Different associations of white matter lesions with depression and cognition

ABSTRACT: BACKGROUND: To test the hypothesis that white matter lesions (WML) are primarily associated with regional frontal cortical volumes, and to determine the mediating effects of these regional frontal cortices on the associations of WML with depressive symptoms and cognitive dysfunction. METHODS: Structural brains MRIs were performed on 161 participants: cognitively normal, cognitive impaired but not demented, and demented participants. Lobar WML volumes, regional frontal cortical volumes, depressive symptom severity, and cognitive abilities were measured. Multiple linear regression analyses were used to identify WML volume effects on frontal cortical volume. Structural equation modeling was used to determine the MRI-depression and the MRI-cognition path relationships. RESULTS: WML predicted frontal cortical volume, particularly in medial orbirtofrontal cortex, irrespective of age, gender, education, and group status. WML directly predicted depressive score, and this relationship was not mediated by regional frontal cortices. In contrast, the association between WML and cognitive function was indirect and mediated by regional frontal cortices. CONCLUSIONS: These findings suggest that the neurobiological mechanisms underpinning depressive symptoms and cognitive dysfunction in older adults may differ.     

First report of Alexandrium taylori and Alexandrium peruvianum (Dinophyceae) in Malaysia waters

The occurrence of Alexandrium taylori and Alexandrium peruvianum is reported for the first time in Malaysia waters. The Malaysian A. taylori isolates were pyriform in shape with a transdiameter range of 36–40 μm and a cell length range of 33–37 μm. The first apical plate (1′) was pentagonal with two distinctive anterior margins. No direct connection between 1′ and the apical pore complex was observed. The posterior sulcal plate (S.p.) was large, elongated and oblique to the right with anterior projections. The ventral pore (vp) was relatively large and situated at a confluence point of 1′, the second apical (2′) and the fourth apical (4′) plates. Cells of A. peruvianum were slightly anteriorly and posteriorly compressed. S.p. had an irregular pentagonal shape, with the anterior margin divided into 2 portions. 1′ was boomerang-shaped with a large and truncated ventral pore in the middle right margin. The anterior right margin of 1′ was straight. The sixth precingular plate (6″) was wider than long. The anterior sulcal plate (S.a.) was triangular and lacked a left portion extension. In laboratory cultures, both A. taylori and A. peruvianum produced paralytic shellfish toxins, with GTX4 and GTX6 as the predominant toxin, respectively. This is the first report of PSP toxins production for both species as well as the occurrences in Malaysia waters.     

Air quality improvement and cognitive decline in community-dwelling older women in the United States: A longitudinal cohort study

BackgroundLate-life exposure to ambient air pollution is a modifiable risk factor for dementia, but epidemiological studies have shown inconsistent evidence for cognitive decline. Air quality (AQ) improvement has been associated with improved cardiopulmonary health and decreased mortality, but to the best of our knowledge, no studies have examined the association with cognitive function. We examined whether AQ improvement was associated with slower rate of cognitive decline in older women aged 74 to 92 years.Methods and findingsWe studied a cohort of 2,232 women residing in the 48 contiguous US states that were recruited from more than 40 study sites located in 24 states and Washington, DC from the Women’s Health Initiative (WHI) Memory Study (WHIMS)-Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO) study. They were predominantly non-Hispanic White women and were dementia free at baseline in 2008 to 2012. Measures of annual (2008 to 2018) cognitive function included the modified Telephone Interview for Cognitive Status (TICSm) and the telephone-based California Verbal Learning Test (CVLT). We used regionalized universal kriging models to estimate annual concentrations (1996 to 2012) of fine particulate matter (PM_2.5) and nitrogen dioxide (NO₂) at residential locations. Estimates were aggregated to the 3-year average immediately preceding (recent exposure) and 10 years prior to (remote exposure) WHIMS-ECHO enrollment. Individual-level improved AQ was calculated as the reduction from remote to recent exposures. Linear mixed effect models were used to examine the associations between improved AQ and the rates of cognitive declines in TICSm and CVLT trajectories, adjusting for sociodemographic (age; geographic region; race/ethnicity; education; income; and employment), lifestyle (physical activity; smoking; and alcohol), and clinical characteristics (prior hormone use; hormone therapy assignment; depression; cardiovascular disease (CVD); hypercholesterolemia; hypertension; diabetes; and body mass index [BMI]). For both PM_2.5 and NO₂, AQ improved significantly over the 10 years before WHIMS-ECHO enrollment. During a median of 6.2 (interquartile range [IQR] = 5.0) years of follow-up, declines in both general cognitive status (β = −0.42/year, 95% CI: −0.44, −0.40) and episodic memory (β = −0.59/year, 95% CI: −0.64, −0.54) were observed. Greater AQ improvement was associated with slower decline in TICSm (β_{PM2.5improvement} = 0.026 per year for improved PM_2.5 by each IQR = 1.79 μg/m³ reduction, 95% CI: 0.001, 0.05; β_{NO2improvement} = 0.034 per year for improved NO₂ by each IQR = 3.92 parts per billion [ppb] reduction, 95% CI: 0.01, 0.06) and CVLT (β_{PM2.5 improvement} = 0.070 per year for improved PM_2.5 by each IQR = 1.79 μg/m³ reduction, 95% CI: 0.02, 0.12; β_{NO2improvement} = 0.060 per year for improved NO₂ by each IQR = 3.97 ppb reduction, 95% CI: 0.005, 0.12) after adjusting for covariates. The respective associations with TICSm and CVLT were equivalent to the slower decline rate found with 0.9 to 1.2 and1.4 to 1.6 years of younger age and did not significantly differ by age, region, education, Apolipoprotein E (ApoE) e4 genotypes, or cardiovascular risk factors. The main limitations of this study include measurement error in exposure estimates, potential unmeasured confounding, and limited generalizability.ConclusionsIn this study, we found that greater improvement in long-term AQ in late life was associated with slower cognitive declines in older women. This novel observation strengthens the epidemiologic evidence of an association between air pollution and cognitive aging.

