Neuroinflammation: A Modifiable Pathway Linking Obesity, Alzheimer's disease, and Depression.

Obesity, depression and Alzheimer's disease (AD) are three major interrelated modern health conditions with complex relationships. Early-life depression may serve as a risk factor for AD, while late-life depression may be a prodrome of AD. Depression affects approximately 23% of obese individuals, and depression itself raises the risk of obesity by 37%. Mid-life obesity independently increases AD risk, while late-life obesity, particularly metabolically healthy obesity, may offer protection against AD pathology. Chronic inflammation serves as a key mechanism linking obesity, AD, and depression, encompassing systemic inflammation from metabolic disturbances, immune dysregulation through the gut microbiome, and direct interactions with amyloid pathology and neuroinflammation. In this review, we explore the biological mechanisms of neuroinflammation in relation to obesity, AD, and depression. We assess the efficacy of therapeutic interventions targeting neuroinflammation and discuss current and future radiological imaging initiatives for studying neuroinflammation. By comprehending the intricate interplay among depression, obesity, and AD, especially the role of neuroinflammation, we can advance our understanding and develop innovative strategies for prevention and treatment.

Paving the Way for Alzheimer's Disease Prevention: A Systematic Review of Global Open-Access Neuroimaging Datasets in Healthy Individuals.

BACKGROUND: Given the advent of large-scale neuroimaging data-driven endeavors for Alzheimer's disease, there is a burgeoning need for well-characterized neuroimaging databases of healthy individuals. With the rise of initiatives around the globe for the rapid and unrestricted sharing of data resources, there is now an abundance of open-source neuroimaging datasets available to the research community. However, there is not yet a systematic review that fully details the demographic information and modalities actually available in all open access neuroimaging databases around the globe. OBJECTIVE: This systematic review aims to provide compile a list of MR structural imaging databases encompassing healthy individuals across the lifespan. METHODS: In this systematic review, we searched EMBASE and PubMed until May 2022 for open-access neuroimaging databases containing healthy control participants of any age, race, with normal development and cognition having at least one structural T1-weighted neuroimaging scan. RESULTS: A total of 403 databases were included, for up to total of 48,268 participants with all available demographic information and imaging modalities detailed in Supplementary Table 1. There were significant trends noted when compiling normative databases for this systematic review, notably that 11.7% of databases included reported ethnicity in their participants, with underrepresentation of many socioeconomic groups globally. CONCLUSIONS: As efforts to improve primary prevention of AD may require a broader perspective including increased relevance of earlier stages in life, and strategies in addressing modifiable risk factors may be individualized to specific demographics, improving data characterization to be richer and more rigorous will greatly enhance these efforts.

Effect of Ultrasound Pulse Length on Sonoreperfusion Therapy.

In recent years, long- and short-pulse ultrasound (US)-targeted microbubble cavitation (UTMC) has been found to increase perfusion in healthy and ischemic skeletal muscle, in pre-clinical animal models of microvascular obstruction and in the myocardium of patients presenting with acute myocardial infarction. There is evidence that the observed microvascular vasodilation is driven by the nitric oxide pathway and purinergic signaling, but the time course of the response and the dependency on US pulse length are not well elucidated. Because our prior data supported that sonoreperfusion efficacy is enhanced by long-pulse US versus short-pulse US, in this study, we sought to compare long-pulse (5000 cycles) and short-pulse (500 × 10 cycles) US at a pressure of 1.5 MPa with an equivalent total number of acoustical cycles, hence constant acoustic energy, and at the same frequency (1 MHz), in a rodent hind limb model with and without microvascular obstruction (MVO). In quantifying perfusion using burst replenishment contrast-enhanced US imaging, we made three findings: (i) Long and short pulses result in different vasodilation kinetics in an intact hind limb model. The long pulse causes an initial spasmic reduction in flow that spontaneously resolved at 4 min, followed by sustained higher flow rates (approximately twofold) compared with baseline, starting 10 min after therapy (p < 0.05). The short pulse caused a short-lived approximately twofold increase in flow rate that peaked at 4 min (p < 0.05), but without the initial spasm. (ii) The sustained increased response with the long pulse is not simply reactive hyperemia. (iii) Both pulses are effective in reperfusion of MVO in our hindlimb model by restoring blood volume, but only the long pulse caused an increase in flow rate after treatment ii, compared with MVO (p < 0.05). Histological analysis of hind limb muscle post-UTMC with either pulse configuration indicates no evidence of tissue damage or hemorrhage. Our findings indicate that the microbubble oscillation induces vasodilation, and therapeutic efficacy for the treatment of MVO can be tuned by varying pulse length; relative to short-pulse US, longer pulses drive greater microbubble cavitation and more rapid microvascular flow rate restoration after MVO, warranting further optimization of the pulse length for sonoreperfusion therapy.

