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Abstract To investigate intestinal health and its potential disruptors in vitro, representative models are required. Human induced pluripotent stem cell (hiPSC)-derived intestinal epithelial cells (IECs) more closely resemble the in vivo intestinal tissue than conventional in vitro models like human colonic adenocarcinoma Caco-2 cells. However, the potential of IECs to study immune-related responses upon external stimuli has not been investigated in detail yet. The aim of the current study was to evaluate immune-related effects of IECs by challenging them with a pro-inflammatory cytokine cocktail. Subsequently, the effects of Lactiplantibacillus plantarum WCFS1 were investigated in unchallenged and challenged IECs. All exposures were compared to Caco-2 cells and in vivo data where possible. Upon the inflammatory challenge, IECs and Caco-2 cells induced a pro-inflammatory response which was strongest in IECs. Heat-killed L. plantarum exerted the strongest effect on immune parameters in the IEC model, while L. plantarum in the stationary growth phase had most pronounced effects on immune-related gene expression in Caco-2 cells. Unfortunately, comparison to in vivo transcriptomics data showed limited similarities, which could be explained by essential differences in the study setups. Altogether, hiPSC-derived IECs show a high potential as a model to study immune-related responses in the intestinal epithelium in vitro.

Background: A promising way to obtain vocal economy and efficiency is by semi-occluding the vocal tract while phonating. Current knowledge about the immediate effects of semi-occluded vocal tract (SOVT) phonation on the laryngeal function and configuration is based mainly on computer modelling or excised larynges studies. In in vivo SOVT studies, electroglottography (EGG) has been the most commonly used laryngeal outcome, showing contradictory results between studies. Therefore, exploring these aspects by direct visualisation of the human larynx during SOVT phonation using strobovideolaryngoscopy (SVL) is needed. Aims: The aim of this study was to investigate and compare the immediate effects of straw phonation (SP) in air, SP in 2 cm water, and SP in 5 cm water (with stirring straws), on the laryngeal function and configuration of a homogeneous group of vocally healthy female speech-language pathology students, visualised with flexible SVL. Methods & Procedure: A randomised controlled trial was used. Fifty-two female speech-language pathology students (mean age: 18.7 years, SD: 0.6) were assigned randomly to one of three experimental groups or a control group: (1) SP in air, (2) SP in 2 cm water, (3) SP in 5 cm water or (4) [u] phonation with similar soft onset and slightly pursed lips as in SP but without a straw (control group). The participants underwent flexible SVL during habitual [u] phonation, followed by the specific SOVT exercise of their group assignment. All video samples were evaluated randomly and blindly by two experienced investigators using the Voice-Vibratory Assessment with Laryngeal Imaging (VALI) rating form, first independently and then by consensus. Outcome & Results: Compared to habitual phonation, the vibrational amplitude decreased during SP in 5 cm water and SP in 2 cm water, being more prominent in the first, more flow-resistant exercise. The mucosal wave also decreased during SP in 5 cm water. The anteroposterior (AP) supraglottic compression similarly increased during SP in air, SP in 2 cm water, and SP in 5 cm water. Further, a rise in mediolateral (ML) compression and a decrease in phase symmetry and regularity were found during SP in 2 cm water. A similar decrease in regularity was observed during SP in 5 cm water. Conclusions & Implications: Both SP in air and SP in water cause positive immediate laryngeal effects for voice training opportunities. More AP supraglottic activity found during each SP exercise might indicate epilarynx narrowing, an economic phenomenon associated with SOVT. Immersing the straw in water additionally diminished the vibrational amplitude, lowering vocal fold impact stress and risk for phonotrauma during the exercise. The decreased regularity of the vibrational cycles during SP in water might be due to the varying back pressure created by the water bubbling. The impact of SP in water on ML supraglottic compression needs further investigation.

