Publications by authors named "Frédéric Lesage"

143 Publications

A functional cerebral endothelium is necessary to protect against cognitive decline.

J Cereb Blood Flow Metab 2021 Sep 13:271678X211045438. Epub 2021 Sep 13.

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Canada.

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included Nemo controls and three Nemo groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in Nemo mice and were not countered by treatments. Cerebrovascular function was compromised in Nemo groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. Nemo mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.
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http://dx.doi.org/10.1177/0271678X211045438DOI Listing
September 2021

Intracranial EEG seizure onset and termination patterns and their association.

Epilepsy Res 2021 Oct 14;176:106739. Epub 2021 Aug 14.

Centre de Recherche du Centre Hospitalier de l'Université de Montreal (CHUM), Montreal, QC, Canada; Neurology Division, Centre Hospitalier de l'Université de Montréal (CHUM), 1000 Saint-Denis, Montreal, H2X 0C1, Canada.

Objective: The study of seizure onset and termination patterns has the potential to enhance our understanding of the underlying mechanisms of seizure generation and cessation. It is largely unclear whether seizures with distinct onset patterns originate from varying network interactions and terminate through different termination pathways.

Methods: We investigated the morphology and location of 103 intracranial EEG seizure onset and termination patterns from 20 patients with drug-resistant focal epilepsy. We determined if seizure onset patterns were associated with specific termination patterns. Finally, we looked at network interactions prior to the generation of distinct seizure onset patterns by calculating directed functional connectivity matrices.

Results: We identified nine seizure onset and six seizure termination patterns. The most common onset pattern was Low-Voltage Fast Activity (36 %), and the most frequent termination pattern was Burst Suppression (44 %). All seizures with fast (>13 Hz) termination patterns had a fast (>13 Hz) onset pattern type. Almost any onset pattern could terminate with the Burst Suppression and rhythmic Spike/PolySpike and Wave (rSW/rPSW) termination patterns. Seizures with a fast activity onset had higher inflow to the seizure onset zone from other regions in the gamma and high gamma frequency ranges prior to their generation compared to seizures with a slow onset.

Significance: Our observations suggest that different mechanisms underlie the generation of different seizure onset patterns although seizure onset patterns can share a common termination pattern. Possible mechanisms underlying these patterns are discussed.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106739DOI Listing
October 2021

Multimodal Autoencoder Predicts fNIRS Resting State From EEG Signals.

Neuroinformatics 2021 Aug 10. Epub 2021 Aug 10.

École Polytechnique de Montréal, Université de Montréal, C.P. 6079, Succ. Centre-Ville, Montréal, H3C 3A7, Canada.

In this work, we introduce a deep learning architecture for evaluation on multimodal electroencephalographic (EEG) and functional near-infrared spectroscopy (fNIRS) recordings from 40 epileptic patients. Long short-term memory units and convolutional neural networks are integrated within a multimodal sequence-to-sequence autoencoder. The trained neural network predicts fNIRS signals from EEG, sans a priori, by hierarchically extracting deep features from EEG full spectra and specific EEG frequency bands. Results show that higher frequency EEG ranges are predictive of fNIRS signals with the gamma band inputs dominating fNIRS prediction as compared to other frequency envelopes. Seed based functional connectivity validates similar patterns between experimental fNIRS and our model's fNIRS reconstructions. This is the first study that shows it is possible to predict brain hemodynamics (fNIRS) from encoded neural data (EEG) in the resting human epileptic brain based on power spectrum amplitude modulation of frequency oscillations in the context of specific hypotheses about how EEG frequency bands decode fNIRS signals.
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http://dx.doi.org/10.1007/s12021-021-09538-3DOI Listing
August 2021

Cortical thinning is associated with brain pulsatility in older adults: An MRI and NIRS study.

Neurobiol Aging 2021 10 24;106:103-118. Epub 2021 May 24.

Research Center, University Institute of Geriatrics of Montreal, Montreal, Quebec, Canada; Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.

Aging is accompanied by global brain atrophy occurring unequally across the brain. Cortical thinning is seen with aging with a larger loss in the frontal and temporal subregions. We explored the link between regional cortical thickness and regional cerebral pulsatility. Sixty healthy individuals were divided into two age groups, young (aged 19-31) and older (aged 65-75) adults. Each participant underwent a near-infrared spectroscopy (NIRS) scan to index regional brain pulsatility from cerebral pulse-transit-time-to-the peak-of-the-pulse (PTTp), an anatomical magnetic resonance imaging (MRI) and a phase-contrast MRI (PC-MRI) scan to measure arterial and cerebrospinal fluid (CSF) pulsatility. In older adults, the greatest association between cerebral pulsatility and cortical thickness was found in superior and middle temporal and superior, middle and inferior frontal areas, which are the regions perfused first by the internal carotid arteries. This association dropped in the postcentral and superior parietal regions. These findings suggest higher brain pulsatility as a potential risk factor contributing to cortical thinning for some brain regions more than others.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.05.002DOI Listing
October 2021

A simulation study investigating potential diffusion-based MRI signatures of microstrokes.

Sci Rep 2021 Jul 9;11(1):14229. Epub 2021 Jul 9.

Laboratory of Optical and Molecular Imaging, École Polytechnique de Montréal, 2900 Edouard Montpetit Blvd, Montreal, QC, H3T 1J4, Canada.

