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\u27s disease, mild cognitive impairment, Parkinson\u27s 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

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

nnResting state fMRI scanner instabilities revealed by longitud inal 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\u27s (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

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Behavioural Distinction between Strategic Control and Spatial Realignment during Visuomotor Adaptation in a Viewing Window Task

<div><p>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 <em>Viewing Window,</em> to investigate visuomotor adaptation to large, apparent distortions. Here, we contrast behavioural measures of visuomotor adaptation during the <em>Viewing Window</em> 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 <em>Viewing Window</em> provides a powerful engaging tool for investigating the neural basis of visuomotor adaptation and impairment following injury and disease.</p> </div

Normalized mean behavioural measures by phase.

<p>Behavioural measures of the early, late, and post distortion values are presented relative to the baseline (measures during the pre distortion phase) of each group. A) Velocity of Viewing Window movement. B) Scan Time required to identify object *Both distortion groups demonstrated a significant reduction in scan time in the post distortion phase (p<0.05). C) Percentage of Time off Object. A significant interaction was found between phase and distortion type was found in the percentage of time spent off the object (p<0.001).</p

Experimental setup of the <i>Viewing Window</i> task.

<p>Subjects sat at a desktop workstation and viewed masked images on a 19″ monitor. In order to identify the images, subjects used a trackball to control the movement of the Viewing Window that would allow part of the image to be seen clearly. Subjects were instructed to, upon identification of the image, press the space bar on the keyboard and enter the name of the object in a text box that would appear on the computer screen. The photographed subject has given written informed consent, as outlined in the PLoS consent form, to publication of their photograph.</p

Sample scan paths from representative participants.

<p>A) gradual rotation group and B) sudden rotation group. The line represents the pathway of the viewing window from image onset until participant signal of image identification.</p

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 towards 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