Random Survival Forests With Competing Events: A Subdistribution-Based Imputation Approach.

Random survival forests (RSF) can be applied to many time-to-event research questions and are particularly useful in situations where the relationship between the independent variables and the event of interest is rather complex. However, in many clinical settings, the occurrence of the event of interest is affected by competing events, which means that a patient can experience an outcome other than the event of interest. Neglecting the competing event (i.e., regarding competing events as censoring) will typically result in biased estimates of the cumulative incidence function (CIF). A popular approach for competing events is Fine and Gray's subdistribution hazard model, which directly estimates the CIF by fitting a single-event model defined on a subdistribution timescale. Here, we integrate concepts from the subdistribution hazard modeling approach into the RSF. We develop several imputation strategies that use weights as in a discrete-time subdistribution hazard model to impute censoring times in cases where a competing event is observed. Our simulations show that the CIF is well estimated if the imputation already takes place outside the forest on the overall dataset. Especially in settings with a low rate of the event of interest or a high censoring rate, competing events must not be neglected, that is, treated as censoring. When applied to a real-world epidemiological dataset on chronic kidney disease, the imputation approach resulted in highly plausible predictor-response relationships and CIF estimates of renal events.

Random forests for the analysis of matched case-control studies.

BACKGROUND: Conditional logistic regression trees have been proposed as a flexible alternative to the standard method of conditional logistic regression for the analysis of matched case-control studies. While they allow to avoid the strict assumption of linearity and automatically incorporate interactions, conditional logistic regression trees may suffer from a relatively high variability. Further machine learning methods for the analysis of matched case-control studies are missing because conventional machine learning methods cannot handle the matched structure of the data. RESULTS: A random forest method for the analysis of matched case-control studies based on conditional logistic regression trees is proposed, which overcomes the issue of high variability. It provides an accurate estimation of exposure effects while being more flexible in the functional form of covariate effects. The efficacy of the method is illustrated in a simulation study and within an application to real-world data from a matched case-control study on the effect of regular participation in cervical cancer screening on the development of cervical cancer. CONCLUSIONS: The proposed random forest method is a promising add-on to the toolbox for the analysis of matched case-control studies and addresses the need for machine-learning methods in this field. It provides a more flexible approach compared to the standard method of conditional logistic regression, but also compared to conditional logistic regression trees. It allows for non-linearity and the automatic inclusion of interaction effects and is suitable both for exploratory and explanatory analyses.

Skeleton density and ellipsoid zone loss are prognostic for progression in Macular Telangiectasia Type 2.

Macular Telangiectasia Type 2 (MacTel) is a chronic, progressive disease of the central retina characterized by vascular and neurodegenerative changes. As there is currently no treatment for non-neovascular MacTel, there is a dearth for biomarkers identifying eyes with an increased risk for disease progression for patient counseling and clinical trial recruitment. Eyes were classified to be stable or progressive, defined by the fundus photography-based grading system by Gass and Blodi. First, structural differences between these two groups were assessed, employing optical coherence tomography (OCT) and OCT-angiography. Univariate regression analyses revealed evidence towards a lower superficial retinal layer (SRL) vessel density (VD), skeleton density (SD) and deep retinal layer (DRL) SD in progressing compared to stable eyes (p = 0.05, p = 0.05, p = 0.07). Second, a multivariable predictive model was employed to examine the predictive value of structural and functional parameters for disease progression. Baseline best corrected visual acuity (BCVA) and SRL SD are prognostic for disease progression (p < 0.001, p = 0.05). The presence of ellipsoid zone (EZ) loss is prognostic for future central retinal thickness (p < 0.01). We propose SRL SD, BCVA, and EZ loss as prognostic biomarkers and as possible outcome measures in future interventional studies in MacTel.

Treatment exit options for non-infectious uveitis registry: participant characteristics at 3 years.