Recent studies suggested that cerebrovascular micro-occlusions, i.e. microstokes, could lead to ischemic tissue infarctions and cognitive deficits. Due to their small size, identifying measurable biomarkers of these microvascular lesions remains a major challenge. This work aims to simulate potential MRI signatures combining arterial spin labeling (ASL) and multi-directional diffusion-weighted imaging (DWI). Driving our hypothesis are recent observations demonstrating a radial reorientation of microvasculature around the micro-infarction locus during recovery in mice. Synthetic capillary beds, randomly- and radially-oriented, and optical coherence tomography (OCT) angiograms, acquired in the barrel cortex of mice (n = 5) before and after inducing targeted photothrombosis, were analyzed. Computational vascular graphs combined with a 3D Monte-Carlo simulator were used to characterize the magnetic resonance (MR) response, encompassing the effects of magnetic field perturbations caused by deoxyhemoglobin, and the advection and diffusion of the nuclear spins. We quantified the minimal intravoxel signal loss ratio when applying multiple gradient directions, at varying sequence parameters with and without ASL. With ASL, our results demonstrate a significant difference (p < 0.05) between the signal-ratios computed at baseline and 3 weeks after photothrombosis. The statistical power further increased (p < 0.005) using angiograms measured at week 4. Without ASL, no reliable signal change was found. We found that higher ratios, and accordingly improved significance, were achieved at lower magnetic field strengths (e.g., B0 = 3T) and shorter echo time TE (< 16 ms). Our simulations suggest that microstrokes might be characterized through ASL-DWI sequence, providing necessary insights for posterior experimental validations, and ultimately, future translational trials.
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http://dx.doi.org/10.1038/s41598-021-93503-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271016PMC
July 2021

Longitudinal Impact of Physical Activity on Brain Pulsatility Index and Cognition in Older Adults with Cardiovascular Risk Factors: A NIRS Study.

Brain Sci 2021 May 31;11(6). Epub 2021 May 31.

Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.

Recent studies have shown that optical indices of cerebral pulsatility, including cerebral pulse amplitude, are linked to cerebrovascular health. A chronically higher cerebral pulsatility is associated with cognitive decline. Although it is widely known that regular physical activity improves cognitive functions, little is known about the association between physical activity and the optical index of cerebral pulsatility. This study assessed the impact of 12 months of regular physical activity on the changes in the optical index of cerebral pulsatility and explored its association with cognition. A total of 19 older adults (aged 59-79 years) with cardiovascular risk factors (CVRF) completed the study. Low-intensity, short-duration walking as a brief cardiovascular challenge was used to study the impact of regular physical activity on post-walking changes in cerebral pulsatility index. The participants walked on a gym track while a near-infrared spectroscopy (NIRS) device recorded hemodynamics data from the frontal and motor cortex subregions. Our data indicated that 12 months of physical activity was associated with lower global cerebral pulse amplitude, which was associated with higher cognitive scores in executive functions. Further, the global cerebral pulsatility index was reduced after short-duration walking, and this reduction was greater after 12 months of regular physical activity compared with the baseline. This may be an indication of improvement in cerebrovascular response to the cardiovascular challenge after regular physical activity. This study suggests that 12 months of physical activity may support cognitive functions through improving cerebral pulsatility in older adults with CVRF.
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http://dx.doi.org/10.3390/brainsci11060730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230110PMC
May 2021

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.

Lancet Respir Med 2021 08 27;9(8):924-932. Epub 2021 May 27.

Montréal Health Innovations Coordinating Center, Montreal, QC, Canada.

Background: Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.

Methods: The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.

Findings: Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).

Interpretation: In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.

Funding: The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.
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http://dx.doi.org/10.1016/S2213-2600(21)00222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159193PMC
August 2021

Coronary artery disease and its impact on the pulsatile brain: A functional NIRS study.

Hum Brain Mapp 2021 Aug 15;42(12):3760-3776. Epub 2021 May 15.

Research Center, University Institute of Geriatrics of Montreal, Montreal, Quebec, Canada.

Recent studies have reported that optical indices of cerebral pulsatility are associated with cerebrovascular health in older adults. Such indices, including cerebral pulse amplitude and the pulse relaxation function (PRF), have been previously applied to quantify global and regional cerebral pulsatility. The aim of the present study was to determine whether these indices are modulated by cardiovascular status and whether they differ between individuals with low or high cardiovascular risk factors (LCVRF and HCVRF) and coronary artery disease (CAD). A total of 60 older adults aged 57-79 were enrolled in the study. Participants were grouped as LCVRF, HCVRF, and CAD. Participants were asked to walk freely on a gym track while a near-infrared spectroscopy (NIRS) device recorded hemodynamics data. Low-intensity, short-duration walking was used to test whether a brief cardiovascular challenge could increase the difference of pulsatility indices with respect to cardiovascular status. Results indicated that CAD individuals have higher global cerebral pulse amplitude compared with the other groups. Walking reduced global cerebral pulse amplitude and PRF in all groups but did not increase the difference across the groups. Instead, walking extended the spatial distribution of cerebral pulse amplitude to the anterior prefrontal cortex when CAD was compared to the CVRF groups. Further research is needed to determine whether cerebral pulse amplitude extracted from data acquired with NIRS, which is a noninvasive, inexpensive method, can provide an index to characterize the cerebrovascular status associated with CAD.
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http://dx.doi.org/10.1002/hbm.25463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288102PMC
August 2021

Sparse channel sampling for ultrasound localization microscopy (SPARSE-ULM).

Phys Med Biol 2021 04 23;66(9). Epub 2021 Apr 23.

Engineering Physics Department, Polytechnique Montréal, Montréal, Canada.

