Citations

Abstract We hypothesized that poorer cerebral perfusion could impair mobility, particularly at lower systolic blood pressure (SBP). Cerebral perfusion was measured via arterial spin-labelled (ASL)-MRI in community-dwelling adults of the Mayo Clinic Study of Aging. Usual-pace gait speed was assessed over 5.6 meters on an electronic mat. Linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP, adjusting for sex and body mass index. Results report differences in gait speed (meter/second) per standard deviation (SD) lower ASL or SBP (mean=139.1 mmHg, SD=19.7 mmHg). Among 479 participants (aged 31-94 years; mean age 67.6 years; 44% women; mean gait speed 1.17m/s), relationships of ASL with gait speed varied by age and SBP (ASL-x-age interaction: p<.007; ASL-x-SBP interaction: p<.007). At age 65, 75 or 85 years and a SBP of 120mmHg, each SD lower ASL was associated with a 0.04 m/s (0.01,0.07), 0.07 m/s (0.04,0.10), and 0.09 m/s (0.05,0.13) slower gait speed at respective ages. At age 65, 75 or 85 years with low ASL (1 SD below the mean), each SD lower SBP was associated with 0.06 (0.02,0.09) m/s, 0.03 (0.01,0.06) m/s or .01 (-0.02,0.04) m/s slower gait speed, respectively. With high ASL (mean ASL+1SD), lower SBP trended towards faster gait at older age, e.g. estimated gait speed was 0.04 m/s (0.00,0.09) faster for each SD lower SBP at age 85years. Poorer cerebral perfusion may contribute to slower gait, particularly with lower SBP. The interrelations of cerebral perfusion, SBP, and age with mobility merit further study.

AbstractBackgroundPreviously, we found that female sex is associated with greater pathology burden in early‐onset Alzheimer’s disease (EOAD) in the Longitudinal EOAD Study (LEADS). Here, we have expanded our analyses by adding APOE‐ε4 carrier status as a further predictor of EOAD pathologic burden.MethodWe included 180 EOAD LEADS participants with available APOE genotype, Flortaucipir PET, Florbetaben PET, and MRI data. Demographic and biomarker differences were analyzed using ANOVA. EOAD participants were split by sex and APOE‐ε4 carrier status. Box plots were created in R and a voxel‐wise multiple linear regression in SPM12 yielded statistical brain maps of gray matter density (GMD), amyloid and tau burden.ResultCompared to males, EOAD females showed significantly greater global amyloid uptake (mean SUVR, p=0.002) and greater tau SUVR in the MetaROI, Braak 3&4 and 5&6 regions (p=0.0007, p=0.001, p=0.01, resp., Table 1). Female APOE‐ε4 carriers showed greater tau SUVR in Braak regions 1&2 than female non‐carriers (p<0.01, Figure 2B). Male APOE‐ε4 carriers showed trend‐level thinner entorhinal cortex than male non‐carriers (p=0.06, Figure 1). Interestingly however, femaleAPOE‐ε4 non‐carriers showed greater global amyloid SUVR than female carriers (p<0.01, Figure 2A). Further, APOE‐ε4 non‐carriers showed significantly thinner medial temporal cortices than carriers in both sexes (M, p<0.05; F, p<0.01). Male APOE‐ε4 non‐carriers also showed significantly lower mean cortical thickness than male carriers (p<0.05, Figure 1). Female APOE‐ε4 non‐carriers showed trend‐level lower mean cortical thickness than female carriers (p=0.06, Figure 1). The FWE corrected SPM12 maps showed significantly greater GM atrophy in the right temporal lobe and greater amyloid burden in a right lateralized occipitoparietal pattern in female APOE‐ε4 non‐carriers compared to female carriers. Further, male APOE‐ε4 non‐carriers showed greater tau uptake in the left frontal lobe than male carriers (Figure 3).ConclusionThese results suggest that APOE‐ε4 non‐carrier status is associated with greater atrophy, amyloid and tau deposition in EOAD. This might be due to the presence of other strong genetic drivers of disease pathology in EOAD.