PURPOSE: The Treatment exit Options For non-infectious Uveitis (TOFU) registry documents disease courses for non-anterior non-infectious uveitis entities with and without treatment to generate more evidence for clinical management recommendations including treatment exit strategies. In this article, we present the participants' baseline characteristics after the first 3 years. METHODS: TOFU is an observational, prospective registry and recruits patients ≥18 years of age with non-anterior non-infectious uveitis with or without a history of previous disease-modifying antirheumatic drugs (DMARDs) treatment. The data are collected in the electronic data capture software REDCap and include ophthalmological and general medical history as well as clinical findings. RESULTS: Between 24.10.2019 and 27.12.2022, 628 patients were enrolled at 25 clinical sites in Germany and Austria. Patients with intermediate uveitis were most frequently included (n=252; 40.1%) followed by posterior uveitis (181; 28.8%), panuveitis (n=154; 24.5%) and retinal vasculitis (n=41, 6.5%). At baseline, 39.6% were treated with systemic corticosteroids, 22.3% with conventional synthetic (cs) DMARDs, 20.5% with biological (b) DMARDs and 3.6% with other systemic treatments. Average best corrected visual acuity (BCVA) was 0.69 decimal. Patients with panuveitis had the worst BCVA with 0.63 decimal. Overall, only 8 patients (1.3%) suffered from severe visual impairment. CONCLUSIONS: Less than half of participants required DMARD treatment at baseline, with csDMARDs used more frequently than bDMARDs. The presence of severe visual impairment was low, mostly affecting patients with panuveitis. These findings are in line with comparable monocentric cross-sectional studies of tertiary uveitis centres in Germany and will allow us to generate generalisable evidence in TOFU.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

OBJECTIVES: Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. MATERIALS AND METHODS: A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. RESULTS: Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD ( P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI ( P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups ( P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. CONCLUSIONS: The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

Vessel density on optical coherence tomography angiography is prognostic for future disease course in intermediate uveitis.

As most rare diseases, intermediate uveitis lacks reliable endpoints necessary for randomized clinical trials. Therefore, we investigated longitudinal changes of retinal and choriocapillaris perfusion on optical coherence tomography angiography (OCT-A) in intermediate uveitis and their prognostic value for future best corrected visual acuity (BCVA) and central retinal thickness (CRT). In this retrospective, longitudinal cohort study eyes of patients with intermediate uveitis were imaged by swept-source OCT-A (macula-centered 3 × 3 mm; PLEX Elite 9000, Zeiss) and stratified into clinically stable, worsened and improved based on changes in clinical parameters. Superficial (SRL) and deep retinal layers (DRL) were automatically analyzed for vessel density (VD) and choriocapillaris layer for non-perfused area (CCNPA) using ImageJ. Mixed-effects regression analysis controlling for age, sex, and OCT-A signal strength index (SSI) was used to evaluate the prognostic value of OCT-A parameters. 91 eyes (62 stable, 12 worsened, and 17 improved) were included in the analysis and mean follow-up time was 296 days. Longitudinal changes of VD were different between all three groups (p = 0.002 for SRL and p = 0.017 for DRL). Clinically worsened eyes showed a decrease in VD (- 0.032 ± 0.055 for SRL and - 0.027 ± 0.025 for DRL), whereas clinically improved eyes showed an increase in VD (0.037 ± 0.039 for SRL and 0.001 ± 0.023 for DRL). No difference was found for CCNPA. When controlling for age, sex, and SSI, observed differences held true in clinically worsened eyes for DRL (p = 0.011) and in clinically improved eyes for SRL (p = 0.002). An increase of CCNPA in clinically worsened eyes (p = 0.03) compared to clinically stable and improved eyes was evident. Predictive analysis revealed an association of VD in SRL and DRL at baseline with BCVA at follow-up (p = 0.039 and p = 0.047, respectively) and of VD in SRL at baseline with CRT at follow-up (p = 0.046). Alterations in retinal perfusion on OCT-A in intermediate uveitis are partly reversible and OCT-A VD may serve to predict future BCVA and CRT. Thus, perfusion parameters on OCT-A might aid monitoring and serve as prognostic imaging-biomarker.

Pseudo-value regression trees.

This paper presents a semi-parametric modeling technique for estimating the survival function from a set of right-censored time-to-event data. Our method, named pseudo-value regression trees (PRT), is based on the pseudo-value regression framework, modeling individual-specific survival probabilities by computing pseudo-values and relating them to a set of covariates. The standard approach to pseudo-value regression is to fit a main-effects model using generalized estimating equations (GEE). PRT extend this approach by building a multivariate regression tree with pseudo-value outcome and by successively fitting a set of regularized additive models to the data in the nodes of the tree. Due to the combination of tree learning and additive modeling, PRT are able to perform variable selection and to identify relevant interactions between the covariates, thereby addressing several limitations of the standard GEE approach. In addition, PRT include time-dependent effects in the node-wise models. Interpretability of the PRT fits is ensured by controlling the tree depth. Based on the results of two simulation studies, we investigate the properties of the PRT method and compare it to several alternative modeling techniques. Furthermore, we illustrate PRT by analyzing survival in 3,652 patients enrolled for a randomized study on primary invasive breast cancer.

