Douglas Teixeira LeffaUniversity of Pittsburgh | Pitt · Department of Psychiatry
Douglas Teixeira Leffa
MD PhD
About
116
Publications
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Introduction
Psychiatry Resident at the University of Pittsburgh Medical Center, interested in ADHD, neuromodulation, and Alzheimer's disease.
Additional affiliations
September 2015 - December 2018
Education
March 2011 - July 2018
Publications
Publications (116)
Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer’s disease (AD). Here, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in the living AD human brain. We studied 101 individuals across the AD spectrum with p...
Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer’s disease(AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synapti...
The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer’s disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living.
In this cohort...
Background
Healthy synapses are the key to proper brain function, ensuring communication between neurons. Recent studies have associated synaptic dysfunction with Alzheimer’s disease (AD) proteins, however, little is known about the role of glial reactivity, another pathology closely linked to AD, in brain synaptic dysfunction (Figure 1).
Method
W...
Background
Neuroinflammation typically involves the activation of microglial cells in the brain and has been linked to Alzheimer’s disease (AD) pathology. However, how microglial activation influences brain neurodegeneration in individuals across the AD continuum is still poorly understood. Here, we aimed to investigate the influence of microglial...
Background
Glial contributions to Alzheimer’s disease (AD) etiology and progression have been increasingly recognized. Experimental and clinical evidence suggests that both microglial activation and astrocyte reactivity have pivotal roles in the progression of tau pathology. However, it remains to be elucidated how microglia and astrocytes compleme...
Background
It has been suggested that phosphorylated tau(p‐tau) at threonine 231 and 217 are markers of amyloid‐β(Aβ) rather than tau pathology. However, most of the studies were conducted in cohorts composed mainly of preclinical Alzheimer Disease(AD) individuals. It remains to be elucidated if p‐tau is still more associated with Aβ than tau patho...
Background
A significant percentage of Aβ‐positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, cognitive decline.Experimental literature suggest that reactive astrocytes are necessary to unleashing Aβ effects in pathological tau phosphorylation.Here we aimed to investigate whether as...
Background
Recent studies have suggested that plasma p‐tau biomarkers are associated with cross‐sectional brain amyloid(Aβ) rather than tau tangle pathology. However, it is still unclear if plasma tau biomarkers are closely related to changes in AD pathophysiology over time. In this work, we aimed to determine if cross‐sectional measures of plasma...
Background
Tau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration i...
Background
Aβ accumulation precedes tau pathology in cognitively unimpaired (CU) individuals, which is an event closely related to the development of cognitive symptoms. However, Aβ leads to tau pathology in some individuals, but not in others, suggesting the presence of other processes triggering the deleterious effects of Aβ in the early Alzheime...
Background
The ATN classification system assumes a sequential model of disease progression. However, there are groups of individuals in the same ATN category that exhibit a predominance of abnormality (higher burden) of one of the biomarkers, creating heterogeneous ATN groups regarding pathological predominance. Thus, we tested the hypothesis that...
Background
Astrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐β (Aβ) and tau pathologies in preclinical A...
Background
Recent epidemiological studies showed that patients with attention‐deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with Alzheimer’s Disease (AD). Additionally, increased genetic risk for ADHD, measured with ADHD polygenic risk scores (ADHD‐PRS), was associated with amyloid‐dependent cognitive decline in older adults...
Background
Previous studies have shown that microglial activation (MA) plays a key role in the physiopathology and progression of Alzheimer’s disease (AD). Unpublished data suggest that MA is highly associated with the development of neuropsychiatric symptoms (NPS) in patients with AD. Thus, we aim to investigate here the contribution of each NPS d...
Background
The mechanisms by which the apolipoprotein E ε4 ( APOE ε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOE ε4 carriership and amyloid‐β (Aβ) burden with longitudinal tau pathology progression.
Method
We studied 104 individuals across the aging and A...
Background
Biomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.
Method
Cerebrospinal fluid (CSF) biomarkers wer...
Background
Activation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate wh...
Background
Previous studies have shown that microglial activation (MA) plays a key role in the pathophysiological and clinical progressions of Alzheimer’s disease (AD). However, little is known whether MA is also associated with the development of neuropsychiatric symptoms typically found in patients with AD. Thus, we aim to investigate here the as...
