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Collins, D. L.

Publications and source records attributed to Collins, D. L..

At least 19 recordsLinked to original sources

VRPTR prediction of individual language activation and uncertainty from resting state fMRI

Resting-state connectivity can predict task-evoked fMRI activation, but correspondence with an individual task map may partly reflect a shared population pattern. We evaluated the Variational Resting-state-to-Task Prediction TransformeR (VRPTR), a three-dimensional encoder-decoder combining a compressed Transformer bottleneck, variational latent sampling, and multiscale skip connections. Models were trained in 360 healthy adults from the WU-Minn Human Connectome Project and evaluated in 40 held-out participants from the same dataset for the story-versus-math language contrast. VRPTR achieved mean voxel-map Pearson r=0.642 and Dice AUC=0.519, exceeding compact volumetric BrainSurfCNN-like and SWIFUN-like comparators by {Delta}r=0.0376 and 0.0335, respectively. A template fixed from the 360 training maps yielded residual correlation 0.364; VRPTR improved correlation but not mean absolute or root mean squared error over this template. A matched factorial ablation associated Transformer processing with improved map correlation ({Delta}r=0.0168); the variational main effect did not survive multiple-comparison correction. Component swaps indicated that subject-specific activation patterns depended more on multiscale skip features than on the bottleneck representation. Latent sampling produced a modest association between posterior standard deviation and voxelwise absolute error (mean Spearman {rho}=0.091). Raw 95% intervals covered only 4.7% of observed values. Five-fold calibration within the held-out cohort increased coverage to 94.8%, and spatially varying uncertainty modestly improved probabilistic scores over a constant-width model. Uncertainty also increased under input degradation. These findings support the contribution of Transformer processing to language-map prediction and distinguish it from subject-specific spatial conditioning and relative uncertainty estimation. Independent validation of calibrated uncertainty and evaluation in clinical cohorts remain necessary.

neuroscience↗

Hippocampal-to-Ventricle Ratio as a Head-Size-IndependentBiomarker: Sex Differences and Cognitive Associations in 27,680UK Biobank Participants

Hippocampal volume is a key biomarker for Alzheimers disease and brain aging, yet reported sex differences vary substantially depending on head-size adjustment methods. We examined whether the hippocampal-to-ventricle ratio (HVR), a self-normalizing measure, provides more consistent sex difference estimates than conventional adjustment approaches. Using a subset of UK Biobank structural MRI data (N = 27,680; 56% female; ages 45-82), we compared sex differences across four adjustment methods (unadjusted, proportions, stereotaxic, residualized) and in samples matched on age and on intracranial volume (ICV). Hippocampal sex differences reversed direction across methods, ranging from d = -0.89 (males larger, unadjusted) to d = 0.58 (females larger, proportions), with a range of 1.5 standard deviations across analytical choices. In contrast, HVR showed a consistent female advantage (d = 0.52) that persisted in the ICV-matched subsample (d = 0.19), confirming this effect is not a head-size artifact. Males exhibited steeper cross-sectional age-related HVR differences (1.7x female rate, p < 10-50), consistent with males showing ventricular expansion at younger ages. Structural equation modeling revealed that HVR predicted general cognition comparably to hippocampal volume ({beta} = 0.04, overlapping CIs), and unlike residualized hippocampal volume, HVR maintained significant brain-cognition associations in both sexes. We provide sex-specific normative centile curves for clinical application. These findings indicate that apparent hippocampal sex differences largely reflect methodological choices rather than biology, while HVR captures consistent morphological variation related to brain aging that may have clinical utility.

neuroscience↗

White Matter Hyperintensities Precede other Biomarkers in GRN Frontotemporal Dementia

