Persistent fatigue in post-acute COVID syndrome is associated with altered T1 MRI texture in subcortical structures: a preliminary investigation.

Post-acute COVID syndrome (PACS) is a global health concern and is often associated with debilitating symptoms. Post-COVID fatigue is a particularly frequent and troubling issue, and its underlying mechanisms remain incompletely understood. One potential contributor is micropathological injury of subcortical and brainstem structures, as has been identified in other patient populations. Texture-based analysis (TA) may be used to measure such changes in anatomical MRI data. The present study develops a methodology of voxel-wise TA mapping in subcortical and brainstem regions, which is then applied to T1-weighted MRI data from a cohort of 48 individuals who had PACS (32 with and 16 without ongoing fatigue symptoms) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19. Both groups were assessed an average of 4-5 months post-infection. There were no significant differences between PACS and control groups, but significant differences were observed within the PACS groups, between those with and without fatigue symptoms. This included reduced texture energy and increased entropy, along with reduced texture correlation, cluster shade and profile in the putamen, pallidum, thalamus and brainstem. These findings provide new insights into the neurophysiological mechanisms that underlie PACS, with altered tissue texture as a potential biomarker of this debilitating condition.

Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

A territory-wide real-world efficacy and toxicity analysis of abiraterone acetate versus docetaxel in 574 Asian patients with metastatic hormone-sensitive prostate cancer.

INTRODUCTION: Abiraterone acetate (ABI) or docetaxel (DOC), in addition to androgen-deprivation therapy (ADT), are current treatment options for metastatic hormone-sensitive prostate cancer (mHSPC). No randomized head-to-head trial has compared these 2 mHSPC treatments, and real-world data regarding their outcomes in Asian patients are lacking. PATIENTS AND METHODS: The medical records of mHSPC patients who began upfront ABI or DOC treatment in addition to ADT at seven public oncology centers in Hong Kong between 2015 and 2021 were reviewed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), prostate-specific antigen (PSA) response, and toxicities. Kaplan-Meier and multivariate Cox regression analyses were performed. RESULTS: A total of 574 patients were included, of whom 419 received DOC and 155 received ABI. The median follow-up duration was 22.4 (DOC group: 23.8; ABI group: 17.3) months. The ABI group demonstrated significantly better PFS than the DOC group (not reached vs. 15.1 months: hazard ratio = 0.37; 95% confidence interval = 0.28-0.50; P < .001). No significant OS difference was observed (P = .58). Failure to achieve a ≥ 90% decline in PSA level at 3 months and failure to achieve an undetectable PSA nadir were each associated with unfavorable PFS and OS. Patients who received DOC had a higher rate of febrile neutropenia, whereas those who received ABI had higher rates of grade ≥ 3 hypokalemia and elevated alanine transaminase. Treatment discontinuation due to toxicities was more common in the DOC (3.6%) than the ABI (0.6%) group. CONCLUSION: In Asian mHSPC patients, upfront ABI + ADT was associated with better PFS than DOC + ADT, with no significant OS difference. PSA kinetics may help stratify the prognosis for treatment intensification. Toxicity profiles were different, with a higher rate of toxicity-related treatment discontinuation in the DOC group.

The diabetes management experiences questionnaire: Psychometric validation among adults with type 1 diabetes.