Diana Younan and colleagues investigate whether air quality improvement is associated with rate of cognitive decline in community-dwelling older women in the United States.     

Cell surface nucleolin is a novel ADAMTS5 receptor mediating endothelial cell apoptosis

A Disintegrin and Metalloproteinase with ThromboSpondin motif (ADAMTS) 5 functions as an anti-angiogenic and anti-cancer protein independent of its metalloproteinase activity. Both full-length ADAMTS5 and TS5-p45, the autocatalytically cleaved C-terminal 45 kDa truncate of ADAMTS5, inhibits angiogenesis, and induces endothelial cell (EC) apoptosis. However, how ADAMTS5 triggers EC apoptosis remains unclear. This work shows that caspase-8 (Cas-8) and caspase-9 (Cas-9) are involved in TS5-p45-induced EC apoptosis. We identify cell surface nucleolin (NCL) as a novel high-affinity receptor for TS5-p45 in ECs, mediating TS5-p45’s cell surface binding and pro-apoptotic function. We show that the central RNA-binding domain (RBD) of NCL is essential and sufficient for its binding to TS5-p45. Upon interacting with EC surface NCL, TS5-p45 is internalized through clathrin- and caveolin-dependent endocytosis and trafficked to the nucleus via late endosomes (LEs). We demonstrate that the nuclear trafficking of TS5-p45 is important for its pro-apoptotic activity as disruption of LE membrane integrity with an endosomolytic peptide suppressed both nuclear trafficking and pro-apoptotic activity of TS5-p45. Through cell surface biotinylation, we revealed that cell surface NCL shuttles extracellular TS5-p45 to the nucleus to mediate apoptosis. Furthermore, blocking the importin α1/ß1 receptor hindered the nuclear trafficking of TS5-p45, suggesting the involvement of the nuclear importing machinery for this nuclear translocation. RNA-seq identified many apoptosis-related genes that are differentially expressed at least two-fold in TS5-p45-treated ECs, with 10 of them qRT-PCR-validated and at least 5 of these genes potentially contributing to TS5-p45-NCL-induced apoptosis. Altogether, our work identifies NCL as a novel cell surface receptor for ADAMTS5 and demonstrates the critical role of NCL-mediated internalization and nuclear trafficking for ADAMTS5-induced EC apoptosis. These findings reveal novel mechanistic insights of the secreted metalloproteinase ADAMTS5 in angiogenesis inhibition.Subject terms: Tumour angiogenesis, Apoptosis, Protein translocation     

A ubiquitin-independent proteasome pathway controls activation of the CARD8 inflammasome

