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Abstract Histopathological assessment has served as the gold standard for diagnosing Alzheimer’s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10−11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10−10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10−201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10−8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10−8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10−7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.

Introduction Cerebellar transcranial direct current stimulation (tDCS) combined with language therapy can aid in chronic aphasia recovery, but the neural mechanisms and biomarkers of treatment efficacy remain uncertain. Methods In this secondary analysis of data from a previously conducted clinical trial, we used a randomized, double-blind, sham-controlled, within-subject crossover design with a study sample of 19 participants with post-stroke aphasia. We assessed the degree to which baseline properties of cerebro-cerebellar white matter tracts can predict or moderate longitudinal treatment effects at three time points: post-treatment, 2 weeks post-treatment, and 2 months post-treatment. Tract properties were measured by fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor imaging (DTI). We also tested whether there are differential effects between trained and untrained language tasks and between cerebellar tDCS polarity (anodal and cathodal). Results Baseline measures of tracts connecting the left lesioned cortex to the right posterolateral cerebellum (stimulation target) influenced treatment gains for untrained tasks, relative to sham control. In contrast, for the trained task, treatment gains were influenced by baseline measures of tracts connecting the non-stimulated left cerebellum with the contralateral right cerebral cortex. Although there were no consistent effects from cerebellar tDCS polarity, a highly consistent pattern emerged across all tasks and tracts. Specifically, language improvements were predicted by a baseline tract profile (i.e., higher FA and lower MD) typically associated with higher white matter integrity, especially within the context of stroke-induced white matter decline. Discussion These findings corroborate the potential for baseline tract properties as a biomarker of treatment efficacy and support the notion that adjuvant (cerebellar tDCS + language) therapy preferentially benefits individuals with relatively preserved structural connections within functionally relevant networks. Clinical trial registration ClinicalTrials.gov , identifier (NCT02901574).

Abstract INTRODUCTION New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. METHODS Harmonized amyloid PET data from 4216 participants were used in genome‐wide survival, tissue‐specific gene expression, and genetic covariance analyses of EAOA. RESULTS Variants in apolipoprotein E ( APOE ), ABCA7 , and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7 , associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7 , which was associated with increased amyloid pathology at autopsy. Multiple immune‐related diseases shared genetic covariance with EAOA. DISCUSSION APOE , ABCA7 , and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue‐specific expression analyses, offering insights into intervenable targets at early stages of AD. Highlights Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E ( APOE ) , ABCA7 , and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue‐specific expression analyses.

Background: Accurate characterization of tumor stiffness and adhesion is crucial when surgically resecting meningiomas. Currently, such determinations are difficult to ascertain through standard preoperative imaging diagnostics and clinical experience. Herein, we explored magnetic resonance elastography (MRE) as a means of assessing these parameters and thereby improving neurosurgical resections. Methods: This prospective study of 193 patients with meningiomas involved three distinct patient subsets (cohort 1, 88 [2017–2021]; cohort 2, 55 [2022–2023]; cohort 3, 50 [2023–2024]. We analyzed preoperatively obtained MRE data on meningioma stiffness (cohorts 1 and 2) and adhesion (cohort 2) for accuracy, while matching subjects with or without MRE studies (cohort 3, 1:1 ratio) to define the role of preoperative MRE in improving operative outcomes. Results: Areas under the curve (AUCs) for MRE in gauging meningioma stiffness and adhesion were 0.87 and 0.89, respectively. Both parameters significantly surpassed empiric predictions of stiffness and adhesion rendered by surgeons and radiologists, based on routine magnetic resonance imaging (MRI). MRE-determined stiffness measures independently correlated with prolonged resection duration, whereas MRE-assessed adhesion showed independent associations with increased blood loss, longer duration of tumor resection, and higher risk of pial injury. Ultimately, results based on cohort 3 demonstrated that MRE has great potential in this setting to improve neurosurgical procedures by significantly reducing intraoperative bleeding, resection duration, and risks of pial injury. Conclusion: MRE is a promising, noninvasive tool for accurately assessing meningioma stiffness and adhesion, standing to improve the precision and safety of needed surgical intervention.

