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.

Neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms.

Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha-synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human-relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF-injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human-relevant pre-clinical measures and suggest that these pre-clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease.

Characterizing Subcortical Structural Heterogeneity in Autism.

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

High spatial overlap but diverging age-related trajectories of cortical magnetic resonance imaging markers aiming to represent intracortical myelin and microstructure.

Statistical effects of cortical metrics derived from standard T1- and T2-weighted magnetic resonance imaging (MRI) images, such as gray-white matter contrast (GWC), boundary sharpness coefficient (BSC), T1-weighted/T2-weighted ratio (T1w/T2w), and cortical thickness (CT), are often interpreted as representing or being influenced by intracortical myelin content with little empirical evidence to justify these interpretations. We first examined spatial correspondence with more biologically specific microstructural measures, and second compared between-marker age-related trends with the underlying hypothesis that different measures primarily driven by similar changes in myelo- and microstructural underpinnings should be highly related. Cortical MRI markers were derived from MRI images of 127 healthy subjects, aged 18-81, using cortical surfaces that were generated with the CIVET 2.1.0 pipeline. Their gross spatial distributions were compared with gene expression-derived cell-type densities, histology-derived cytoarchitecture, and quantitative R1 maps acquired on a subset of participants. We then compared between-marker age-related trends in their shape, direction, and spatial distribution of the linear age effect. The gross anatomical distributions of cortical MRI markers were, in general, more related to myelin and glial cells than neuronal indicators. Comparing MRI markers, our results revealed generally high overlap in spatial distribution (i.e., group means), but mostly divergent age trajectories in the shape, direction, and spatial distribution of the linear age effect. We conclude that the microstructural properties at the source of spatial distributions of MRI cortical markers can be different from microstructural changes that affect these markers in aging.

The impact of quality control on cortical morphometry comparisons in autism.

Structural magnetic resonance imaging (MRI) quality is known to impact and bias neuroanatomical estimates and downstream analysis, including case-control comparisons, and a growing body of work has demonstrated the importance of careful quality control (QC) and evaluated the impact of image and image-processing quality. However, the growing size of typical neuroimaging datasets presents an additional challenge to QC, which is typically extremely time and labour intensive. One of the most important aspects of MRI quality is the accuracy of processed outputs, which have been shown to impact estimated neurodevelopmental trajectories. Here, we evaluate whether the quality of surface reconstructions by FreeSurfer (one of the most widely used MRI processing pipelines) interacts with clinical and demographic factors. We present a tool, FSQC, that enables quick and efficient yet thorough assessment of outputs of the FreeSurfer processing pipeline. We validate our method against other existing QC metrics, including the automated FreeSurfer Euler number, two other manual ratings of raw image quality, and two popular automated QC methods. We show strikingly similar spatial patterns in the relationship between each QC measure and cortical thickness; relationships for cortical volume and surface area are largely consistent across metrics, though with some notable differences. We next demonstrate that thresholding by QC score attenuates but does not eliminate the impact of quality on cortical estimates. Finally, we explore different ways of controlling for quality when examining differences between autistic individuals and neurotypical controls in the Autism Brain Imaging Data Exchange (ABIDE) dataset, demonstrating that inadequate control for quality can alter results of case-control comparisons.

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo.

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-ß and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-ß and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-ß, tau, and class I histone deacetylase (HDAC I isoforms 1-3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-ß PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-ß and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-ß plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.

Involvement of the habenula in the pathophysiology of autism spectrum disorder.

The habenula is a small epithalamic structure with widespread connections to multiple cortical, subcortical and brainstem regions. It has been identified as the central structure modulating the reward value of social interactions, behavioral adaptation, sensory integration and circadian rhythm. Autism spectrum disorder (ASD) is characterized by social communication deficits, restricted interests, repetitive behaviors, and is frequently associated with altered sensory perception and mood and sleep disorders. The habenula is implicated in all these behaviors and results of preclinical studies suggest a possible involvement of the habenula in the pathophysiology of this disorder. Using anatomical magnetic resonance imaging and automated segmentation we show that the habenula is significantly enlarged in ASD subjects compared to controls across the entire age range studied (6-30 years). No differences were observed between sexes. Furthermore, support-vector machine modeling classified ASD with 85% accuracy (model using habenula volume, age and sex) and 64% accuracy in cross validation. The Social Responsiveness Scale (SRS) significantly differed between groups, however, it was not related to individual habenula volume. The present study is the first to provide evidence in human subjects of an involvement of the habenula in the pathophysiology of ASD.

