IL-34 exacerbates pathogenic features of Alzheimer's disease and calvaria osteolysis in triple transgenic (3x-Tg) female mice.

Hallmark features of Alzheimer's disease (AD) include elevated accumulation of aggregated Aß40 and Aß42 peptides, hyperphosphorylated Tau (p-Tau), and neuroinflammation. Emerging evidence indicated that interleukin-34 (IL-34) contributes to AD and inflammatory osteolysis via the colony-stimulating factor-1 receptor (CSF-1r). In addition, CSF-1r is also activated by macrophage colony-stimulating factor-1 (M-CSF). While the role of M-CSF in bone physiology and pathology is well addressed, it remains controversial whether IL-34-mediated signaling promotes osteolysis, neurodegeneration, and neuroinflammation in relation to AD. In this study, we injected 3x-Tg mice with mouse recombinant IL-34 protein over the calvaria bone every other day for 42 days. Then, behavioral changes, brain pathology, and calvaria osteolysis were evaluated using various behavioral maze and histological assays. We demonstrated that IL-34 administration dramatically elevated AD-like anxiety and memory loss, pathogenic amyloidogenesis, p-Tau, and RAGE expression in female 3x-Tg mice. Furthermore, IL-34 delivery promoted calvaria inflammatory osteolysis compared to the control group. In addition, we also compared the effects of IL-34 and M-CSF on macrophages, microglia, and RANKL-mediated osteoclastogenesis in relation to AD pathology in vitro. We observed that IL-34-exposed SIM-A9 microglia and 3x-Tg bone marrow-derived macrophages released significantly elevated amounts of pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, compared to M-CSF treatment in vitro. Furthermore, IL-34, but not M-CSF, elevated RANKL-primed osteoclastogenesis in the presence of Aß40 and Aß42 peptides in bone marrow derived macrophages isolated from female 3x-Tg mice. Collectively, our data indicated that IL-34 elevates AD-like features, including behavioral changes and neuroinflammation, as well as osteoclastogenesis in female 3x-Tg mice.

Serum Urate Levels and Ultrasound Characteristics of Carotid Atherosclerosis across Obesity Phenotypes.

BACKGROUND: Existing evidence suggests a close link among high levels of serum urate (SU), obesity and carotid atherosclerosis. The aim of the present study was to evaluate the interrelations between SU levels and carotid atherosclerosis in subjects with different obesity phenotypes. METHODS: In this study, a total of 2076 subjects (mean age 48.1 ± 13.1 years; 1307 women) were recruited: 59 with general obesity, 616 with central obesity, 715 with mixed (general-central) obesity and 686 non-obese. Anthropometric measurements, vascular risk factors, blood biochemistry analysis (including SU levels), and carotid ultrasound were performed. Ultrasound assessment included evaluation of intima-media thickness (IMT) and plaque characteristics, including number, total area and type (vulnerable vs. stable) of plaques. RESULTS: After adjustment for potential confounders, the highest levels of SU were observed in subjects with mixed obesity, followed by subjects with central obesity, general obesity and the non-obese (309.4 ± 82.2 vs. 301.2 ± 73.1 vs. 272.9 ± 61.8 vs. 234.2 ± 59.8 µmol/L, respectively; F = 149.2, post hoc p < 0.001). Similarly, subjects with mixed and central obesity presented higher values of IMT compared to subjects with general obesity and the non-obese (0.68 ± 0.16 vs. 0.67 ± 0.16 vs. 0.62 ± 0.14 vs. 0.57 ± 0.13 mm, respectively; F = 54.2, post hoc p < 0.001). No difference in number, total area and type of plaques among obesity groups were attested (all p > 0.05). Significantly higher IMT values were observed in subjects with increased SU levels compared to subjects with normal SU levels (0.70 ± 0.10 vs. 0.62 ± 0.14 mm, p = 0.02) only within the central obesity group. Increasing levels of SU were associated with a higher frequency of increased IMT only in subjects with central obesity (OR 1.033, 95% CI 1.025-1.041). Similarly, SU levels yielded a satisfactory performance in detecting subjects with increased IMT (AUC 0.65, 95% CI 0.50-0.73, subjects with carotid plaques (0.62, 95% CI 0.55-0.68) and subjects with vulnerable plaque types (0.68, 0.59-0.76) only within the central obesity group. CONCLUSIONS: Among the studied obesity types, the association between SU levels and markers of carotid atherosclerosis was of particular significance in subjects with central obesity.

