Citations

Abstract Background Most existing biomarkers for Alzheimer’s disease (AD) inform on core AD pathologies in the central nervous system, namely amyloid, tau and neurodegeneration (ATN). However, molecular disease mechanisms underlying AD are complex and heterogeneous, highlighting the need for cost‐effective blood‐based biomarkers that reflect brain molecular changes in AD beyond ATN. Method Using peripheral blood transcriptome data from the Mayo Clinic Study of Aging(MCSA) and the Alzheimer's Disease Neuroimaging Initiative, we identified genes associated with AD or mild cognitive impairment (MCI) diagnosis, cognitive, and harmonized neuroimaging measures in two cohorts, followed by meta‐analysis. We identified consensus gene co‐expression modules in MCSA and ADNI using WGCNA and assessed the association between module eigengenes and aforementioned measures. Using seven bulk brain RNAseq cohorts, we confirmed the preservation of coexpression modules across blood and brain. Enrichment analyses of Gene Ontology (GO) terms and cell‐types were performed using significant and/or hub genes. The MCSA transcriptome was further deconvoluted to obtain cell‐type proportions and cell‐type specific expression. Result Blood transcriptome modules M5 and M8 are upregulated in AD/MCI and associate with worse cognition, whereas M1, M10, M13, M16, and M21 are downregulated in AD/MCI and associate with better cognition. M17 associates with more microhemorrhages. Cell‐type enrichment analysis revealed that M5 is enriched in basophils, monocytes, and neutrophils; M8 in monocytes and neutrophils; M13 in natural kills cells; M17 in megakaryocytes; M21 in B cells. GO analysis shows broad consistency with the cell‐type enrichment analysis. M1, 5, and 8 are preserved in the brain network modules. From these modules, we prioritized transcripts significantly associated with at least one AD‐related phenotype in both blood and brain. Cell‐type deconvolution analysis shows that prioritized transcripts in M1 associate with better cognition and higher metabolic activity in B cells. Conclusion We identified blood transcripts and modules associated with AD/MCI, cognition, or neuroimaging, with three preserved in brain networks. These three modules represent centrally linked peripheral molecular signatures that can reveal perturbed brain pathways and cell level transcriptional changes in AD/MCI. We aim to further investigate the prioritized transcripts in additional datasets to establish them as potential novel biomarkers and therapeutic targets.

Abstract Background The Alzheimer's disease (AD) Braak staging is a key framework for classifying tau pathology progression in AD based on histopathological post‐mortem brain examinations. However, adapting it to PET imaging can be challenging due to differences in tracer uptake patterns and binding properties, which affect sensitivity, specificity, and regional staging. This study compares Braak staging across four tau PET tracers: Flortaucipir, MK6240, PI2620, and RO948. Methods We assessed 90 participants across the AD spectrum (46 CU, 31 MCI, 13 dementia; mean age 66.1 ± 7.8) using Aβ PET and four tau PET tracers: (Flortaucipir, MK6240, PI2620, and RO948). Braak positivity was defined based on Aβ− CU individuals (mean +2.5 SD, SUVR). To evaluate systematic bias and agreement between tracers, we computed pairwise differences at corresponding Braak stage estimates and applied the Bland‐Altman method to assess mean bias and limits of agreement. Additionally, Tau PET Braak region trajectories were modeled as functions of Aβ burden (Centiloid scale) using the Lowess method. Results Braak stage trajectories as a function of Aβ differ depending on the tracer and the sequential order of abnormality is highly variable. For instance, while for MK6240, RO948 and PI2620, Braak I is the first region to became abnormal, for Flortaucipir the earliest region to became abnormal is Braak IV (Figure 1). This variable pattern of abnormality impacts in the concordance of Braak staging between tracers with the highest Braak staging agreement resulting in concordance levels of approximately 70%. The highest levels of agreement between tracers usually happen at Braak 0 or Braak IV‐V, with intermediate stages showing very low concordance (Figure 2). The Bland‐Altman analysis identified wide limits of agreement, suggesting high variability and high tracer‐specific differences (Figure 3). On the other hand, it also identified that mean differences between tracers were small, indicating minimal systematic bias. Conclusion These preliminary findings reveal discrepancies in Braak staging when comparing Flortaucipir, MK6240, PI2620 and RO948. These findings suggest that while the tracers provide comparable stages on average, they may not be fully interchangeable in individual cases.