AbstractBackgroundAmyloidosis‐driven tau deposition has been a significant focus of imaging research in Alzheimer’s disease (AD). However, the 3R/4R tau seen in AD can be observed in the transentorhinal/entorhinal regions (Braak I/II) in the absence of amyloidosis. The underlying drivers of this phenomenon are not well understood. Our goal was to examine amyloid‐independent pathways of longitudinal Tau‐PET SUVR progression in the entorhinal cortex (ERC) using a broad range of risk and protective factors.MethodWe identified 449 participants from the population‐based sample of Mayo Clinic Study of Aging >50 years old with baseline amyloid PET and at least two serial tau PET scans (mean number of scans=2.3; mean follow‐up time=3.2 years). Using an amyloid SUVR cut‐point of 1.48, we categorized participants into A+ (n=167; mean age=77.5 years; 56% male; baseline ERC tau=1.20; 83% cognitively unimpaired) and A‐ (n=282; mean age=67.5; 56% male; baseline ERC tau=1.07; 92% cognitively unimpaired). We used an ERC tau SUVR cut‐point of 1.21 to determine T+. We fit mixed effects and growth curve models with age, sex, baseline amyloid, risk factors (midlife activities, sleep, stress, education/occupation, cardiovascular metabolic conditions) as predictors and longitudinal ERC tau as the outcome. We fit separate models in A‐, A+, and all participants.ResultsFor models of all participants and A+ participants, the only predictors of higher rates of ERC tau deposition were increasing age and amyloid SUVR (p<0.05). In the A‐ models (figure below), amyloid SUVR and age were predictors of baseline, but not longitudinal ERC tau. However, a greater number of cardiovascular metabolic conditions predicted a higher rate of ERC tau accumulation (0.007 (0.002), p<0.05). Only 13% of the 23 A‐T+ participants were APOE4 carriers (compared to 31% in the overall sample), suggesting the role of non‐APOE4 pathways to tau deposition.ConclusionOur results support previous evidence that significant amyloidosis is causal to higher rates of tau deposition. However, in those without significant amyloidosis, cardiovascular metabolic conditions predicted higher rates of ERC tau accumulation. Further work is warranted to investigate the mechanisms through which genetics, comorbidities, and lifestyle may play a role in early tau deposition.

AbstractBackgroundStudies of aging and dementia often acquire brain MRI and PET images, then de‐identify and share these widely with other researchers. It is known that research participants can potentially be re‐identified from brain MRI and CT using face recognition, but this has not been tested with PET imaging.MethodWe generated face reconstruction images of 182 volunteers using their existing amyloid (PiB), tau (FTP), and FDG PET scans from clinical GE PET/CT scanners, and we measured how often commercial automatic face recognition (Microsoft Azure) correctly matched these reconstructions with photographs of their faces. We additionally compared these match rates with face reconstructions from CT (from PET/CT) and MRI. When testing face recognition from PET scans, CT was used only during PET reconstruction, not for face recognition. We also validated our updated mri_reface software, originally developed to de‐identify (“de‐face”) faces in MRI, with new support for PET images. We measured face recognition rates before and after applying mri_reface to PET, CT, and MRI. In addition, we measured effects of de‐facing on biomarker measurements (global and regional SUVR) using 244 ADNI Florbetapir (FBP) amyloid PET scans with two automated pipelines: FreeSurfer 6.0 (PETSurfer) and an in‐house SPM12‐based pipeline.ResultRates of successful face recognition with PET ranged from 32‐41% (Table 1) across tracers. These were lower than MRI (98%) and CT (78%) but still concerning for participant privacy. Using mri_reface reduced face recognition to 0‐3.5% for PET, 5% for CT, and 8% for MRI. mri_reface had little effect on global amyloid SUVR measurements from ADNI PET images (Figure 1). ICC values between original and de‐faced images were 1.00 with biases and median absolute differences < 0.5%, across both pipelines. Effects on individual regions all had ICC values > 0.98 with biases and median absolute differences < 2%.ConclusionFace reconstructions from PET images have sufficient quality for potential re‐identification using publicly available face recognition technology. Research studies should consider using face de‐identification (de‐facing) software on PET images in addition to CT and structural MRI. Our free, automatic mri_reface software greatly reduced the potential for face recognition without substantially affecting SUVR measurements.