INTRODUCTIONIncreased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. METHODSUsing a large dataset (n=763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stages. Cortical and subcortical volumes were parcellated, and serum neurofilament light chain (NfL) levels were measured. Biomarker progression was assessed with discriminative event-based and regression modeling. RESULTSSymptomatic GRN carriers showed elevated WMHs, primarily in the frontal lobe, while no significant increase was observed in C9orf72 or MAPT carriers. WMH abnormalities preceded NfL elevation, ventricular enlargement, and cortical atrophy. Longitudinally, baseline WMHs predicted subcortical changes, while subcortical volumes did not predict WMH changes, suggesting WMHs may precede neurodegeneration. DISCUSSIONWMHs are elevated in a subset of GRN-related FTD. When present, they appear early and should be considered in disease progression models. HighlightsO_LIElevated WMH volumes in symptomatic GRN carriers, but not in other mutations. C_LIO_LIWMH accumulation is mostly observed in the frontal lobe. C_LIO_LIWMH abnormalities appear early in GRN-FTD, before NfL, atrophy, and ventriculomegaly. C_LIO_LILongitudinally, WMH volumes can predict subcortical changes, but not vice versa. C_LIO_LIWMHs are key early markers in GRN-FTD and should be included in progression models. C_LI RESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSWe systematically reviewed the literature on white matter hyperintensities (WMHs) in frontotemporal dementia (FTD) using PubMed. While a few small studies reported increased WMHs in GRN mutation carriers, their sample sizes were limited, and they did not assess the timing of WMHs within disease progression or their temporal relationship to other biomarkers. InterpretationWe identified a sequence of key biomarkers in GRN-related FTD and demonstrated that WMHs are among the earliest biomarkers, preceding cortical and subcortical atrophy as well as blood biomarkers. This aligns with neuropathological evidence of early white matter involvement in FTLD-GRN. Additionally, using a larger dataset, we validated previous reports of elevated WMHs in GRN carriers, confirming their reliability. Future directionsFuture studies should integrate WMHs into FTD progression models to enhance early diagnosis. Understanding why only a subset of GRN carriers exhibit high WMH volumes remains a key research priority.

neuroscience↗

Early cell cycle genes in cortical organoid progenitors predict interindividual variability in infant brain growth trajectories

Human induced pluripotent stem cell (iPSC) derived cortical organoids (hCOs) model neurogenesis on an individuals genetic background. The degree to which hCO phenotypes recapitulate the brain growth of the participants from which they were derived is not well established. We generated up to 3 iPSC clones from each of 18 participants in the Infant Brain Imaging Study, who have undergone longitudinal brain imaging during infancy. We identified consistent hCO morphology and cortical cell types across clones from the same participant. hCO cross-sectional area and production of cortical hem cells were associated with in vivo cortical growth rates. Cell cycle associated genes expression in early progenitors at the crux of fate decision trajectories were correlated with cortical growth rate from 6-12 months of age, and were enriched in microcephaly and neurodevelopmental disorder genes. Our data suggest the hCOs capture inter-individual variation in cortical cell types influencing infant cortical surface area expansion.

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Network Spreading and Local Biological Vulnerability in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that predominantly targets the motor system. Spread of pathology is thought to be driven by both local vulnerability and network architecture. Namely, molecular and cellular features may confer vulnerability to specific neuronal populations, while synaptic contacts may also increase exposure to pathology in connected neuronal populations. However, these principles are typically studied in isolation and it remains unknown how local vulnerability and network spreading interact to shape cortical atrophy. Here we investigate how network structure and local biological features jointly shape the spatial patterning of atrophy in ALS. We analyze the Canadian ALS Neuroimaging Consortium (CALSNIC) dataset and estimate cortical atrophy using deformation-based morphometry (DBM). We find that structural connectivity closely aligns with the course of atrophy. Atrophy is also more likely to occur in regions that share similar transcriptomic, neurotransmitter receptor and metabolic profiles. We identify disease epicenters in motor cortex. Epicenter probability maps show transcriptomic enrichment for biological pathways involved in mitochondrial function as well as support cells, including endothelial cells and pericytes. Finally, individual differences in epicenter location correspond to individual differences in clinical and cognitive symptoms, and differentiate patient subtypes.