Abstract Background Tau‐PET tracers are essential for visualizing pathology in Alzheimer’s (AD). High detectability to tau is crucial for early detection and monitoring of tau deposition. This study compares the noise to dynamic range ratio (NRR) of [ 18 F]FTP, [ 18 F]MK6240, [ 18 F]PI2620, and [ 18 F]RO948, cross‐sectionally and longitudinally. Methods 460 individuals from the HEAD study (23 cognitively unimpaired (CU) young, 249 CU old and 188 cognitively impaired) underwent [ 18 F]FTP and [ 18 F]MK6240 tau‐PET scans; 94 additionally received [ 18 F]PI2620 and [ 18 F]RO948. A subset of 28 individuals (15 CU and 13 CI) underwent [ 18 F]FTP and [ 18 F]MK6240 follow‐up scans (1.5 ± 0.1 years later). Annual change was measured as [(followup‐baseline)/time between scans]. Noise was calculated as the standard deviation (SD) of CU Aβ‐ participants aged ≤65 (SD CUAβ‐≤65 ). The dynamic range was calculated as the SD across all subjects (SD range ). A lower the NRR (=SD CUAβ‐≤65 /SD range ) indicates more detectability. Analyses were performed at both region‐of‐interest and voxel‐wise levels. Results Across the whole cohort, [ 18 F]MK6240 exhibited lower NRR than [ 18 F]FTP in all regions. Voxel‐wise, differences were most pronounced in the frontal medial temporal regions (Figure 1). Within the four‐tracers subset, [ 18 F]PI2620 and [ 18 F]FTP showed the highest NRR in Braak II, followed by [ 18 F]RO948 and [ 18 F]MK6240. In Braak IV‐VI, [ 18 F]MK6240 consistently demonstrated the lowest values, followed by [ 18 F]PI2620, [ 18 F]FTP and [ 18 F]RO948. Similarly, in metatemporal‐ROI and Braak III, [ 18 F]MK6240 remained the lowest, however followed by [ 18 F]FTP, [ 18 F]PI2620 and [ 18 F]RO948 (Figure 2). Lower [ 18 F]MK6240 NRR was due to larger SD range , while [ 18 F]FTP's lower values stemmed from smaller SD CUAβ‐≤65 . Conversely, high [ 18 F]PI2620 and [ 18 F]RO948 values are driven by larger SD CUAβ‐≤65 . Longitudinal analyses further confirmed that [ 18 F]MK6240 exhibited the lowest NRR across the entire brain, including AD‐related regions, with voxel‐wise differences mainly in the temporal and parietal lobes. Conclusion Tau‐PET tracers exhibit significant variability in detectability. [ 18 F]MK6240 consistently demonstrated lower NRR, implying better detectability across all regions, cross‐sectionally and longitudinally. Despite differences in NRR, [ 18 F]FTP, [ 18 F]RO948 and [ 18 F]PI2620 followed similar pattern. These results provide insights into the differential tracer detectability, helping guide their optimal use in detecting and tracking tau pathology. Ongoing follow‐up scans will further clarify longitudinal tracer detectability and its implications for tau progression in AD.

Abstract Background Tau‐PET tracers have been used to monitor the progression of Alzheimer’s disease (AD). However, different tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their findings. Leveraging the HEAD Study, the largest head‐to‐head study of tau‐PET tracers, we recently developed the Uniτ scale, which cross‐sectionally harmonizes Flortaucipir and MK6240 onto a universal tau‐PET measurement. Here, we provide a preliminary evaluation of the Uniτ scale’s longitudinal performance in HEAD and two independent cohorts. Methods We assessed 422 individuals across the AD spectrum with longitudinal tau‐PET from three cohorts: HEAD [13 cognitively unimpaired (CU), 9 cognitively impaired (CI) individuals, scanned head‐to‐head with Flortaucipir and MK6240], ADNI [74 CU, 208 CI, tracer: Flortaucipir], and TRIAD [72 CU, 46 CI, tracer: MK6240]. Standardized uptake ratios (SUVRs) were harmonized to Uniτ using the Uniτ Ecosystem ( unitau.app ). Braak I‐II and the Meta‐Temporal regions were used as regions of interest. Annual tau‐PET uptake change was calculated, and the effect size was defined as the mean annual change divided by its standard deviation. Results In HEAD, annual change in tau‐PET uptake in Braak I‐II across CU and CI was only detectable in MK6240 (Figure 1A). However, both tracers detected significant annual changes in the Meta‐Temporal ROI for CI (Figure 1B). In both ADNI (Flortaucipir) and TRIAD (MK6240), changes in tau‐PET uptake in Braak I‐II regions were not significant (Figures 2‐3A). However, across all cohorts, the Meta‐Temporal ROI consistently showed detectable annual tau‐PET increases—most pronounced among CI—leading to larger effect sizes than in Braak I‐II (Figures 1‐3B). The Uniτ harmonization did not fundamentally alter the pattern of the findings. However, in ADNI (Flortaucipir), Uniτ yielded a slightly higher effect size than SUVR in CU for both Braak I‐II and Meta‐Temporal regions. Conclusion In this large longitudinal sample, our findings confirm that Flortaucipir and MK6240 can detect tau PET changes over time likely associated with the progression of tau tangle pathology. While MK6240 appears to show greater progression in CU, both tracers progress similarly in CI. Our data also suggested that Uniτ harmonized tau PET measurements maintain the longitudinal characteristics of each tau PET tracer for use in clinical trials.

