Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation.

White matter hyperintensities (WMHs) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D convolutional neural network with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control, and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. Four hundred thirty-two subjects were recruited to train the CNNs from four multisite imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multisite study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on "clinical adversarial cases" simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at: https://hypermapp3r.readthedocs.io.

Resting state fMRI scanner instabilities revealed by longitudinal phantom scans in a multi-center study.

Quality assurance (QA) is crucial in longitudinal and/or multi-site studies, which involve the collection of data from a group of subjects over time and/or at different locations. It is important to regularly monitor the performance of the scanners over time and at different locations to detect and control for intrinsic differences (e.g., due to manufacturers) and changes in scanner performance (e.g., due to gradual component aging, software and/or hardware upgrades, etc.). As part of the Ontario Neurodegenerative Disease Research Initiative (ONDRI) and the Canadian Biomarker Integration Network in Depression (CAN-BIND), QA phantom scans were conducted approximately monthly for three to four years at 13 sites across Canada with 3T research MRI scanners. QA parameters were calculated for each scan using the functional Biomarker Imaging Research Network's (fBIRN) QA phantom and pipeline to capture between- and within-scanner variability. We also describe a QA protocol to measure the full-width-at-half-maximum (FWHM) of slice-wise point spread functions (PSF), used in conjunction with the fBIRN QA parameters. Variations in image resolution measured by the FWHM are a primary source of variance over time for many sites, as well as between sites and between manufacturers. We also identify an unexpected range of instabilities affecting individual slices in a number of scanners, which may amount to a substantial contribution of unexplained signal variance to their data. Finally, we identify a preliminary preprocessing approach to reduce this variance and/or alleviate the slice anomalies, and in a small human data set show that this change in preprocessing can have a significant impact on seed-based connectivity measurements for some individual subjects. We expect that other fMRI centres will find this approach to identifying and controlling scanner instabilities useful in similar studies.

Neural Correlates of Perceptual Grouping Under Conditions of Inattention and Divided Attention.

Grouping local elements of the visual environment together is crucial for meaningful perception. While our attentional system facilitates perception, it is limited in that we are unaware of some aspects of our environment that can still influence how we experience it. In this study, the neural mechanisms underlying the Ponzo illusion were examined under inattention and divided-attention conditions using functional magnetic resonance imaging to investigate the brain regions responsible for accessing visual stimuli. A line discrimination task was performed in which two horizontal lines were superimposed on a background of black and white dots that, on occasion, induced the Ponzo illusion if perceptually grouped together. Our findings revealed activation for perceptual grouping in the frontal, parietal, and occipital regions of the brain and activation in the bilateral frontal, temporal, and cingulate gyrus in response to divided attention compared with inattention trials. A direct comparison between grouping and attention showed involvement of the right supramarginal gyrus in grouping specifically under conditions of inattention, suggesting that even during implicit grouping complex visual processing occurs. Given that much of the visual world is not represented in conscious perception, these findings provide crucial information about how we make sense of visual scenes in the world.

Soluble Epoxide Hydrolase Derived Linoleic Acid Oxylipins, Small Vessel Disease Markers, and Neurodegeneration in Stroke.

Background Cerebral small vessel disease is associated with higher ratios of soluble-epoxide hydrolase derived linoleic acid diols (12,13-dihydroxyoctadecenoic acid [DiHOME] and 9,10-DiHOME) to their parent epoxides (12(13)-epoxyoctadecenoic acid [EpOME] and 9(10)-EpOME); however, the relationship has not yet been examined in stroke. Methods and Results Participants with mild to moderate small vessel stroke or large vessel stroke were selected based on clinical and imaging criteria. Metabolites were quantified by ultra-high-performance liquid chromatography-mass spectrometry. Volumes of stroke, lacunes, white matter hyperintensities, magnetic resonance imaging visible perivascular spaces, and free water diffusion were quantified from structural and diffusion magnetic resonance imaging (3 Tesla). Adjusted linear regression models were used for analysis. Compared with participants with large vessel stroke (n=30), participants with small vessel stroke (n=50) had a higher 12,13-DiHOME/12(13)-EpOME ratio (ß=0.251, P=0.023). The 12,13-DiHOME/12(13)-EpOME ratio was associated with more lacunes (ß=0.266, P=0.028) but not with large vessel stroke volumes. Ratios of 12,13-DiHOME/12(13)-EpOME and 9,10-DiHOME/9(10)-EpOME were associated with greater volumes of white matter hyperintensities (ß=0.364, P<0.001; ß=0.362, P<0.001) and white matter MRI-visible perivascular spaces (ß=0.302, P=0.011; ß=0.314, P=0.006). In small vessel stroke, the 12,13-DiHOME/12(13)-EpOME ratio was associated with higher white matter free water diffusion (ß=0.439, P=0.016), which was specific to the temporal lobe in exploratory regional analyses. The 9,10-DiHOME/9(10)-EpOME ratio was associated with temporal lobe atrophy (ß=-0.277, P=0.031). Conclusions Linoleic acid markers of cytochrome P450/soluble-epoxide hydrolase activity were associated with small versus large vessel stroke, with small vessel disease markers consistent with blood brain barrier and neurovascular-glial disruption, and temporal lobe atrophy. The findings may indicate a novel modifiable risk factor for small vessel disease and related neurodegeneration.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

Improved Segmentation of the Intracranial and Ventricular Volumes in Populations with Cerebrovascular Lesions and Atrophy Using 3D CNNs.