Background
The use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐β (Aβ) pathology and the apolipoprotein E ε4 ( APOE ε4) genotype have been shown to accelerate tau accumulation, it is still not cl...
Background
Deep learning models, particularly convolutional neural networks (CNNs), have shown promise in Alzheimer’s disease (AD) classification using tau PET data. However, limited sample sizes and unharmonized tau tracers present challenges to developing an agnostic tau tracer tool to predict AD using machine learning. Transfer learning, which l...
Background
Growing evidence suggests an increased prevalence of Alzheimer’s disease (AD) in females compared to males. Elucidating how disease biomarkers correlate in females and males is critical to understanding the basis of sex differences in AD. Our aim was to evaluate sex‐related differences in the association of plasma Glial fibrillary acidic...
Background
The preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma pho...
Background
CSF total tau (t‐tau) is postulated as a marker of neuronal degeneration in the ATN criteria. Here, we hypothesize that CSF t‐tau is more closely related to synaptic loss than over neurodegeneration.
Method
We evaluated 128 older individuals (75 CU,33 MCI,20 AD) in the TRIAD cohort (McGill, Canada) with CSF t‐tau, SNAP25long and Neurofi...
Background
A significant percentage of Aß‐positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, cognitive decline.Experimental literature suggest that reactive astrocytes are necessary to unleashing Aß effects in pathological tau phosphorylation.Here we aimed to investigate whether as...
Background
Tau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration i...
Background
The ATN classification system assumes a sequential model of disease progression. However, there are groups of individuals in the same ATN category that exhibit a predominance of abnormality (higher burden) of one of the biomarkers, creating heterogeneous ATN groups regarding pathological predominance. Thus, we tested the hypothesis that...
Background
Healthy synapses are the key to proper brain function, ensuring communication between neurons. Recent studies have associated synaptic dysfunction with Alzheimer’s disease (AD) proteins, however, little is known about the role of glial reactivity, another pathology closely linked to AD, in brain synaptic dysfunction (Figure 1).
Method
W...
Background
Astrocyte reactivity is a common finding in individuals across the Alzheimer’s disease (AD) continuum. Recently, we demonstrated that individuals with higher levels of plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, present a stronger association between amyloid‐ß (Aß) and tau pathologies in preclinical A...
Background
Previous studies have shown that microglial activation (MA) plays a key role in the pathophysiological and clinical progressions of Alzheimer’s disease (AD). However, little is known whether MA is also associated with the development of neuropsychiatric symptoms typically found in patients with AD. Thus, we aim to investigate here the as...
Background
Glial contributions to Alzheimer’s disease (AD) etiology and progression have been increasingly recognized. Experimental and clinical evidence suggests that both microglial activation and astrocyte reactivity have pivotal roles in the progression of tau pathology. However, it remains to be elucidated how microglia and astrocytes compleme...
Background
Previous studies have shown that microglial activation (MA) plays a key role in the physiopathology and progression of Alzheimer’s disease (AD). Unpublished data suggest that MA is highly associated with the development of neuropsychiatric symptoms (NPS) in patients with AD. Thus, we aim to investigate here the contribution of each NPS d...
Background
The mechanisms by which the apolipoprotein E e4 (APOEe4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOEe4 carriership and amyloid‐ß (Aß) burden with longitudinal tau pathology progression.
Method
We studied 104 individuals across the aging and AD c...
Background
Activation of microglial cells in the brain, more commonly known as neuroinflammation, has often been linked to the pathophysiology of Alzheimer’s disease (AD). However, how microglial activation is associated with longitudinal tau tangle accumulation and consequent cognitive decline is poorly understood. Here, we aimed to investigate wh...
Background
The use of enrichment strategies is crucial for selecting individuals with the highest probability of Alzheimer’s disease (AD)‐related progression in typical clinical trial time frames. Although both amyloid‐ß (Aß) pathology and the apolipoprotein E e4 (APOEe4) genotype have been shown to accelerate tau accumulation, it is still not clea...
Background
The preclinical stage of Alzheimer’s disease (AD) is one of the main focuses of clinical trials. Plasma and positron emission tomography (PET) biomarkers have already been proposed to monitor participants’ disease progression in clinical trials targeting cognitively unimpaired (CU) individuals. Although longitudinal changes in plasma pho...