Arabinoxylans have been identified for a wide range of purported health-promoting applications, primarily attributed to its immunomodulatory effects. Previously, we have reported the ability of arabinoxylans to induce non-specific memory in innate immune cells, commonly referred to as “trained innate immunity”. In the present study, we investigated the effect of particle size on innate immune training and resilience in primary human macrophages as well as in a more physiologically relevant macrophage-intestinal epithelial cell co-culture model. We demonstrated that smaller (>45 & 90 μm) particle size fractions of rice bran-derived arabinoxylan preparations have a higher enhancing effect on training and resilience in both models. Smaller particle size fractions elevated TNF-α production in primary macrophages and enhanced Dectin-1 receptor activation in reporter cell lines compared to larger particles. Responses were arabinoxylan source specific as only the rice-derived arabinoxylans showed these immune-supportive effects. This particle size-dependent induction of trained immunity was confirmed in the established co-culture model. These findings demonstrate the influence of particle size on the immunomodulatory potential of arabinoxylans, provide further insight into the structure-activity relationship, and offer new opportunities to optimize the immune-enhancing effects of these dietary fibers.

Abstract Background There is increasing evidence that dietary fat, especially saturated fat, promotes the translocation of lipopolysaccharide (LPS) via chylomicron production in the gut. Chylomicrons can subsequently transport LPS to other parts of the body, where they can induce low-grade chronic inflammation that is linked to various metabolic and gut-related diseases. To identify promising (food) compounds that can prevent or ameliorate LPS-related low-grade inflammation, we developed and optimized a bicameral in vitro model for dietary fat-induced LPS translocation that closely mimics the in vivo situation and facilitates high-throughput screening. Methods Caco-2 cells were cultured in monolayers and differentiated to a small intestinal phenotype in 21 days. Thereafter, optimal conditions for fat-induced chylomicron production were determined by apical exposure of Caco-2 cells to a dilution range of in vitro digested palm oil and sunflower oil, optionally preceded by a 1-week apical FBS deprivation (cultured without apical fetal bovine serum). Chylomicron production was assessed by measuring basolateral levels of the chylomicron-related marker apolipoprotein B. Next, LPS was coincubated at various concentrations with the digested oils, and fat-induced LPS translocation to the basolateral side was assessed. Results We found that dietary fat-induced LPS translocation in Caco-2 cells was optimal after apical exposure to digested oils at a 1:50 dilution in combination with 750 ng/mL LPS, preceded by 1 week of apical FBS deprivation. Coincubation with the chylomicron blocker Pluronic L81 confirmed that fat-induced LPS translocation is mediated via chylomicron production in this Caco-2 cell model. Conclusion We developed a robust Caco-2 cell model for dietary fat-induced LPS translocation that can be used for high-throughput screening of (food) compounds that can reduce LPS-related low-grade inflammation.

Abstract Background: What combination of risk factors for Alzheimer’s disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-β pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. Methods: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-β status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-β status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-β status, and their interaction on changes in cognitive functioning over time. Results: Fifty-two participants (19%) had abnormal amyloid-β, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-β status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-β status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-β×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE β(SE)=-0.05(0.02); AD-PRS β(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-β status and AD-PRS predicted a steeper decline in memory functioning (amyloid-β β(SE)=-0.07(0.04); AD-PRS β(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-β status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-β abnormal individuals only (β(SE)=-0.13(0.06); β(SE)=-0.22(0.07), respectively). Conclusion: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-β only. Furthermore, independent of amyloid-β status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

Abstract Background Chronic radiation-associated dysphagia (C-RAD) is considered to be one of the most severe functional impairments in head and neck cancer survivors treated with radiation (RT) or chemoradiation (CRT). Given the major impact of these late toxicities on patients’ health and quality of life, there is a strong need for evidence-based dysphagia management. Although studies report the benefit of strengthening exercises, transference of changes in muscle strength to changes in swallowing function often remains limited. Therefore, combining isolated strengthening exercises with functional training in patients with C-RAD may lead to greater functional gains. Methods This 3-arm multicenter randomized trial aims to compare the efficacy and possible detraining effects of mere strengthening exercises (group 1) with a combination of strengthening exercises and functional swallowing therapy (group 2) and non-invasive brain stimulation added to that combination (group 3) in 105 patients with C-RAD. Patients will be evaluated before and during therapy and 4 weeks after the last therapy session by means of swallowing-related and strength measures and quality of life questionnaires. Discussion Overall, this innovative RCT is expected to provide new insights into the rehabilitation of C-RAD to optimize post-treatment swallowing function. Trial registration International Standard Randomized Controlled Trials Number (ISRCTN) registry ID ISRCTN57028065. Registration was accepted on 15 July 2021.

