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Publications (121)
Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three...
White matter hyperintensities (WMHs) are radiological abnormalities reflecting cerebrovascular dysfunction detectable using magnetic resonance imaging (MRI). WMHs are often present in individuals at the later stages of the lifespan and in prodromal stages in the Alzheimer’s Disease spectrum. Tissue alterations underlying WMHs may include demyelinat...
Aggregation of the hyperphosphorylated tau protein is a central driver of Alzheimer’s disease, and its accumulation exhibits a rich spatio-temporal pattern that unfolds during the course of the disease, sequentially progressing through the brain across axonal connections. It is unclear how this spatio-temporal process is orchestrated – namely, to w...
Neurodegenerative diseases are the most common cause of dementia. Although their underlying molecular pathologies have been identified, there is substantial heterogeneity in the patterns of progressive brain alterations across and within these diseases. Recent advances in neuroimaging methods have revealed that pathological proteins accumulate alon...
Neuroimaging is commonly used to infer human brain connectivity, but those measurements are far-removed from the molecular underpinnings at synapses. To uncover the molecular basis of human brain connectivity, we analyzed a unique cohort of 98 individuals who provided neuroimaging and genetic data contemporaneous with dendritic spine morphometric,...
Background
TDP-43 proteinopathies represents a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study aimed to us...
Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic work-up of dementia in clinical practice and the design of clinical trials. Here, we created a staging model using the Subtype and Stage Inference (SuStaIn) algorithm by evaluating cerebrospinal fluid (CSF) amyloid-β (Aβ) and tau biomarkers in 426...
Amyloid-β is thought to facilitate the spread of tau throughout the neocortex in Alzheimer's disease, though how this occurs is not well understood. This is because of the spatial discordance between amyloid-β, which accumulates in the neocortex, and tau, which accumulates in the medial temporal lobe during ageing. There is evidence that in some ca...
Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer’s disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related mechanisms which vary between individuals, such a...
Importance:
Longitudinal tau positron emission tomography (PET) is a relevant outcome in clinical trials evaluating disease-modifying therapies in Alzheimer disease (AD). A key unanswered question is whether the use of participant-specific (individualized) regions of interest (ROIs) is superior to conventional approaches where the same ROI (group-...
TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use...
Hierarchical processing requires activity propagating between higher- and lower-order cortical areas. However, functional neuroimaging studies have chiefly quantified fluctuations within regions over time rather than propagations occurring over space. Here, we leverage advances in neuroimaging and computer vision to track cortical activity propagat...
Pathological aggregation of tar DNA‐binding protein 43 (TDP‐43) in the brain is the primary cause of many cases of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE). It is therefore imperative to establish empirical staging systems to characterize and distin...
Longitudinal tau‐PET is increasingly used as an outcome in clinical trials evaluating disease‐modifying therapies in Alzheimer’s disease (AD). In order to quantify change in tau‐PET signal over time, regions of interest (ROIs) are used; to date, these have been based on neuropathological studies or data‐driven approaches where the same ROI is used...
Evidence from previous PET imaging studies suggests that increased neocortical tau seen in APOE‐ε4 carriers can be explained by the higher levels of neocortical amyloid‐β (Aβ) pathology also seen in this group. However, these studies also suggest an amyloid‐independent association between APOE‐ε4 and medial temporal lobe (MTL) tau. Using neuropatho...
Tau pathology is a hallmark of Alzheimer’s disease, but measuring this pathology in vivo with PET is expensive. MRI represents a low‐cost alternative for measuring in vivo disease progression, but is non‐specific. We present an MR‐based marker of tau‐specific pathology using machine learning (ML). 1851 pairs of RO948 tau‐PET and T1‐weighted MRI sca...
Tau pathology is a hallmark of Alzheimer’s disease, but measuring this pathology in vivo with PET is expensive. MRI represents a low‐cost alternative for measuring in vivo disease progression, but is non‐specific. We present an MR‐based marker of tau‐specific pathology using machine learning (ML). 1851 pairs of RO948 tau‐PET and T1‐weighted MRI sca...
Background:
Excess weight in adulthood leads to health complications such as diabetes, hypertension, or dyslipidemia. Recently, excess weight has also been related to brain atrophy and cognitive decline. Reports show that obesity is linked with Alzheimer's disease (AD)-related changes, such as cerebrovascular damage or amyloid-β accumulation. Howe...
Several studies have shown decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD). However, the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, PET, and CSF biomarkers, we investigated the associations between gray matter (GM)-CBF and the key mechanisms in AD including amyloid-β (Aβ)...