AbstractBackgroundThe dynamics of white matter (WM) changes are understudied in Alzheimer’s disease (AD). Leveraging tau deposition measured from Tau‐PET, our goal was to study the association between tau and white matter health using NODDI from multi‐shell diffusion MRI (dMRI). Specifically, we focused on the Neurite Density Index (NDI) from NODDI, which in WM captures the signal from axons.MethodWe identified 251 participants (126 cognitively normal, 58 MCI, 67 dementia) from the Mayo ADRC and Mayo Clinic Study of Aging with Aβ‐PET, Tau‐PET, and multi‐shell dMRI who were Aβ‐positive (mean age of 77 years and 55% male). We limited to Aβ‐positive participants because Aβ deposition accelerates tau deposition. For Tau‐PET, we estimated SUVRs from three regions corresponding to Braak I/II, III/IV, and V/VI (Figure 1.a). To understand the associations between Tau‐PET SUVRs at three Braak regions and NDIs at 30 candidate WM tracts, we implemented three analyses methods ‐ Pearson correlation, linear regression, and multilayer perceptron machine learning regression.ResultHigher tau burden in all three Braak regions was associated with lower neurite density in 10 significant WM tracts (Table 1). Interestingly, uncinate fasciculus (UNC) was found significantly associated with all three Braak regions. All three analysis methods consistently showed differential involvement of WM pathways for Braak staging such as ‐ Cingulum adjoining Hippocampus (CGH) for Braak I/II regions, Medial Temporal WM (MTWM) for Braak III/IV regions, and Inferior Occipital WM (IOWM) for Braak V/VI regions (Figure 1.b). The linear regression and machine learning regression models also suggested that WM measurements reflected 18‐35% of variance due to tau depositionConclusionWe found that CGH and UNC WM were the most impacted ROIs associated with Braak I/II regions as expected. UNC, directly connecting anterior temporal lobes to the orbitofrontal cortex, was a key WM tract identified as important for all Braak I‐VI regions and warrants further investigation in the study of AD progression. This study highlights the significant impact tau deposition may have on WM. This work also demonstrates the feasibility of using NODDI as an informative supplementary imaging modality for monitoring AD progression.

AbstractBackgroundBlood‐based biomarkers of amyloid and neurodegeneration are increasingly used in clinical trials and entering clinical use. Differentially mapping the plasma markers to post‐mortem neuropathology in a community‐based sample is critical for interpretation.MethodWe identified 64 Mayo Clinic Study of Aging (MCSA) participants with antemortem plasma markers (Aβ42, Aβ40, NfL, T‐tau, Aβ42/40 ratio) measured on the Quanterix Simoa HD‐1 analyzer and with postmortem neuropathologic assessments of Alzheimer’s pathology (Braak tangle stage, Thal phase, neuritic plaque burden) and cerebrovascular pathology (Strozyk scale focused on macrovascular brain changes and Kalaria scale focused on detailed micro‐ and macro‐ vascular brain changes). Weighted linear regression models with adjustment for time between plasma markers and death were conducted with exact permutation tests to evaluate the relationships between antemortem plasma and postmortem neuropathology markers.ResultHigher plasma NfL levels and Aβ42/40 ratio were associated with both cerebrovascular neuropathologic scales (p<0.05) but were not associated with Braak neurofibrillary tangle stage, neuritic plaque score, or Thal stage (p>0.5). Plasma T‐tau was not associated with any pathological assessment. Plasma Aβ42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales.ConclusionIn this community sample of participants predominantly without dementia, plasma markers for amyloid (Aβ42/40) and neurodegeneration (NfL) were associated with cerebrovascular neuropathology at autopsy. NfL is a non‐specific marker of brain injury, therefore, its association with cerebrovascular neuropathology was in the expected direction. The association between greater cerebrovascular neuropathology and elevated Aβ42/40 requires further investigation. These findings provide evidence that cerebrovascular disease may significantly influence levels of plasma biomarkers proposed for Alzheimer’s disease. This information will be important to consider for accurate clinical interpretation of the proposed biomarkers.

AbstractBackgroundNeurite Orientation Dispersion and Density Imaging (NODDI) is becoming increasingly common as multiband acceleration becomes available for clinical scanning, but fitting the model can be extremely slow. Since the release of the original MATLAB implementation in 2012, three alternatives have become popular: Accelerated Microstructure Imaging via Convex Optimization (AMICO), the Microstructure Diffusion Toolbox (MDT), and the CUDA Diffusion Modelling Toolbox (cuDIMOT). They accelerate fitting through reformulation and/or using GPUs, but the implementation differences raise the question of which approach is best. To our knowledge all previous comparisons lacked knowledge of the true values and used the original implementation as the nominally correct one, with in vivo data. We remedy that using simulations with known NODDI values, in addition to in vivo scans.MethodWe created a software phantom with Neurite Density Index (NDI) values linearly increasing from 0.1 to 1.0 in x, Orientation Dispersion (ODI) from 0 to 1 in y, and Isotropic water Volume Fraction (ISOVF) from 0 to 0.9 in z. We simulated five scans using the ADNI3 advanced diffusion MRI protocol. The phantom had 20 voxels in each direction, and the fiber bundle principal direction randomly varied between the simulations. The simulations were fit by the original, AMICO, MDT, and cuDIMOT implementations, and root mean square errors were calculated as shown in Table 1. A discrepancy measure was also calculated using the brain voxels of three in vivo human scans acquired using the same protocol on a Siemens Prisma, substituting the original implementation’s values for the truth since the latter is unknown for in vivo scans.ResultcuDIMOT had the least error (for ODI < 0.8) and was fastest. The original implementation was a close second in accuracy but much slower. cuDIMOT’s ODI underestimation can be corrected with a transfer function in the noise‐free case, but that approach fails with actual scans.ConclusionThe original or cuDIMOT implementations should be used, with cuDIMOT the favorite when at least one CUDA‐capable GPU is available and the number of scans are large. Correcting cuDIMOT’s ODI underestimation using a different initialization or form of Dawson’s integral should be investigated.