Background: Prophylactic cranial irradiation (PCI) for limited-stage small-cell lung cancer (LS-SCLC) patients has become more controversial. Since the publication of the systematic review by Aupérin et al. in 1999, no randomized controlled trials regarding PCI in LS-SCLC have been completed. The aim of this study was to systematically review and meta-analyze the effect of PCI on overall survival (OS) in patients with LS-SCLC. Methods: A systematic search was conducted in the databases of MEDLINE (PubMed), Embase and the Cochrane library. Only studies that reported an adjusted hazard ratio (aHR), indicating the effect of PCI versus no PCI on OS (adjusted for confounders) in patients with LS-SCLC were included for critical appraisal and meta-analysis. A pooled aHR estimate was calculated using a random-effects model. Results: Pooling of 28 retrospective studies including a total of 18,575 patients demonstrated a significant beneficial effect of PCI versus no PCI on OS with a pooled aHR of 0.62 (95% CI: 0.57–0.69). Substantial heterogeneity of reported aHRs among studies was observed (I2 = 65.9%). Subgroup analyses revealed that this heterogeneity could partly be explained by study sample size. The pooled aHR among 7 versus 21 studies with a sample size of > 300 versus ≤ 300 patients was 0.79 (95% CI: 0.64–0.97) versus 0.56 (95% CI: 0.46–0.69; p

BackgroundIn the nursing home sector, reusing routinely recorded data from electronic health records (EHRs) for knowledge development and quality improvement is still in its infancy. Trust in appropriate and responsible reuse is crucial for patients and nursing homes deciding whether to share EHR data for these purposes. A data governance framework determines who may access the data, under what conditions, and for what purposes. This can help obtain that trust. Although increasing attention is being paid to data governance in the health care sector, little guidance is available on development and implementation of a data governance framework in practice. ObjectiveThis study aims to describe the development process of a governance framework for the “Registry Learning from Data in Nursing Homes,” a national registry for EHR data on care delivered by nursing home physicians (in Dutch: specialist ouderengeneeskunde) in Dutch nursing homes—to allow data reusage for research and quality improvement of care. MethodsRelevant stakeholders representing practices, policies, and research in the nursing home sector were identified. Semistructured interviews were conducted with 20 people from 14 stakeholder organizations. The main aim of the interviews was to explore stakeholders’ perspectives regarding the Registry’s aim, data access criteria, and governing bodies’ tasks and composition. Interview topics and analyses were guided by 8 principles regarding governance for reusing health data, as described in the literature. Interview results, together with legal advice and consensus discussions by the Registry’s consortium partners, were used to shape the rules, regulations, and governing bodies of the governance framework. ResultsStakeholders valued the involvement of nursing home residents and their representatives, nursing home physicians, nursing homes’ boards of directors, and scientists and saw this as a prerequisite for a trustworthy data governance framework. For the Registry, involvement of these groups can be achieved through a procedure in which residents can provide their consent or objection to the reuse of the data, transparency about the decisions made, and providing them a position in a governing body. In addition, a data request approval procedure based on predefined assessment criteria indicates that data reuse by third parties aligns with the aims of the Registry, benefits the nursing home sector, and protects the privacy of data subjects. ConclusionsThe stakeholders’ views, expertise, and knowledge of other frameworks and relevant legislation serve to inform the application of governance principles to the contexts of both the nursing home sector and the Netherlands. Many different stakeholders were involved in the development of the Registry Learning from Data in Nursing Homes’ governance framework and will continue to be involved. Engagement of the full range of stakeholders in an early stage of governance framework development is important to generate trust in appropriate and responsible data reuse.

Abstract Objective We assessed the performance of plasma amyloid oligomerization tendency (OAβ) as a marker for abnormal amyloid status. Additionally, we examined long-term storage effects on plasma OAβ. Methods We included 399 subjects regardless of clinical diagnosis from the Amsterdam Dementia Cohort and European Medical Information Framework for AD project (age, 63.8 ± 6.6; 44% female). Amyloid status was determined by visual read on positron emission tomography (PET; nabnormal = 206). Plasma OAβ was measured using the multimer detection system (MDS). Long-term storage effects on MDS-OAβ were assessed using general linear models. Associations between plasma MDS-OAβ and Aβ-PET status were assessed using logistic regression and receiver operating characteristics analyses. Correlations between plasma MDS-OAβ and CSF biomarker levels were evaluated using Pearson correlation analyses. Results MDS-OAβ was higher in individuals with abnormal amyloid, and it identified abnormal Aβ-PET with an area under the curve (AUC) of 0.74 (95% CI, 0.67–0.81), especially in samples with a storage duration < 4 years. Combining APOEe4 and age with plasma MDS-OAβ revealed an AUC of 81% for abnormal amyloid PET status (95% CI, 74–87%). Plasma MDS-OAβ correlated negatively with MMSE (r = − 0.29, p < .01) and CSF Aβ42 (r = − 0.20, p < 0.05) and positively with CSF Tau (r = 0.20, p = 0.01). Conclusions Plasma MDS-OAβ combined with APOEe4 and age accurately identifies brain amyloidosis in a large Aβ-confirmed population. Using plasma MDS-OAβ as a screener reduced the costs and number of PET scans needed to screen for amyloidosis, which is relevant for clinical trials. Additionally, plasma MDS-OAβ levels appeared affected by long-term storage duration, which could be of interest for others measuring plasma Aβ biomarkers.

