Iron Deposition and Distribution Across the Hippocampus Is Associated with Pattern Separation and Pattern Completion in Older Adults at Risk for Alzheimer's Disease.

Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD (N = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD.

Assessment of white matter hyperintensity severity using multimodal magnetic resonance imaging.

White matter hyperintensities are radiological abnormalities reflecting cerebrovascular dysfunction detectable using MRI. White matter hyperintensities are often present in individuals at the later stages of the lifespan and in prodromal stages in the Alzheimer's disease spectrum. Tissue alterations underlying white matter hyperintensities may include demyelination, inflammation and oedema, but these are highly variable by neuroanatomical location and between individuals. There is a crucial need to characterize these white matter hyperintensity tissue alterations in vivo to improve prognosis and, potentially, treatment outcomes. How different MRI measure(s) of tissue microstructure capture clinically-relevant white matter hyperintensity tissue damage is currently unknown. Here, we compared six MRI signal measures sampled within white matter hyperintensities and their associations with multiple clinically-relevant outcomes, consisting of global and cortical brain morphometry, cognitive function, diagnostic and demographic differences and cardiovascular risk factors. We used cross-sectional data from 118 participants: healthy controls (n = 30), individuals at high risk for Alzheimer's disease due to familial history (n = 47), mild cognitive impairment (n = 32) and clinical Alzheimer's disease dementia (n = 9). We sampled the median signal within white matter hyperintensities on weighted MRI images [T1-weighted (T1w), T2-weighted (T2w), T1w/T2w ratio, fluid-attenuated inversion recovery (FLAIR)] as well as the relaxation times from quantitative T1 (qT1) and T2* (qT2*) images. qT2* and fluid-attenuated inversion recovery signals within white matter hyperintensities displayed different age- and disease-related trends compared to normal-appearing white matter signals, suggesting sensitivity to white matter hyperintensity-specific tissue deterioration. Further, white matter hyperintensity qT2*, particularly in periventricular and occipital white matter regions, was consistently associated with all types of clinically-relevant outcomes in both univariate and multivariate analyses and across two parcellation schemes. qT1 and fluid-attenuated inversion recovery measures showed consistent clinical relationships in multivariate but not univariate analyses, while T1w, T2w and T1w/T2w ratio measures were not consistently associated with clinical variables. We observed that the qT2* signal was sensitive to clinically-relevant microstructural tissue alterations specific to white matter hyperintensities. Our results suggest that combining volumetric and signal measures of white matter hyperintensity should be considered to fully characterize the severity of white matter hyperintensities in vivo. These findings may have implications in determining the reversibility of white matter hyperintensities and the potential efficacy of cardio- and cerebrovascular treatments.

Long-term consequences of neonatal encephalopathy in the hypothermia era: protocol for a follow-up cohort study at 9 years of age.

INTRODUCTION: Therapeutic hypothermia (TH) became the standard of care treatment for neonates with moderate and severe neonatal encephalopathy (NE) in most industrialized countries about 10 years ago. Although TH is effective in reducing mortality and the incidence of severe developmental disabilities, the recent literature converges in reporting frequent cognitive and behavioural difficulties at school entry in children with NE-TH. Although these challenges are deemed minor compared with cerebral palsy and intellectual disability, their impacts on a child's self-determination and family's well-being are quite significant. Therefore, the nature and extent of these difficulties need to be comprehensively described so that appropriate care can be offered. METHODS AND ANALYSIS: The current study will be the largest follow-up study of neonates with NE treated with TH to characterize their developmental outcomes and associated brain structural profiles at 9 years of age. Specifically, we will compare executive function, attention, social cognition, behaviour, anxiety, self-esteem, peer problems, brain volume, cortical features, white matter microstructure and myelination between children with NE-TH and matched peers without NE. Associations of perinatal risk factors and structural brain integrity with cognitive, behavioural and psycho-emotional deficits will be evaluated to inform about the potential aggravating and protective factors associated with function. ETHICS AND DISSEMINATION: This study is supported by the Canadian Institute of Health Research (202203PJT-480065-CHI-CFAC-168509), and received approval from the Pediatric Ethical Review Board of the McGill University Health Center (MP-37-2023-9320). The study findings will be disseminated in scientific journals and conferences and presented to parental associations and healthcare providers to inform best practices. TRIAL REGISTRATION NUMBER: NCT05756296.

Distribution of [11C]-JNJ-42491293 in the marmoset brain: a positron emission tomography study.