AbstractBackgroundDiffusion MRI (dMRI) based quantification of microstructural changes in white matter (WM) are increasingly proposed to measure cerebrovascular disease (CVD) related changes. Our objective was to compare the proposed dMRI markers using postmortem neuropathologic CVD data and then evaluate the predictors of longitudinal dMRI markers using serial scans.MethodWe identified n=51 participants (mean age: 83.8 years, 63% males) with ante‐mortem dMRI and postmortem CVD evaluation and n=718 participants (mean age: 71.1 years, 56% males) with at least two dMRI scans from the population‐based sample of Mayo Clinic Study of Aging. We computed dMRI measures proposed for measuring CVD: Free Water (FW), Fractional Anisotropy (FA) adjusted for FW (FAadj), Peak width Skeletonized Mean Diffusivity (PSMD), and FA of the genu of corpus callosum (Genu‐FA). We used the FW and PSMD (PSMD release 1.8.1) kits from the MarkVCID consortium.Using weighted linear regression models with adjustments for MRI scan time to death, we evaluated associations between the baseline dMRI and two pathology CVD scores: Strozyk (represents the presence and number of macroscopic lesions) and Kalaria (represents the summary score of vessel wall modifications) scales. We ran linear mixed effect models with all available serial dMRI measures as outcomes and vascular risk (measured by the number of cardiovascular and metabolic conditions‐CMC), baseline imaging measures (amyloid and white matter hyperintensities (WMH)) and their interaction with time as key predictors.ResultMost dMRI markers were predictors of postmortem CVD pathology (Table 1). In longitudinal dMRI models, terms associated with amyloid explained little variability in dMRI (<1%) (Table 2). WMH was a significant predictor of baseline and decline in dMRI measures with WMH explaining a considerable percentage of variability in FW (34%) and PSMD (28%). Vascular risk measures were significant predictors of three out of the four dMRI measures.ConclusionThe diffusion measures proposed as surrogate markers of CVD map reasonably well to CVD pathological scales and do not change substantially as a function of baseline amyloidosis. Our findings shed light on variability in the proposed diffusion markers using postmortem data and longitudinal imaging data. Further work is needed to evaluate their clinical utility.

AbstractBackgroundCerebral Microbleeds (CMBs) are tracked in anti‐amyloid drug safety monitoring. T2*GRE or SWI MRI images are visually assessed for the presence of CMBs. Automated methods tuned for sensitivity often have unacceptably high false positive rates requiring extensive human cleanup.MethodAssume contemporaneous T2*GRE and T1‐weighted images. CMB detection (Figures 1,2) has three steps: 1) Segmentation outputs from the T1‐weighted image are resampled into the T2*GRE image voxel raster; 2) Normalized cross‐correlation of the T2*GRE with a CMB template identifies “candidate CMBs”; 3) a neural network using voxel patches centered on each candidate CMB rejects false positives. Patches presented to the network are 4D and include five contrasts drawn from the T2*GRE, correlation, T1‐weighted, WM probability and CSF probability images. The simple network architecture consists of convolutional blocks followed by dense blocks. The system is trained using images from ADNI, ARIC, MCSA, and the Mayo Clinic ADRC that have been previously visually graded for CMBs (Table in Figure 3). Importantly, we include participants with and without CMBs in our data reflecting the fact that the majority of people (even the elderly) have no CMBs. Data is split 70:10:20 by subject for training, validation, and testing. Various network configurations were evaluated.ResultHigh candidate detection sensitivity can be achieved at the expense of presenting hundreds to thousands of false positive candidates per input image to the rejection network. Our best performing network configuration to date has AUC 0.982 (95% bootstrap CI 0.971 to 0.990 based on the 10% validation subset). Choosing an operating point with 95% sensitivity in the validation set and admits, on average, 0.6 false positive CMB candidates per input T2*GRE image. Sensitivity is hindered by a small number of obvious errors in the ground truth visual assessment. Validation loss tracks training loss with no indication of over‐fitting. Example patches are shown in Figure 4.ConclusionExcessive false positive detection requires significant human correction and effort, preventing automated CMB detection from being widely adopted. We have an automated detection system that is sensitive (95%) and provides excellent false positive rejection (<1 false positive CMB/input image) reducing needed human effort.