Lipid nitroalkene nanoparticles for the focal treatment of ischemia reperfusion.

Rationale: The treatment of microvascular obstruction (MVO) using ultrasound-targeted LNP cavitation (UTC) therapy mechanically relieves the physical obstruction in the microcirculation but does not specifically target the associated inflammatory milieu. Electrophilic fatty acid nitroalkene derivatives (nitro-fatty acids), that display pleiotropic anti-inflammatory signaling and transcriptional regulatory actions, offer strong therapeutic potential but lack a means of rapid targeted delivery. The objective of this study was to develop nitro-fatty acid-containing lipid nanoparticles (LNP) that retain the mechanical efficacy of standard LNP and can rapidly target delivery of a tissue-protective payload that reduces inflammation and improves vascular function following ischemia-reperfusion. Methods: The stability and acoustic behavior of nitro-fatty acid LNP (NO2-FA-LNP) were characterized by HPLC-MS/MS and ultra-high-speed microscopy. The LNP were then used in a rat hindlimb model of ischemia-reperfusion injury with ultrasound-targeted cavitation. Results: Intravenous administration of NO2-FA-LNP followed by ultrasound-targeted LNP cavitation (UTC) in both healthy rat hindlimb and following ischemia-reperfusion injury showed enhanced NO2-FA tissue delivery and microvascular perfusion. In addition, vascular inflammatory mediator expression and lipid peroxidation were decreased in tissues following ischemia-reperfusion revealed NO2-FA-LNP protected against inflammatory injury. Conclusions: Vascular targeting of NO2-FA-LNP with UTC offers a rapid method of focal anti-inflammatory therapy at sites of ischemia-reperfusion injury.

Accelerated brain aging in chronic low back pain.

Chronic low back pain (CLBP) is a leading cause of disability and is associated with neurodegenerative changes in brain structure. These changes lead to impairments in cognitive function and are consistent with those seen in aging, suggesting an accelerated aging pattern. In this study we assessed this using machine-learning estimated brain age (BA) as a holistic metric of morphometric changes associated with aging. Structural imaging data from 31 non-depressed CLBP patients and 32 healthy controls from the Pain and Interoception Imaging Network were included. Using our previously developed algorithm, we estimated BA per individual based on grey matter density. We then conducted multivariable linear modeling for effects of group, chronological age, and their interaction on BA. We also performed two voxel-wise analyses comparing grey matter density between CLBP and control individuals and the association between gray matter density and BA. There was an interaction between CLBP and greater chronological age on BA such that the discrepancy in BA between healthy and CLBP individuals was greater for older individuals. In CLBP individuals, BA was not associated with sex, current level of pain, duration of CLBP, or mild to moderate depressive symptoms. CLBP individuals had lower cerebellar grey matter density compared to healthy individuals. Brain age was associated with lower gray matter density in numerous brain regions. CLBP was associated with greater BA, which was more profound in later life. BA as a holistic metric was sensitive to differences in gray matter density in numerous regions which eluded direct comparison between groups.

Obesity and White Matter Neuroinflammation Related Edema in Alzheimer's Disease Dementia Biomarker Negative Cognitively Normal Individuals.