Human brain size increases dynamically through early development, peaks in adolescence, and varies up to two-fold among adults. Although previous studies have elucidated changes in brain size across evolution, development, traits, and diseases, the molecular underpinnings of interindividual variation in brain size remain unknown. Here, we leverage...
Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, how these gradients relate to adult brain function, and whether they are maintained in the adult brain, remains unknown. Here we uncover three axes of topographic variati...
The Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions...
Importance:
Preventive trials of anti-amyloid agents might preferably recruit persons showing earliest biologically relevant β-amyloid (Aβ) binding on positron emission tomography (PET).
Objective:
To investigate the timing at which Aβ-PET binding starts showing associations with other markers of Alzheimer disease.
Design, setting, and particip...
Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography. However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here, we leveraged an advanced machine learning method...
Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morp...
Importance:
National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD).
Objective:
To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-te...
Background
Cognitive reserve and resilience are terms used to explain interindividual variability in maintenance of cognitive health in response to adverse factors, such as brain pathology in the context of aging or neurodegenerative disorders. There is substantial interest in identifying tractable substrates of resilience to potentially leverage t...
Hierarchical processing requires activity propagating between higher and lower-order cortical areas. However, studies of brain development have chiefly quantified fluctuations within regions over time rather than propagations occurring over space. Here, we leveraged advances in neuroimaging and computer vision to track cortical activity propagation...
The Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions...
BACKGROUND
The spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in association cortex implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth.
METHODS
T...
Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight ¹ . Here we assemble an...
Background: Cognitive reserve and resilience are terms used to explain interindividual variability in maintenance of cognitive health in response to adverse factors, such as brain pathology in the context of aging or neurodegenerative disorders. There is substantial interest in identifying tractable substrates of resilience to potentially leverage...
The distribution of Alzheimer’s disease (AD) tau pathology varies systematically and causes a diverse array of syndromes. This forum article provides a brief overview of key controversies in untangling the complexity of AD subtypes, explores potential causes of AD variability in the population, and discusses clinical relevance and future directions...
Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morp...
Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morp...
Accurate prediction of progression in subjects at risk of Alzheimer's disease is crucial for enrolling the right subjects in clinical trials. However, a prospective comparison of state-of-the-art algorithms for predicting disease onset and progression is currently lacking. We present the findings of "The Alzheimer's Disease Prediction Of Longitudin...
Importance
There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD).
Objective
To describe longitudinal [¹⁸F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the...
Objective: We investigated the mediation effects of subcortical volume change in the relationship of amyloid beta (Aβ) and lacune with cognitive function in patients with mild cognitive impairment (MCI).
Methods: We prospectively recruited 101 patients with MCI who were followed up with neuropsychological tests, MRI, or Pittsburgh compound B (PiB)...
Background
A large body of evidence has shown decreased cerebral blood flow (CBF) in Alzheimer’s disease (AD). However, the link between CBF and the primary AD pathologies as well as synaptic integrity remains unclear.
Method
Baseline CBF was measured using arterial spin labeling (ASL) in a 3T MRI scanner in 137 cognitively unimpaired individuals...
Background
In Alzheimer’s disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau‐PET imaging to investigate the sequence of tau pathology progres...
Regulation of gene expression drives protein interactions that govern synaptic wiring and neuronal activity. The resulting coordinated activity among neuronal populations supports complex psychological processes, yet how gene expression shapes cognition and emotion remains unknown. Here, we directly bridge the microscale and macroscale by mapping g...
The spatial layout of large-scale functional brain networks differs between individuals and is particularly variable in association cortex that has been implicated in a broad range of psychiatric disorders. However, it remains unknown whether this variation in functional topography is related to major dimensions of psychopathology in youth. Capital...
Subtype and Stage Inference (SuStaIn) is an unsupervised learning algorithm that uniquely enables the identification of subgroups of individuals with distinct pseudo-temporal disease progression patterns from cross-sectional datasets. SuStaIn has been used to identify data-driven subgroups and perform patient stratification in neurodegenerative dis...
Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in...
Amyloid-beta (Aβ) deposition is one of the hallmark pathologies in both sporadic Alzheimer's disease (sAD) and autosomal dominant Alzheimer's disease (ADAD), the latter of which is caused by mutations in genes involved in Aβ processing. Despite Aβ deposition being a centerpiece to both sAD and ADAD, some differences between these AD subtypes have b...