AbstractBackgroundGenome‐wide association studies (GWAS) in Alzheimer’s disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.MethodWe conducted a meta‐analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.67% female, age = 71) and an autopsy GWAS of brain amyloidosis (N = 6,519, 63.08% amyloid positive, 51.34% female, age at death = 83), both adjusted for covariates including age, sex and principal components of genetic ancestry. All participants in both GWAS were unrelated individuals of European descent. We defined amyloid positivity as moderate or frequent neuritic plaques using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores within each autopsy cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET imaging cohort to identify the cohort and tracer‐specific cut‐offs that differentiate amyloid positive and negative populations.ResultThe genome‐wide significant results from the meta‐analysis identified three known AD loci (APOE, CR1, and BIN1) and a novel chromosome 17 locus (rs35635959, intergenic, MAF = 0.27, OR = 1.18, p = 1.47 × 10‐8). The MAGMA gene‐level analysis excluding the APOE region suggests significant associations between rs35635959 and COASY, PLEKHH3, and TUBG2 on chromosome 17, implying the potential roles of these genes on amyloidosis. Functional annotations of rs35635959 leveraging brain eQTL databases indicate its association with differential gene expression of COASY and TUBG2 in AD brains. ROSMAP bulk and single‐nucleus RNAseq analyses link TUBG2 downregulation to the higher amyloid burden and AD diagnosis while suggesting such observations are enriched in excitatory and inhibitory neurons, reaching FDR significance.ConclusionThis study is the most extensive European GWAS of brain amyloidosis, and our findings replicate known AD loci and identify a possible novel locus (index SNP rs35635959) on chromosome 17. Functional annotations of the novel variant indicate TUBG2, implicating in microtubule organization, warrants further assessment. Ongoing efforts aim to validate these novel effects using independent datasets.

Introduction: Progression-free survival (PFS), a common endpoint used in multiple myeloma (MM) trials, is defined as the time to the earliest occurrence of disease progression or death. Disease progression in MM is determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria based on imaging and biomarkers from blood, urine, and bone marrow biopsy testing. In clinical trials, IMWG-recommended assessments are protocol-based. However, in routine care, they are often performed and recorded differently based on a multitude of factors. Algorithms to ascertain progression events using routinely collected biomarker data are important to classify disease progression and align with trial-defined endpoints. The aim of this study was to construct and evaluate an optimized real-world Progression (rwP) algorithm using real-world data (RWD) and demonstrate how biomarker data are captured and used to derive endpoints in routine practice. Method: A cohort of 270 transplant ineligible newly diagnosed MM (NDMM) patients starting on lenalidomide and dexamethasone (Rd) and meeting select MAIA (NCT02252172) trial eligibility criteria were included from the nationwide Flatiron Health electronic health record-derived deidentified database from 2015 to 2023. A rwP algorithm was developed using key IMWG-recommended biomarkers, including serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chains (FLCs). The initial baseline value for each biomarker was identified, if available, during either the pre-treatment period (45 days prior through 7 days after first line treatment (1L) start) or the on-treatment period (8 days after 1L start through 1L end). Available biomarkers were followed for disease assessment. If any subsequent lab value during 1L treatment was less than the initial baseline value, the subsequent “on-treatment baseline” value was adopted as the new lowest value; otherwise, the initial value was used as the “on-treatment baseline” value for assessing progression events. Three hierarchies, which describe the order of utilizing key IMWG-recommended biomarkers to define rwP events, were explored, including: i) strict hierarchy (SH) [SPEP > UPEP > FLCs], ii) partial hierarchy (PH) [SPEP = UPEP > FLCs], and iii) no hierarchy (NH) [SPEP = UPEP = FLCs]. The PH option closely resembles the IMWG criteria, with FLCs only used for rwP assessments when no measurable SPEP/UPEP are identified. The NH approach considers all available biomarkers equally and resembles how they are utilized in real-world clinical practice. The feasibility of requiring confirmatory events following the first suggestion of progression was also explored. Assays following the progression event up to the end of 1L were considered as confirmatory progression events if they met IMWG criteria. Results: We applied the rwP algorithm with each hierarchy to all eligible NDMM patients (N = 270). The SH, PH, and NH approaches respectively identified 106 (39.3%), 106 (39.3%), and 123 (45.6%) patients with progression events. Results from the SH and PH approach are consistent likely due to the rarity of UPEP usage in clinical practice. The NH approach captured more progression events because FLCs are used in the presence of measurable SPEP or UPEP, resulting in 73 progression events captured by FLCs in comparison to 32 from other approaches, potentially increasing false-positive capture due to the volatility of FLC results. Among the 106 PH-identified patients who progressed, 84 (79.2%) had IMWG-recommended tests following their progression event, and 74 (69.8%) had their progression confirmed before the end of 1L, with 35 (33.0%) receiving their confirmatory reading within 2 months after progression. These results suggest that requiring confirmatory testing as part of the rwP is feasible, though it may introduce false negatives for patients receiving clinical progression confirmation instead of getting confirmatory labs in routine clinical practice. Conclusion: We present a comprehensive assessment of important design choices for an rwP algorithm for NDMM, including a hierarchy of key assays and the inclusion of confirmatory testing. Further validation of the algorithm with health care provider assessments and the inclusion of bone marrow biopsy and imaging data is important for evaluating the performance of the algorithm in RWD.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4 , we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