BACKGROUND: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. OBJECTIVE: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer's disease (AD) dementia. METHODS: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. RESULTS: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. CONCLUSION: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly.

Ultrasound-Targeted Microbubble Cavitation with Sodium Nitrite Synergistically Enhances Nitric Oxide Production and Microvascular Perfusion.

Microvascular obstruction is a common repercussion of percutaneous coronary intervention for distal microembolization, ischemia-reperfusion injury and inflammation, which increases post-myocardial infarction heart failure and mortality. Ultrasound-targeted microbubble cavitation (UTMC) may resolve microvascular obstruction while activating endothelial nitric oxide synthase (eNOS) and increasing endothelium-derived nitric oxide (NO) bioavailability. Nitrite, a cardioprotective agent, offers an additional source of NO and potential synergy with UTMC. UTMC and nitrite co-therapy increased microvascular perfusion and NO concentration in a rat hindlimb model. Using N-nitro-L-arginine methyl ester for eNOS blockade, we found a three-way interaction effect between nitrite, UTMC and eNOS on microvascular perfusion and NO production. Modulating ultrasound peak negative acoustic pressure (0.33-1.5 MPa) significantly affected outcomes, while microbubble dosage (2 × 108 bubbles/mL, 1.5 mL/h to 1 × 109 bubbles/mL, 3 mL/h) did not. Nitrite co-therapy also protected against oxidative stress. Comparison of nitrite to sodium nitroprusside with UTMC revealed synergistic effects were specific to nitrite. Synergy between UTMC and nitrite holds therapeutic potential for cardiovascular disease.

Improving brain age prediction models: incorporation of amyloid status in Alzheimer's disease.

Brain age prediction is a machine learning method that estimates an individual's chronological age from their neuroimaging scans. Brain age indicates whether an individual's brain appears "older" than age-matched healthy peers, suggesting that they may have experienced a higher cumulative exposure to brain insults or were more impacted by those pathological insults. However, contemporary brain age models include older participants with amyloid pathology in their training sets and thus may be confounded when studying Alzheimer's disease (AD). We showed that amyloid status is a critical feature for brain age prediction models. We trained a model on T1-weighted MRI images participants without amyloid pathology. MRI data were processed to estimate gray matter density voxel-wise, which were then used to predict chronological age. Our model performed accurately comparable to previous models. Notably, we demonstrated more significant differences between AD diagnostic groups than other models. In addition, our model was able to delineate significant differences in brain age relative to chronological age between cognitively normal individuals with and without amyloid. Incorporation of amyloid status in brain age prediction models ultimately improves the utility of brain age as a biomarker for AD.

Sonoreperfusion therapy for microvascular obstruction: A step toward clinical translation.

Sonoreperfusion therapy is being developed as an intervention for the treatment of microvascular obstruction. We investigated the reperfusion efficacy of two clinical ultrasound systems (a modified Philips EPIQ and a Philips Sonos 7500) in a rat hindlimb microvascular obstruction model. Four ultrasound conditions were tested using 20 min treatments: Sonos single frame, Sonos multi-frame, EPIQ low pressure and EPIQ high pressure. Contrast-enhanced perfusion imaging of the microvasculature was conducted at baseline and after treatment to calculate microvascular blood volume (MBV). EPIQ high pressure treatment resulted in significant recovery of MBV from microvascular obstruction, returning to baseline levels after treatment. EPIQ low pressure and Sonos multi-frame treatment resulted in significantly improved MBV after treatment but below baseline levels. Sonos single-frame and control groups showed no improvement post-treatment. This study demonstrates that the most effective sonoreperfusion therapy occurs at high acoustic pressure coupled with high acoustic intensity. Moreover, a clinically available ultrasound system is readily capable of delivering these effective therapeutic pulses.

Enhancing chondrogenesis and mechanical strength retention in physiologically relevant hydrogels with incorporation of hyaluronic acid and direct loading of TGF-ß.

