Citations

AbstractKidney transplantation is the preferred treatment for individuals with end‐stage kidney disease. From a modeling perspective, our understanding of kidney function trajectories after transplantation remains limited. Current modeling of kidney function post‐transplantation is focused on linear slopes or percent decline and often excludes the highly variable early timepoints post‐transplantation, where kidney function recovers and then stabilizes. Using estimated glomerular filtration rate (eGFR), a well‐known biomarker of kidney function, from an aggregated dataset of 4904 kidney transplant patients including both observational studies and clinical trials, we developed a longitudinal model of kidney function trajectories from time of transplant to 6 years post‐transplant. Our model is a nonlinear, mixed‐effects model built in NONMEM that captured both the recovery phase after kidney transplantation, where the graft recovers function, and the long‐term phase of stabilization and slow decline. Model fit was assessed using diagnostic plots and individual fits. Model performance, assessed via visual predictive checks, suggests accurate model predictions of eGFR at the median and lower 95% quantiles of eGFR, ranges which are of critical clinical importance for assessing loss of kidney function. Various clinically relevant covariates were also explored and found to improve the model. For example, transplant recipients of deceased donors recover function more slowly after transplantation and calcineurin inhibitor use promotes faster long‐term decay. Our work provides a generalizable, nonlinear model of kidney allograft function that will be useful for estimating eGFR up to 6 years post‐transplant in various clinically relevant populations.

Abstract Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88–1.22; MR-Egger OR, 0.89; 95% CI, 0.65–1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90–1.27; MR-Egger OR, 0.93; 95% CI, 0.67–1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Abstract Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer’s disease (AD). While alpha‐synuclein pathology is the hallmark of DLB, AD and cerebrovascular pathologies are common in DLB patients. However, the contribution of these pathologies towards neurodegeneration in DLB is largely unknown. We investigated associations of amyloid‐beta, tau, and cerebrovascular biomarkers with regional gray matter (GM) volume in DLB patients and cognitively unimpaired (CU) controls.MethodWe included 30 DLB patients (69.3±10.2 years old, 87% men) and 100 CU individuals balanced on age and sex (Table 1). We used 11C‐Pittsburgh Compound‐B (PiB) and 18F‐Flortaucipir positron emission tomography (PET) to assess amyloid‐beta and tau in‐vivo. We used structural MRI to assess white matter hyperintensity (WMH) volume, a marker of cerebrovascular lesion load, and regional GM volume (a marker of neurodegeneration). We used correlations and ANCOVA in the whole dataset and structural equation modelling in the DLB patients to investigate associations of WMH volume and regional amyloid‐beta and tau PET standardized uptake value ratios (SUVRs) with regional GM volume.ResultDLB patients showed lower GM volume across all cortical and subcortical regions except for cuneus, putamen, and pallidum (Fig.1). Greater WMH volume was associated with lower volume in the medial and orbital frontal cortices, insula, fusiform cortex, and thalamus in DLB patients (Fig.2). Greater PiB SUVR was associated with lower volume in the inferior temporal cortex, while Flortaucipir SUVR did not correlate with GM volume (Fig.2). Structural equation modelling showed that higher age and positivity for the APOE e4 genotype were significant predictors of greater WMH, and WMH in turn was a significant predictor of GM volume in medial and orbital frontal cortices, insula, and inferior temporal cortex (Fig.3). In contrast, we observed two distinct paths for the fusiform cortex, with age having an effect through PiB and Flortaucipir SUVRs on the one path, and through WMH on the other path (Fig.3).ConclusionDLB patients have widespread cortical atrophy, most of which likely is influenced by alpha‐synuclein pathology. Although amyloid‐beta, tau, and cerebrovascular pathologies often coexist in DLB, their contributions to neurodegeneration seem to be region specific.