Ultrasound localization microscopy (ULM) has recently enabled the mapping of the cerebral vasculaturewith a resolution ten times smaller than the wavelength used, down to ten microns. However, with frame rates up to 20000 frames per second, this method requires large amount of data to be acquired, transmitted, stored, and processed. The transfer rate is, as of today, one of the main limiting factors of this technology. Herein, we introduce a novel reconstruction framework to decrease this quantity of data to be acquired and the complexity of the required hardware by randomly subsampling the channels of a linear probe. Method performance evaluation as well as parameters optimization were conductedusing the SIMUS simulation software in an anatomically realistic phantom and then compared toacquisitions in a rat brain after craniotomy. Results show that reducing the number of active elements deteriorates the signal-to-noise ratio and could lead to false microbubbles detections but has limited effect on localization accuracy. In simulation, the false positive rate on microbubble detection deteriorates from 3.7% for 128 channels in receive and 7 steered angles to 11% for 16 channels and 7 angles. The average localization accuracy ranges from 10.6m and 9.93m for 16 channels/3 angles and 128 channels/13 angles respectively. These results suggest that a compromise can be found between the number of channels and the quality of the reconstructed vascular network and demonstrate feasibility of performing ULM with a reduced number of channels in receive, paving the way for low-cost devices enabling high-resolution vascular mapping.
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http://dx.doi.org/10.1088/1361-6560/abf1b6DOI Listing
April 2021

A Longitudinal Pilot Study on Cognition and Cerebral Hemodynamics in a Mouse Model of Preeclampsia Superimposed on Hypertension: Looking at Mothers and Their Offspring.

Front Physiol 2021 1;12:611984. Epub 2021 Feb 1.

Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

Preeclampsia is a common hypertensive disorder in pregnant women and whose causes and consequences have focused primarily on cardiovascular outcomes on the mother and offspring, often without taking into consideration the possible effects on the brain. One possible cause of preeclampsia has been attributed to alterations in the renin-angiotensin system, which has also been linked to cognitive decline. In this pilot study, we use a transgenic mouse model that chronically overexpresses human angiotensinogen and renin (RA mice) that displayed characteristics of preeclampsia such as proteinuria during gestation. Offspring of these mothers as well as from control mothers were also examined. We were primarily interested in detecting whether cognitive deficits were present in the mothers and offspring in the long term and used a spatial learning and memory task as well as an object recognition task at three timepoints: 3, 8, and 12 months post-partum or post-natal, while measuring blood pressure and performing urine analysis after each timepoint. While we did not find significant deficits in preeclamptic mothers at the later timepoints, we did observe negative consequences in the pups of RA mice that coincided with hemodynamic alterations whereby pups had higher whisker-evoked oxygenated hemoglobin levels and increased cerebral blood flow responses compared to control pups. Our study provides validation of this preeclampsia mouse model for future studies to decipher the underlying mechanisms of long-term cognitive deficits found in offspring.
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http://dx.doi.org/10.3389/fphys.2021.611984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878560PMC
February 2021

Errata: Best practices for fNIRS publications.

Neurophotonics 2021 Jan 8;8(1):019802. Epub 2021 Feb 8.

University Hospital Zurich, University of Zurich, Department of Neonatology, Biomedical Optics Research Laboratory, Neonatology Research, Zurich, Switzerland.

[This corrects the article DOI: 10.1117/1.NPh.8.1.012101.].
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http://dx.doi.org/10.1117/1.NPh.8.1.019802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868645PMC
January 2021

The Benefits of Physical Activity in Individuals with Cardiovascular Risk Factors: A Longitudinal Investigation Using fNIRS and Dual-Task Walking.

J Clin Med 2021 Feb 4;10(4). Epub 2021 Feb 4.

Montreal Heart Institute, Research Centre and Centre EPIC, Montreal, QC H1T 1N6, Canada.

Cardiovascular fitness is linked to better executive functions, preserved gait speed, and efficient cortical activity. Older adults with cardiovascular risk factors (CVRFs) typically show poor cognitive performance, low physical fitness, and altered brain functioning compared with healthy individuals. In the current study, the impact of regular physical activity on cognition, locomotion, and brain functions was explored in a cohort of older adults with low or high CVRFs. Cortical activation of the frontal areas was investigated using functional Near-Infrared Spectroscopy (fNIRS) at baseline, at 6 months and at 12 months. Evoked cortical response and behavioral performance were assessed using the dual-task walking paradigm, consisting of three conditions: single cognitive task (2-back task), single walking task (walking), and dual-task (2-back whilst walking). Results show greater task-related cortical response at baseline in individuals with high CVRFs compared to those with low CVRFs. Moreover, participants with high CVRFs benefitted the most from participating in regular physical activity, as their cortical response decreased at the 12-month follow-up and became comparable to that of participants with low CVRFs. These changes were observed in conjunction with improved cognitive performance and stable gait speed throughout the 12-month period in both groups. Our findings provide evidence that participation in regular physical activity may be especially beneficial in individuals with CVRFs by promoting brain and cognitive health, thus potentially contributing to prevention of cognitive decline. Future research may explore whether such effects are maintained in the long-term in order to design ad-hoc interventions in this specific population.
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http://dx.doi.org/10.3390/jcm10040579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913805PMC
February 2021

A Deep Learning Framework for Spatiotemporal Ultrasound Localization Microscopy.

IEEE Trans Med Imaging 2021 05 30;40(5):1428-1437. Epub 2021 Apr 30.