Cell-loaded hydrogels are frequently applied in cartilage tissue engineering for their biocompatibility, ease of application, and ability to conform to various defect sites. As a bioactive adjunct to the biomaterial, transforming growth factor beta (TGF-ß) has been shown to be essential for cell differentiation into a chondrocyte phenotype and maintenance thereof, but the low amounts of endogenous TGF-ß in the in vivo joint microenvironment necessitate a mechanism for controlled delivery and release of this growth factor. In this study, TGF-ß3 was directly loaded with human bone marrow-derived mesenchymal stem cells (MSCs) into poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid (PDLLA-PEG) hydrogel, or PDLLA-PEG with the addition of hyaluronic acid (PDLLA/HA), and cultured in vitro. We hypothesize that the inclusion of HA within PDLLA-PEG would result in a controlled release of the loaded TGF-ß3 and lead to a robust cartilage formation without the use of TGF-ß3 in the culture medium. ELISA analysis showed that TGF-ß3 release was effectively slowed by HA incorporation, and retention of TGF-ß3 in the PDLLA/HA scaffold was detected by immunohistochemistry for up to 3 weeks. By means of both in vitro culture and in vivo implantation, we found that sulfated glycosaminoglycan production was higher in PDLLA/HA groups with homogenous distribution throughout the scaffold than PDLLA groups. Finally, with an optimal loading of TGF-ß3 at 10 µg/mL, as determined by RT-PCR and glycosaminoglycan production, an almost twofold increase in Young's modulus of the construct was seen over a 4-week period compared to TGF-ß3 delivery in the culture medium. Taken together, our results indicate that the direct loading of TGF-ß3 and stem cells in PDLLA/HA has the potential to be a one-step point-of-care treatment for cartilage injury. STATEMENT OF SIGNIFICANCE: Stem cell-seeded hydrogels are commonly used in cell-based cartilage tissue engineering, but they generally fail to possess physiologically relevant mechanical properties suitable for loading. Moreover, degradation of the hydrogel in vivo with time further decreases mechanical suitability of the hydrogel due in part to the lack of TGF-ß3 signaling. In this study, we demonstrated that incorporation of hyaluronic acid (HA) into a physiologically stiff PDLLA-PEG hydrogel allowed for slow release of one-time preloaded TGF-ß3, and when loaded with adult mesenchymal stem cells and cultured in vitro, it resulted in higher chondrogenic gene expression and constructs of significantly higher mechanical strength than constructs cultured in conventional TGF-ß3-supplemented medium. Similar effects were also observed in constructs implanted in vivo. Our results indicate that direct loading of TGF-ß3 combined with HA in the physiologically stiff PDLLA-PEG hydrogel has the potential to be used for one-step point-of-care treatment of cartilage injury.

Biomimetic Rotated Lamellar Plywood Motifs by Additive Manufacturing of Metal Alloy Scaffolds for Bone Tissue Engineering.

Additive manufacturing presents opportunities to treat bone defects using biomimetic tissue scaffolds. Past investigations have explored modulating scaffold mechanical properties through varying materials and geometric motifs. Herein, we applied the rotated plywood structure of bone tissue to a 3D printed scaffold with the goal of improving mechanical performance compared to an orthogonal mesh design commonly used in tissue scaffold applications. The scaffolds were subjected to uniaxial compression followed by scanning electron microscopy and microcomputer tomography. The uniaxial compression test was characterized through elastic modulus (mean 1.32 GPa biomimetic, 0.196 GPa orthogonal, p < 0.001), ultimate compressive strength (mean 16.546 MPa biomimetic, 6.309 MPa orthogonal design, p < 0.001), and ultimate compressive strain values (4.867% biomimetic, 9.000% orthogonal, p < 0.005). Correlation of microfracture imaging to bulk scaffold mode of failure suggest that utilizing the biomimetic plywood design not only improved mechanical performance, but also reduced asymmetrtic buckling, plastic deformation, and fracture propagation similar to bone tissue.