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Automatization and validation of the hippocampal-to-ventricle ratio in a clinical sample

BackgroundThe hippocampal-to-ventricle ratio (HVR) is a biomarker of medial temporal atrophy, particularly useful in the assessment of neurodegeneration in diseases such as Alzheimers disease (AD). To minimize subjectivity and inter-rater variability, an automated, accurate, precise, and reliable segmentation technique for the hippocampus (HC) and surrounding cerebro-spinal fluid (CSF) filled spaces -- such as the temporal horns of the lateral ventricles -- is essential. MethodsWe trained and evaluated three automated methods for the segmentation of both HC and CSF (Multi-Atlas Label Fusion (MALF), Nonlinear Patch-Based Segmentation (NLPB), and a Convolutional Neural Network (CNN)). We then evaluated these methods, including the widely used FreeSurfer technique, using baseline T1w MRIs of 1,641 participants from the AD Neuroimaging Initiative study with various degree of atrophy associated with their cognitive status on the spectrum from cognitively healthy to clinically probable AD. Our gold standard consisted in manual segmentation of HC and CSF from 80 cognitively healthy individuals. We calculated HC volumes and HVR and compared all methods in terms of segmentation reliability, similarity across methods, sensitivity in detecting between-group differences and associations with age, scores of the learning subtest of the Rey Auditory Verbal Learning Test (RAVLT) and the Alzheimers Disease Assessment Scale 13 (ADAS13) scores. ResultsCross validation demonstrated that the CNN method yielded more accurate HC and CSF segmentations when compared to MALF and NLPB, demonstrating higher volumetric overlap (Dice Kappa = 0.94) and correlation (rho = 0.99) with the manual labels. It was also the most reliable method in clinical data application, showing minimal failures. Our comparisons yielded high correlations between FreeSurfer, CNN and NLPB volumetric values. HVR yielded higher control:AD effect sizes than HC volumes among all segmentation methods, reinforcing the significance of HVR in clinical distinction. AssociationsThe positive association with age was significantly stronger for HVR compared to HC volumes on all methods except FreeSurfer. Memory associations with HC volumes or HVR were only significant for individuals with mild cognitive impairment. Finally, the HC volumes and HVR showed comparable negative associations with ADAS13, particularly in the mild cognitive impairment cohort. ConclusionThis study provides an evaluation of automated segmentation methods centered to estimate HVR, emphasizing the superior performance of a CNN-based algorithm. The findings underscore the pivotal role of accurate segmentation in HVR calculations for precise clinical applications, contributing valuable insights into medial temporal lobe atrophy in neurodegenerative disorders, especially AD. AuthorshipO_LISofia Fernandez-Lozano: Conceptualization, Methodology, Software, Investigation, Writing - Original Draft, Visualization. C_LIO_LIVladimir Fonov: Software, Data Curation. C_LIO_LIDorothee Schoemaker: Resources, Writing - Review & Editing. C_LIO_LIJens Pruessner: Resources, Writing - Review & Editing. C_LIO_LIOlivier Potvin: Resources, Writing - Review & Editing. C_LIO_LISimon Duchesne: Resources, Writing - Review & Editing. C_LIO_LID. Louis Collins: Conceptualization, Writing - Review & Editing, Supervision. C_LI

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The FinnBrain Multimodal Neonatal Template and Atlas Collection: T1, T2, and DTI brain templates, and accompanying cortical and subcortical atlases

The accurate processing of neonatal and infant brain MRI data is crucially important for developmental neuroscience, but presents challenges that child and adult data do not. Tissue segmentation and image coregistration accuracy can be improved by optimizing template images and / or related segmentation procedures. Here, we describe the construction of the FinnBrain Neonate (FBN-125) template; a multi-contrast template with T1- and T2-weighted as well as diffusion tensor imaging derived fractional anisotropy and mean diffusivity images. The template is symmetric and aligned to the Talairach-like MNI 152 template and has high spatial resolution (0.5 mm3). In addition, we provide atlas labels, constructed from manual segmentations, for cortical grey matter, white matter, cerebrospinal fluid, brainstem, and cerebellum as well as the bilateral hippocampi, amygdalae, caudate nuclei, putamina, globi pallidi, and thalami. We provide this multi-contrast template along with the labelled atlases for the use of the neuroscience community in the hope that it will prove useful in advancing developmental neuroscience, for example, by helping to achieve reliable means for spatial normalization and measures of neonate brain structure via automated computational methods. Additionally, we provide standard co-registration files that will enable investigators to reliably transform their statistical maps to the adult MNI space, which has the potential to improve the consistency and comparability of neonatal studies or the use of adult MNI space atlases in neonatal neuroimaging.