Over the past 25 years, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, there are no reference standards against which to anchor measures of individual differences in brain morphology, in contrast to growth charts for traits such as height and weight. Here, we built an interactive online...
Prior work has shown that there is substantial interindividual variation in the spatial distribution of functional networks across the cerebral cortex, or functional topography . However, it remains unknown whether there are sex differences in the topography of individualized networks in youth. Here we leveraged an advanced machine learning method...
Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we ident...
In Alzheimer's disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau-PET imaging to investigate the sequence of tau pathology progression within...
Resting-state functional connectivity is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. However, evidence is lacking regarding longitudinal changes in functional connectivity. This study includes 247 cognitively unimpaired individuals with a family history of sporadic AD (185 women/ 62...
Background
Studies in cells, animals and humans have each provided evidence that, in an Alzheimer’s disease (AD) context, tau may be spreading through the brain transneuronally. This information may be useful for modeling the spread of tau in humans. However, such models are confounded by the substantial heterogeneity in spreading patterns observed...
Background
The Braak staging scheme describes a stereotypical spread of tau pathology in Alzheimer’s disease (AD). However, apparent subtypes described at autopsy and clinical variants of AD both suggest variability in the pattern of tau spreading across the population. To address this discrepancy, we applied a validated spatiotemporal clustering a...
Alzheimer's disease (AD) is characterized by the progressive spread of tau pathology throughout the cerebral cortex. The pattern of spread is thought to be fairly consistent across individuals, though more recent work has demonstrated substantial variability in the AD population that is often associated with distinct clinical phenotypes. Still, a s...
Objective
To determine whether atrophy relates to phenotypical variants of posterior cortical atrophy (PCA) recently proposed in clinical criteria; dorsal, ventral, dominant-parietal and caudal, we assessed associations between latent atrophy factors and cognition.
Methods
We employed a data-driven Bayesian modelling framework based on latent Diri...
Regulation of gene expression drives protein interactions that govern synaptic wiring and neuronal activity. The resulting coordinated activity among neuronal populations supports complex psychological processes, yet how gene expression shapes cognition and emotion remains unknown. Here we directly bridge the microscale and macroscale by mapping ge...
Tau is a hallmark pathology of Alzheimer’s disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by β-amyloid (Aβ). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-P...
The impact of multisite acquisition on rsfMRI connectivity has recently gained attention. We provide consistency values (Pearson's correlation) between resting-state fMRI (rsfMRI) connectivity maps of an adult volunteer (Csub) scanned 25 times over 3.5 years at 13 sites using the Canadian Dementia Imaging Protocol (CDIP, www.cdip-pcid.ca). This dat...
Introduction
Cross-sectional studies suggest that cardiovascular risk factors and Alzheimer’s disease (AD) biomarkers are associated with abnormal brain resting-state functional connectivity in aging and AD; however, evidence is missing regarding longitudinal changes in functional connectivity. In this study, we investigate whether cholesterol leve...
The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the adult human hippocampus can be predicted within 2mm using the expression pattern...
We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of...
We present the findings of "The Alzheimer's Disease Prediction Of Longitudinal Evolution" (TADPOLE) Challenge, which compared the performance of 92 algorithms from 33 international teams at predicting the future trajectory of 219 individuals at risk of Alzheimer's disease. Challenge participants were required to make a prediction, for each month of...
Age being the main risk factor for Alzheimer's disease, it is particularly challenging to disentangle structural changes related to normal brain ageing from those specific to Alzheimer's disease. Most studies aiming to make this distinction focused on older adults only and on a priori anatomical regions. Drawing on a large, multi-cohort dataset ran...
Studies using resting-state functional magnetic resonance imaging (rsfMRI) are increasingly collecting data at multiple sites in order to speed up recruitment or increase sample size. The main objective of this study was to assess the long-term consistency of rsfMRI connectivity maps derived at multiple sites and vendors using the Canadian Dementia...
Posterior cortical atrophy is a clinical-radiological syndrome characterized by visual processing deficits and atrophy in posterior parts of the brain, most often caused by Alzheimers disease pathology. Recent consensus criteria describe four distinct phenotypical variants of posterior cortical atrophy defined by clinical and radiological features;...
It remains unclear which grey matter (GM) changes are associated with Alzheimer's disease (AD), and how these changes might differ from normal brain aging. Using independent component analysis of GM maps on a large, multi-cohort dataset, we derived morphometric networks and investigated GM volume in such networks in young, old adulthood, and AD. GM...