Clinical use of the manchester triage system in patients with dizziness - An observational study in the emergency department.

INTRODUCTION: Dizziness is a common symptom with diverse causes, including ear-nose-throat, internal, neurological, or psychiatric origins. While for most parts treatable in nonemergency settings, it can also signal time-critical conditions, like an unnoticed stroke, requiring prompt diagnosis and treatment to prevent lasting harm or death. The aim of this study was to evaluate the validity of the Manchester Triage System in classifying patients presenting with dizziness based on final diagnoses and patient outcomes, as no specific flow chart exists for this symptom in the MTS. METHODS: Monocentric, retrospective observational study. To test the validity of the MTS in the triage of dizziness patients, the treatment level was used as a surrogate parameter. We grouped the patients into outpatient, normal ward and intermediate care/intensive care unit (IMC/ICU) patients. Furthermore, we analyzed the dizziness patients in subgroups based on the origin of their dizziness to identify potential improvements for the MTS. Patients with dizziness and stroke, who represent the most vulnerable group of dizziness patients, were also evaluated separately. RESULTS: During the observation period, 2958 patients presented at the ED with the symptom dizziness and 52 017 without, who formed the reference group. When examining the relationship between triage level and subsequent treatment level, a larger deviation is observed compared to the reference group. The receiver operating characteristics (ROC) regarding hospital admission in general showed an area under the curve (AUC) in the subgroup with dizziness due to a central nervous system causes (n=838) of 0.69 (95% CI 0.65 - 0.72) and in the subgroup of dizziness by other organic cause (n=901), an AUC of 0.64 (95% CI 0.60 - 0.68). The reference group had an AUC 0.75 (95% CI 0.75 - 0.76) here. In relation to admission to IMC/ICU, the results were similar. The sensitivity of the MTS in terms of an adequate initial assessment of dizziness patients with stroke or transient ischemic attack (TIA) was 0.39, the specificity was 0.91 (reference group sensitivity 0.72, specificity 0.82). CONCLUSION: In terms of construct validity, the present study revealed that the use of MTS as a priority triage assessment tool was found to be less accurate in emergency patients with dizziness, particularly those diagnosed with stroke/TIA, when compared to other emergency patients.

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.

Pre-Interventional Risk Assessment in The Elderly (PIRATE): Development of a scoring system to predict 30-day mortality using data of the Peri-Interventional Outcome Study in the Elderly.

Risk assessment before interventions in elderly patients becomes more and more vital due to an increasing number of elderly patients requiring surgery. Existing risk scores are often not tailored to marginalized groups such as patients aged 80 years or older. We aimed to develop an easy-to-use and readily applicable risk assessment tool that implements pre-interventional predictors of 30-day mortality in elderly patients (≥80 years) undergoing interventions under anesthesia. Using Cox regression analysis, we compared different sets of predictors by taking into account their ease of availability and by evaluating predictive accuracy. Coefficient estimates were utilized to set up a scoring system that was internally validated. Model building and evaluation were based on data from the Peri-Interventional Outcome Study in the Elderly (POSE), which was conducted as a European multicenter, observational prospective cohort study. Our risk assessment tool, named PIRATE, contains three predictors assessable at admission (urgency, severity and living conditions). Discriminatory power, as measured by the concordance index, was 0.75. The estimated prediction error, as measured by the Brier score, was 0.036 (covariate-free reference model: 0.043). PIRATE is an easy-to-use risk assessment tool that helps stratifying elderly patients undergoing interventions with anesthesia at increased risk of mortality. PIRATE is readily available and applies to a wide variety of settings. In particular, it covers patients needing elective or emergency surgery and undergoing in-hospital or day-case surgery. Also, it applies to all types of interventions, from minor to major. It may serve as a basis for multidisciplinary and informed shared decision-making.

Early combination therapy of COVID-19 in high-risk patients.