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Nucleus basalis of Meynert degeneration signals earliest stage of Alzheimer's disease progression

The Nucleus Basalis of Meynert (NbM) is the main source of cholinergic projection to the entorhinal cortex (EC) and hippocampus (HC), where acetylcholine plays a key role in their function. Both cholinergic cells of NbM and their receptive targets in the EC and HC show sensitivity to neurofibrillary degeneration during the early stages of Alzheimers disease. Precise delineation of the NbM region on T1w scans is challenging due to limited spatial resolution and contrast. Using deformation-based morphometry (DBM), we sought to quantify NbM degeneration along the Alzheimers disease trajectory and confirm recent studies suggesting that NbM degeneration happens before degeneration in the EC or HC. MRI scans of 1447 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI1, 2 and GO) were up-sampled to 0.5 mm voxel-size in each direction (0.125 mm3) before non-linear registration to an ADNI-based unbiased symmetric average MRI template. A subgroup of 677 amyloid-positive participants were chosen for volume time course analysis where the resulting deformation fields were used to compute a high-resolution Jacobian determinant map for each participant as a proxy for local volume change within NbM, EC, and HC masks. Scores of volume change were corrected for age and sex and z-scored using normative data from cognitively healthy amyloid-negative (CN-) participants (n = 219). Two-sample t-tests were then used to compare the baseline differences between NbM, EC, and HC for amyloid-positive cognitively normal controls (CN+), amyloid-positive early mild cognitive impairment (eMCI), and amyloid-positive late mild cognitive impairment (lMCI). Longitudinal linear mixed-effect models were used to compare trajectories of volume change after realigning all participants into a common timeline based on their cognitive decline. Results showed a significant cross-sectional difference at baseline between CN+ and eMCI, and eMCI and lMCI for both left and right Z-scored NbM volumes. There was no difference in z-scored EC and HC volumes between CN+ and eMCI groups but results from eMCI and lMCI differed significantly in these regions. Longitudinal analysis, with a focus on the early disease stages showed the earliest deviation from the CN- trajectory in the NbM and HC in the subject-specific time realigned data. Contrary to the notion that Alzheimers disease originates in EC, we found that NbM volume changes earlier in the disease trajectory than EC or HC. Converging evidence from cross-sectional and longitudinal models suggest that the NbM may be a focal target of early AD progression, which is often obscured by normal age-related decline.

bioinformatics↗

QRATER: a collaborative and centralized imaging quality control web-based application.

Quality control (QC) is an important part of all scientific analysis, including neuroscience. With manual curation considered the gold standard, there remains a lack of available tools that make manual neuroimaging QC accessible, fast, and easy. In this article we present Qrater, a containerized web-based python application that enables viewing and rating of previously generated QC images. A group of raters with varying amounts of experience in QC evaluated Qrater in three different tasks: QC of MRI raw acquisition (10,196 images), QC of non-linear registration to a standard template (10,196 images) and QC of skull segmentation (6,968 images). We measured the proportion of failed images, timing and intra- and inter-rater agreement. Raters spent vastly different amounts of time on each image depending on their experience and the task at hand. QC of MRI raw acquisition was the slowest. While an expert rater needed approximately one minute, trained raters spent 2-6 minutes evaluating an image. The fastest was the curation of a skull segmentation image, where expert raters spent on average 3 seconds per image before assigning a rating. Rating agreement also varied depending on the experience of the raters and the task at hand: trained raters inter-rater agreement with the experts gold standard ranged from fair to substantial in raw acquisition (Cohens chance corrected kappa agreement scores up to 0.72) and from fair to excellent in linear registration (kappa scores up to 0.82), while the experts inter-rater agreement of the skull segmentation task was excellent (kappa = 0.83). These results demonstrate that Qrater is a useful asset for QC tasks that rely on manual curation of images.

bioinformatics↗

White matter hyperintensities may be an early marker for age-related cognitive decline in the ADNI cohort