Abstract Background Alzheimer's disease (AD) is pathologically characterized by the presence of extracellular amyloid beta plaques and intracellular tau tangles. Related disorders share aspects of AD pathology including progressive supranuclear palsy (PSP), a tauopathy, and pathologic aging (PA) defined by presence of amyloid but not tau. We hypothesize that there are shared, and distinct, brain molecular changes associated with amyloid and tau protein levels in AD and related disorders and that identifying these will provide novel insights into disease pathogenesis. Methods We collected brain multiomics measures (genetic, transcriptomic, epigenomic, proteomic and metabolomic) from donors diagnosed with AD, PSP, PA and controls. Following quality control and normalization, omics measures were tested for association with disease diagnosis and amyloid and tau neuropathology using regression models adjusting for relevant covariates. Association with biochemical measures of core AD proteins were also assessed in a subset of AD cases. Gene sets were evaluated for enrichment of cellular pathways and cell type signatures. Results We found remarkably conserved transcriptomic changes associated with AD and PSP, and downregulation of myelination pathway genes in both diseases. Among PSP cases, we found divergent patterns of transcriptional associations with distinct tau lesions. In a cohort of AD cases, we found broad transcriptional and epigenetic dysregulation associated with levels of tau protein, but not amyloid beta. Conversely a genetic analysis implicated more variants associated with amyloid levels than tau. Conclusion Multi‐omics studies across various proteinopathies can identify convergent and divergent molecular signatures that are candidates for shared therapeutic targets and disease differentiating biomarkers.

Context.— Giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are rare but serious inflammatory heart diseases that pose significant diagnostic and therapeutic challenges. The relationship between the 2 has been debated for decades, sparked in part by a 1980 study using immunohistochemistry and electron microscopy to examine their histopathologic overlap. Objective.— To review and synthesize the historical, pathologic, clinical, and molecular understanding of GCM, explore its overlap and distinctions with CS, and outline future directions for diagnosis and treatment. Data Sources.— Historical literature, clinicopathologic studies, imaging studies, and molecular research including transcriptomic and proteomic analyses. Conclusions.— GCM is characterized by a fulminant clinical course, diffuse myocardial necrosis with multinucleated giant cells and eosinophilic infiltrate, and a predominantly CD8 + T-cell response. In contrast, CS typically presents with more indolent cardiac symptoms, well-formed nonnecrotizing granulomas with Langhans-type giant cells, and a CD4 + T-cell predominant response. GCM and CS share overlapping clinical and imaging features, and sometimes have histopathologic similarities as well. Emerging molecular data suggest transcriptional differences, but a subset of cases exhibit mixed or intermediate features, suggesting a possible disease spectrum. Advances in molecular profiling, standardized diagnostic criteria, noninvasive imaging modalities, and targeted immunosuppression may help refine diagnosis and treatment. Clarifying whether these conditions lie along a shared pathobiologic continuum remains an important goal for future research.

Abstract Introduction Periacetabular osteotomy (PAO) is performed in the setting of hip dysplasia to increase acetabular coverage of the femoral head and improve joint biomechanics and longevity. PAO fixation is generally achieved with two or three 4.5 mm screws, as compared to the generally more substantial plate and screw constructs used in the setting of acetabular fractures or pelvic ring injuries. The purpose of this study was to evaluate postoperative changes in hip joint center medialization and lateral acetabular coverage following PAO, understanding that these radiographic measures are generally used to guide intra-operative assessment of correction. Methods A retrospective chart review of 100 consecutive PAOs during 2021-2023 at a single academic institution by four surgeons was performed. Perioperative radiographs and fluoroscopy images were evaluated to measure lateral center edge angle (LCEA), Tönnis angle, and medialization of the hip joint center. The hip joint center was measured at one-third of the diameter of the femoral head from inferior to superior, to the ilioischial line, as previously validated by Fowler and colleagues. Results One hundred PAOs in 87 patients (87% female, mean age: 23.0 years) were included. Average preoperative radiographic parameters were 19.9° for LCEA, 12.5° for Tönnis angle, and 12.6 mm for distance from the femoral head to ilioischial line. Ninety-four cases (94%) used three screws, and 6 cases (6%) used two screws for unstable fragment fixation. On immediate postoperative films, average correction was to 28.3° for LCEA, 4.9° for Tönnis angle, and 1.9 mm of pre- to postoperative femoral head medialization (p≤0.001). Patients were radiographically followed for an average of 13.3 months, with an average time to radiographic union of 7.1 months. During the course of follow-up, LCEA increased to 29.3°, Tönnis angle remained to 5.0° (p=0.47), and medialization increased to 2.7 mm (p≤0.02), suggesting further significant but clinically modest increases in lateral coverage and femoral head medialization. Conclusion While the majority of lateral acetabular coverage and femoral head medialization occurs intra-operatively at the time of PAO, patients undergo modest but statistically significant postoperative increases in lateral coverage and medialization prior to radiographic union.

