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Featured researches published by Tharick A. Pascoal.


Molecular Psychiatry | 2017

Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease

Tharick A. Pascoal; Sulantha Mathotaarachchi; Sara Mohades; Andrea Lessa Benedet; Chang-Oh Chung; Monica Shin; Seqian Wang; Tom Beaudry; Min Su Kang; Jean-Paul Soucy; Aurelie Labbe; Serge Gauthier; Pedro Rosa-Neto

This study was designed to test the interaction between amyloid-β and tau proteins as a determinant of metabolic decline in preclinical Alzheimer’s disease (AD). We assessed 120 cognitively normal individuals with [18F]florbetapir positron emission tomography (PET) and cerebrospinal fluid (CSF) measurements at baseline, as well as [18F]fluorodeoxyglucose ([18F]FDG) PET at baseline and at 24 months. A voxel-based interaction model was built to test the associations between continuous measurements of CSF biomarkers, [18F]florbetapir and [18F]FDG standardized uptake value ratios (SUVR). We found that the synergistic interaction between [18F]florbetapir SUVR and CSF phosphorylated tau (p-tau) measurements, rather than the sum of their independent effects, was associated with a 24-month metabolic decline in basal and mesial temporal, orbitofrontal, and anterior and posterior cingulate cortices (P<0.001). In contrast, interactions using CSF amyloid-β1–42 and total tau biomarkers did not associate with metabolic decline over a time frame of 24 months. The interaction found in this study further support the framework that amyloid-β and hyperphosphorylated tau aggregates synergistically interact to cause downstream AD neurodegeneration. In fact, the regions displaying the metabolic decline reported here were confined to brain networks affected early by amyloid-β plaques and neurofibrillary tangles. Preventive clinical trials may benefit from using a combination of amyloid-β PET and p-tau biomarkers to enrich study populations of cognitively normal subjects with a high probability of disease progression in studies, using [18F]FDG as a biomarker of efficacy.


Neurology | 2017

Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease

Kok Pin Ng; Tharick A. Pascoal; Sulantha Mathotaarachchi; Chang-Oh Chung; Andrea Lessa Benedet; Monica Shin; Min Su Kang; Xiaofeng Li; Maowen Ba; Nagaendran Kandiah; Pedro Rosa-Neto; Serge Gauthier; Alzheimer's Disease Neuroimaging Initiative; Michael W. Weiner; Paul S. Aisen; Ronald C. Petersen; Clifford R. Jack; William J. Jagust; John C. Morris; Andrew J. Saykin; John Q. Trojanowski; Arthur W. Toga; Laurel Beckett

Objective: To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). Methods: We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [18F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [18F]fluorodeoxyglucose (FDG) PET. Results: Individuals with preclinical AD with higher NPI scores had higher [18F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. Conclusions: The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology.


Alzheimers & Dementia | 2017

Synergistic interaction between amyloid and tau predicts the progression to dementia

Tharick A. Pascoal; Sulantha Mathotaarachchi; Monica Shin; Andrea Lessa Benedet; Sara Mohades; Seqian Wang; Tom Beaudry; Min Su Kang; Jean-Paul Soucy; Aurelie Labbe; Serge Gauthier; Pedro Rosa-Neto

Recent literature proposes that amyloid β (Aβ) and phosphorylated tau (p‐tau) synergism accelerates biomarker abnormalities in controls. Yet, it remains to be answered whether this synergism is the driving force behind Alzheimer disease (AD) dementia.


