Petersen, Ronald

Abstract Background Diffusion MRI (dMRI) measures are increasingly being used as biomarkers for aging and dementia in multi‐center studies. Measurements in longitudinal studies are often acquired on different systems, which can result in systematic differences of machine origin (e.g. vendor, hardware, algorithms). This may warrant harmonization prior to pooling multi‐site data. However, harmonization algorithms may introduce a risk of removing valuable information content and reducing sensitivity to physiological factors (e.g. sex, age, disease). Here, we tested the hypothesis that protocol standardization may minimize machine‐origin differences, obviating a need for post‐acquisition harmonization in a two‐site (Mississippi‐MS and Minnesota‐MN) cohort of the longitudinal Mayo Clinic Study of Aging (MCSA). Methods Two data sets were analyzed: first, a crossover dataset with 80 participants (scanned within 2 days) bridging two different protocols on GE and Siemens scanners; second, participants scanned using standardized protocols from the ongoing MCSA ( N MN‐MCSA =204; N MS‐MCSA =52). Parameters are listed in Figure 1. For crossover data, analyses were repeated with GE data resampled to 2‐mm isotropic resolution, and discarding Siemens‐only b‐shells to artificially reduce protocol disparities. Analysis encompassed visualization of overlain subjectwise histogram‐derived densities obtained from whole‐brain masks for dMRI measures; and median dMRI measures from within the genu of the corpus callosum (GCC) with nonparametric statistical testing. When available, both DTI and NODDI measures were compared. Results Pronounced visual distributional differences seen between MD and FA in crossover data were reduced with resampling of GE data and including only b‐shells shared across acquisitions. For the resampled/reshelled data, significant differences remained for all GCC‐FA comparisons, but not all GCC‐MD (Figure 2). For the ongoing MCSA data from two sites, MD and FA whole‐brain densities were more closely aligned, with GCC‐FA and GCC‐MD showing no significant differences (Figure 3). NODDI measures showed more discordant densities than DTI measures, including shifts in most probable values and differences in distributional arrangement. Conclusions Our work provides further evidence supporting protocol and processing standardization for minimizing machine‐origin differences prior to considering harmonization. Differences in dMRI metrics seen when comparing across unstandardized protocols were reduced when protocols were standardized. NODDI metrics had more apparent sensitivity to site than DTI measures.

Abstract Background Use of software to “de‐face” research brain images has grown as advances in automated face recognition have made it increasingly possible to re‐identify participants. Imaging studies of Alzheimer's Disease and related diseases have included more participants from historically underrepresented groups, but de‐facing software have primarily been validated using images from mostly non‐Hispanic White participants, and its performance has not been directly compared across ethnoracial groups. Method From The Health and Aging Brain Study: Health Disparities (HABS‐HD) study, we constructed a sample of 305 T1‐weighted MRI from HABS‐HD baseline visits, matched across three ethnoracial groups (non‐Hispanic White (NHW, n = 104), non‐Hispanic African American (AA, n = 104), Mexican American (MA, n = 97)) according to age‐decade, sex, cognitive status (impaired/unimpaired), and MRI scanner model. We ran mri_reface 0.3.5 on each image, and we ran FreeSurfer 7.4.1 on each unmodified image and on each de‐faced output. We then compared regional gray matter (GM) volume and cortical thickness measurements by subtracting each de‐faced image measurement from the corresponding unmodified image measurement. We compared these differences between de‐faced and unmodified images across the three matched groups using GLM analyses adjusted for age, sex, and cognitive status, and Bonferroni corrected. Result When aggregating across all brain regions, differences in cortical thickness measures due to de‐facing were significantly different between the NHW and MA groups, and between AA and MA, but not between NHW and AA (Figure 1). Differences between these group means were <0.005mm. For GM volume, differences were significant between AA and MA (magnitude < 0.2%), but not between NHW and AA or NHW and MA (Figure 2). Examining each region individually (Figure 3), cortical thickness differences were significant for only 4 regions (all with magnitudes <0.03mm), and GM volume differences were significant for only 6 regions (all with magnitudes <2%). Conclusion Effects of mri_reface on FreeSurfer brain measurements were significantly different across ethnoracial groups. Our future work will optimize mri_reface to eliminate these differences. However, the magnitudes of these differences are sufficiently small that they are unlikely to have a practical effect on analyses of data using current versions.