Ultrasound Localization Microscopy (ULM) can resolve the microvascular bed down to a few micrometers. To achieve such performance, microbubble contrast agents must perfuse the entire microvascular network. Microbubbles are then located individually and tracked over time to sample individual vessels, typically over hundreds of thousands of images. To overcome the fundamental limit of diffraction and achieve a dense reconstruction of the network, low microbubble concentrations must be used, which leads to acquisitions lasting several minutes. Conventional processing pipelines are currently unable to deal with interference from multiple nearby microbubbles, further reducing achievable concentrations. This work overcomes this problem by proposing a Deep Learning approach to recover dense vascular networks from ultrasound acquisitions with high microbubble concentrations. A realistic mouse brain microvascular network, segmented from 2-photon microscopy, was used to train a three-dimensional convolutional neural network (CNN) based on a V-net architecture. Ultrasound data sets from multiple microbubbles flowing through the microvascular network were simulated and used as ground truth to train the 3D CNN to track microbubbles. The 3D-CNN approach was validated in silico using a subset of the data and in vivo in a rat brain. In silico, the CNN reconstructed vascular networks with higher precision (81%) than a conventional ULM framework (70%). In vivo, the CNN could resolve micro vessels as small as 10 μ m with an improvement in resolution when compared against a conventional approach.
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http://dx.doi.org/10.1109/TMI.2021.3056951DOI Listing
May 2021

Voxelized simulation of cerebral oxygen perfusion elucidates hypoxia in aged mouse cortex.

PLoS Comput Biol 2021 01 28;17(1):e1008584. Epub 2021 Jan 28.

Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, United States of America.

Departures of normal blood flow and metabolite distribution from the cerebral microvasculature into neuronal tissue have been implicated with age-related neurodegeneration. Mathematical models informed by spatially and temporally distributed neuroimage data are becoming instrumental for reconstructing a coherent picture of normal and pathological oxygen delivery throughout the brain. Unfortunately, current mathematical models of cerebral blood flow and oxygen exchange become excessively large in size. They further suffer from boundary effects due to incomplete or physiologically inaccurate computational domains, numerical instabilities due to enormous length scale differences, and convergence problems associated with condition number deterioration at fine mesh resolutions. Our proposed simple finite volume discretization scheme for blood and oxygen microperfusion simulations does not require expensive mesh generation leading to the critical benefit that it drastically reduces matrix size and bandwidth of the coupled oxygen transfer problem. The compact problem formulation yields rapid and stable convergence. Moreover, boundary effects can effectively be suppressed by generating very large replica of the cortical microcirculation in silico using an image-based cerebrovascular network synthesis algorithm, so that boundaries of the perfusion simulations are far removed from the regions of interest. Massive simulations over sizeable portions of the cortex with feature resolution down to the micron scale become tractable with even modest computer resources. The feasibility and accuracy of the novel method is demonstrated and validated with in vivo oxygen perfusion data in cohorts of young and aged mice. Our oxygen exchange simulations quantify steep gradients near penetrating blood vessels and point towards pathological changes that might cause neurodegeneration in aged brains. This research aims to explain mechanistic interactions between anatomical structures and how they might change in diseases or with age. Rigorous quantification of age-related changes is of significant interest because it might aide in the search for imaging biomarkers for dementia and Alzheimer's disease.
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http://dx.doi.org/10.1371/journal.pcbi.1008584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842915PMC
January 2021

Best practices for fNIRS publications.

Neurophotonics 2021 Jan 7;8(1):012101. Epub 2021 Jan 7.

University Hospital Zurich, University of Zurich, Department of Neonatology, Biomedical Optics Research Laboratory, Neonatology Research, Zurich, Switzerland.

The application of functional near-infrared spectroscopy (fNIRS) in the neurosciences has been expanding over the last 40 years. Today, it is addressing a wide range of applications within different populations and utilizes a great variety of experimental paradigms. With the rapid growth and the diversification of research methods, some inconsistencies are appearing in the way in which methods are presented, which can make the interpretation and replication of studies unnecessarily challenging. The Society for Functional Near-Infrared Spectroscopy has thus been motivated to organize a representative (but not exhaustive) group of leaders in the field to build a consensus on the best practices for describing the methods utilized in fNIRS studies. Our paper has been designed to provide guidelines to help enhance the reliability, repeatability, and traceability of reported fNIRS studies and encourage best practices throughout the community. A checklist is provided to guide authors in the preparation of their manuscripts and to assist reviewers when evaluating fNIRS papers.
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http://dx.doi.org/10.1117/1.NPh.8.1.012101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793571PMC
January 2021

Large-Scale Desynchronization During Interictal Epileptic Discharges Recorded With Intracranial EEG.

Front Neurol 2020 23;11:529460. Epub 2020 Dec 23.

University of Montreal Hospital Research Center (CRCHUM), University of Montreal, Montreal, QC, Canada.