BackgroundResearch suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another, nor how they jointly contribute to cognitive decline in normal aging. This project examines the association between these pathologies and their relationship to cognitive decline in cognitively normal older adults without subjective cognitive decline. MethodsA total of 230 subjects with CSF A{beta}42, CSF pTau181, white matter hyperintensities (WMHs) used as a proxy of CSVD and cognitive scores from the Alzheimers Disease Neuroimaging Initiative were included. Associations between each pathology and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models. ResultsAt baseline, there was an inverse association between WMH load and A{beta}42 (t=-4.20, p<.001). There was no association between WMH load and pTau (t=0.32, p=0.75), nor with A{beta}42 and pTau (t=0.51, p=.61). Correcting for age, sex and education, baseline WMH load was associated with baseline ADAS-13 scores (t=2.59, p=.01) and lower follow-up executive functioning (t= -2.84, p=.005). Baseline A{beta}42 was associated with executive function at baseline (t=3.58, p<.004) but not at follow-up (t=1.05, p=0.30), nor with ADAS-13 at baseline (t=-0.24, p0.81) or follow-up (t=0.09, p=0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up. ConclusionBoth baseline A{beta}42 and WMH load are associated with some baseline cognition scores, but only baseline WMH load is associated with follow-up executive functioning, indicating that it may be one of the earliest pathologies that contributes to future cognitive decline, in cognitively healthy older adults. Given that healthy older adults with WMH pathology exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMHs.

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Global network structure and local transcriptomic vulnerability shape atrophy in sporadic and genetic behavioral variant frontotemporal dementia

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioral variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). We first identify distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbors, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicenter of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and anteromedial temporal areas. Finally, we find that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, effectively modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability.

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DARQ: Deep learning of quality control for stereotaxic registration of human brain MRI

Linear registration to stereotaxic space is a common first step in many automated image-processing tools for analysis of human brain MRI scans. This step is crucial for the success of the subsequent image-processing steps. Several well-established algorithms are commonly used in the field of neuroimaging for this task, but none have a 100% success rate. Manual assessment of the registration is commonly used as part of quality control. To reduce the burden of this time-consuming step, we propose Deep Automated Registration Qc (DARQ), a fully automatic quality control method based on deep learning that can replace the human rater and accurately perform quality control assessment for stereotaxic registration of T1w brain scans. In a recently published study from our group comparing linear registration methods, we used a database of 9325 MRI scans and 64476 registrations from several publicly available datasets and applied seven linear registration tools to them. In this study, the resulting images that were assessed and labeled by a human rater are used to train a deep neural network to detect cases when registration failed. We further validated the results on an independent dataset of patients with multiple sclerosis, with manual QC labels available (n=1200). In terms of agreement with a manual rater, our automated QC method was able to achieve 89%accuracy and 85% true negative rate (equivalently 15% false positive rate) in detecting scans that should pass quality control in a balanced cross-validation experiments, and 96.1% accuracy and 95.5% true negative rate (or 4.5% FPR) when evaluated in a balanced independent sample, similar to manual QC rater (test-retest accuracy of 93%). The results show that DARQ is robust, fast, accurate, and generalizable in detecting failure in linear stereotaxic registrations and can substantially reduce QC time (by a factor of 20 or more) when processing large datasets.

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Diffusely abnormal white matter converts to T2 lesion volume in the absence of acute inflammation