AIMS: To examine the psychometric properties of the Diabetes Management Experiences Questionnaire (DME-Q). Adapted from the validated Glucose Monitoring Experiences Questionnaire, the DME-Q captures satisfaction with diabetes management irrespective of treatment modalities. METHODS: The DME-Q was completed by adults with type 1 diabetes as part of a randomized controlled trial comparing hybrid closed loop (HCL) to standard therapy. Most psychometric properties were examined with pre-randomization data (n = 149); responsiveness was examined using baseline and 26-week follow-up data (n = 120). RESULTS: Pre-randomization, participants' mean age was 44 ± 12 years, 52% were women. HbA1c was 61 ± 11 mmol/mol (7.8 ± 1.0%), diabetes duration was 24 ± 12 years and 47% used an insulin pump prior to the trial. A forced three-factor analysis revealed three expected domains, that is, 'Convenience', 'Effectiveness' and 'Intrusiveness', and a forced one-factor solution was also satisfactory. Internal consistency reliability was strong for the three subscales ( α range = 0.74-0.84) and 'Total satisfaction' ( α = 0.85). Convergent validity was demonstrated with moderate correlations between DME-Q 'Total satisfaction' and diabetes distress (PAID: rs = -0.57) and treatment satisfaction (DTSQ; rs = 0.58). Divergent validity was demonstrated with a weak correlation with prospective/retrospective memory (PRMQ: rs = -0.16 and - 0.13 respectively). Responsiveness was demonstrated, as participants randomized to HCL had higher 'Effectiveness' and 'Total satisfaction' scores than those randomized to standard therapy. CONCLUSIONS: The 22-item DME-Q is a brief, acceptable, reliable measure with satisfactory structural and construct validity, which is responsive to intervention. The DME-Q is likely to be useful for evaluation of new pharmaceutical agents and technologies in research and clinical settings.

Persistent post-COVID headache is associated with suppression of scale-free functional brain dynamics in non-hospitalized individuals.

INTRODUCTION: Post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is a growing concern, with headache being a particularly debilitating symptom with high prevalence. The long-term effects of COVID-19 and post-COVID headache on brain function remain poorly understood, particularly among non-hospitalized individuals. This study focused on the power-law scaling behavior of functional brain dynamics, indexed by the Hurst exponent (H). This measure is suppressed during physiological and psychological distress and was thus hypothesized to be reduced in individuals with post-COVID syndrome, with greatest reductions among those with persistent headache. METHODS: Resting-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging data were collected for 57 individuals who had COVID-19 (32 with no headache, 14 with ongoing headache, 11 recovered) and 17 controls who had cold and flu-like symptoms but  tested negative for COVID-19. Individuals were assessed an average of 4-5 months after COVID testing, in a cross-sectional, observational study design. RESULTS: No significant differences in H values were found between non-headache COVID-19 and control groups., while those with ongoing headache had significantly reduced H values, and those who had recovered from headache had elevated H values, relative to non-headache groups. Effects were greatest in temporal, sensorimotor, and insular brain regions. Reduced H in these regions was also associated with decreased BOLD activity and local functional connectivity. CONCLUSIONS: These findings provide new insights into the neurophysiological mechanisms that underlie persistent post-COVID headache, with reduced BOLD scaling as a potential biomarker that is specific to this debilitating condition.

A Protease-Responsive Polymer/Peptide Conjugate and Reversible Assembly of Silver Clusters for the Detection of Porphyromonas gingivalis Enzymatic Activity.

We report the reversible aggregation of silver nanoparticle (AgNP) assemblies using the combination of a cationic arginine-based peptide and sulfur-capped polyethylene glycol (PEG). The formation and dissociation of the aggregates were studied by optical methods and electron microscopy. The dissociation of silver clusters depends on the peptide sequence and PEG size. A molecular weight of 1 kDa for PEG was optimal for the dissociation. The most important feature of this dissociation method is that it can operate in complex biofluids such as plasma, saliva, bile, urine, cell media, or even seawater without a significant decrease in performance. Moreover, the peptide-particle assemblies are highly stable and do not degrade (or express of loss of signal upon dissociation) when dried and resolubilized, frozen and thawed, or left in daylight for a month. Importantly, the dissociation capacity of PEG can be reduced via the conjugation of a peptide-cleavable substrate. The dissociation capacity is restored in the presence of an enzyme. Based on these findings, we designed a PEG-peptide hybrid molecule specific to the Porphyromonas gingivalis protease RgpB. Our motivation was that this bacterium is a key pathogen in periodontitis, and RgpB activity has been correlated with chronic diseases including Alzheimer's disease. The RgpB limit of detection was 100 pM RgpB in vitro. This system was used to measure RgpB in gingival crevicular fluid (GCF) samples with a detection rate of 40% with 0% false negatives versus PCR for P. gingivalis (n = 37). The combination of PEG-peptide and nanoparticles dissociation method allows the development of convenient protease sensing that can operate independently of the media composition.