Introduction: Controversy has arisen regarding the benefit of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC), particularly since the 2017 Takahashi trial publication that supports MRI surveillance in extensive-stage (ES-)SCLC. The primary aim of this study was to assess trends and determinants in PCI use over the years 2010–2018. A secondary aim was to determine contemporary practice considerations among radiation oncologists (ROs). Methods: A nationwide population-based cohort study was conducted using the Netherlands Cancer Registry data on all newly diagnosed SCLC patients (2010–2018). The change in PCI frequency over the years and determinants for PCI were analyzed using logistic regression models. Second, an online survey was performed among Dutch lung cancer ROs in 2020. Results: Among 10,264 eligible patients, 4,894 (47%) received PCI. Compared to 2010–2014, PCI use significantly decreased in 2017–2018 in ES-SCLC (OR 0.68, 95%CI 0.60–0.77) and LS-SCLC (OR 0.56, 95%CI 0.47–0.67). Incidence year, age, performance status, and thoracic radiotherapy were independent determinants for PCI. Among 41 survey participants, PCI was recommended always/sometimes/never by 22%/71%/7% in ES-SCLC and 54%/44%/2% in LS-SCLC. For ES-SCLC and LS-SCLC, 63% and 25% of ROs, respectively, confirmed influence of the Takahashi trial on PCI recommendations. Denial of such influence was associated with insufficient institutional MRI capacity. Conclusions: A significant declining trend of PCI use in both ES-SCLC and LS-SCLC was observed in The Netherlands since 2017. The Takahashi trial seems an explanation for this trend even in LS-SCLC, with differential influence of the trial depending on institutional MRI capacity. An alarming increase in practice variation regarding PCI was found which stresses the importance of ongoing trials.

Abstract Food security is under increased pressure due to the ever-growing world population. To tackle this, alternative protein sources need to be evaluated for nutritional value, which requires information on digesta peptide composition in comparison to established protein sources and coupling to biological parameters. Here, a combined experimental and computational approach is presented, which compared seventeen protein sources with cow’s whey protein concentrate (WPC) as the benchmark. In vitro digestion of proteins was followed by proteomics analysis and statistical model-based clustering. Information on digesta peptide composition resulted in 3 cluster groups, primarily driven by the peptide overlap with the benchmark protein WPC. Functional protein data was then incorporated in the computational model after evaluating the effects of eighteen protein digests on intestinal barrier integrity, viability, brush border enzyme activity, and immune parameters using a bioengineered intestine as microphysiological gut system. This resulted in 6 cluster groups. Biological clustering was driven by viability, brush border enzyme activity, and significant differences in immune parameters. Finally, a combination of proteomic and biological efficacy data resulted in 5 clusters groups, driven by a combination of digesta peptide composition and biological effects. The key finding of our holistic approach is that protein source (animal, plant or alternative derived) is not a driving force behind the delivery of bioactive peptides and their biological efficacy.