It is increasingly recognized that deep understanding of epileptic seizures requires both localizing and characterizing the functional network of the region where they are initiated, i. e., the epileptic focus. Previous investigations of the epileptogenic focus' functional connectivity have yielded contrasting results, reporting both pathological increases and decreases during resting periods and seizures. In this study, we shifted paradigm to investigate the time course of connectivity in relation to interictal epileptiform discharges. We recruited 35 epileptic patients undergoing intracranial EEG (iEEG) investigation as part of their presurgical evaluation. For each patient, 50 interictal epileptic discharges (IEDs) were marked and iEEG signals were epoched around those markers. Signals were narrow-band filtered and time resolved phase-locking values were computed to track the dynamics of functional connectivity during IEDs. Results show that IEDs are associated with a transient decrease in global functional connectivity, time-locked to the peak of the discharge and specific to the high range of the gamma frequency band. Disruption of the long-range connectivity between the epileptic focus and other brain areas might be an important process for the generation of epileptic activity. Transient desynchronization could be a potential biomarker of the epileptogenic focus since 1) the functional connectivity involving the focus decreases significantly more than the connectivity outside the focus and 2) patients with good surgical outcome appear to have a significantly more disconnected focus than patients with bad outcomes.
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http://dx.doi.org/10.3389/fneur.2020.529460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785800PMC
December 2020

Validation of red blood cell flux and velocity estimations based on optical coherence tomography intensity fluctuations.

Sci Rep 2020 11 11;10(1):19584. Epub 2020 Nov 11.

Department of Electrical Engineering, Polytechnique Montreal, Montreal, Canada.

We present a validation of red blood cell flux and speed measurements based on the passage of erythrocytes through the OCT's focal volume. We compare the performance of the so-called RBC-passage OCT technique to co-localized and simultaneously acquired two-photon excitation fluorescence microscopy (TPEF) measurements. Using concurrent multi-modal imaging, we show that fluctuations in the OCT signal display highly similar features to TPEF time traces. Furthermore, we demonstrate an overall difference in RBC flux and speed of 2.5 ± 3.27 RBC/s and 0.12 ± 0.67 mm/s (mean ± S.D.), compared to TPEF. The analysis also revealed that the OCT RBC flux estimation is most accurate between 20 RBC/s to 60 RBC/s, and is severely underestimated at fluxes beyond 80 RBC/s. Lastly, our analysis shows that the RBC speed estimations increase in accuracy as the speed decreases, reaching a difference of 0.16 ± 0.25 mm/s within the 0-0.5 mm/s speed range.
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http://dx.doi.org/10.1038/s41598-020-76774-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658245PMC
November 2020

Automated Analysis of Brain Microvasculature: From Segmentation to Anatomical Modeling.

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:1907-1910

Two-photon microscopy (TPM) can provide a detailed microscopic information of cerebrovascular structures. Extracting anatomical vascular models from TPM angiograms remains a tedious task due to image degeneration associated with TPM acquisitions and the complexity of microvascular networks. Here, we propose a fully automated pipeline capable of providing useful anatomical models of vascular structures captured with TPM. In the proposed method, we segment blood vessels using a fully convolutional neural network and employ the resulting binary labels to create an initial geometric graph enclosed within vessels boundaries. The initial geometry is then decimated and refined to form graphed curve skeletons that can retain both the vascular shape and its topology. We validate the proposed method on 3D realistic TPM angiographies and compare our results with that obtained through manual annotations.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176322DOI Listing
July 2020

Laplacian Flow Dynamics on Geometric Graphs for Anatomical Modeling of Cerebrovascular Networks.

IEEE Trans Med Imaging 2021 01 29;40(1):381-394. Epub 2020 Dec 29.

Generating computational anatomical models of cerebrovascular networks is vital for improving clinical practice and understanding brain oxygen transport. This is achieved by extracting graph-based representations based on pre-mapping of vascular structures. Recent graphing methods can provide smooth vessels trajectories and well-connected vascular topology. However, they require water-tight surface meshes as inputs. Furthermore, adding vessels radii information on their graph compartments restricts their alignment along vascular centerlines. Here, we propose a novel graphing scheme that works with relaxed input requirements and intrinsically captures vessel radii information. The proposed approach is based on deforming geometric graphs constructed within vascular boundaries. Under a laplacian optimization framework, we assign affinity weights on the initial geometry that drives its iterative contraction toward vessels centerlines. We present a mechanism to decimate graph structure at each run and a convergence criterion to stop the process. A refinement technique is then introduced to obtain final vascular models. Our implementation is available on https://github.com/Damseh/VascularGraph. We benchmarked our results with that obtained using other efficient and state-of-the-art graphing schemes, validating on both synthetic and real angiograms acquired with different imaging modalities. The experiments indicate that the proposed scheme produces the lowest geometric and topological error rates on various angiograms. Furthermore, it surpasses other techniques in providing representative models that capture all anatomical aspects of vascular structures.
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http://dx.doi.org/10.1109/TMI.2020.3027500DOI Listing
January 2021

Cerebral tissue pO response to treadmill exercise in awake mice.

Sci Rep 2020 08 7;10(1):13358. Epub 2020 Aug 7.

Research Center of Montreal Heart Institute, Montréal, QC, Canada.

We exploited two-photon microscopy and Doppler optical coherence tomography to examine the cerebral blood flow and tissue pO response to forced treadmill exercise in awake mice. To our knowledge, this is the first study performing both direct measure of brain tissue pO during acute forced exercise and underlying microvascular response at capillary and non-capillary levels. We observed that cerebral perfusion and oxygenation are enhanced during running at 5 m/min compared to rest. At faster running speeds (10 and 15 m/min), decreasing trends in arteriolar and capillary flow speed were observed, which could be due to cerebral autoregulation and constriction of arterioles in response to blood pressure increase. However, tissue pO was maintained, likely due to an increase in RBC linear density. Higher cerebral oxygenation at exercise levels 5-15 m/min suggests beneficial effects of exercise in situations where oxygen delivery to the brain is compromised, such as in aging, atherosclerosis and Alzheimer Disease.
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http://dx.doi.org/10.1038/s41598-020-70413-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414913PMC
August 2020

Identification of global and local states during seizures using quantitative functional connectivity and recurrence plot analysis.

