derived danger signals and antigens. iNKT cells can serve both as helpers for effector B cells and negatively regulate autoreactive B cells. Specifically, iNKT cells drive B cell proliferation, class switch, and antibody production to induce primary antigen-specific immune responses. On the other hand, inflammasome-mediated activation drives accumulation of neutrophils, which license iNKT cells to negatively regulate autoreactive B cells via Fas ligand (FasL). This positions iNKT cells at an apex to support or inhibit B cell responses in inflammation. However, it is unknown which effector mechanism dominates in the face of cognate glycolipid activation during chronic inflammation, as might result from glycolipid vaccination or infection during chronic autoimmune disease. We stimulated iNKT cells by cognate glycolipid antigen α-galactosylceramide (αGalCer) and measured B cell activation during interleukin 18 (IL-18)-induced chronic inflammation. Moreover, glycolipid-activated iNKT cells increased the serum concentration of autoantibodies, frequency of germinal center (GC) B cells, and antigen-specific plasma cells induced during chronic IL-18-mediated inflammation, as compared with IL-18 alone. Further, activation of iNKT cells via cognate glycolipid during IL-18-mediated inflammation overrides the licensing function of neutrophils, instead inducing iNKT follicular helper (iNKTfh) cells that in turn promote autoimmunity. Thus, our data demonstrate that glycolipids which engage iNKT cells support antigen-specific B cell help during inflammasome-mediated inflammation.

Biological Consequences of Vanadium Effects on Formation of Reactive Oxygen Species and Lipid Peroxidation.

Lipid peroxidation (LPO), a process that affects human health, can be induced by exposure to vanadium salts and compounds. LPO is often exacerbated by oxidation stress, with some forms of vanadium providing protective effects. The LPO reaction involves the oxidation of the alkene bonds, primarily in polyunsaturated fatty acids, in a chain reaction to form radical and reactive oxygen species (ROS). LPO reactions typically affect cellular membranes through direct effects on membrane structure and function as well as impacting other cellular functions due to increases in ROS. Although LPO effects on mitochondrial function have been studied in detail, other cellular components and organelles are affected. Because vanadium salts and complexes can induce ROS formation both directly and indirectly, the study of LPO arising from increased ROS should include investigations of both processes. This is made more challenging by the range of vanadium species that exist under physiological conditions and the diverse effects of these species. Thus, complex vanadium chemistry requires speciation studies of vanadium to evaluate the direct and indirect effects of the various species that are present during vanadium exposure. Undoubtedly, speciation is important in assessing how vanadium exerts effects in biological systems and is likely the underlying cause for some of the beneficial effects reported in cancerous, diabetic, neurodegenerative conditions and other diseased tissues impacted by LPO processes. Speciation of vanadium, together with investigations of ROS and LPO, should be considered in future biological studies evaluating vanadium effects on the formation of ROS and on LPO in cells, tissues, and organisms as discussed in this review.

Immediate effects of Dynamic Tape™ on hip muscle activation and torque and on lower limb kinematics: A randomized controlled clinical trial.

This study aimed to evaluate the immediate effect of Dynamic TapeTM (DT) on hip muscle activation and torque and on lower limb kinematics. Forty-five healthy, recreationally active women were randomly assigned to three groups: 1) submitted to the application of DT in the active form in the gluteus medius (GMed) muscle (BG; n = 15), 2) submitted to the application of DT in the placebo form in the GMed muscle (PG; n = 15), and 3) not submitted to any intervention (CG; n = 15). Participants were evaluated for GMed and gluteus maximus (GMax) muscle activation in a maximal voluntary isometric contraction, simultaneously with the assessment of the hip abductor and extensor torques, as well as during two functional tasks - single leg squat (SLS) and jump landing + maximum vertical jump (VJ) - simultaneously with a 2-D kinematic assessment of the lower limb. After DT application in BG, there was a significant decrease in the hip abductor time to peak torque (P = 0.004), hip extensor torque (P = 0.02), excursion to hip adduction (P = 0.007), and to knee flexion (P = 0.02) during the SLS, as well as in GMed activation during VJ (P < 0.05). DT was able to reduce GMed activation and modify lower limb torque and kinematics.

Association of amygdala size with stress perception: Findings of a transversal study across the lifespan.

Daily routines are getting increasingly stressful. Interestingly, associations between stress perception and amygdala volume, a brain region implicated in emotional behaviour, have been observed in both younger and older adults. Life stress, on the other hand, has become pervasive and is no longer restricted to a specific age group or life stage. As a result, it is vital to consider stress as a continuum across the lifespan. In this study, we investigated the relationship between perceived stress and amygdala size in 272 healthy participants with a broad age range. Participants were submitted to a structural magnetic resonance imaging (MRI) to extract amygdala volume, and the Perceived Stress Scale (PSS) scores were used as the independent variable in volumetric regressions. We found that perceived stress is positively associated with the right amygdala volume throughout life.

Magnetic resonance elastography of the ageing brain in normal and demented populations: A systematic review.

The aim of this systematic review was to evaluate the ability of magnetic resonance elastography (MRE) to identify significant changes in brain mechanical properties during normal and pathological aging. PubMed, Web of Science and Scopus were searched for human studies using MRE to assess brain mechanical properties in cognitively healthy individuals, individuals at risk of dementia or patients diagnosed with dementia. Study characteristics, sample demographics, clinical characterization and main MRE outcomes were summarized in a table. A total of 19 studies (nine aging, 10 dementia), comprising 700 participants, were included. The main findings were decreased cerebral stiffness along aging, with rates of annual change ranging from -0.008 to -0.025 kPa per year. Also, there were regional differences in the age effect on brain stiffness. Concerning demented patients, differential patterns of stiffness were found for distinct dementia subtypes. Alzheimer's disease and frontotemporal dementia exhibited decreased brain stiffness in comparison to cognitively healthy controls and significant declines were found in regions known to be affected by the disease. In normal pressure hydrocephalus, the results were not consistent across studies, and in dementia with Lewy bodies no significant differences in brain stiffness were found. In conclusion, aging is characterized by the softening of brain tissue and this event is even more pronounced in pathological aging, such as dementia. MRE technique could be applied as a sensible diagnostic tool to identify deviations from normal aging and develop new brain biomarkers of cognitive decline/dementia that would help promote healthier cognitive aging.