Goldilocks Energy Minimum: Peptide-Based Reversible Aggregation and Biosensing.

Colorimetric biosensors based on gold nanoparticle (AuNP) aggregation are often challenged by matrix interference in biofluids, poor specificity, and limited utility with clinical samples. Here, we propose a peptide-driven nanoscale disassembly approach, where AuNP aggregates induced by electrostatic attractions are dissociated in response to proteolytic cleavage. Initially, citrate-coated AuNPs were assembled via a short cationic peptide (RRK) and characterized by experiments and simulations. The dissociation peptides were then used to reversibly dissociate the AuNP aggregates as a function of target protease detection, i.e., main protease (Mpro), a biomarker for severe acute respiratory syndrome coronavirus 2. The dissociation propensity depends on peptide length, hydrophilicity, charge, and ligand architecture. Finally, our dissociation strategy provides a rapid and distinct optical signal through Mpro cleavage with a detection limit of 12.3 nM in saliva. Our dissociation peptide effectively dissociates plasmonic assemblies in diverse matrices including 100% human saliva, urine, plasma, and seawater, as well as other types of plasmonic nanoparticles such as silver. Our peptide-enabled dissociation platform provides a simple, matrix-insensitive, and versatile method for protease sensing.

Investigating causal relationships between obesity and skin barrier function in a multi-ethnic Asian general population cohort.

BACKGROUND: Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. OBJECTIVES: We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. METHODS: We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort (n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. RESULTS: Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144-0.298) increase in TEWL (P = 2.82E-08), a 0.336% (95%CI: 0.148-0.524) decrease in skin moisture (P = 4.66E-04) and a 0.184% (95%CI: 0.144-0.224) decrease in pH (P = 1.36E-19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189-0.520 and Beta -0.170; 95%CI: -0.253 to -0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI's possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. CONCLUSION: We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore opportunity for primary prevention.

Rasch analyses of the Quick Inventory of Depressive Symptomatology Self-Report in neurodegenerative and major depressive disorders.

Background: Symptoms of depression are present in neurodegenerative disorders (ND). It is important that depression-related symptoms be adequately screened and monitored in persons living with ND. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) is a widely-used self-report measure to assess and monitor depressive severity across different patient populations. However, the measurement properties of the QIDS-SR have not been assessed in ND. Aim: To use Rasch Measurement Theory to assess the measurement properties of the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) in ND and in comparison to major depressive disorder (MDD). Methods: De-identified data from the Ontario Neurodegenerative Disease Research Initiative (NCT04104373) and Canadian Biomarker Integration Network in Depression (NCT01655706) were used in the analyses. Five hundred and twenty participants with ND (Alzheimer's disease or mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia and Parkinson's disease) and 117 participants with major depressive disorder (MDD) were administered the QIDS-SR. Rasch Measurement Theory was used to assess measurement properties of the QIDS-SR, including unidimensionality and item-level fit, category ordering, item targeting, person separation index and reliability and differential item functioning. Results: The QIDS-SR fit well to the Rasch model in ND and MDD, including unidimensionality, satisfactory category ordering and goodness-of-fit. Item-person measures (Wright maps) showed gaps in item difficulties, suggesting poor precision for persons falling between those severity levels. Differences between mean person and item measures in the ND cohort logits suggest that QIDS-SR items target more severe depression than experienced by the ND cohort. Some items showed differential item functioning between cohorts. Conclusion: The present study supports the use of the QIDS-SR in MDD and suggest that the QIDS-SR can be also used to screen for depressive symptoms in persons with ND. However, gaps in item targeting were noted that suggests that the QIDS-SR cannot differentiate participants falling within certain severity levels. Future studies would benefit from examination in a more severely depressed ND cohort, including those with diagnosed clinical depression.

Feasibility of diffusion-tensor and correlated diffusion imaging for studying white-matter microstructural abnormalities: Application in COVID-19.