Hippocampal shape across the healthy lifespan and its relationship with cognition.

The study of the hippocampus across the healthy adult lifespan has rendered inconsistent findings. While volumetric measurements have often been a popular technique for analysis, more advanced morphometric techniques have demonstrated compelling results that highlight the importance and improved specificity of shape-based measures. Here, the MAGeT Brain algorithm was applied on 134 healthy individuals aged 18-81 years old to extract hippocampal subfield volumes and hippocampal shape measurements, namely: local surface area (SA) and displacement. We used linear-, second- or third-order natural splines to examine the relationships between hippocampal measures and age. In addition, partial least squares analyses were performed to relate volume and shape measurements with cognitive and demographic information. Volumetric results indicated a relative preservation of the right cornus ammonis 1 with age and a global volume reduction linked with older age, female sex, lower levels of education and cognitive performance. Vertex-wise analysis demonstrated an SA preservation in the anterior hippocampus with a peak during the sixth decade, while the posterior hippocampal SA gradually decreased across lifespan. Overall, SA decrease was linked to older age, female sex and, to a lesser extent lower levels of education and cognitive performance. Outward displacement in the lateral hippocampus and inward displacement in the medial hippocampus were enlarged with older age, lower levels of cognition and education, indicating an accentuation of the hippocampal "C" shape with age. Taken together, our findings suggest that vertex-wise analyses have higher spatial specifity and that sex, education, and cognition are implicated in the differential impact of age on hippocampal subregions throughout its anteroposterior and medial-lateral axes. This article is part of the Virtual Special Issue titled COGNITIVE NEU- ROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

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.

Examining the Boundary Sharpness Coefficient as an Index of Cortical Microstructure in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

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.

Large-scale analyses of the relationship between sex, age and intelligence quotient heterogeneity and cortical morphometry in autism spectrum disorder.

Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.

MR-based age-related effects on the striatum, globus pallidus, and thalamus in healthy individuals across the adult lifespan.

While numerous studies have used magnetic resonance imaging (MRI) to elucidate normative age-related trajectories in subcortical structures across the human lifespan, there exists substantial heterogeneity among different studies. Here, we investigated the normative relationships between age and morphology (i.e., volume and shape), and microstructure (using the T1-weighted/T2-weighted [T1w/T2w] signal ratio as a putative index of myelin and microstructure) of the striatum, globus pallidus, and thalamus across the adult lifespan using a dataset carefully quality controlled, yielding a final sample of 178 for the morphological analyses, and 162 for the T1w/T2w analyses from an initial dataset of 253 healthy subjects, aged 18-83. In accordance with previous cross-sectional studies of adults, we observed age-related volume decrease that followed a quadratic relationship between age and bilateral striatal and thalamic volumes, and a linear relationship in the globus pallidus. Our shape indices consistently demonstrated age-related posterior and medial areal contraction bilaterally across all three structures. Beyond morphology, we observed a quadratic inverted U-shaped relationship between T1w/T2w signal ratio and age, with a peak value occurring in middle age (at around 50 years old). After permutation testing, the Akaike information criterion determined age relationships remained significant for the bilateral globus pallidus and thalamus, for both the volumetric and T1w/T2w analyses. Our findings serve to strengthen and expand upon previous volumetric analyses by providing a normative baseline of morphology and microstructure of these structures to which future studies investigating patients with various disorders can be compared.

Warping an atlas derived from serial histology to 5 high-resolution MRIs.

Previous work from our group demonstrated the use of multiple input atlases to a modified multi-atlas framework (MAGeT-Brain) to improve subject-based segmentation accuracy. Currently, segmentation of the striatum, globus pallidus and thalamus are generated from a single high-resolution and -contrast MRI atlas derived from annotated serial histological sections. Here, we warp this atlas to five high-resolution MRI templates to create five de novo atlases. The overall goal of this work is to use these newly warped atlases as input to MAGeT-Brain in an effort to consolidate and improve the workflow presented in previous manuscripts from our group, allowing for simultaneous multi-structure segmentation. The work presented details the methodology used for the creation of the atlases using a technique previously proposed, where atlas labels are modified to mimic the intensity and contrast profile of MRI to facilitate atlas-to-template nonlinear transformation estimation. Dice's Kappa metric was used to demonstrate high quality registration and segmentation accuracy of the atlases. The final atlases are available at https://github.com/CobraLab/atlases/tree/master/5-atlas-subcortical.