PURPOSE: Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised hosts. Early monotherapy with direct-acting antivirals or monoclonal antibodies, as recommended by the international guidelines, does not prevent this with certainty. Dual therapies may therefore have a synergistic effect. METHODS: This retrospective, multicentre study compared treatment strategies for corona virus disease-19 (COVID-19) with combinations of nirmatrelvir/ritonavir, remdesivir, molnupiravir, and/ or mABs during the Omicron surge. Co-primary endpoints were prolonged viral shedding (≥ 106 copies/ml at day 21 after treatment initiation) and days with SARS-CoV-2 viral load ≥ 106 copies/ml. Therapeutic strategies and risk groups were compared using odds ratios and Fisher's tests or Kaplan-Meier analysis and long-rank tests. Multivariable regression analysis was performed. RESULTS: 144 patients were included with a median duration of SARS-CoV-2 viral load ≥ 106 copies/ml of 8.0 days (IQR 6.0-15.3). Underlying haematological malignancies (HM) (p = 0.03) and treatment initiation later than five days after diagnosis (p < 0.01) were significantly associated with longer viral shedding. Prolonged viral shedding was observed in 14.6% (n = 21/144), particularly in patients with underlying HM (OR 3.5; 95% CI 1.2-9.9; p = 0.02). Clinical courses of COVID-19 were mild to moderate with only few adverse effects potentially related to combination treatment. CONCLUSION: Early combination treatment of COVID-19 effectively prevented prolonged viral shedding in 85.6% of cases. Considering the rapid viral clearance rates and low toxicity, individualized dual therapy approaches may be beneficial in high-risk patients.

Deficient Immune Response following SARS-CoV-2 Vaccination in Patients with Hepatobiliary Carcinoma: A Forgotten, Vulnerable Group of Patients.

Introduction: Data on immune response rates following vaccination for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in patients with hepatobiliary carcinoma (HBC) are rare. However, impaired immunogenicity must be expected due to the combination of chronic liver diseases (CLDs) with malignancy and anticancer treatment. Methods: In this prospective, longitudinal study, 101 patients were included, of whom 59 were patients with HBC under anticancer treatment. A cohort of patients with a past medical history of gastrointestinal cancer, of whom 28.6% had HBC without detectable active tumor disease having been off therapy for at least 12 months, served as control. Levels of SARS-CoV-2 anti-spike IgG, surrogate neutralization antibodies (sNABs), and cellular immune responses were compared. In uni- and multivariable subgroup analyses, risk factors for impaired immunogenicity were regarded. Data on rates and clinical courses of SARS-CoV-2 infections were documented. Results: In patients with HBC under active treatment, levels of SARS-CoV-2 anti-spike IgG were significantly lower (2.55 log10 BAU/mL; 95% CI: 2.33-2.76; p < 0.01) than in patients in follow-up care (3.02 log10 BAU/mL; 95% CI: 2.80-3.25) 4 weeks after two vaccinations. Antibody levels decreased over time, and differences between the groups diminished. However, titers of SARS-CoV-2 sNAB were for a longer time significantly lower in patients with HBC under treatment (64.19%; 95% CI: 55.90-72.48; p < 0.01) than in patients in follow-up care (84.13%; 95% CI: 76.95-91.31). Underlying CLD and/or liver cirrhosis Child-Pugh A or B (less than 8 points) did not seem to further impair immunogenicity. Conversely, chemotherapy and additional immunosuppression were found to significantly reduce antibody levels. After a third booster vaccination for SARS-CoV-2, levels of total and neutralization antibodies were equalized between the groups. Moreover, cellular response rates were balanced. Clinically, infection rates with SARS-CoV-2 were low, and no severe courses were observed. Conclusion: Patients with active HBC showed significantly impaired immune response rates to basic vaccinations for SARS-CoV-2, especially under chemotherapy, independent of underlying cirrhotic or non-cirrhotic CLD. Although booster vaccinations balanced differences, waning immunity was observed over time and should be monitored for further recommendations. Our data help clinicians decide on individual additional booster vaccinations and/or passive immunization or antiviral treatment in patients with HBC getting infected with SARS-CoV-2.

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach.

Background: Cognitive decline is a key outcome of clinical studies in Alzheimer's disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid.

Mathematical approach improves predictability of length of hospitalisation due to oral squamous cell carcinoma: a retrospective investigation of 153 patients.