Background: A subset of follicular lymphoma (FL) patients will experience a ‘high-risk defining event’ (HRDE) that portends poor survival due to early progression of disease or transformation to diffuse large B cell lymphoma (TFL). Progression of disease within 24 months (POD24) from front-line immunochemotherapy (ICT) identifies patients with a subsequent five-year OS of 50% compared to a reference group of 90% (Casulo et al. JCO 2015). Although a robust surrogate endpoint for OS in clinical trials (Casulo et al. Blood 2022), it remains to be established if the OS of patents is influenced by the nature of the HRDE. In this study, we examined whether characteristics and clinical trajectory of those with relapsed/progressive FL is the same as that of patients experiencing TFL. Methods: We conducted an international retrospective analysis of newly diagnosed FL patients requiring treatment across 14 academic centres between 2002 and 2021 in the era of rituximab and PET-CT staging. Patients were included with grade 1-3A FL requiring first-line (1L) treatment (ICT, rituximab monotherapy or radiotherapy). We excluded patients with untreated FL, de novo TFL and those with <24 months follow up provided they did not experience a HRDE. Baseline clinical, imaging and laboratory values, treatment details and outcomes were collected. We defined HRDE groups as persistent (relapse or progression) FL within 24 months of 1L treatment (FL24), early TFL (<24 months of 1L treatment) or late TFL (>24 months of 1L treatment). Patients not experiencing a HRDE formed the FL reference group. Landmark overall survival (OS) analysis was performed by Cox regression using risk status as a time-varying covariate for time of HRDE. For the FL reference group, landmark was defined at 24 months after 1L treatment. Results: 501 patients met the inclusion criteria and were categorised as: reference FL (n=378), FL24 (n=50), early TFL (n=28), late TFL (n=15). 24 patients who died within 24 months of 1L treatment without documentation of preceding HRDE and were omitted. Median follow up for patients alive beyond 24 months was 5.1 years. Median age at diagnosis was 60 years, 91% had ECOG performance status 0-1 and 38% were high-risk (>3) FLIPI. 1L chemotherapy regimens included: bendamustine (59%), CHOP (24%), CVP (8%), other (9%); a majority received rituximab (80%) vs obinutuzumab (20%). Maintenance therapy was used in 54% of pts. Expectedly, those experiencing HRDE had an inferior OS compared to the reference group (HR 5.23, p<0.001)(Figure 1). However, among HRDE group, median OS significantly differed: early TFL patients (3.0 yrs) and FL24 (12.6yrs)(HR 2.27, p=0.02) (Table 1). There was no difference in OS after HRDE between early TFL and late TFL ( p=0.81). Biopsy was performed in 84% of TFL cases with no difference in OS between biopsy-proven vs clinically suspected cases ( p=0.23). Multivariate OS analysis assessing HRDE and treatment demonstrated no significant interaction between HRDE group and 1L chemotherapy ( p=0.52), monoclonal antibody ( p=0.29) or maintenance therapy ( p=0.27). Several established prognostic features at baseline were enriched in patients who went on to experience HRDE including: ECOG >1 ( p<0.001), raised LDH ( p<0.001), advanced-stage disease (( p<0.011) and high risk FLIPI ( p=0.005). Baseline FDG-PET was available in 259 patients. Adverse PET metrics were enriched in only early TFL, and not FL24 or late TFL patients, including high SUV max( p=0.009), total metabolic tumor volume ( p=0.015) and total lesional glycolysis ( p=0.01). Conclusions: HRDEs after 1L treatment are associated with inferior OS in FL compared with standard-risk patients. Unlike POD24, this study demonstrates disparate clinical outcomes between patients experiencing early progression with persistent FL and those experiencing TFL. Adverse metabolic characteristics on baseline FDG-PET also suggest biological distinction between HRDE subsets. These findings have important implications for epidemiological studies, biomarker development and clinical trials aiming to improve outcomes in this underserved high-risk FL cohort.

Abstract Accurate biomarkers for predicting COVID‐19 severity have remained an unmet need due to an incomplete understanding of virus pathogenesis and heterogeneity among patients. Cellular senescence and its pro‐inflammatory phenotype are suggested to be a consequence of SARS‐CoV‐2 infection and potentially drive infection‐dependent pathological sequelae. Senescence‐associated markers in infected individuals have been identified primarily in the lower respiratory tract, while little is known about their presence in more easily accessible bio‐specimens. Here, we measured the abundance of senescence‐associated signatures in whole blood, plasma and peripheral blood mononuclear cells (PBMCs) of COVID‐19 patients and patients without an infection. Bulk transcriptomic and targeted proteomic assays revealed that the level of senescence‐associated markers, including the senescence‐associated secretory phenotype (SASP), is predictive of SARS‐CoV‐2 infection. Single‐cell RNA‐sequencing data demonstrated that a senescence signature is particularly enriched in monocytes of COVID‐19 patients, partially correlating with disease severity. Our findings suggest that monocytes are prematurely induced to senescence by SARS‐CoV‐2 infection, might contribute to exacerbating a SASP‐like inflammatory response and can serve as markers and predictors for COVID‐19 and its sequelae.