Frontiers in Neuroinformatics | 2016

VoxelStats: A MATLAB Package for Multi-Modal Voxel-Wise Brain Image Analysis

Sulantha Mathotaarachchi; Seqian Wang; Monica Shin; Tharick A. Pascoal; Andrea Lessa Benedet; Min Su Kang; Thomas Beaudry; Vladimir Fonov; Serge Gauthier; Aurelie Labbe; Pedro Rosa-Neto

In healthy individuals, behavioral outcomes are highly associated with the variability on brain regional structure or neurochemical phenotypes. Similarly, in the context of neurodegenerative conditions, neuroimaging reveals that cognitive decline is linked to the magnitude of atrophy, neurochemical declines, or concentrations of abnormal protein aggregates across brain regions. However, modeling the effects of multiple regional abnormalities as determinants of cognitive decline at the voxel level remains largely unexplored by multimodal imaging research, given the high computational cost of estimating regression models for every single voxel from various imaging modalities. VoxelStats is a voxel-wise computational framework to overcome these computational limitations and to perform statistical operations on multiple scalar variables and imaging modalities at the voxel level. VoxelStats package has been developed in Matlab® and supports imaging formats such as Nifti-1, ANALYZE, and MINC v2. Prebuilt functions in VoxelStats enable the user to perform voxel-wise general and generalized linear models and mixed effect models with multiple volumetric covariates. Importantly, VoxelStats can recognize scalar values or image volumes as response variables and can accommodate volumetric statistical covariates as well as their interaction effects with other variables. Furthermore, this package includes built-in functionality to perform voxel-wise receiver operating characteristic analysis and paired and unpaired group contrast analysis. Validation of VoxelStats was conducted by comparing the linear regression functionality with existing toolboxes such as glim_image and RMINC. The validation results were identical to existing methods and the additional functionality was demonstrated by generating feature case assessments (t-statistics, odds ratio, and true positive rate maps). In summary, VoxelStats expands the current methods for multimodal imaging analysis by allowing the estimation of advanced regional association metrics at the voxel level.


Journal of Neuroinflammation | 2015

Epistasis analysis links immune cascades and cerebral amyloidosis.

Andrea Lessa Benedet; Aurelie Labbe; Philippe Lemay; Eduardo Rigon Zimmer; Tharick A. Pascoal; Antoine Leuzy; Sulantha Mathotaarachchi; Sara Mohades; Monica Shin; Alexandre Dionne-Laporte; Thomas Beaudry; Cynthia Picard; Serge Gauthier; Judes Poirier; Guy A. Rouleau; Pedro Rosa-Neto

BackgroundSeveral lines of evidence suggest the involvement of neuroinflammatory changes in Alzheimer’s disease (AD) pathophysiology such as amyloidosis and neurodegeneration. In fact, genome-wide association studies (GWAS) have shown a link between genes involved in neuroinflammation and AD. In order to further investigate whether interactions between candidate genetic variances coding for neuroinflammatory molecules are associated with brain amyloid β (Aβ) fibrillary accumulation, we conducted an epistasis analysis on a pool of genes associated with molecular mediators of inflammation.Methods[18F]Florbetapir positron emission tomography (PET) imaging was employed to assess brain Aβ levels in 417 participants from ADNI-GO/2 and posteriorly 174 from ADNI-1. IL-1β, IL4, IL6, IL6r, IL10, IL12, IL18, C5, and C9 genes were chosen based on previous studies conducted in AD patients. Using the [18F]florbetapir standardized uptake value ratio (SUVR) as a quantitative measure of fibrillary Aβ, epistasis analyses were performed between two sets of markers of immune-related genes using gender, diagnosis, and apolipoprotein E (APOE) as covariates. Voxel-based analyses were also conducted. The results were corrected for multiple comparison tests. Cerebrospinal fluid (CSF) Aβ1-42/phosphorylated tau (p-tau) ratio concentrations were used to confirm such associations.ResultsEpistasis analysis unveiled two significant single nucleotide polymorphism (SNP)-SNP interactions (false discovery rate (FDR) threshold 0.1), both interactions between C9 gene (rs261752) and IL6r gene (rs4240872, rs7514452). In a combined sample, the interactions were confirmed (p ≤ 10–5) and associated with amyloid accumulation within cognitively normal and AD spectrum groups. Voxel-based analysis corroborated initial findings. CSF biomarker (Aβ1-42/p-tau) confirmed the genetic interaction. Additionally, rs4240872 and rs7514452 SNPs were shown to be associated with CSF and plasma concentrations of IL6r protein.ConclusionsCertain allele combinations involving IL6r and C9 genes are associated with Aβ burden in the brain. Hypothesis-driven search for epistasis is a valuable strategy for investigating imaging endophenotypes in complex neurodegenerative diseases.


