Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

Potential cognitive and neural benefits of a computerised cognitive training programme based on Structure Learning in healthy adults: study protocol for a randomised controlled trial.

BACKGROUND: Cognitive flexibility refers to the capacity to shift between conceptual representations particularly in response to changes in instruction and feedback. It enables individuals to swiftly adapt to changes in their environment and has significant implications for learning. The present study focuses on investigating changes in cognitive flexibility following an intervention programme-Structure Learning training. METHODS: Participants are pseudo-randomised to either the Training or Control group, while matched on age, sex, intelligence and cognitive flexibility performance. In the Training group, participants undergo around 2 weeks of training (at least 13 sessions) on Structure Learning. In the Control group, participants do not have to undergo any training and are never exposed to the Structure Learning task. The effects of Structure Learning training are investigated at both the behavioural and neural level. We measured covariates that can influence an individual's training performance before the training phase and outcome measures that can potentially show training benefits after the training phase. At the behavioural level, we investigated outcomes in both cognitive and social aspects with a primary focus on executive functions. At the neural level, we employed a multimodality approach and investigated potential changes to functional connectivity patterns, neurometabolite concentration in the frontal brain regions, and brain microstructure and myelination. DISCUSSION: We reported the development of a novel training programme based on Structure Learning that aims to hone a general learning ability to potentially achieve extensive transfer benefits across various cognitive constructs. Potential transfer benefits can be exhibited through better performance in outcome measures between Training and Control participants, and positive associations between training performance and outcomes after the training in Training participants. Moreover, we attempt to substantiate behavioural findings with evidence of neural changes across different imaging modalities by the Structure Learning training. TRIAL REGISTRATION: National Institutes of Health U.S. National Library of Medicine ClinicalTrials.gov NCT05611788. Registered on 7 November 2022. PROTOCOL VERSION: 11 May 2023.

The prediction of Alzheimer's disease through multi-trait genetic modeling.

To better capture the polygenic architecture of Alzheimer's disease (AD), we developed a joint genetic score, MetaGRS. We incorporated genetic variants for AD and 24 other traits from two independent cohorts, NACC (n = 3,174, training set) and UPitt (n = 2,053, validation set). One standard deviation increase in the MetaGRS is associated with about 57% increase in the AD risk [hazard ratio (HR) = 1.577, p = 7.17 E-56], showing little difference from the HR for AD GRS alone (HR = 1.579, p = 1.20E-56), suggesting similar utility of both models. We also conducted APOE-stratified analyses to assess the role of the e4 allele on risk prediction. Similar to that of the combined model, our stratified results did not show a considerable improvement of the MetaGRS. Our study showed that the prediction power of the MetaGRS significantly outperformed that of the reference model without any genetic information, but was effectively equivalent to the prediction power of the AD GRS.

Bioinformatic Analyses of Peripheral Blood Transcriptome Identify Altered Neutrophil-Related Pathway and Different Transcriptomic Profiles for Acute Pancreatitis in Patients with and without Chylomicronemia Syndrome.

Acute pancreatitis (AP) is a serious inflammatory condition of the pancreas that can be associated with chylomicronemia syndrome (CS). Currently, no study has explored the differences between non-CS-associated AP and CS-associated AP in terms of gene expression. Transcriptomic profiles of blood samples from patients with AP were retrieved from GSE194331 (non-CS-associated) and GSE149607 (CS-associated). GSE31568 was used to examine the linkage between non-CS-associated AP and the expression of micro RNAs (miRNAs). Differentially expressed genes (DEGs) were identified, a gene regulatory network was constructed, and hub genes were defined. Subsequently, single-sample gene set enrichment analysis (ssGSEA) scores of hub genes were calculated to represent their regulatory-level activity. A total of 1851 shared DEGs were identified between non-CS-associated and CS-associated AP. Neutrophils were significantly enriched in both conditions. In non-CS-associated AP, miRNAs including hsa-miR-21, hsa-miR-146a, and hsa-miR-106a demonstrated a lower expression level as compared with the healthy control. Furthermore, the expression patterns and regulatory activities were largely opposite between non-CS-associated and CS-associated AP, with significantly lower estimated neutrophils in the latter case. In summary, we found that the regulation of neutrophils was altered in AP. There was a different gene expression pattern and lower estimated neutrophil infiltration in CS-associated AP. Whether these findings are clinically significant requires further investigation.