Comput Biol Med 2020 07 15;122:103858. Epub 2020 Jun 15.

Neurology Division, Centre Hospitalier de l'Université de Montréal (CHUM), 1000 Saint-Denis, Montreal, H2X 0C1, Canada.

Introduction: As a dynamical system, the brain constantly modulates its state and epileptic seizures have been hypothesized to be low dimensional periodic states of the brain. With this assumption, seizures have previously been investigated to identify patterns of these recurrent states; however, these attempts have generated conflicting results. These discrepant observations led us to reconsider the dynamic of state transitions during seizures.

Methods: Using intracerebral recordings of 17 refractory epilepsy patients assessed prior to surgery, we studied ictal states with several state-of-the-art methods in order to investigate their dynamics. Global states were identified based on distinct functional connectivity measures in the time domain, frequency domain, and phase-space. We further investigated the state transitions in different brain regions locally using a univariate measure based on dynamical system analysis named the Recurrence Plot (RP).

Results: For the ictal period, we detected lower global state transition rates compared to pre- and post-ictal periods (p < 0.05 for seizure-free (SF) and p > 0.05 for non-seizure-free (NSF) groups post-surgery); however, the structure of RPs pointed towards higher state transition rates in some regions like the seizure-onset-zone (p < 0.001 for SF and p > 0.05 for NSF group). Moreover, a direct comparison of state transition dynamics between SF and NSF patients revealed different patterns for local state transitions between SF and NSF patients (p < 0.05 for seizure-onset-zone while p > 0.05 for other regions) and no significant difference in global state transition rates (p > 0.05).

Conclusion: Our findings pointed to distinct dynamics for state transitions at different spatial scales. While the pattern of global state transitions led to the conclusion that the brain changes state less frequently during ictal activity, locally, it experienced a higher rate of state transition. Furthermore, our results for different patterns of state transitions in the seizure-onset-zone between SF and NSF patients could have a practical application in predicting surgical outcome.
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http://dx.doi.org/10.1016/j.compbiomed.2020.103858DOI Listing
July 2020

Association between Statin Use and Balance in Older Adults.

Int J Environ Res Public Health 2020 06 29;17(13). Epub 2020 Jun 29.

Research Center, Institut Universitaire de Gériatrie de Montréal, Montreal, QC H3W 1W5, Canada.

Several medications have been associated with an increased risk of balance deficits and greater likelihood to sustain a fall, representing a large health and economic issue. Statins are regularly prescribed to prevent strokes and heart attacks, but their impact on balance is unknown. The aim of this paper was to determine whether statin use is associated with poorer balance performances in older adults. All participants, one group taking statins (n = 34), and the other group not taking statins (n = 31), completed a balance assessment with their eyes closed and their eyes opened on a MatScan Pressure Sensing Mat. Center of Pressure (CoP) velocity, peak-to-peak distance, and standard deviation were collected in both anteroposterior (AP) and mediolateral (ML) directions. Multiple linear regression analyses were performed for each balance outcome, testing the statin use status as a predictor and controlling for appropriate factors including participants characteristics, lipid profile, and cardiovascular disease. After controlling for confounding factors, statin use significantly predicted both CoP ML-Amplitude (β = 0.638, = 0.004) and ML-Velocity (β = 0.653, = 0.002) in the eyes-opened condition. The present study detected a negative association between statin use and balance control in the ML direction, suggesting that caution should be taken when prescribing statins in older adults, as this could decrease ML stability and ultimately increase fall and fracture risks.
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http://dx.doi.org/10.3390/ijerph17134662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369856PMC
June 2020

Quantitative spectral quality assessment technique validated using intraoperative in vivo Raman spectroscopy measurements.

J Biomed Opt 2020 04;25(4):1-8

Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.

Significance: Ensuring spectral quality is prerequisite to Raman spectroscopy applied to surgery. This is because the inclusion of poor-quality spectra in the training phase of Raman-based pathology detection models can compromise prediction robustness and generalizability to new data. Currently, there exists no quantitative spectral quality assessment technique that can be used to either reject low-quality data points in existing Raman datasets based on spectral morphology or, perhaps more importantly, to optimize the in vivo data acquisition process to ensure minimal spectral quality standards are met.

Aim: To develop a quantitative method evaluating Raman signal quality based on the variance associated with stochastic noise in important tissue bands, including C─C stretch, CH2  /  CH3 deformation, and the amide bands.

Approach: A single-point hand-held Raman spectroscopy probe system was used to acquire 315 spectra from 44 brain cancer patients. All measurements were classified as either high or low quality based on visual assessment (qualitative) and using a quantitative quality factor (QF) metric. Receiver-operator-characteristic (ROC) analyses were performed to evaluate the performance of the quantitative metric to assess spectral quality and improve cancer detection accuracy.

Results: The method can separate high- and low-quality spectra with a sensitivity of 89% and a specificity of 90% which is shown to increase cancer detection sensitivity and specificity by up to 20% and 12%, respectively.

Conclusions: The QF threshold is effective in stratifying spectra in terms of spectral quality and the observed false negatives and false positives can be linked to limitations of qualitative spectral quality assessment.
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http://dx.doi.org/10.1117/1.JBO.25.4.040501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171512PMC
April 2020

Longitudinal optical coherence tomography imaging of tissue repair and microvasculature regeneration and function after targeted cerebral ischemia.