Oral squamous cell carcinoma (OSCC), a common cancer of the head and neck, is a major public health problem. The length of stay in hospital (LOS) of patients with OSCC, which can range from a few days to several months, has implications for the patient's recovery. The aim of the study was to identify and evaluate risk factors that have an impact on the prolongation of inpatient hospital stay. A four-year retrospective study reviewed hospital records of 153 inpatients with OSCC. A statistical model for discrete time-to-event data, with the LOS in hospital measured in days for which the event of interest was discharge from hospital, was applied. The model utilises a tree-building algorithm to identify relevant risk factors for a prolonged LOS. Age, type of flap, and occurrence of complications turned out to be relevant variables. Before, and on day 12, the LOS was mainly dependent on flap type and age, whereas after day 12 it was influenced by the presence of early complications. Predicting the likelihood of discharge can improve the management and resource utilisation of the healthcare system among inpatients.

Impaired immunogenicity after vaccination for SARS-CoV-2 in patients with gastrointestinal cancer: does tumor entity matter?

Background: SARS-CoV-2 immunogenicity in patients with gastrointestinal cancer (GI cancer) following second and third vaccination was analyzed. Methods: A total of 125 patients under active anticancer therapy or in follow-up care were included in this prospective study. Seroprevalence of SARS-CoV-2 anti-spike and surrogate neutralization antibodies (NABs) was measured. Results: Four weeks after second vaccination, adequate titers of SARS-CoV-2 anti-spike immunoglobulin G (IgG) [≥282.0 binding antibody units (BAU)/mL] were found in 62.2% of patients under treatment versus 96.3% of patients in follow-up care (P<0.01). Sufficient titers of SARS-CoV-2 surrogate NAB (≥85.0%) were found in 32.7% of patients under treatment versus 70.6% in follow-up care (P<0.01). Titers of SARS-CoV-2 anti-spike IgG were especially low in patients with colorectal cancer (CRC). For SARS-CoV-2 surrogate NAB, patients with hepatocellular carcinoma (HCC) and with pancreaticobiliary cancer showed the lowest titers (P<0.01). SARS-CoV-2 anti-spike IgG and SARS-CoV-2 surrogate NAB were associated with a correlation coefficient of 0.93. Reaching a titer of SARS-CoV-2 anti-spike IgG ≥482.0 BAU/mL, protective levels of SARS-CoV-2 surrogate NAB (≥85.0%) could be assumed. Following booster vaccination, all patients reached effective antibody titers. Conclusions: Patients with active GI cancer showed impaired immunogenicity after second SARS-CoV-2 vaccination which was overcome by booster vaccination. Our findings were tumor-related and pronounced in patients with CRC and HCC. Waning immunity over time and antibody escape phenomena by variant of concern Omicron must be considered in these especially vulnerable patients.

Stage-dependent biomarker changes in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3.

Arterial hypertension and ß-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study.

BACKGROUND: White matter hyperintensities (WMH) in subjects across the Alzheimer's disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology-not just arterial hypertension-impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aß positivity on WMH, and their impact on cognition. METHODS: We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function-derived from multiple neuropsychological tests using confirmatory factor analysis-, baseline preclinical Alzheimer's cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5). RESULTS: Subjects with hypertension or Aß positivity presented the largest WMH volumes (pFDR < 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aß: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aß: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aß: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aß: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aß: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aß: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (pFDR < 0.05). Aß positivity was negatively associated with cognitive performance (direct effect-memory: - 0.33 ± 0.08, pFDR < 0.001; executive: - 0.21 ± 0.08, pFDR < 0.001; PACC5: - 0.29 ± 0.09, pFDR = 0.006; ΔPACC5: - 0.34 ± 0.04, pFDR < 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect-memory: - 0.05 ± 0.02, pFDR = 0.029; executive: - 0.04 ± 0.02, pFDR = 0.067; PACC5: - 0.05 ± 0.02, pFDR = 0.030; ΔPACC5: - 0.09 ± 0.03, pFDR = 0.043) and WMH in the optic radiation partially mediated that between Aß positivity and memory (indirect effect-memory: - 0.05 ± 0.02, pFDR = 0.029). CONCLUSIONS: Posterior white matter is susceptible to hypertension and Aß accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00007966, 04/05/2015).

Exploring the ATN classification system using brain morphology.

BACKGROUND: The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort. METHODS: We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aß42/Aß40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups. RESULTS: The ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead. CONCLUSION: Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy. TRIAL REGISTRATION: DRKS00007966, 04/05/2015, retrospectively registered.