Alzheimer's Disease Variant Portal: A Catalog of Genetic Findings for Alzheimer's Disease.

BACKGROUND: Recent Alzheimer's disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic variants and genes with functional and genomic annotations. OBJECTIVE: Create an integrated/harmonized, and literature-derived collection of population-specific AD genetic associations. METHODS: We developed the Alzheimer's Disease Variant Portal (ADVP), an extensive collection of associations curated from >200 GWAS publications from Alzheimer's Disease Genetics Consortium and other consortia. Genetic associations were systematically extracted, harmonized, and annotated from both the genome-wide significant and suggestive loci reported in these publications. To ensure consistent representation of AD genetic findings, all the extracted genetic association information was harmonized across specifically designed publication, variant, and association categories. RESULTS: ADVP V1.0 (February 2021) catalogs 6,990 associations related to disease-risk, expression quantitative traits, endophenotypes, or neuropathology. This extensive harmonization effort led to a catalog containing >900 loci, >1,800 variants, >80 cohorts, and 8 populations. Besides, ADVP provides investigators with a seamless integration of genomic and publicly available functional annotations across multiple databases per harmonized variant and gene records, thus facilitating further understanding and analyses of these genetics findings. CONCLUSION: ADVP is a valuable resource for investigators to quickly and systematically explore high-confidence AD genetic findings and provides insights into population-specific AD genetic architecture. ADVP is continually maintained and enhanced by NIAGADS and is freely accessible at https://advp.niagads.org.

Reconcile the debate over protective effects of BCG vaccine against COVID-19.

While awaiting the COVID-19 vaccines, researchers have been actively exploring the effectiveness of existing vaccines against the new virus, among which the BCG vaccine (Bacillus Calmette-Guérin) receives the most attention. While many reports suggest a potential role for BCG immunization in ameliorating SARS-CoV-2 infection, these findings remain controversial. With country-level COVID-19 outbreak data from Johns Hopkins University Coronavirus Resource Center, and BCG program data from World Atlas of BCG Policies and Practices and WHO/UNICE, we estimated a dynamic model to investigate the effect of BCG vaccination across time during the pandemic. Our results reconcile these varying reports regarding protection by BCG against COVID-19 in a variety of clinical scenarios and model specifications. We observe a notable protective effect of the BCG vaccine during the early stage of the pandemic. However, we do not see any strong evidence for protection during the later stages. We also see that a higher proportion of vaccinated young population may confer some level of communal protection against the virus in the early pandemic period, even when the proportion of vaccination in the older population is low. Our results highlight that while BCG may offer some protection against COVID-19, we should be cautious in interpreting the estimated effectiveness as it may vary over time and depend on the age structure of the vaccinated population.

Unfolded protein response regulates yeast small GTPase Arl1p activation at late Golgi via phosphorylation of Arf GEF Syt1p.

ADP ribosylation factor (Arf) GTPases are key regulators of membrane traffic at the Golgi complex. In yeast, Arf guanine nucleotide-exchange factor (GEF) Syt1p activates Arf-like protein Arl1p, which was accompanied by accumulation of golgin Imh1p at late Golgi, but whether and how this function of Syt1p is regulated remains unclear. Here, we report that the inositol-requiring kinase 1 (Ire1p)-mediated unfolded protein response (UPR) modulated Arl1p activation at late Golgi. Arl1p activation was dependent on both kinase and endo-RNase activities of Ire1p. Moreover, constitutively active transcription factor Hac1p restored the Golgi localization of Arl1p and Imh1p inIRE1-deleted cells. Elucidating the mechanism of Ire1p-Hac1p axis actions, we found that it regulated phosphorylation of Syt1p, which enhances Arl1p activation, recruitment of Imh1p to the Golgi, and Syt1p interaction with Arl1p. Consistent with these findings, the induction of UPR by tunicamycin treatment increases phosphorylation of Syt1p, resulting in Arl1p activation. Thus, these findings clarify how the UPR influences the roles of Syt1p, Arl1p, and Imh1p in Golgi transport.