AbstractBackgroundPure Alzheimer’s disease (AD), characterized by combined amyloid and tau pathology, is not the most prevalent form of the disease as non‐AD pathologies (e.g., alpha‐synuclein and TDP‐43) are commonly observed postmortem. The role of AD and non‐AD pathologies is unclear in relation to disease heterogeneity. Therefore, we investigated whether antemortem MRI‐based atrophy subtypes of AD differ in postmortem neuropathological features and comorbid non‐AD pathologies.MethodsWe selected individuals from the ADNI with antemortem MRI evaluating brain atrophy within 2 years before death; antemortem diagnosis of AD dementia/mild cognitive impairment; and a postmortem‐confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena using a recent conceptual framework: typicality (spanning limbic predominant AD to hippocampal sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathological evaluation included AD hallmarks (amyloid‐beta, tau), non‐AD pathologies (alpha‐synuclein, TDP‐43) and concomitant pathological burden. Partial correlations assessed the associations between antemortem atrophy subtype dimensions and postmortem neuropathological outcomes.ResultsIn 31 individuals (mean age = 80y, 26% females), antemortem typicality was significantly associated with neuropathological features: amyloid‐beta (rho = ‐0.39 overall), tau (rho = ‐0.38 regionally), neuritic plaque density (rho = ‐0.4 overall), alpha‐synuclein (rho = ‐0.39 regionally), TDP‐43 (rho = ‐0.49 overall), and concomitance pathological burden (rho = ‐0.59 regionally). This suggests that limbic predominant AD was associated with higher burden of these pathologies compared to hippocampal sparing AD. Antemortem severity was significantly associated with concomitant pathological burden (rho = ‐0.43 regionally), such that typical AD showed higher burden than minimal atrophy AD.ConclusionsBased on our direct antemortem‐to‐postmortem validation, we hypothesize that: (a) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non‐AD pathologies; (b) limbic predominant AD and typical AD subtypes may share similar biological pathways, making them more vulnerable to the investigated AD and non‐AD pathologies compared to hippocampal sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing prevailing knowledge of biological heterogeneity in AD.

AbstractBackgroundSubjective cognitive decline (SCD) is topic of mayor interest when identifying individuals at risk for future cognitive impairment and dementia. The degeneration of the cholinergic system is linked to the onset of cognitive symptoms in mild cognitive impairment (MCI) and dementia. Yet, it is uncertain whether the neurodegeneration of the cholinergic system is already present in SCD individuals. This review is the first to synthetize the available data on the association of SCD with multiple markers of degeneration in the cholinergic system.MethodFollowing the PRISMA guidelines, original articles focused on the association of SCD and the cholinergic system were extracted from three databases: Pubmed, WOS and Scopus, in November 2021. Two researchers reviewed the studies independently in a 2‐stepwise approach. The quality of the studies and risk of bias were assessed using FLC 3.0, that allows to systematically evaluate the studies and summarize them easily.ResultAmong 119 studies found in our systematic search, 11 were included in the current review. Seven were cross‐sectional and 4 had a longitudinal design. Most of the studies operationalized SCD based on amnestic cognitive complaints (n = 9, 82%). The cholinergic system measures were based on neuroimaging markers for volume of the basal forebrain and/or functional connectivity, transcranial magnetic stimulation, or biofluid markers (i.e. cerebrospinal fluid (CSF) and plasma). The studies focused on association of SCD with basal brain atrophy, 75% reported reduce volumes in SCD; From those focused on functional connectivity of the cholinergic system, 33% reported poorer connectivity in SCD.ConclusionBased on scientific evidence, neurodegeneration of the cholinergic system is already evident during SCD. Using multiple cholinergic biomarkers, degeneration of cholinergic system in SCD seems to occur with significant structural and functional degeneration of cholinergic nuclei in the basal forebrain and their connections with other brain areas. These findings have implications on identifying individuals with increased vulnerability to cognitive impairment and for targeting individuals that might benefit from cholinergic‐target treatments. Further research is needed to elucidate potential contributors to the cholinergic degeneration in SCD and its impact on cognition and clinical progression.

