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Abstract The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout the brain’s white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.

Diffusion MRI (dMRI) is a valuable imaging technique to study the connectivity and microstructure of the brain in vivo. However, the resolution of dMRI is limited by the low signal-to-noise ratio (SNR) of this technique. Various multi-shot acquisition strategies have been developed to achieve sub-millimeter resolution, but they require long scan times which can be restricting for patient scans. Alternatively, the SNR of single-shot acquisitions can be increased by using a spiral readout trajectory to minimize the sequence echo time. Imaging at ultra-high fields (UHF) could further increase the SNR of single-shot dMRI; however, the shorter T2* of brain tissue and the greater field non-uniformities at UHFs will degrade image quality, causing image blurring, distortions, and signal loss.In this study, we investigated the trade-off between the SNR and resolution of different k-space trajectories, including echo planar imaging (EPI), partial Fourier EPI, and spiral trajectories, over a range of dMRI resolutions at 7T. The effective resolution, spatial specificity and sharpening effect were measured from the point spread function (PSF) of the simulated diffusion sequences for a nominal resolution range of 0.6–1.8 mm. In-vivo partial brain scans at a nominal resolution of 1.5 mm isotropic were acquired using the three readout trajectories to validate the simulation results. Field probes were used to measure dynamic magnetic fields offline up to the 3rd order of spherical harmonics. Image reconstruction was performed using static ΔB0 field maps and the measured trajectories to correct image distortions and artifacts, leaving T2* effects as the primary source of blurring. The effective resolution was examined in fractional anisotropy (FA) maps calculated from a multi-shell dataset with b-values of 300, 1000, and 2000 s/mm2 in 5, 16, and 48 directions, respectively. In-vivo scans at nominal resolutions of 1, 1.2, and 1.5 mm were acquired and the SNR of the different trajectories calculated using the multiple replica method to investigate the SNR. Finally, in-vivo whole brain scans with an effective resolution of 1.5 mm isotropic were acquired to explore the SNR and efficiency of different trajectories at a matching effective resolution. FA and intra-cellular volume fraction (ICVF) maps calculated using neurite orientation dispersion and density imaging (NODDI) were used for the comparison. The simulations and in vivo imaging results showed that for matching nominal resolutions, EPI trajectories had the highest specificity and effective resolution with maximum image sharpening effect. However, spirals have a significantly higher SNR, in particular at higher resolutions and even when the effective image resolutions are matched. Overall, this work shows that the higher SNR of single-shot spiral trajectories at 7T allows us to achieve higher effective resolutions compared to EPI and PF-EPI to map the microstructure and connectivity of small brain structures.

To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information, sensitive by nature, is accessible by qualified researchers at https://registeredpreventad.loris.ca. In addition to being a living resource for continued data acquisition, PREVENT-AD offers opportunities to facilitate understanding of AD pathogenesis.

In this work we use non-negative matrix factorization to identify patterns of microstructural variance in the human hippocampus. We utilize high-resolution structural and diffusion magnetic resonance imaging data from the Human Connectome Project to query hippocampus microstructure on a multivariate, voxelwise basis. Application of non-negative matrix factorization identifies spatial components (clusters of voxels sharing similar covariance patterns), as well as subject weightings (individual variance across hippocampus microstructure). By assessing the stability of spatial components as well as the accuracy of factorization, we identified 4 distinct microstructural components. Furthermore, we quantified the benefit of using multiple microstructural metrics by demonstrating that using three microstructural metrics (T1-weighted/T2-weighted signal, mean diffusivity and fractional anisotropy) produced more stable spatial components than when assessing metrics individually. Finally, we related individual subject weightings to demographic and behavioural measures using a partial least squares analysis. Through this approach we identified interpretable relationships between hippocampus microstructure and demographic and behavioural measures. Taken together, our work suggests non-negative matrix factorization as a spatially specific analytical approach for neuroimaging studies and advocates for the use of multiple metrics for data-driven component analyses.