Abstract Background Ocular imaging receives much attention as a source of potential biomarkers for dementia. In the present study, we analyze these ocular biomarkers in cognitively impaired and healthy participants in a population aged over 90 years (= nonagenarian), and elucidate the effects of age on these biomarkers. Methods For this prospective cross-sectional study, we included individuals from the EMIF-AD 90+ study, consisting of a cognitively healthy (N = 67) and cognitively impaired group (N = 33), and the EMIF-AD PreclinAD study, consisting of cognitively healthy controls aged ≥60 (N = 198). Participants underwent Optical Coherence Tomography (OCT) and fundus photography of both eyes. OCT was used to asses total and individual inner retinal layer thickness in the macular region (Early Treatment Diabetic Retinopathy Study circles) as well as peripapillary retinal nerve fiber layer thickness, fundus images were analyzed with Singapore I Vessel Assessment to obtain 7 retinal vascular parameters. Values for both eyes were averaged. Differences in ocular biomarkers between the 2 nonagenarian groups were analyzed using linear regression, differences between the individual nonagenarian groups and controls were analyzed using generalized estimating equations. Results Ocular biomarkers did not differ between the healthy and cognitively impaired nonagenarian groups. 19 out of 22 ocular biomarkers assessed in this study differed between either nonagenarian group and the younger controls. Conclusion The ocular biomarkers assessed in this study were not associated with cognitive impairment in nonagenarians, making their use as a screening tool for dementing disorders in this group limited. However, ocular biomarkers were significantly associated with chronological age, which were very similar to those ascribed to occur in Alzheimer’s Disease.

Abstract Introduction The contribution of genetic and environmental factors to the relation between cerebrospinal fluid (CSF) biomarkers and cognitive decline in preclinical Alzheimer's disease remains unclear. We studied this in initially cognitively normal monozygotic twins. Methods We included 122 cognitively normal monozygotic twins (51 pairs) with a follow‐up of 4.3 ± 0.4 years. We first tested associations of baseline CSF Aβ1‐42/1‐40 ratio, total tau (t‐tau), and 181‐phosphorylated‐tau (p‐tau) status with subsequent cognitive decline using linear mixed models, and then performed twin specific analyses. Results Baseline abnormal amyloid‐β and tau CSF markers predicted steeper decline on memory (p ≤ .003) and language (p ≤ 0.04). Amyloid‐β and p‐tau markers in one twin predicted decline in memory in the co‐twin and tau markers in one twin predicted decline in language in the co‐twin (r range ‐0.26,0.39; p’s ≤ .02). Discussion These results suggest that memory and language decline are early features of AD that are in part determined by the same genetic factors that influence amyloid‐β and tau regulation.

INTRODUCTION: We assessed whether co‐morbid small vessel disease (SVD) has clinical predictive value in preclinical or prodromal Alzheimer's disease. METHODS: In 1090 non‐demented participants (65.4 ± 10.7 years) SVD was assessed with magnetic resonance imaging and amyloid beta (Aβ) with lumbar puncture and/or positron emission tomography scan (mean follow‐up for cognitive function 3.1 ± 2.4 years). RESULTS: Thirty‐nine percent had neither Aβ nor SVD (A–V–), 21% had SVD only (A–V+), 23% Aβ only (A+V–), and 17% had both (A+V+). Pooled cohort linear mixed model analyses demonstrated that compared to A–V– (reference), A+V– had a faster rate of cognitive decline. Co‐morbid SVD (A+V+) did not further increase rate of decline. Cox regression showed that dementia risk was modestly increased in A–V+ (hazard ratio [95% confidence interval: 1.8 [1.0–3.2]) and most strongly in A+ groups. Also, mortality risk was increased in A+ groups. DISCUSSION: In non‐demented persons Aβ was predictive of cognitive decline, dementia, and mortality. SVD modestly predicts dementia in A–, but did not increase deleterious effects in A+. Highlights: Amyloid beta (Aβ; A) was predictive for cognitive decline, dementia, and mortality.Small vessel disease (SVD) had no additional deleterious effects in A+.SVD modestly predicted dementia in A–.Aβ should be assessed even when magnetic resonance imaging indicates vascular cognitive impairment. [ABSTRACT FROM AUTHOR]

Abstract Introduction Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort. Methods We included 179 individuals from the European Medical Information Framework for AD (EMIF‐AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract‐level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden. Results Regression analyses showed a non‐linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC. Discussion Early amyloid deposition is associated with changes in WM microstructure. The non‐linear relationship might reflect multiple stages of axonal damage.

Abstract Background Amyloid pathology is the pathological hallmark in Alzheimer’s disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. Methods From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [18F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. Results We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. Conclusions A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.