JNJ-42491293 is a metabotropic glutamate 2 (mGlu2) positive allosteric modulator (PAM) that was radiolabelled with [11C]- to serve as a positron emission tomography (PET) ligand. Indeed, in vitro, the molecule displays high selectivity at mGlu2 receptors. However, PET experiments performed in rats, macaques and humans, have suggested that [11C]-JNJ-42491293 could interact with an unidentified, non-mGlu2 receptor binding site. The brain distribution of [11C]-JNJ-42491293 has not been determined in the brain of the common marmoset, a small non-human primate increasingly used in neuroscience research. Here, we investigated the distribution of [11C]-JNJ-42491293 in the marmoset brain. Three marmosets underwent brain magnetic resonance imaging (MRI) and 90-min dynamic PET scans with [11C]-JNJ-42491293 in combination with vehicle or the mGlu2 PAM AZD8529 (0.1, 1 and 10 mg/kg). In the scans in which [11C]-JNJ-42491293 was co-administered with vehicle, the brain areas with the highest standardised uptake values (SUVs) were the midbrain, cerebellum and thalamus, while the lowest SUVs were found in the pons. The addition of AZD8529 (0.1, 1 and 10 mg/kg) to [11C]-JNJ-42491293 did not modify the SUVs obtained with [11C]-JNJ-42491293 alone, and ex vivo blocking autoradiography with PAM AZD8529 (10, 100, 300 µM) on marmoset brain sections showed increased signals in the blocking conditions compared to vehicle, suggesting that no competition occurred between the 2 ligands. The results we obtained here do not suggest that [11C]-JNJ-42491293 interacts selectively, or even at all, with mGlu2 receptors in the marmoset, in agreement with findings previously reported in macaque and human.

The impact of the Siemens Tim Trio to Prisma upgrade and the addition of volumetric navigators on cortical thickness, structure volume, and 1H-MRS indices: An MRI reliability study with implications for longitudinal study designs.

Many magnetic resonance imaging (MRI) measures are being studied longitudinally to explore topics such as biomarker detection and clinical staging. A pertinent concern to longitudinal work is MRI scanner upgrades. When upgrades occur during the course of a longitudinal MRI neuroimaging investigation, there may be an impact on the compatibility of pre- and post-upgrade measures. Similarly, subject motion is another issue that may be detrimental to MRI work and embedding volumetric navigators (vNavs) within acquisition sequences has emerged as a technique that allows for prospective motion correction. Our research group recently underwent an upgrade from a Siemens MAGNETOM 3T Tim Trio system to a Siemens MAGNETOM 3T Prisma Fit system. The goals of the current work were to: 1) investigate the impact of this upgrade on commonly used structural imaging measures and proton magnetic resonance spectroscopy indices ("Prisma Upgrade protocol") and 2) examine structural imaging measures in a sequence with vNavs alongside a standard acquisition sequence ("vNav protocol"). While high reliability was observed for most of the investigated MRI outputs, suboptimal reliability was observed for certain indices. Across the scanner upgrade, increases in frontal, temporal, and cingulate cortical thickness (CT) and thalamus volume, along with decreases in parietal CT and amygdala, globus pallidus, hippocampus, and striatum volumes, were observed. No significant impact of the upgrade was found in 1H-MRS analyses. Further, CT estimates were found to be larger in MPRAGE acquisitions compared to vNav-MPRAGE acquisitions mainly within temporal areas, while the opposite was found mostly in parietal brain regions. The results from this work should be considered in longitudinal study designs and comparable prospective motion correction investigations are warranted in cases of marked head movement.

Hippocampal subfield volumes across the healthy lifespan and the effects of MR sequence on estimates.

The hippocampus has been extensively studied in various neuropsychiatric disorders throughout the lifespan. However, inconsistent results have been reported with respect to which subfield volumes are most related to age. Here, we investigate whether these discrepancies may be explained by experimental design differences that exist between studies. Multiple datasets were used to collect 1690 magnetic resonance scans from healthy individuals aged 18-95 years old. Standard T1-weighted (T1w; MPRAGE sequence, 1 mm3 voxels), high-resolution T2-weighted (T2w; SPACE sequence, 0.64 mm3 voxels) and slab T2-weighted (Slab; 2D turbo spin echo, 0.4 × 0.4 × 2 mm3 voxels) images were included. The MAGeT Brain algorithm was used for segmentation of the hippocampal grey matter (GM) subfields and peri-hippocampal white matter (WM) subregions. Linear mixed-effect models and Akaike information criterion were used to examine linear, second or third order natural splines relationship between hippocampal volumes and age. We demonstrated that stratum radiatum/lacunosum/moleculare and fornix subregions expressed the highest relative volumetric decrease, while the cornus ammonis 1 presented a relative volumetric preservation of its volume with age. We also found that volumes extracted from slab images demonstrated different age-related relationships compared to volumes extracted from T1w and T2w images. The current work suggests that although T1w, T2w and slab derived subfield volumetric outputs are largely homologous, modality choice plays a meaningful role in the volumetric estimation of the hippocampal subfields.

Advanced MRI techniques to improve our understanding of experience-induced neuroplasticity.

Over the last two decades, numerous human MRI studies of neuroplasticity have shown compelling evidence for extensive and rapid experience-induced brain plasticity in vivo. To date, most of these studies have consisted of simply detecting a difference in structural or functional images with little concern for their lack of biological specificity. Recent reviews and public debates have stressed the need for advanced imaging techniques to gain a better understanding of the nature of these differences - characterizing their extent in time and space, their underlying biological and network dynamics. The purpose of this article is to give an overview of advanced imaging techniques for an audience of cognitive neuroscientists that can assist them in the design and interpretation of future MRI studies of neuroplasticity. The review encompasses MRI methods that probe the morphology, microstructure, function, and connectivity of the brain with improved specificity. We underline the possible physiological underpinnings of these techniques and their recent applications within the framework of learning- and experience-induced plasticity in healthy adults. Finally, we discuss the advantages of a multi-modal approach to gain a more nuanced and comprehensive description of the process of learning.