Abstract Background Chronic kidney disease (CKD) is associated with increased blood‐based biomarker concentrations, potentially confounding their utility in Alzheimer's disease (AD) evaluation. While plasma phosphorylated tau217 ( p ‐tau217) is elevated in the presence of amyloid related pathology, amyloid beta 1‐42 (Aβ42) is decreased. We investigated the association of plasma p ‐tau217, non‐phosphorylated tau217 (np‐tau217), Aβ42, Aβ40, as well as the Aβ42/Aβ40 and p ‐tau217/Aβ42 ratios, versus decreased estimated glomerular filtration rate (eGFR in mL/min/1.73 m 2 ) in individuals without amyloid pathology. Method This study included participants with CKD stages 1‐2 (eGFR 60‐98, n = 50), and stages 3‐4 (eGFR 25‐59, n = 33), who were Pittsburgh 11 C‐Compound B amyloid‐PET negative (Centiloid of < 25). Plasma p ‐tau217, np‐tau217, Aβ42, and Aβ40 were measured by immunoprecipitation mass spectrometry (C 2 N Diagnostics). %p‐tau217 [( p ‐tau217/np‐tau217) x100], Aβ42/Aβ40 ratio, and p ‐tau217/Aβ42 ratio were calculated. Log‐Log (power function) best‐fit regression analysis was used to quantitatively predict effects of changes in eGFR (2021 CKD‐EPI equation) versus each single analyte or ratio (Figure 1). Result Selected best‐fit analyte equations versus eGFR are shown in Table 1. The predicted percent increase of p ‐tau217 as eGFR decreases from 60 to 45 was 52% (95% CI: 30–78%). Significantly smaller increases of 16% were predicted for Aβ42 (95% CI: 12–21%), and 19% for Aβ40 (95% CI: 16–23%) over the same eGFR range. The best‐fit predicted increase for the p ‐tau217/Aβ42 ratio and %p‐tau217 as eGFR decreases from 60 to 45 was 31% (95% CI: 12–53%), and 19% (95% CI: 2–38%), respectively. While not recommended for assessment of amyloid pathology, the Aβ42/Aβ40 ratio did not exhibit a predicted increase (‐2.3% decrease, 95% CI: ‐5.2–0.6%) versus decreasing eGFR from 60 to 45. Conclusion The use of either %p‐tau217 or the p ‐tau217/Aβ42 ratio (to a lesser degree) reduced the confounding effects of decreasing eGFR as compared to p ‐tau217 alone. Aβ42 and Aβ40 exhibited similar reduced predicted increases versus decreasing eGFR as compared to p ‐tau217. Relative to the predicted effects of decreasing eGFR on p ‐tau217 measurements, the p ‐tau217/Aβ42 ratio relative increase was reduced by 40%, while the relative increase was reduced by 63% for %p‐tau217 measurements.

Abstract Background Clinically available plasma p ‐tau217 assays may be utilized in the determination of eligibility for amyloid‐lowering therapies. Our institution recently introduced a plasma p ‐tau217 assay in clinical practice using a two‐cutpoint approach that optimizes the accuracy while minimizing false positive risk and categorizing ≤20% of results as intermediate. In this study, we prospectively evaluate the performance of a plasma p ‐tau217 assay for detection of amyloid pathology using these predefined cutpoints. Method Patients recruited were being considered for lecanemab therapy at a tertiary care subspecialty clinic. Plasma p ‐tau217 was measured using the clinically available Fujirebio Lumipulse p ‐tau217 assay at Mayo Clinic, and results (pg/mL) were classified as either negative (≤0.185), intermediate (0.186–0.324) or positive (≥0.325). Amyloid pathology was determined by amyloid‐PET and/or CSF p ‐tau181/Aβ42. Result Ninety‐three patients were recruited between November 2023 and December 2024. Of these, 49 underwent amyloid‐PET, 4 had CSF p ‐tau181/Aβ42 measurements, and 40 had both PET and CSF results (with 3/40 discordant cases), for use in the assessment of amyloid pathology. The three discordant cases were considered amyloid positive for purposes of plasma p ‐tau217 comparison. Overall amyloid positivity was 90%. Plasma p ‐tau217 results were positive in 83% (77/93), negative in 6% (6/93), and intermediate in 11% (10/93) of patients. An elevated p ‐tau217 predicted the presence of amyloid positivity with a diagnostic accuracy of 96% (95% CI 90% − 99%). In the intermediate range, 80% of patients were positive for amyloid pathology. In patients with a definitive p ‐tau217 result (positive or negative), the positive and negative predictive values were 97% and 83%. There were three patients with discordant results: one PET+/p‐tau217‐, one PET‐/p‐tau217+, and one CSF‐/p‐tau217+. Clinical presentation of these discordant cases was examined, and relevant findings will be discussed. Conclusion The Lumipulse plasma p ‐tau217 assay exhibited acceptable diagnostic accuracy for the determination of amyloid pathology when compared to either amyloid‐PET or CSF p ‐tau181/Aβ42. This prospective study confirms the utility a two‐cutpoint approach for interpreting plasma p ‐tau217 for the assessment of amyloid pathology eligibility for amyloid‐lowering therapies in a heterogenous clinical cohort.