Background: As cerebrovascular and Alzheimer's proteinopathy have previously shown to affect cerebral blood flow (CBF) as well as cognition, CBF could be a potential early hemodynamic biomarker of cognitive decline. Here, we investigated to what extent cardiovascular risk factors and amyloid burden affect CBF in an elderly cognitively unimpaired (CU) population. Method: We included 153 CU participants (minimal MMSE = 28) from the EMIF‐AD PreclinAD Twin60++ cohort (Table 1), who underwent [18F]flutemetamol PET and arterial spin labeling (ASL) MRI. Amyloid‐PET scans were visually assessed as negative or positive, upon which participants were grouped based on their longitudinal changes in amyloid positivity (visual read groups). Cortical amyloid burden was quantified with the Centiloid method globally and for 4 early amyloid accumulation regions of interest (ROIs). ASL scans were processed and quantified with ExploreASL for total gray matter (GM), and for vascular territories overlapping with the amyloid ROIs (Figure 1). Longitudinal analysis including baseline Centiloid values and yearly CBF change rates (Delta CBF) was performed for 98 participants with longitudinal imaging data available (4.23 years ± 0.43 follow‐up time). Associations between CBF and amyloid — with and without the interaction of vascular risk factors (i.e., Framingham score) — were assessed using generalized estimating equations (GEEs), both for baseline and rates of change measurements. Models were adjusted for age, sex, and twin dependency. Result: While no association between amyloid burden and CBF was observed across the cohort, in participants with a high Framingham vascular risk score, higher amyloid was associated with increased CBF, for most ROIs (Table 2, Figure 2). Additionally, precuneus amyloid burden was predictive of CBF change in the corresponding vascular territory (Figure 3). Visual reading shows that subjects with high amyloid burden at baseline had a higher increase of CBF at follow‐up (Stable AB+, Figure 4). Conclusion: We found that the combination of cardiovascular risk and amyloid burden in AD signature regions was associated with increased CBF in CU individuals, which may reflect a vascular or inflammatory compensatory response to early Alzheimer pathology. Future studies may help understanding how these mechanisms affect cognition. [ABSTRACT FROM AUTHOR]

Previous studies on the endotyping of chronic rhinosinusitis (CRS) that were based on inflammatory factors have broadened our understanding of the disease. However, the endotype of CRS combined with inflammatory and remodeling features has not yet been clearly elucidated. We sought to identify the endotypes of patients with CRS according to inflammatory and remodeling factors. Forty-eight inflammatory and remodeling factors in the nasal mucosal tissues of 128 CRS patients and 24 control subjects from northern China were analyzed by Luminex, ELISA, and ImmunoCAP. Sixteen factors were used to perform the cluster analysis. The characteristics of each cluster were analyzed using correlation analysis and validated by immunofluorescence staining. Patients were classified into 5 clusters. Clusters 1 and 2 showed non-type 2 signatures with low biomarker concentrations, except for IL-19 and IL-27. Cluster 3 involved a low type 2 endotype with the highest expression of neutrophil factors, such as granulocyte colony-stimulating factor, IL-8, and myeloperoxidase, and remodeling factors, such as matrix metalloproteinases and fibronectin. Cluster 4 exhibited moderate type 2 inflammation. Cluster 5 exhibited high type 2 inflammation, which was associated with relatively higher levels of neutrophil and remodeling factors. The proportion of CRS with nasal polyps, asthma, allergies, anosmia, aspirin sensitivity, and the recurrence of CRS increased from clusters 1 to 5. Diverse inflammatory mechanisms result in distinct CRS endotypes and remodeling profiles. The explicit differentiation and accurate description of these endotypes will guide targeted treatment decisions. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Grey matter covariance networks become disrupted early in Alzheimer's disease (AD), when amyloid starts aggregating, and before the onset of irreversible atrophy. However, the precise relationship of grey matter network breakdown and the AD pathophysiological process remains unclear. Here, we studied to what extent shared familial (genes and family environment) or environmental factors unique to a twin contribute to these relationships in a sample of older monozygotic twins with intact cognition. Method: From the EMIF‐AD PreclinAD study we included monozygotic twins who had at least an MRI scan (n=197) and CSF available (n=124). We assessed the upper limit of genetic contribution to grey matter network measures (size, degree, connectivity density, clustering, path length, small‐world measures) with within‐twin pair correlations. Associations between CSF AD markers (Aβ42/40, t‐tau, p‐tau) and other markers related to AD pathophysiology (neurogranin, Aβ38, Aβ40, BACE1) with grey matter network disruptions were assessed with linear mixed models. Twin analyses (cross‐twin cross‐trait, twin difference analyses) were used to assess the contribution of shared familial and/or unique environmental factors to these associations. Result: Twenty individuals (16%) had abnormal CSF Aβ42/40 levels. Grey matter network measures were highly correlated within twin pairs (r=0.54‐0.97; all p<0.001, Fig.1), suggesting a moderate to strong genetic background. Across the whole sample, more abnormal Aβ42/40 ratios were moderately related to lower connectivity density (β±SE = 0.176±0.09, p=0.055, Fig.2). The strongest associations with grey matter network measures were observed for t‐tau and p‐tau levels (range β=‐0.344‐0.182), followed by Aβ production markers (Aβ38, Aβ40, BACE1) (range β=‐0.202‐0.165). We observed no relationships between neurogranin and grey matter network measures. Cross‐twin cross‐trait analyses showed that levels for t‐tau, p‐tau and Aβ38 in one twin were associated with grey matter network measures in their co‐twin (r=‐0.27 to ‐0.21; p range=0.02 to 0.07, Fig.3). Within‐pair differences in BACE1 were related to within‐pair differences in normalized path length values (r=0.35; p=0.01; Fig.4). Conclusion: Our results suggest a shared familial background for the relationship of grey matter network disruptions and AD‐related processes as measured in CSF. In addition, unique environmental factors influencing BACE1 may also affect grey matter network disruptions. [ABSTRACT FROM AUTHOR]