Dementia & Neuropsychologia | 2016

Imaging Alzheimer's disease pathophysiology with PET

Lucas Porcello Schilling; Eduardo Rigon Zimmer; Monica Shin; Antoine Leuzy; Tharick A. Pascoal; Andrea Lessa Benedet; Wyllians Vendramini Borelli; André Palmini; Serge Gauthier; Pedro Rosa-Neto

ABSTRACT Alzheimers disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD.


Neurology | 2018

Anosognosia predicts default mode network hypometabolism and clinical progression to dementia

Joseph Therriault; Kok Pin Ng; Tharick A. Pascoal; Sulantha Mathotaarachchi; Min Su Kang; Hanne Struyfs; Monica Shin; Andrea Lessa Benedet; Ishan C. Walpola; Vasavan Nair; Serge Gauthier; Pedro Rosa-Neto

Objective To identify the pathophysiologic mechanisms and clinical significance of anosognosia for cognitive decline in mild cognitive impairment. Methods We stratified 468 patients with amnestic mild cognitive impairment into intact and impaired awareness groups, determined by the discrepancy between the patient and the informant score on the Everyday Cognition questionnaire. Voxel-based linear regression models evaluated the associations between self-awareness status and baseline β-amyloid load, measured by [18F]florbetapir, and the relationships between awareness status and regional brain glucose metabolism measured by [18F]fluorodeoxyglucose at baseline and at 24-month follow-up. Multivariate logistic regression tested the association of awareness status with conversion from amnestic mild cognitive impairment to dementia. Results We found that participants with impaired awareness had lower [18F]fluorodeoxyglucose uptake and increased [18F]florbetapir uptake in the posterior cingulate cortex at baseline. In addition, impaired awareness in mild cognitive impairment predicted [18F]fluorodeoxyglucose hypometabolism in the posterior cingulate cortex, left basal forebrain, bilateral medial temporal lobes, and right lateral temporal lobe over 24 months. Furthermore, participants with impaired awareness had a nearly 3-fold increase in likelihood of conversion to dementia within a 2-year time frame. Conclusions Our results suggest that anosognosia is linked to Alzheimer disease pathophysiology in vulnerable structures, and predicts subsequent hypometabolism in the default mode network, accompanied by an increased risk of progression to dementia. This highlights the importance of assessing awareness of cognitive decline in the clinical evaluation and management of individuals with amnestic mild cognitive impairment.


Alzheimers & Dementia | 2015

Association between apolipoprotein a-i levels and white matter hyperintensities depends on CSF tau levels in a high-risk cohort of aging cognitively normal persons: The prevent-alzheimer's disease study

Tharick A. Pascoal; Mahsa Dadar; Sarinporn Manitsirikul; John C.S. Breitner; D. Louis Collins; Judes Poirier; Anne Labonté; Pedro Rosa-Neto

Values Nelly Joseph-Mathurin, Yi Su, Andrei Vlassenko, Lars Couture, Tyler Blazey, Karl A. Friedrichsen, Christopher J. Owen, Russ C. Hornbeck, Lisa Cash, Trish A. Stevenson, Beau Ances, Chengjie Xiong, Virginia Buckles, Krista L. Moulder, John C. Morris, Randall Bateman, Marcus E. Raichle, Tammie L. S. Benzinger,Washington University School ofMedicine, St Louis, MO, USA. Contact e-mail: [email protected]


Neurology Genetics | 2018

CYP2C19 variant mitigates Alzheimer disease pathophysiology in vivo and postmortem