AbstractBackgroundThe relation between cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and neurodegeneration and brain regions of relevance for very early pathological processes in AD is poorly understood. This study aims to investigate cross‐sectional associations between the CSF biomarkers amyloid‐β1‐42 (Aβ42), total‐tau (T‐tau), phosphorylated‐tau (P‐tau), neurogranin (Ng) and neurofilament light (NfL) protein and normalized intracranial volumes of the hippocampus, amygdala, entorhinal cortex and basal forebrain observed on structural magnetic resonance imaging (MRI) in cognitively healthy 70‐year olds from the general population.MethodThe analyses included 226 cognitively normal individuals (clinical dementia rating of zero), examined during 2014‐2016 as part of the population‐based Gothenburg H70 Birth Cohort Studies in Sweden. The study participants had undergone lumbar puncture examination to extract CSF samples for biomarker measurements (pg/mL), MRI scan (volumes in mm³), and apolipoprotein E (APOE) genotyping. Linear regressions, adjusted for sex, were used to examine potential associations.ResultElevated CSF T‐tau, P‐tau, and Ng concentrations were associated with smaller volumes of the hippocampus, amygdala, and entorhinal cortex among individuals with amyloid pathology (p = 8×10−8 – 0.04) and among APOE ε4 carriers (p = 8×10−5 – 0.04). In addition, elevated CSF T‐tau, P‐tau, and Ng concentrations were associated with larger basal forebrain among individuals without pathological Aβ42 (p = 0.001 – 0.01) and among APOE ε4 non‐carriers (p = 0.004 – 0.02).ConclusionThe results of our study suggest that among cognitively normal adults who have amyloid pathology or genetic susceptibility to AD, there are associations between axonal degeneration, tangle pathology, and synapse loss and decreased volumes of AD vulnerable brain regions. The associations between elevated CSF biomarkers and larger basal forebrain in cognitively normal individuals were unexpected, but could possibly be explained by compensatory mechanisms or an inflammatory response (generating neuronal or glial swelling) as a very early reaction to the presence of increased levels of tau and Ng. Our findings highlight the clinical pathophysiological relevance of CSF biomarkers of AD and neurodegeneration and how they relate to AD specific brain regions seen on structural MRI in 70‐year‐olds that may be at risk to develop dementia.

Background: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. Objectives: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). Methods: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients’ history of COVID-19 infection. Results: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. Conclusion: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Abstract Aims Calmodulinopathy due to mutations in any of the three CALM genes (CALM1–3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5–19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter–defibrillator.

Introduction: Relatively little is known about outcomes following return of secondary findings detected in large scale sequencing projects. We assessed 1-year outcomes following return of pathogenic/likely pathogenic (P/LP) variants associated with familial hypercholesterolemia (FH) in phase III of the eMERGE network (2015-2019). Methods: Adult participants (n=18,544) at 7 sites were enrolled in a prospective cohort study to study the clinical impact of returning results from targeted sequencing of 68 actionable genes, including LDLR , APOB , and PCSK9 . Process, intermediate, and/or clinical outcomes within 1-year after return of results (RoR) were ascertained by electronic health record (EHR) review. A process outcome was defined as referral to a specialist or ordering new tests, including lipid profile and screening tests for coronary heart disease. An intermediate outcome was defined as new diagnosis of FH or atherosclerotic cardiovascular disease. A clinical outcome was defined as initiation or change in lipid-lowering medication. The primary outcomes were a new diagnosis of FH and modification of lipid lowering therapy. Results: Results were returned to 134 individuals, and data for 119 participants were available for the outcomes analysis. Process (86%), intermediate (49%), and/or clinical (26%) outcomes occurred in 92% of participants. Process outcomes included 72% with new tests ordered and 61% referred to a specialist. Before RoR, 86.5% of individuals with FH associated P/LP variants had a diagnosis of hypercholesterolemia but only 17.6% had a diagnosis of FH; 89% were on a statin but only 58% were on a high intensity statin. Following RoR, 44% (52/119) received a new diagnosis of FH. Lipid lowering treatment was modified in 26% (31/119), including initiation of a statin in 5%, increasing statin dose in 13%, and adding ezetimibe or a PCSK9 inhibitor in 12.6%. Conclusions: In a multisite cohort of EHR-linked biobanks, monogenic FH was underdiagnosed (only 17.6% had a specific diagnosis) and undertreated (only 58% were on a high intensity statin); 44% of participants received a new diagnosis of FH and 26% had lipid lowering treatment modified after RoR. These results highlight the clinical utility of returning FH variants in EHR-linked biobanks.