Abstract Introduction Labral reconstruction has seen an increase in utilization over the last decade. As a result of the increasing number of labral reconstructions being performed, there has been a subsequent increase in the number of failed labral reconstructions requiring revision. The purpose of the present study was to report the short-term survivorship and outcomes of patients who underwent segmental acetabular labral reconstruction in the setting of a failed prior labral reconstruction. Methods A retrospective review of all labral reconstructions performed by the senior author between 01/01/2010-04/01/2022 was conducted. Patients who underwent a labral reconstruction and were over 18 at the time of surgery were included. Patients with a history of avascular necrosis, Legg-Calvé-Perthes, or with a lateral center edge angle < 18° were excluded. Demographics, radiographic parameters, and patient reported outcomes (PROs) were collected. Patients who underwent a labral reconstruction in the setting of a prior failed labral reconstruction (Group B) were matched in a 1:1 fashion to patients in a control group who underwent only one labral reconstruction (Group A) by age, sex, LCEA, minimum joint space, and the presence of an Outerbridge Grade 3 or 4 defect. Results A total of 24 hips (23 patients) were included in Group B. Mean age at the time of surgery was 36 ± 13 years, and most hips were female (n=14, 58%). Twenty-two (92%) of the hips met a study endpoint, with 3 (14%) converting to total hip arthroplasty (THA) and 3 (14%) undergoing a subsequent hip-preserving surgery. The remaining 16 hips reported 2-year minimum PROs and had a median patient satisfaction of 9.5 (Range: 6-10). Additionally, they demonstrated significant improvement from baseline in SF-12 PCS (p=0.004), WOMAC Total (p<0.001), mHHS (p=0.004), HOS-ADL (p=0.002), and HOS-Sport (p=0.002). Notably, patients in Group B demonstrated similar improvement in PROs from baseline compared to the matched-control group (Group A). Conclusion Patients who undergo revision labral reconstruction in the setting of a failed prior labral reconstruction demonstrate significant improvement in PROs post-operatively compared to baseline at a rate similar to patients who underwent only one labral reconstruction.

Abstract In phase 3 oncology clinical trials, identifying and understanding potential sources of differential censoring (DC), which describes censoring imbalance between treatment arms, in overall survival (OS) endpoints is vital to reduce bias and misinterpretation of OS benefit. Among 322 trials, 34 (11%) trials exhibited DC overrepresented in the control arm (DCC). Compared to trials without DC or those with DC overrepresented in the experimental arm (DCE), trials with DCC showed higher rates of OS benefit (56% vs. 32%; odds ratio [OR] = 2.26, 95% CI = 1.04 to 4.90; P = .04) and were associated with patient withdrawal (median 8.0% vs. 3.8%; P = .0002), lack of double blinding (15% vs. 48%, OR = 0.19, 95% CI = 0.06 to 0.56; P = .003), and better global quality of life in the experimental arm (32% vs. 13%, OR = 3.01, 95% CI = 1.26 to 7.19; P = .01). OS DCC is a prominent challenge that requires rigorous trial design and comprehensive patient and mortality follow-up to reduce bias in interpreting OS benefit.

ABSTRACT Plerixafor (PLX) is FDA approved for use in autologous peripheral blood stem cell donors but not in allogeneic donors. This study was completed by members of the ASFA HPC Donor Subcommittee to examine the incidence and characteristics of poor mobilizers (PM) among matched related donors (MRD), as well as factors associated with PLX use in MRD. Risks of poor mobilization in MRD were older age, especially donors older than 60 years, lower baseline platelet counts, and heavier recipients. PLX use in PM was low but safe, tripling the success rate for collection. This study adds evidence to the body of literature to support use of PLX in allogeneic donors who are PM.