Far-space neglect in conjunction but not feature search following transcranial magnetic stimulation over right posterior parietal cortex.

Near- and far-space coding in the human brain is a dynamic process. Areas in dorsal, as well as ventral visual association cortex, including right posterior parietal cortex (rPPC), right frontal eye field (rFEF), and right ventral occipital cortex (rVO), have been shown to be important in visuospatial processing, but the involvement of these areas when the information is in near or far space remains unclear. There is a need for investigations of these representations to help explain the pathophysiology of hemispatial neglect, and the role of near and far space is crucial to this. We used a conjunction visual search task using an elliptical array to investigate the effects of transcranial magnetic stimulation delivered over rFEF, rPPC, and rVO on the processing of targets in near and far space and at a range of horizontal eccentricities. As in previous studies, we found that rVO was involved in far-space search, and rFEF was involved regardless of the distance to the array. It was found that rPPC was involved in search only in far space, with a neglect-like effect when the target was located in the most eccentric locations. No effects were seen for any site for a feature search task. As the search arrays had higher predictability with respect to target location than is often the case, these data may form a basis for clarifying both the role of PPC in visual search and its contribution to neglect, as well as the importance of near and far space in these.

The dorsal attentional system in oculomotor learning of predictive information.

The dorsal attentional network is known for its role in directing top-down visual attention toward task-relevant stimuli. This goal-directed nature of the dorsal network makes it a suitable candidate for processing and extracting predictive information from the visual environment. In this review we briefly summarize some of the findings that delineate the neural substrates that contribute to predictive learning at both levels within the dorsal attentional system: including the frontal eye field (FEF) and posterior parietal cortex (PPC). We also discuss the similarities and differences between these two regions when it comes to learning predictive information. The current findings from the literature suggest that the FEFs may be more involved in top-down spatial attention, whereas the parietal cortex is involved in processing task-relevant attentional influences driven by stimulus salience, both contribute to the processing of predictive cues at different time points.

The location probability effects of saccade reaction times are modulated in the frontal eye fields but not in the supplementary eye field.

The visual system constantly utilizes regularities that are embedded in the environment and by doing so reduces the computational burden of processing visual information. Recent findings have demonstrated that probabilistic information can override attentional effects, such as the cost of making an eye movement away from a visual target (antisaccade cost). The neural substrates of such probability effects have been associated with activity in the superior colliculus (SC). Given the immense reciprocal connections to SC, it is plausible that this modulation originates from higher oculomotor regions, such as the frontal eye field (FEF) and the supplementary eye field (SEF). To test this possibility, the present study employed theta burst transcranial magnetic stimulation (TMS) to selectively interfere with FEF and SEF activity. We found that TMS disrupted the effect of location probability when TMS was applied over FEF. This was not observed in the SEF TMS condition. Together, these 2 experiments suggest that the FEF plays a critical role not only in initiating saccades but also in modulating the effects of location probability on saccade production.

Antisaccade cost is modulated by contextual experience of location probability.

It is well known that pro- and antisaccades may deploy different cognitive processes. However, the specific reason why antisaccades have longer latencies than prosaccades is still under debate. In three experiments, we studied the factors contributing to the antisaccade cost by taking attentional orienting and target location probabilities into account. In experiment 1, using a new antisaccade paradigm, we directly tested Olk and Kingstone's hypothesis, which attributes longer antisaccade latency to the time it takes to reorient from the visual target to the opposite saccadic target. By eliminating the reorienting component in our paradigm, we found no significant difference between the latencies of the two saccade types. In experiment 2, we varied the proportion of prosaccades made to certain locations and found that latencies in the high location-probability (75%) condition were faster than those in the low location-probability condition. Moreover, antisaccade latencies were significantly longer when location probability was high. This pattern can be explained by the notion of competing pathways for pro- and antisaccades in findings of others. In experiment 3, we further explored the degrees of modulation of location probability by decreasing the magnitude of high probability from 75 to 65%. We again observed a pattern similar to that seen in experiment 2 but with smaller modulation effects. Together, these experiments indicate that the reorienting process is a critical factor in producing the antisaccade cost. Furthermore, the antisaccade cost can be modulated by probabilistic contextual information such as location probabilities.