Diffusely abnormal white matter (DAWM), characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive MS (SPMS). However, little is known about changes of DAWM over time and their relation to focal white matter lesions (FWML). The objectives of this work were: 1) To characterize the longitudinal evolution of FWML, DAWM, and DAWM that transforms into FWML, and 2) To determine whether gadolinium enhancement, known to be associated with the development of new FWML, is also related to DAWM voxels that transform into FWML. Our data included 4220 MRI scans of 689 SPMS participants, followed for 156 weeks and 2677 scans of 686 RRMS participants, followed for 96 weeks. FWML and DAWM were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, DAWM voxels at each visit that transformed into FWML on the last MRI scan as well as their overlap with gadolinium enhancing lesion masks were identified. Our results showed that the average yearly rate of conversion of DAWM-to-FWML was 1.27cc for SPMS and 0.80cc for RRMS. FWML in SPMS participants significantly increased (t=3.9; p=0.0001) while DAWM significantly decreased (t=-4.3 p<0.0001) and the ratio FWML:DAWM increased (t=12.7; p<0.00001). RRMS participants also showed an increase in the FWML:DAWM Ratio (t=6.9; p<0.00001) but without a significant change of the individual volumes. Gadolinium enhancement was associated with 7.3% and 18.7% of focal New T2 lesion formation in the infrequent scans of the RRMS and SPMS cohorts, respectively. In comparison, only 0.1% and 0.0% of DAWM-to-FWML voxels overlapped with gadolinium enhancement. We conclude that DAWM transforms into FWML over time, in both RRMS and SPMS. DAWM appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.

neuroscience↗

BigBrainWarp: Toolbox for integration of BigBrain 3D histology with mutlimodal neuroimaging

AO_SCPLOWBSTRACTC_SCPLOWNeuroimaging stands to benefit from emerging ultrahigh-resolution histological atlases of the human brain; the first of which is "BigBrain". Ongoing research aims to characterise regional differentiation of cytoarchitecture with BigBrain and to optimise registration of BigBrain with standard neuroimaging templates. Together, this work paves the way for multi-scale investigations of brain organisation. However, working with BigBrain can present new challenges for neuroimagers, including dealing with cellular resolution neuroanatomy and complex transformation procedures. To simplify workflows and support adoption of best practices, we developed BigBrainWarp, a toolbox for integration of BigBrain with multimodal neuroimaging. The primary BigBrainWarp function wraps multiple state-of-the-art deformation matrices into one line of code, allowing users to easily map data between BigBrain and standard MRI spaces. Additionally, the toolbox contains ready-to-use cytoarchitectural features to improve accessibility of histological information. The present article discusses recent contributions to BigBrain-MRI integration and demonstrates the utility of BigBrainWarp for further investigations.

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White Matter Hyperintensities, Grey Matter Atrophy, and Cognitive Decline in Neurodegenerative Diseases

IntroductionWhite matter hyperintensities (WMHs) as seen on T2w and FLAIR scans represent small-vessel disease related changes in the brain. WMHs are associated with cognitive decline in the normal aging population in general and more specifically in patients with neurodegenerative diseases. In this study, we assessed the different spatial patterns and relationships between WMHs and grey matter (GM) atrophy in normal aging, individuals with mild cognitive impairment (MCI), Alzheimers dementia (AD), fronto-temporal dementia (FTD), and de novo Parkinsons disease (PD). MethodsImaging and clinical data were obtained from 3 large multi-center databases: The Alzheimers Disease Neuroimaging Initiative (ADNI), the frontotemporal lobar degeneration neuroimaging initiative (NIFD), and the Parkinsons Progression Markers Initiative (PPMI). WMHs and GM atrophy maps were measured in normal controls (N= 571), MCI (N= 577), AD (N= 222), FTD (N= 144), and PD (N= 363). WMHs were segmented using T1w and T2w/PD or FLAIR images and mapped onto 45 white matter tracts using the Yeh WM atlas. GM volume was estimated from the Jacobian determinant of the nonlinear deformation field required to map the subjects MRI to a standard template. The CerebrA atlas was used to obtain volume estimates in 84 GM regions. Mixed effects models were used to compare WMH in different WM tracts and volume of multiple GM structures between patients and controls, assess the relationship between regional WMHs and GM loss for each disease, and investigate their impact on cognition. ResultsMCI, AD, and FTD patients had significantly higher WMH loads than the matched controls. There was no significant difference in WMHs between PD and controls. For each cohort, significant interactions between WMH load and GM atrophy were found for several regions and tracts, reflecting additional contribution of WMH burden to GM atrophy. While these associations were more relevant for insular and parieto-occipital regions in MCI and AD cohorts, WMH burden in FTD subjects had greater impact on frontal and basal ganglia atrophy. Finally, we found additional contribution of WMH burden to cognitive deficits in AD and FTD subjects compared with matched controls, whereas their impact on cognitive performance in MCI and PD were not significantly different from controls. ConclusionsWMHs occur more extensively in MCI, AD, and FTD patients than age-matched normal controls. WMH burden on WM tracts also correlates with regional GM atrophy in regions anatomically and functionally related to those tracts, suggesting a potential involvement of WMHs in the neurodegenerative process.