There has been growing attention on the effect of COVID-19 on white-matter microstructure, especially among those that self-isolated after being infected. There is also immense scientific interest and potential clinical utility to evaluate the sensitivity of single-shell diffusion magnetic resonance imaging (MRI) methods for detecting such effects. In this work, the performances of three single-shell-compatible diffusion MRI modeling methods are compared for detecting the effect of COVID-19, including diffusion-tensor imaging, diffusion-tensor decomposition of orthogonal moments and correlated diffusion imaging. Imaging was performed on self-isolated patients at the study initiation and 3-month follow-up, along with age- and sex-matched controls. We demonstrate through simulations and experimental data that correlated diffusion imaging is associated with far greater sensitivity, being the only one of the three single-shell methods to demonstrate COVID-19-related brain effects. Results suggest less restricted diffusion in the frontal lobe in COVID-19 patients, but also more restricted diffusion in the cerebellar white matter, in agreement with several existing studies highlighting the vulnerability of the cerebellum to COVID-19 infection. These results, taken together with the simulation results, suggest that a significant proportion of COVID-19 related white-matter microstructural pathology manifests as a change in tissue diffusivity. Interestingly, different b-values also confer different sensitivities to the effects. No significant difference was observed in patients at the 3-month follow-up, likely due to the limited size of the follow-up cohort. To summarize, correlated diffusion imaging is shown to be a viable single-shell diffusion analysis approach that allows us to uncover opposing patterns of diffusion changes in the frontal and cerebellar regions of COVID-19 patients, suggesting the two regions react differently to viral infection.

Effects of post-acute COVID-19 syndrome on the functional brain networks of non-hospitalized individuals.

Introduction: The long-term impact of COVID-19 on brain function remains poorly understood, despite growing concern surrounding post-acute COVID-19 syndrome (PACS). The goal of this cross-sectional, observational study was to determine whether there are significant alterations in resting brain function among non-hospitalized individuals with PACS, compared to symptomatic individuals with non-COVID infection. Methods: Data were collected for 51 individuals who tested positive for COVID-19 (mean age 41±12 yrs., 34 female) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19 (mean age 41±14 yrs., 9 female), with both groups assessed an average of 4-5 months after COVID testing. None of the participants had prior neurologic, psychiatric, or cardiovascular illness. Resting brain function was assessed via functional magnetic resonance imaging (fMRI), and self-reported symptoms were recorded. Results: Individuals with COVID-19 had lower temporal and subcortical functional connectivity relative to controls. A greater number of ongoing post-COVID symptoms was also associated with altered functional connectivity between temporal, parietal, occipital and subcortical regions. Discussion: These results provide preliminary evidence that patterns of functional connectivity distinguish PACS from non-COVID infection and correlate with the severity of clinical outcome, providing novel insights into this highly prevalent disorder.

'Is Insulin Right for Me?': Web-based intervention to reduce psychological barriers to insulin therapy among adults with non-insulin-treated type 2 diabetes-A randomised controlled trial.

AIMS: To test 'Is Insulin Right for Me?', a theory-informed, self-directed, web-based intervention designed to reduce psychological barriers to insulin therapy among adults with type 2 diabetes. Further, to examine resource engagement and associations between minimum engagement and outcomes. METHODS: Double-blind, two-arm randomised controlled trial (1:1), comparing the intervention with freely available online information (control). Eligible participants were Australian adults with type 2 diabetes, taking oral diabetes medications, recruited primarily via national diabetes registry. EXCLUSION CRITERIA: prior use of injectable medicines; being 'very willing' to commence insulin. Data collections were completed online at baseline, 2-week and 6-month follow-up. PRIMARY OUTCOME: negative insulin treatment appraisal scale (ITAS) scores; secondary outcomes: positive ITAS scores and hypothetical willingness to start insulin. ANALYSES: intention-to-treat (ITT); per-protocol (PP) examination of outcomes by engagement. TRIAL REGISTRATION: ACTRN12621000191897. RESULTS: No significant ITT between-arm (intervention: n = 233; control: n = 243) differences were observed in primary (2 weeks: Mdiff [95% CI]: -1.0 [-2.9 to 0.9]; 6 months: -0.01 [-1.9 to 1.9]), or secondary outcomes at either follow-up. There was evidence of lower Negative ITAS scores at 2-week, but not 6-month, follow-up among those with minimum intervention engagement (achieved by 44%) compared to no engagement (-2.7 [-5.1 to -0.3]). CONCLUSIONS: Compared to existing information, 'Is insulin right for me?' did not improve outcomes at either timepoint. Small intervention engagement effects suggest it has potential. Further research is warranted to examine whether effectiveness would be greater in a clinical setting, following timely referral among those for whom insulin is clinically indicated.