Open Science CBS Neuroimaging Repository: Sharing ultra-high-field MR images of the brain.

Magnetic resonance imaging at ultra high field opens the door to quantitative brain imaging at sub-millimeter isotropic resolutions. However, novel image processing tools to analyze these new rich datasets are lacking. In this article, we introduce the Open Science CBS Neuroimaging Repository: a unique repository of high-resolution and quantitative images acquired at 7 T. The motivation for this project is to increase interest for high-resolution and quantitative imaging and stimulate the development of image processing tools developed specifically for high-field data. Our growing repository currently includes datasets from MP2RAGE and multi-echo FLASH sequences from 28 and 20 healthy subjects respectively. These datasets represent the current state-of-the-art in in-vivo relaxometry at 7 T, and are now fully available to the entire neuroimaging community.

A subject-specific framework for in vivo myeloarchitectonic analysis using high resolution quantitative MRI.

Structural magnetic resonance imaging can now resolve laminar features within the cerebral cortex in vivo. A variety of intracortical contrasts have been used to study the cortical myeloarchitecture with the purpose of mapping cortical areas in individual subjects. In this article, we first briefly review recent advances in MRI analysis of cortical microstructure to portray the potential and limitations of the current state-of-the-art. We then present an integrated framework for the analysis of intracortical structure, composed of novel image processing tools designed for high resolution cortical images. The main features of our framework are the segmentation of quantitative T1 maps to delineate the cortical boundaries (Bazin et al., 2014), and the use of an equivolume layering model to define an intracortical coordinate system that follows the anatomical layers of the cortex (Waehnert et al., 2014). We evaluate the framework with 150µm isotropic post mortem T2(∗)-weighted images and 0.5mm isotropic in vivo T1 maps, a quantitative index of myelin content. We study the laminar structure of the primary visual cortex (Brodmann area 17) in the post mortem and in vivo data, as well as the central sulcus region in vivo, in particular Brodmann areas 1, 3b and 4. We also investigate the impact of the layering models on the relationship between T1 and cortical curvature. Our experiments demonstrate that the equivolume intracortical surfaces and transcortical profiles best reflect the laminar structure of the cortex in areas of curvature in comparison to the state-of-the-art equidistant and Laplace implementations. This framework generates a subject specific intracortical coordinate system, the basis for subsequent architectonic analyses of the cortex. Any structural or functional contrast co-registered to the T1 maps, used to segment the cortex, can be sampled on the curved grid for analysis. This work represents an important step towards in vivo structural brain mapping of individual subjects.

Multi-contrast multi-scale surface registration for improved alignment of cortical areas.

The position of cortical areas can be approximately predicted from cortical surface folding patterns. However, there is extensive inter-subject variability in cortical folding patterns, prohibiting a one-to-one mapping of cortical folds in certain areas. In addition, the relationship between cortical area boundaries and the shape of the cortex is variable, and weaker for higher-order cortical areas. Current surface registration techniques align cortical folding patterns using sulcal landmarks or cortical curvature, for instance. The alignment of cortical areas by these techniques is thus inherently limited by the sole use of geometric similarity metrics. Magnetic resonance imaging T1 maps show intra-cortical contrast that reflects myelin content, and thus can be used to improve the alignment of cortical areas. In this article, we present a new symmetric diffeomorphic multi-contrast multi-scale surface registration (MMSR) technique that works with partially inflated surfaces in the level-set framework. MMSR generates a more precise alignment of cortical surface curvature in comparison to two widely recognized surface registration algorithms. The resulting overlap in gyrus labels is comparable to FreeSurfer. Most importantly, MMSR improves the alignment of cortical areas further by including T1 maps. As a first application, we present a group average T1 map at a uniquely high-resolution and multiple cortical depths, which reflects the myeloarchitecture of the cortex. MMSR can also be applied to other MR contrasts, such as functional and connectivity data.

A histology-based model of quantitative T1 contrast for in-vivo cortical parcellation of high-resolution 7 Tesla brain MR images.

A conclusive mapping of myeloarchitecture (myelin patterns) onto the cortical sheet and, thus, a corresponding mapping to cytoarchitecture (cell configuration) does not exist today. In this paper we present a generative model which can predict, on the basis of known cytoarchitecture, myeloarchitecture in different primary and non-primary cortical areas, resulting in simulated in-vivo quantitative T1 maps. The predicted patterns can be used in brain parcellation. Our model is validated using a similarity distance metric which enables quantitative comparison of the results with empirical data measured using MRI. The work presented may provide new perspectives for this line of research, both in imaging and in modelling the relationship with myelo- and cytoarchitecture, thus leading the way towards in-vivo histology using MRI.