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MNI-FTD Templates: Unbiased Average Templates of Frontotemporal Dementia Variants

Standard anatomical templates are widely used in human neuroimaging processing pipelines to facilitate group level analyses and comparisons across different subjects and populations. The MNI-ICBM152 template is the most commonly used standard template, representing an average of 152 healthy young adult brains. However, in patients with neurodegenerative diseases such as frontotemporal dementia (FTD), the high levels of atrophy lead to significant differences between the brain shape of the individuals and the MNI-ICBM152 template. Such differences might inevitably lead to registration errors or subtle biases in downstream analyses and results. Disease-specific templates are therefore desirable to reflect the anatomical characteristics of the populations of interest and to reduce potential registration errors when processing data from such populations. Here, we present MNI-FTD136, MNI-bvFTD70, MNI-svFTD36, and MNI-pnfaFTD30, four unbiased average templates of 136 FTD patients, 70 behavioural variant (bv), 36 semantic variant (sv), and 30 progressive nonfluent aphasia (pnfa) variant FTD patients as well as a corresponding age matched average template of 133 healthy controls (MNI-CN133), along with probabilistic tissue maps for each template. The public availability of these templates will facilitate analyses of FTD cohorts and enable comparisons between different studies in a common standardized space appropriate to FTD populations.

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Multimodal imaging evidence for the brain basis of cognitive dysfunction in older HIV+ men

ObjectiveThis study used converging methods to define the structural and functional characteristics of the neural substrates underlying variation in cognitive ability in older men with well-controlled HIV infection. MethodsSeventy-six HIV+ men treated with combination antiretrovirals completed attention and inhibitory control tasks tapping different cortico-subcortical circuits while time-locked high-density EEG was acquired. Fifty-four also underwent structural MRI. We investigated relationships between task-evoked EEG responses, cognitive ability and immunocompromise. MRI suggested a subcortical basis for the observed EEG effects. ResultsEEG activity was associated with cognitive ability at later (P300) but not earlier processing stages of both tasks. However, only the P300 evoked by the attention task was associated with past HIV infection severity. Source localization confirmed that the tasks engaged different brain circuits. Thalamus volumes correlated with P300 amplitudes evoked by the attention task, while globus pallidus volumes were related to the P300 in both tasks. InterpretationThis is the first study to combine structural and functional imaging in an overlapping sample to address the neural circuits related to cognitive dysfunction in HIV. Neural substrates of attention were more affected than those supporting inhibitory control. Preliminary evidence suggests these differences may relate to vulnerability of the thalamus to the effects of HIV. Our results suggest high-yield tasks and circuit targets for future work.

neuroscience↗

Bundle-specific associations between white matter microstructure and Aβ and tau pathology at their connecting cortical endpoints in older adults at risk of Alzheimer's disease

Beta-amyloid (A{beta}) and tau proteins, the pathological hallmarks of Alzheimers disease (AD), are believed to spread through connected regions. Combining diffusion imaging and positron emission tomography, we investigated associations between A{beta}, tau and white matter microstructure specifically in bundles connecting brain regions in which AD pathology accumulates. In 126 cognitively normal elderly at risk of AD, we focussed on free-water corrected diffusion measures in the cingulum, posterior cingulum, fornix and uncinate fasciculus. We found higher tissue fractional anisotropy and lower mean and radial diffusivity related to increased A{beta} at the cortical endpoints of the cingulum and fornix. We observed similar but stronger associations in the uncinate fasciculus, but with increased A{beta} and tau at the endpoints of this bundle. This consistent pattern of associations, with opposite directionality to the usual degeneration pattern in symptomatic individuals, suggests more restricted diffusion in bundles vulnerable to preclinical AD pathology.

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