A 78-year-old female presented with complaints of unilateral clear otorrhea, which worsened after consuming meals. The complaints started acutely four weeks before. There were no associated complaints of otalgia, craniofacial pain, hearing loss or tinnitus. During clinical examination, otomicroscopy revealed marked edema of the external ear canal with a limited amount of clear fluid and debris, and a normal tympanic membrane, as well as an anterior canal wall which was highly mobile during jaw movement. Pure tone audiometry showed bilateral symmetrical high frequency sensorineural hearing loss. Repetitive culture of the debris in the ear canal only detected commensal flora.

Background: Age related hearing loss has been associated with increased prevalence and incidence of dementia. Underlying mechanisms that connect hearing loss with dementia remain largely unclear. Methods: We studied the association of hearing loss and other risk markers for dementia in two cohorts with normal cognition and different age: 65 participants from the EMIF‐AD 90+ study (mean age 92.7 years, 56.9% female) and 60 participants from the EMIF‐AD PreclinAD study (mean age 74.4, 43.3% female). Individuals were selected when they had hearing function ('digits‐in‐noise test') and neuropsychological testing available. Amyloid binding potential (BPND) was derived from dynamic PET scans. We used linear regression analysis and generalized estimating equations to test the association of hearing loss and BPND. We used linear mixed models to test the association of hearing function and cognition over time. In the oldest‐to‐old individuals, magnetic resonance imaging was available at the time of hearing function testing, and we performed mediation analyses to study whether cognitive decline is mediated through regional brain regions. All models included age, sex, and amyloid status as covariates, and longitudinal analyses were corrected for education years. Results: Oldest‐to‐old individuals showed worse hearing functioning than the younger cohort (p<.001). In oldest‐to‐old hearing loss was not associated with BPND (p =.70), whereas younger individuals showed an association of hearing loss with higher BPND (p =.003, figure 1). Oldest‐to‐old individuals showed associations of worse hearing with a steeper decline in memory (β ± SE = ‐0.018 ± 0.007), global cognition (β ± SE = ‐0.017 ± 0.007) and language (β ± SE = ‐0.014 ± 0.007), while in the younger cohort worse hearing was associated with steeper decline in language only (β ± SE = ‐0.086 ± 0.02, figure 2). Mediation analyses demonstrated that the hippocampus and nucleus accumbens fully mediate the effects of hearing loss on memory and global cognition in the older individuals (figure 3‐4). Conclusions: Hearing loss was associated with amyloid burden in younger individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age. [ABSTRACT FROM AUTHOR]