Successful segmentation of the total intracranial vault (ICV) and ventricles is of critical importance when studying neurodegeneration through neuroimaging. We present iCVMapper and VentMapper, robust algorithms that use a convolutional neural network (CNN) to segment the ICV and ventricles from both single and multi-contrast MRI data. Our models were trained on a large dataset from two multi-site studies (N = 528 subjects for ICV, N = 501 for ventricular segmentation) consisting of older adults with varying degrees of cerebrovascular lesions and atrophy, which pose significant challenges for most segmentation approaches. The models were tested on 238 participants, including subjects with vascular cognitive impairment and high white matter hyperintensity burden. Two of the three test sets came from studies not used in the training dataset. We assessed our algorithms relative to four state-of-the-art ICV extraction methods (MONSTR, BET, Deep Extraction, FreeSurfer, DeepMedic), as well as two ventricular segmentation tools (FreeSurfer, DeepMedic). Our multi-contrast models outperformed other methods across many of the evaluation metrics, with average Dice coefficients of 0.98 and 0.96 for ICV and ventricular segmentation respectively. Both models were also the most time efficient, segmenting the structures in orders of magnitude faster than some of the other available methods. Our networks showed an increased accuracy with the use of a conditional random field (CRF) as a post-processing step. We further validated both segmentation models, highlighting their robustness to images with lower resolution and signal-to-noise ratio, compared to tested techniques. The pipeline and models are available at: https://icvmapp3r.readthedocs.io and https://ventmapp3r.readthedocs.io to enable further investigation of the roles of ICV and ventricles in relation to normal aging and neurodegeneration in large multi-site studies.

Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI Methods and Outcome Measures.

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online.

Continuous Descending Modulation of the Spinal Cord Revealed by Functional MRI.

Spontaneous variations in spinal cord activity may arise from regulation of any of a number of functions including sensory, motor, and autonomic control. Here, we use functional MRI (fMRI) of healthy participants to identify properties of blood oxygenation-level dependent (BOLD) variations in the spinal cord in response to knowledge that either a noxious stimulus is impending, or that no stimulus is to be expected. Expectation of a noxious stimulus, or no stimulus, is shown to have a significant effect on wide-spread BOLD signal variations in the spinal cord over the entire time period of the fMRI acquisition. Coordination of BOLD responses between/within spinal cord and brainstem regions are also influenced by this knowledge. We provide evidence that such signal variations are the result of continuous descending modulation of spinal cord function. BOLD signal variations in response to noxious stimulation of the hand are also shown, as in previous studies. The observation of both continuous and reactive BOLD responses to emotional/cognitive factors and noxious peripheral stimulation may have important implications, not only for our understanding of endogenous pain modulation, but also in showing that spinal cord activity is under continuous regulatory control.

Posterior cortical atrophy: an investigation of scan paths generated during face matching tasks.

When viewing a face, healthy individuals focus more on the area containing the eyes and upper nose in order to retrieve important featural and configural information. In contrast, individuals with face blindness (prosopagnosia) tend to direct fixations toward individual facial features-particularly the mouth. Presented here is an examination of face perception deficits in individuals with Posterior Cortical Atrophy (PCA). PCA is a rare progressive neurodegenerative disorder that is characterized by atrophy in occipito-parietal and occipito-temporal cortices. PCA primarily affects higher visual processing, while memory, reasoning, and insight remain relatively intact. A common symptom of PCA is a decreased effective field of vision caused by the inability to "see the whole picture." Individuals with PCA and healthy control participants completed a same/different discrimination task in which images of faces were presented as cue-target pairs. Eye-tracking equipment and a novel computer-based perceptual task-the Viewing Window paradigm-were used to investigate scan patterns when faces were presented in open view or through a restricted-view, respectively. In contrast to previous prosopagnosia research, individuals with PCA each produced unique scan paths that focused on non-diagnostically useful locations. This focus on non-diagnostically useful locations was also present when using a restricted viewing aperture, suggesting that individuals with PCA have difficulty processing the face at either the featural or configural level. In fact, it appears that the decreased effective field of view in PCA patients is so severe that it results in an extreme dependence on local processing, such that a feature-based approach is not even possible.

Behavioural distinction between strategic control and spatial realignment during visuomotor adaptation in a viewing window task.

We must frequently adapt our movements in order to successfully perform motor tasks. These visuomotor adaptations can occur with or without our awareness and so, have generally been described by two mechanisms: strategic control and spatial realignment. Strategic control is a conscious modification used when discordance between an intended and actual movement is observed. Spatial realignment is an unconscious recalibration in response to subtle differences between an intended and efferent movement. Traditional methods of investigating visuomotor adaptation often involve simplistic, repetitive motor goals and so may be vulnerable to subject boredom or expectation. Our laboratory has recently developed a novel, engaging computer-based task, the Viewing Window, to investigate visuomotor adaptation to large, apparent distortions. Here, we contrast behavioural measures of visuomotor adaptation during the Viewing Window task when either gradual progressive rotations or large, sudden rotations are introduced in order to demonstrate that this paradigm can be utilized to investigate both strategic control and spatial realignment. The gradual rotation group demonstrated significantly faster mean velocities and spent significantly less time off the object compared to the sudden rotation group. These differences demonstrate adaptation to the distortion using spatial realignment. Scan paths revealed greater after-effects in the gradual rotation group reflected by greater time spent scanning areas off of the object. These results demonstrate the ability to investigate both strategic control and spatial realignment. Thus, the Viewing Window provides a powerful engaging tool for investigating the neural basis of visuomotor adaptation and impairment following injury and disease.