J Biomed Opt 2020 04;25(4):1-15

Polytechnique Montréal, Canada.

Significance: Understanding how the brain recovers from cerebral tissue and vascular damage after an ischemic event can help develop new therapeutic strategies for the treatment of stroke.

Aim: We investigated cerebral tissue repair and microvasculature regeneration and function after a targeted ischemic stroke.

Approach: Following photothrombosis occlusion of microvasculature, chronic optical coherence tomography (OCT)-based angiography was used to track ischemic tissue repair and microvasculature regeneration at three different cortical depths and up to 28 days in awake animals. Capillary network orientation analysis was performed to study the structural pattern of newly formed microvasculature. Based on the time-resolved OCT-angiography, we also investigated capillary stalling, which is likely related to ischemic stroke-induced inflammation.

Results: Deeper cerebral tissue was found to have a larger ischemic area than shallower regions at any time point during the course of poststroke recovery, which suggests that cerebral tissue located deep in the cortex is more vulnerable. Regenerated microvasculature had a highly organized pattern at all cortical depths with a higher degree of structural reorganization in deeper regions. Additionally, capillary stalling event analysis revealed that cerebral ischemia augmented stalling events considerably.

Conclusion: Longitudinal OCT angiography reveals that regenerated capillary network has a highly directional pattern and an increased density and incidence of capillary stalling event.
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http://dx.doi.org/10.1117/1.JBO.25.4.046002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152803PMC
April 2020

A Pilot Study Investigating Changes in Capillary Hemodynamics and Its Modulation by Exercise in the APP-PS1 Alzheimer Mouse Model.

Front Neurosci 2019 4;13:1261. Epub 2019 Dec 4.

Biomedical Engineering Institute, École Polytechnique de Montréal, Montreal, QC, Canada.

Dysfunction in neurovascular coupling that results in a mismatch between cerebral blood flow and neuronal activity has been suggested to play a key role in the pathogenesis of Alzheimer's disease (AD). Meanwhile, physical exercise is a powerful approach for maintaining cognitive health and could play a preventive role against the progression of AD. Given the fundamental role of capillaries in oxygen transport to tissue, our pilot study aimed to characterize changes in capillary hemodynamics with AD and AD supplemented by exercise. Exploiting two-photon microscopy, intrinsic signal optical imaging, and magnetic resonance imaging, we found hemodynamic alterations and lower vascular density with AD that were reversed by exercise. We further observed that capillary properties were branch order-dependent and that stimulation-evoked changes were attenuated with AD but increased by exercise. Our study provides novel indications into cerebral microcirculatory disturbances with AD and the modulating role of voluntary exercise on these alterations.
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http://dx.doi.org/10.3389/fnins.2019.01261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915102PMC
December 2019

Voluntary exercise increases brain tissue oxygenation and spatially homogenizes oxygen delivery in a mouse model of Alzheimer's disease.

Neurobiol Aging 2020 04 27;88:11-23. Epub 2019 Nov 27.

Biomedical Engineering Institute, École Polytechnique de Montréal, Montréal, Quebec, Canada; Montreal Heart Institute, Research Center, Montreal, Quebec, Canada. Electronic address:

Although vascular contributions to dementia and Alzheimer's disease (AD) are increasingly recognized, the potential brain oxygenation disruption associated with AD and whether preventive strategies to maintain tissue oxygenation are beneficial remain largely unknown. This study aimed to examine (1) whether brain oxygenation is compromised by the onset of AD and (2) how voluntary exercise modulates the influence of AD on brain oxygenation. In vivo 2-photon phosphorescence lifetime microscopy was used to investigate local changes of brain tissue oxygenation with the progression of AD and its modulation by exercise in the barrel cortex of awake transgenic AD mice. Our results show that cerebral tissue oxygen partial pressure (PO) decreased with the onset of AD. Reduced PO was associated with the presence of small near-hypoxic areas, an increased oxygen extraction fraction, and reduced blood flow, observations that were all reverted by exercise. AD and age also increased the spatial heterogeneity of brain tissue oxygenation, which was normalized by exercise. Ex vivo staining also showed fewer amyloid-β (Aβ) deposits in the exercise group. Finally, we observed correlations between voluntary running distance and cerebral tissue oxygenation/blood flow, suggesting a dose-response relationship of exercise on the brain. Overall, this study suggests that compromised brain oxygenation is an indicator of the onset of AD, with the emergence of potential deleterious mechanisms associated with hypoxia. Furthermore, voluntary exercise enhanced the neurovascular oxygenation process, potentially offering a means to delay these changes.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.11.015DOI Listing
April 2020

Hypertension accelerates cerebral tissue PO disruption in Alzheimer's disease.

Neurosci Lett 2020 01 11;715:134626. Epub 2019 Nov 11.

Biomedical Engineering Institute, École Polytechnique de Montréal, Montréal, QC, Canada; Montreal Heart Institute, Research Center, Montreal, Quebec, Canada. Electronic address:

This study measured stimulus-evoked brain tissue oxygenation changes in a mouse model of Alzheimer disease (AD) and further explored the influence of exercise and angiotensin II-induced hypertension on these changes. in vivo two-photon phosphorescence lifetime microscopy was used to investigate local changes in brain tissue oxygenation following whisker stimulation. During rest periods, PO values close to the arteriolar wall were lower in the AD groups and the PO spatial decay as a function of distance to arteriole was increased by hypertension. During stimulation, tissue PO response had a similar spatial dependence across groups. Tissue PO response in post-stimulation period was larger in AD groups (e.g., AD6 and ADH6) than in the controls (WT6 and WTH6). After a 3-month voluntary exercise period, some of these changes were reversed in AD mice. This provides novel insight into tissue oxygen delivery and the impact of blood pressure control and exercise on brain tissue oxygenation in AD.
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http://dx.doi.org/10.1016/j.neulet.2019.134626DOI Listing
January 2020

Wearable SiPM-Based NIRS Interface Integrated With Pulsed Laser Source.