Background: The amyloid‐cascade hypothesis of Alzheimer's disease posits that there is a causal relationship between amyloid‐β (Aβ) and tau pathology. However, the mechanism through which Aβ would cause tau remains unclear. We cannot exclude the possibility of an additional underlying factor influencing Aβ at one time‐point and tau at a later time‐point. One such potential underlying factor can be genetic variation among individuals. This study aimed to examine the relationship between Aβ and tau, taking potential genetic confounding into account using a genetically identical twin design. Methods: We included 70 identical twins (35 pairs) from the EMIF‐AD PreclinAD study with normal baseline cognition. We extracted baseline global [18F]flutemetamol (Aβ)‐PET binding potential (BPND) and 4‐year follow‐up [18F]flortaucipir (tau)‐PET BPND in a temporal meta‐region‐of‐interest. If Aβ is causally related to tau, the twin with more Aβ should also have more tau compared to the co‐twin. We tested this using regional and voxel‐wise within‐pair difference models, in which the within‐pair difference in Aβ is regressed on the within‐pair difference in tau. The resulting effect represents an association that is free of confounding due to factors that are shared between twins of the same pair, which includes genetic factors (twins are genetically identical), but also shared demographic (e.g. sex, age) and shared environmental (e.g. raised in the same family) factors. Results: Participant characteristics are shown in Table 1. Total group analysis showed that global Aβ‐PET BPND was associated with temporal tau‐PET BPND (β=0.49, p<0.001) (Fig‐1A). The twin‐difference model replicated this. We observed a highly comparable effect size for the association between within‐pair differences in global Aβ‐PET and within‐pair differences in temporal tau‐PET (β=0.56, p<0.001) (Fig‐1B). Compared to the total group voxel‐wise analysis, we observed an overlapping (and more widespread) pattern when regressing within‐pair differences in global Aβ‐PET on within‐pair differences in voxel‐wise tau‐PET, except for effects on tau in the medial temporal lobe (Fig‐2). Conclusion: Our within‐pair difference results show that the association between Aβ and tau is minimally affected by confounding by genetic variation. Our voxel‐wise results support a causal association between global Aβ and tau outside of the medial temporal lobe. [ABSTRACT FROM AUTHOR]

Background: Plasma levels of amyloid‐β1‐42/1‐40, phosphorylated‐tau (P‐tau) and glial fibrillary acidic protein (GFAP) can be used to predict amyloid‐β pathology in elderly cognitively unimpaired individuals, but their prognostic value in early Alzheimer's Disease (AD) stages in the normal aging population needs further study. We aimed to investigate the value of these plasma biomarkers for predicting memory change in cognitively unimpaired individuals in a population‐based cohort. Method: From the EMIF‐AD PreclinAD study we selected 188 individuals with normal cognition, who had plasma samples, amyloid‐β status and at least one cognitive follow‐up available (total follow‐up years (mean(SD) = 4.3(.42)) (Table 1). Amyloid‐β status was defined using visual read of dynamic [18F]flutemetamol‐PET images or CSF amyloid‐β1‐42/1‐40<0.066 (Euroimmun). Simoa assays were used to measure plasma amyloid‐β1‐42/1‐40 (AMYBLOOD), P‐tau181 (Eli Lilly) and GFAP (Quanterix) levels. Linear mixed models, adjusted for age, sex and years of education, were applied to test associations of baseline plasma biomarker levels with subsequent change in memory (plasma*time), and its interaction with amyloid‐β status (plasma*time*amyloid‐β status). Result: From the total cohort tested, 31 subjects (16.5%) were amyloid‐positive. These individuals were older, showed worse baseline memory performance, lower plasma amyloid‐β1‐42/1‐40, and higher plasma P‐tau181 and GFAP levels compared to amyloid‐negative individuals (Table 1). Higher plasma GFAP levels at baseline were significantly associated with worse memory performance over time (GFAP*time: β=‐.03, p=.01). Interestingly, this relation was significantly stronger in amyloid‐positive compared to amyloid‐negative individuals (GFAP*time*amyloid‐β status: β=‐.07, p=.001) (Table 2, Figure 1). No significant associations were observed for baseline plasma amyloid‐β1‐42/1‐40 and P‐tau181 levels with change in memory over time (P‐tau181*time: β=‐.02, p=.07; amyloid‐β1‐42/1‐40*time: β=.02, p=.12) (Table 2). Conclusion: Our data suggest plasma GFAP can be used as a predictor of future memory decline in cognitively unimpaired, amyloid‐positive, individuals in the normal aging population. This supports the use of plasma GFAP as a prognostic marker for disease and treatment‐effect monitoring in the early stages of AD development. [ABSTRACT FROM AUTHOR]