From a complex systems perspective, clinical syndromes emerging from neurodegenerative diseases are thought to result from multiscale interactions between aggregates of misfolded proteins and the disequilibrium of large-scale networks coordinating functional operations underpinning cognitive phenomena. Across all syndromic presentations of Alzheimer’s disease, age-related disruption of the default mode network is accelerated by amyloid deposition. Conversely, syndromic variability may reflect selective neurodegeneration of modular networks supporting specific cognitive abilities. In this study, we leveraged the breadth of the Human Connectome Project-Aging cohort of non-demented individuals (N = 724) as a normative cohort to assess the robustness of a biomarker of default mode network dysfunction in Alzheimer’s disease, the network failure quotient, across the aging spectrum. We then examined the capacity of the network failure quotient and focal markers of neurodegeneration to discriminate patients with amnestic (N = 8) or dysexecutive (N = 10) Alzheimer’s disease from the normative cohort at the patient-level, as well as between Alzheimer’s disease phenotypes. Importantly, all participants and patients were scanned using the Human Connectome Project-Aging protocol, allowing for the acquisition of high-resolution structural imaging and longer resting-state connectivity acquisition time. Using a regression framework, we found that the network failure quotient related to age, global and focal cortical thickness, hippocampal volume, and cognition in the normative Human Connectome Project-Aging cohort, replicating previous results from the Mayo Clinic Study of Aging that used a different scanning protocol. Then, we used quantile curves and group-wise comparisons to show that the network failure quotient commonly distinguished both dysexecutive and amnestic Alzheimer’s disease patients from the normative cohort. In contrast, focal neurodegeneration markers were more phenotype-specific, where the neurodegeneration of parieto-frontal areas associated with dysexecutive Alzheimer’s disease while the neurodegeneration of hippocampal and temporal areas associated with amnestic Alzheimer’s disease. Capitalizing on a large normative cohort and optimized imaging acquisition protocols, we highlight a biomarker of default mode network failure reflecting shared system-level pathophysiological mechanisms across aging and dysexecutive and amnestic Alzheimer’s disease and biomarkers of focal neurodegeneration reflecting distinct pathognomonic processes across the amnestic and dysexecutive Alzheimer’s disease phenotypes. These findings provide evidence that variability in inter-individual cognitive impairment in Alzheimer’s disease may relate to both modular network degeneration and default mode network disruption. These results provide important information to advance complex systems approaches to cognitive aging and degeneration, expand the armamentarium of biomarkers available to aid diagnosis, monitor progression, and inform clinical trials.

BackgroundDisruption of the default mode network (DMN) is thought to be a common feature of aging and across Alzheimer’s disease (AD) clinical phenotypes, while syndromic variability could be reflected in selective degeneration of macro‐scale networks optimally supporting specific mental abilities (Fig 1). As part of a collaborative effort between Mayo Clinic and the Human Connectome Project‐Aging (HCP‐A), we aimed to delineate a biomarker of global network failure across aging and the dysexecutive (dAD) and amnestic phenotypes of AD, and biomarkers of focal degeneration specific to each AD phenotype.MethodWe used a regression framework to assess the relationships between a marker of DMN dysfunction, the network failure quotient (NFQ), and factors relevant to AD such as age, cortical thickness (global cortical thickness, inferior parietal lobe), hippocampal volume, and cognition (episodic memory, cognitive flexibility) in the HCP‐A cohort, which consists of 725 non‐demented older adults. We then fit centile curves to the HCP‐A cohort to assess whether the NFQ and focal degeneration markers could distinguish dAD (n=10) and amnestic AD (n=8) patients from the HCP‐A cohort at the group‐ and individual‐level. Participants were scanned using the HCP‐A protocol, allowing for the acquisition of high‐resolution multi‐echo structural images and longer resting‐state connectivity acquisition time compared to traditional protocols.ResultThe NFQ related to age, cortical thickness, hippocampal volume, and cognition in the HCP‐A cohort. It also strongly discriminated dAD and amnestic AD from the HCP‐A cohort but did not discriminate between AD phenotypes. In contrast, markers of focal degeneration were phenotype‐specific; parieto‐frontal areas yielded largest effect sizes for dAD patients, and hippocampal and temporal areas best discriminated patients with amnestic AD (Fig 2).ConclusionThe NFQ may reflect shared system‐level pathophysiological mechanisms across aging and the dysexecutive and amnestic phenotypes of AD whereas focal degeneration markers highlight distinct pathognomonic processes across AD phenotypes. These findings suggest that inter‐individual variability in cognitive impairment in AD would be closely tied to modular, phenotype‐specific network degeneration combined with a common global functional disruption of the DMN. Such information has crucial implications for clinical biomarkers and to provide a deeper understanding of heterogeneity in AD.

Objective: This work evaluates the rate-dependent and relaxation properties of native porcine heart valves, glutaraldehyde fixed porcine pericardium, and decellularized sterilized porcine pericardium. Biaxial tension testing was performed at strain-rates of 0.001 s-1 , 0.01 s-1 , 0.1 s-1 , and 1 s-1. Finally, relaxation testing for 300 s was performed on all heart valve biomaterials. Results: No notable rate-dependent response was observed for any of the three biomaterials with few significant differences between any strain-rates. For relaxation testing, native tissues showed the most pronounced drop in stress and glutaraldehyde the lowest drop in stress although no tissues showed anisotropy in the relaxation. Conclusion: Increasing the strain-rate of the three biomaterials considered does not increase the stress within the tissue. This indicates that there will not be increased fatigue from accelerated wear testing compared to loading at physiological strain-rates as the increase strain-rates would likely not significantly alter the tissue stress. INDEX TERMS Aortic Valve Replacement, Biaxial Tension, Rate-Dependency, Relaxation Testing, Tissue Engineered Heart Valve IMPACT STATEMENT No observed mechanical rate-dependency for both glutaraldehyde fixed and decellularized pericardium despite notable tissue relaxation. Indicates no increased stress on tissue during accelerated wear testing compared to physiological loading.

BackgroundDiffusion 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.

BackgroundNeurite 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.