IEEE Trans Biomed Circuits Syst 2019 12 4;13(6):1313-1323. Epub 2019 Nov 4.

We present the design of a miniaturized probe integrating silicon photomultiplier and light-pulsing electronics in a single 2 × 2 mm complementary metal-oxide-semiconductor (CMOS) chip which includes functional blocks such as a fast pulse-laser driver and synchronized single-photon detection circuit. The photon pulses can be either counted on-chip or processed by an external high-speed electronic module such as time-corelated single photon counting (TCSPC) unit. The integrated circuit was assembled on a printed circuit board (PCB) and also on a 2.5D silicon interposer platform of size 1 cm and interfaced with a silicon photomultiplier (SiPM), vertical cavity surface emitting laser (VCSEL) and other ancillary components such as capacitors and resistors. Our approach of integrating an optical interface to optimize light collection on the small active area and light emission from the vertical-cavity surface-emitting laser (VSCEL) will facilitate clinical adoption in many applications and change the landscape of Near Infrared Spectroscopy (NIRS) hardware commercially due to significant optode-size reduction and the elimination of optical fibers.
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http://dx.doi.org/10.1109/TBCAS.2019.2951539DOI Listing
December 2019

Impact of atherosclerotic disease on cerebral microvasculature and tissue oxygenation in awake LDLR-/-hApoB+/+ transgenic mice.

Neurophotonics 2019 Oct 24;6(4):045003. Epub 2019 Oct 24.

École Polytechnique de Montréal, Laboratoire d'Imagerie optique et moléculaire, Montréal, Québec, Canada.

We explore cortical microvasculature changes during the progression of atherosclerosis using young and old transgenic atherosclerotic (ATX) mice with thinned-skull cranial window. In awake animals, exploiting intrinsic signal optical imaging, Doppler optical coherence tomography, and two-photon microscopy, we investigate how the progression of atherosclerotic disease affects the morphology and function of cortical microvasculature as well as baseline cerebral tissue oxygenation. Results show that aged ATX mice exhibited weaker hemodynamic response in the somatosensory cortex to whisker stimulation and that the diameter of their descending arterioles and associated mean blood flow decreased significantly compared with the young ATX group. Data from two-photon phosphorescence lifetime microscopy indicate that old ATX mice had lower and more heterogeneous partial pressure of oxygen ( ) in cortical tissue than young ATX mice. In addition, hypoxic micropockets in cortical tissue were found in old, but not young, ATX mice. Capillary red blood cell (RBC) flux, RBC velocity, RBC velocity heterogeneity, hematocrit, and diameter were also measured using line scans with two-photon fluorescence microscopy. When compared with the young group, RBC flux, velocity, and hematocrit decreased and RBC velocity heterogeneity increased in old ATX mice, presumably due to disturbed blood supply from arterioles that were affected by atherosclerosis. Finally, dilation of capillaries in old ATX mice was observed, which suggests that capillaries play an active role in compensating for an oxygen deficit in brain tissue.
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http://dx.doi.org/10.1117/1.NPh.6.4.045003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811703PMC
October 2019

Vascular retinal biomarkers improves the detection of the likely cerebral amyloid status from hyperspectral retinal images.

Alzheimers Dement (N Y) 2019 14;5:610-617. Epub 2019 Oct 14.

Genie Electrique, Polytechnique Montreal, Montreal, Quebec, Canada.

Introduction: This study investigates the relationship between retinal image features and β-amyloid (Aβ) burden in the brain with the aim of developing a noninvasive method to predict the deposition of Aβ in the brain of patients with Alzheimer's disease.

Methods: Retinal images from 20 cognitively impaired and 26 cognitively unimpaired cases were acquired (3 images per subject) using a hyperspectral retinal camera. The cerebral amyloid status was determined from binary reads by a panel of 3 expert raters on F-florbetaben positron-emission tomography (PET) studies. Image features from the hyperspectral retinal images were calculated, including vessels tortuosity and diameter and spatial-spectral texture measures in different retinal anatomical regions.

Results: Retinal venules of amyloid-positive subjects (Aβ+) showed a higher mean tortuosity compared with the amyloid-negative (Aβ-) subjects. Arteriolar diameter of Aβ+ subjects was found to be higher than the Aβ- subjects in a zone adjacent to the optical nerve head. Furthermore, a significant difference between texture measures built over retinal arterioles and their adjacent regions were observed in Aβ+ subjects when compared with the Aβ-. A classifier was trained to automatically discriminate subjects combining the extracted features. The classifier could discern Aβ+ subjects from Aβ- subjects with an accuracy of 85%.

Discussion: Significant differences in texture measures were observed in the spectral range 450 to 550 nm which is known as the spectral region known to be affected by scattering from amyloid aggregates in the retina. This study suggests that the inclusion of metrics related to the retinal vasculature and tissue-related textures extracted from vessels and surrounding regions could improve the discrimination performance of the cerebral amyloid status.
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http://dx.doi.org/10.1016/j.trci.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804547PMC
October 2019
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