Andrea Lessa Benedet; Lei Yu; Aurelie Labbe; Sulantha Mathotaarachchi; Tharick A. Pascoal; Monica Shin; Min Su Kang; Serge Gauthier; Guy A. Rouleau; Judes Poirier; David A. Bennett; Pedro Rosa-Neto

Objective To verify whether CYP polymorphisms are associated with amyloid-β (Aβ) pathology across the spectrum of clinical Alzheimer disease using in vivo and postmortem data from 2 independent cohorts. Methods A candidate-gene approach tested the association between 5 genes (28 single nucleotide polymorphisms) and Aβ load measured in vivo by the global [18F]florbetapir PET standardized uptake value ratio (SUVR) in 338 Alzheimers Disease Neuroimaging Initiative participants. Significant results were then tested using plasma Aβ and CSF Aβ and Aβ/phosphorylated tau (Aβ/p-tau) ratio in the same cohort. The significant association was also generalized to postmortem Aβ load measurement in the Rush Religious Orders Study/Memory and Aging Project cohorts. In addition, global cognition was used as a phenotype in the analysis in both cohorts. Results Analysis of Aβ PET identified a variant in the CYP2C19 gene (rs4388808; p = 0.0006), in which carriers of the minor allele (MA) had a lower global SUVR. A voxel-wise analysis revealed that the variant is associated with a lower Aβ load in the frontal, inferior temporal, and posterior cingulate cortices. MA carriers also had higher CSF Aβ (p = 0.003) and Aβ/p-tau ratio (p = 0.02) but had no association with Aβ plasma levels. In postmortem brains, MA carriers had a lower Aβ load (p = 0.03). Global cognition was higher in MA carriers, which was found to be mediated by Aβ. Conclusions Together, these findings point to an association between CYP2C19 polymorphism and Aβ pathology, suggesting a protective effect of the MA of rs4388808. Despite the several possibilities in which CYP2C19 affects brain Aβ, the biological mechanism by which this genetic variation may act as a protective factor merits further investigation.


Alzheimers & Dementia | 2015

Should a global or a regional measure of amyloidosis be used in a longitudinal study

Sulantha Mathotaarachchi; Sara Mohades; Monica Shin; Thomas Beaudry; Andrea Lessa Benedet; Tharick A. Pascoal; Seqian Wang; Sarinporn Manitsirikul; Maxime Parent; Min Su Kang; Vladimir Fonov; Chang Oh Chung; Serge Gauthier; Pedro Rosa-Neto

Figure 1. Vertex-based multivariate linear regression model showing the effect of amyloid load on the rate of hypo-metabolism in each disease stage, corrected for baseline glucose metabolism, age, gender and apoe genotype. Only LMCI and AD stages show positive effect from amyloid load on hypometabolism in temporo-parietal and precuneus regions. Sulantha S. Mathotaarachchi, Sara Mohades, Monica Shin, Thomas Beaudry, Andrea Lessa Benedet, Tharick Ali Pascoal, Seqian Wang, Sarinporn Manitsirikul, Maxime J. Parent, Min Su Kang, Vladimir Fonov, Chang Oh Chung, Sr., Serge Gauthier, Pedro RosaNeto, McGill University, Montreal, QC, Canada; McGill Centre for Studies in Aging, Montreal, QC, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, QC, Canada; McGill Centre for Studies in Aging, Verdun, QC, Canada; McGill University Centre for Studies in Aging, Verdun, QC, Canada; Image Processing Laboratory, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Centre for Studies on Prevention of Alzheimer’s Disease (StoP-AD Centre), Douglas Mental Health Institute, Montreal, QC, Canada; Douglas Hospital Research Centre, Montreal, QC, Canada; Translational Imaging Laboratory, Montreal, QC, Canada. Contact e-mail: [email protected]

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Jean-Paul Soucy

Montreal Neurological Institute and Hospital

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Mira Chamoun

Université de Montréal

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