CARD8 is a pattern-recognition receptor that forms a caspase-1-activating inflammasome. CARD8 undergoes constitutive autoproteolysis, generating an N-terminal (NT) fragment with a disordered region and a ZU5 domain and a C-terminal (CT) fragment with UPA and CARD domains. Dipeptidyl peptidase 8 and dipeptidyl peptidase 9 inhibitors, including Val-boroPro, accelerate the degradation of the NT fragment via a poorly characterized proteasome-mediated pathway, thereby releasing the inflammatory CT fragment from autoinhibition. Here, we show that the core 20S proteasome, which degrades disordered and misfolded proteins independent of ubiquitin modification, controls activation of the CARD8 inflammasome. In unstressed cells, we discovered that the 20S proteasome degrades just the NT disordered region, leaving behind the folded ZU5, UPA, and CARD domains to act as an inhibitor of inflammasome assembly. However, in Val-boroPro–stressed cells, we show the 20S proteasome degrades the entire NT fragment, perhaps due to ZU5 domain unfolding, freeing the CT fragment from autoinhibition. Taken together, these results show that the susceptibility of the CARD8 NT domain to 20S proteasome-mediated degradation controls inflammasome activation.     

Adverse events of special interest and mortality following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines in Hong Kong: A retrospective study

BackgroundSafety monitoring of coronavirus disease 2019 (COVID-19) vaccines is crucial during mass vaccination rollout to inform the choice of vaccines and reduce vaccine hesitancy. Considering the scant evidence directly comparing the safety profiles of mRNA and inactivated SARS-CoV-2 vaccines, this territory-wide cohort study aims to compare the incidence of various adverse events of special interest (AESIs) and all-cause mortality between CoronaVac (inactivated vaccine) and BNT162b2 (mRNA-based vaccine). Our results can help vaccine recipients make an informed choice.Methods and findingsA retrospective, population-based cohort of individuals who had received at least 1 dose of BNT162b2 or CoronaVac from 23 February to 9 September 2021 in Hong Kong, and had data linkage to the electronic medical records of the Hong Kong Hospital Authority, were included. Those who had received mixed doses were excluded. Individuals were observed from the date of vaccination (first or second dose) until mortality, second dose vaccination (for first dose analysis), 21 days after vaccination, or 30 September 2021, whichever came first. Baseline characteristics of vaccinated individuals were balanced between groups using propensity score weighting. Outcome events were AESIs and all-cause mortality recorded during 21 days of post-vaccination follow-up after each dose, except anaphylaxis, for which the observation period was restricted to 2 days after each dose. Incidence rate ratios (IRRs) of AESIs and mortality comparing between CoronaVac and BNT162b2 recipients were estimated after each dose using Poisson regression models. Among 2,333,379 vaccinated individuals aged 18 years or above, the first dose analysis included 1,308,820 BNT162b2 and 955,859 CoronaVac recipients, while the second dose analysis included 1,116,677 and 821,560 individuals, respectively. The most frequently reported AESI among CoronaVac and BNT162b2 recipients was thromboembolism (first dose: 431 and 290 per 100,000 person-years; second dose: 385 and 266 per 100,000 person-years). After the first dose, incidence rates of overall AESIs (IRR = 0.98, 95% CI 0.89–1.08, p = 0.703) and mortality (IRR = 0.96, 95% CI 0.63–1.48, p = 0.868) associated with CoronaVac were generally comparable to those for BNT162b2, except for Bell palsy (IRR = 1.95, 95% CI 1.12–3.41, p = 0.018), anaphylaxis (IRR = 0.34, 95% CI 0.14–0.79, p = 0.012), and sleeping disturbance or disorder (IRR = 0.66, 95% CI 0.49–0.89, p = 0.006). After the second dose, incidence rates of overall AESIs (IRR = 0.97, 95% CI 0.87–1.08, p = 0.545) and mortality (IRR = 0.85, 95% CI 0.51–1.40, p = 0.516) were comparable between CoronaVac and BNT162b2 recipients, with no significant differences observed for specific AESIs. The main limitations of this study include residual confounding due to its observational nature, and the possibility of its being underpowered for some AESIs with very low observed incidences.ConclusionsIn this study, we observed that the incidences of AESIs (cumulative incidence rate of 0.06%–0.09%) and mortality following the first and second doses of CoronaVac and BNT162b2 vaccination were very low. The safety profiles of the vaccines were generally comparable, except for a significantly higher incidence rate of Bell palsy, but lower incidence rates of anaphylaxis and sleeping disturbance or disorder, following first dose CoronaVac versus BNT162b2 vaccination. Our results could help inform the choice of inactivated COVID-19 vaccines, mainly administered in low- and middle-income countries with large populations, in comparison to the safety of mRNA vaccines. Long-term surveillance on the safety profile of COVID-19 vaccines should continue.

In a retrospective study, Carlos King Ho Wong, Kristy Tsz Kwan Lau, and colleagues study adverse events reported following COVID-19 vaccination in Hong Kong.