Dissecting the Spectrum of Stroke Risk Factors in an Apparently Healthy Population: Paving the Roadmap to Primary Stroke Prevention.

We aimed to investigate, for the first time, the spectrum of stroke risk factors specific to the population of the Republic of Moldova. The subjects were examined according to a pre-established protocol of risk factor estimation. The study involved 300 subjects, including 60% women and 40% men, with a mean age of 49.9 ± 14.5 years. The most common risk factor was abdominal obesity, identified in 75% of subjects; general obesity was detected in 48%, while 32% of subjects were overweight and 20% were normally weighted. Hypertension was observed in 44%; 8% of those examined had atrial fibrillation, and 9% had diabetes mellitus. Left myocardial hypertrophy on ECG was present in 53% of subjects, and acute ischemic changes in 2%. Laboratory observations detected that glycosylated hemoglobin increased by 7%, and >50% had dyslipidemia. Total cholesterol was significantly elevated by 58%, LDL-cholesterol was increased by 32%, and HDL-cholesterol was decreased by 9%. Homocysteine was increased in 55% and high-sensitivity C-reactive protein in 28% of subjects. These results indicate the presence of modifiable risk factors and the necessity to elaborate on the primary prevention strategies aimed at minimizing the burden of stroke in the population of the Republic of Moldova.

Molecular Mechanisms of SARS-CoV-2/COVID-19 Pathogenicity on the Central Nervous System: Bridging Experimental Probes to Clinical Evidence and Therapeutic Interventions.

The coronavirus disease 2019 (COVID-19) pandemic, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has dramatically impacted the global healthcare systems, constantly challenging both research and clinical practice. Although it was initially believed that the SARS-CoV-2 infection is limited merely to the respiratory system, emerging evidence indicates that COVID-19 affects multiple other systems including the central nervous system (CNS). Furthermore, most of the published clinical studies indicate that the confirmed CNS inflammatory manifestations in COVID-19 patients are meningitis, encephalitis, acute necrotizing encephalopathy, acute transverse myelitis, and acute disseminated encephalomyelitis. In addition, the neuroinflammation along with accelerated neurosenescence and susceptible genetic signatures in COVID-19 patients might prime the CNS to neurodegeneration and precipitate the occurrence of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Thus, this review provides a critical evaluation and interpretive analysis of existing published preclinical as well as clinical studies on the key molecular mechanisms modulating neuroinflammation and neurodegeneration induced by the SARS-CoV-2. In addition, the essential age- and gender-dependent impacts of SARS-CoV-2 on the CNS of COVID-19 patients are also discussed.

Clinical and Radiological Deterioration in a Case of Creutzfeldt-Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration.

Systemic inflammation and the host immune responses associated with certain viral infections may accelerate the rate of neurodegeneration in patients with Creutzfeldt-Jakob disease (CJD), a rare, transmissible neurodegenerative disease. However, the effects of the newly emerged SARS-CoV-2 infection on the pathogenesis of CJD are unknown. In this study, we describe the case of an elderly female patient with sporadic CJD that exhibited clinical deterioration with the emergence of seizures and radiological neurodegenerative progression following an infection with SARS-CoV-2 and severe COVID-19. Despite efforts to control the progression of the disease, a dismal outcome ensued. This report further evidences the age-dependent neurological effects of SARS-CoV-2 infection and proposes a vulnerability to CJD and increased CJD progression following COVID-19.

Extensive cerebellar involvement and cognitive impairment in COVID-19-associated acute necrotizing encephalopathy.

Neurological complications of the newly appeared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly recognized. Here, we report a case of a young male presenting with a clinical and neuroimaging scenario of an acute necrotizing encephalopathy related to the coronavirus disease 2019 (COVID-19). This case is notable by its distinct pattern of magnetic resonance imaging findings of an extensive involvement of the cerebellum, and emergence of cognitive and behavioral impairment.