The impact of obesity: a narrative review.

Obesity is a disease with a major negative impact on human health. However, people with obesity may not perceive their weight to be a significant problem and less than half of patients with obesity are advised by their physicians to lose weight. The purpose of this review is to highlight the importance of managing overweight and obesity by discussing the adverse consequences and impact of obesity. In summary, obesity is strongly related to >50 medical conditions, with many of them having evidence from Mendelian randomisation studies to support causality. The clinical, social and economic burdens of obesity are considerable, with these burdens potentially impacting future generations as well. This review highlights the adverse health and economic consequences of obesity and the importance of an urgent and concerted effort towards the prevention and management of obesity to reduce the burden of obesity.

Nanoscale Iron Redistribution during Thermochemical Decomposition of CaTi1-x Fe x O3-δ Alters the Electrical Transport Pathway: Implications for Oxygen-Transport Membranes, Electrocatalysis, and Photocatalysis.

Potential applications of the earth-abundant, low-cost, and non-critical perovskite CaTi1-x Fe x O3-δ in electrocatalysis, photocatalysis, and oxygen-transport membranes have motivated research to tune its chemical composition and morphology. However, investigations on the decomposition mechanism(s) of CaTi1-x Fe x O3-δ under thermochemically reducing conditions are limited, and direct evidence of the nano- and atomic-level decomposition process is not available in the literature. In this work, the phase evolution of CaTi1-x Fe x O3-δ (x = 0-0.4) was investigated in a H2-containing atmosphere after heat treatments up to 600 °C. The results show that CaTi1-x Fe x O3-δ maintained a stable perovskite phase at low Fe contents while exhibiting a phase decomposition to Fe/Fe oxide nanoparticles as the Fe content increases. In CaTi0.7Fe0.3O3-δ and CaTi0.6Fe0.4O3-δ, the phase evolution to Fe/Fe oxide was greatly influenced by the temperature: Only temperatures of 300 °C and greater facilitated phase evolution. Fully coherent Fe-rich and Fe-depleted perovskite nanodomains were observed directly by atomic-resolution scanning transmission electron microscopy. Prior evidence for such nanodomain formation was not found, and it is thought to result from a near-surface Kirkendall-like phenomenon caused by Fe migration in the absence of Ca and Ti co-migration. Density functional theory simulations of Fe-doped bulk models reveal that Fe in an octahedral interstitial site is energetically more favorable than in a tetrahedral site. In addition to coherent nanodomains, agglomerated Fe/Fe oxide nanoparticles formed on the ceramic surface during decomposition, which altered the electrical transport mechanism. From temperature-dependent electrical conductivity measurements, it was found that heat treatment and phase decomposition change the transport mechanism from thermally activated p-type electronic conductivity through the perovskite to electronic conduction through the iron oxide formed by thermochemical decomposition. This understanding will be useful to those who are developing or employing this and similar earth-abundant functional perovskites for use under reducing conditions, at elevated temperatures, and when designing materials syntheses and processes.

Adiposity impacts cognitive function in Asian populations: an epidemiological and Mendelian Randomization study.

Background: Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study. Methods: The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30-84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ' g ' was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ' g ' using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ' g ', using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition. Findings: Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ' g ' at P < 0.05. In multivariable analyses, reduced ' g ' was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in ' g ' associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ' g ' is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition. Interpretation: We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia-Pacific region. Funding: The Nanyang Technological University-the Lee Kong Chian School of Medicine, National Healthcare Group, National Medical Research Council, Ministry of Education, Singapore.

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-ß42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.