Background
Biomarkers of astrocyte reactivity have the potential to improve diagnostic precision, disease monitoring, and treatment efficacy. Glial fibrillary acidic protein (GFAP) protein is expressed in astrocytes, which is important to synaptic plasticity, cell communication, and reactive gliosis.
Method
Cerebrospinal fluid (CSF) biomarkers wer...
Background
It has been suggested that phosphorylated tau(p‐tau) at threonine 231 and 217 are markers of amyloid‐ß(Aß) rather than tau pathology. However, most of the studies were conducted in cohorts composed mainly of preclinical Alzheimer Disease(AD) individuals. It remains to be elucidated if p‐tau is still more associated with Aß than tau patho...
Background
CSF total tau (t‐tau) is postulated as a marker of neuronal degeneration in the ATN criteria. Here, we hypothesize that CSF t‐tau is more closely related to synaptic loss than over neurodegeneration.
Method
We evaluated 128 older individuals (75 CU,33 MCI,20 AD) in the TRIAD cohort (McGill, Canada) with CSF t‐tau, SNAP25long and Neurofi...
Background
Neuroinflammation typically involves the activation of microglial cells in the brain and has been linked to Alzheimer’s disease (AD) pathology. However, how microglial activation influences brain neurodegeneration in individuals across the AD continuum is still poorly understood. Here, we aimed to investigate the influence of microglial...
Importance
Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.
Objective
To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across...
The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer’s disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum wh...
INTRODUCTION
Phosphorylated tau (p‐tau) biomarkers have been recently proposed to represent brain amyloid‐β (Aβ) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aβ and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI)...
An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effec...
Gene-environment interactions (GxE) have been increasingly explored in psychiatry but with low replication rates. Attention-deficit/hyperactivity disorder (ADHD) is a suitable candidate for studying GxE due to its high heritability and well-defined environmental risk factors. Here, we explored GxE using polygenic risk score (PRS) to represent the g...
Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-...
Introduction:
Amyloid-β (Aβ) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarker...
Objective:
To test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations.
Methods:
We estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing cha...
An unresolved question for the understanding of Alzheimer’s disease (AD) pathophysiology is why a significant percentage of amyloid β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes are key to unlea...
Neurodevelopmental disorders – including attention‐deficit/hyperactivity disorder (ADHD), autism spectrum disorder, communication disorders, intellectual disability, motor disorders, specific learning disorders, and tic disorders – manifest themselves early in development. Valid, reliable and broadly usable biomarkers supporting a timely diagnosis...
Background
Although it has been already demonstrated that plasma amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillar protein (GFAP) can predict with high accuracy Alzheimer's disease (AD) pathophysiology, no previous study has compared their performance in the same set of individuals. Here, we compare the performance of plasma Aβ42/40,...
Inflammation has long been pointed out as a key feature in Alzheimer’s disease (AD). However, the heterogeneity of AD pathology might trigger different aspects of the immune response. Here, we aimed to study the association of the newly proposed concept of inflammatory composite indexes with Aβ and tau pathologies across the aging and AD spectra. W...
[18F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [1...
It has already been shown that longitudinal changes in plasma phosphorylated tau 181 (p‐tau181) correlate with longitudinal Alzheimer’s disease (AD) progression. However, it is unclear whether longitudinal plasma p‐tau181 is a suitable measure to be used as a surrogate variable in clinical trials. This study aims to evaluate the utility of using lo...
Vascular risk factors (VRFs) have an important role in the etiology and progression of Alzheimer´s Disease (AD). We recently described that VRF burden interacts with AD pathophysiology increasing plasma neurofilament light (NfL) levels, a biomarker of neuroaxonal damage. However, whether individual VRFs interact with AD pathophysiology to promote l...
Mid‐life hypertension (HTN) is considered a risk factor for the development of clinical Alzheimer´s Disease (AD). Yet, it is not known whether late‐life hypertension relates to AD´s pathophysiology, with current literature being contradictory. We recently demonstrated that a vascular risk factor composite, which includes HTN, interact with the AD p...
The mechanisms by which the apolipoprotein E ε4 ( APOE ε4) allele influences Alzheimer’s disease (AD) pathophysiological progression are poorly understood. Here, we tested the association of APOE ε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology progression. We studied 104 individuals across the aging and AD spectrum who unde...
Importance
The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles.
Objective
To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflec...
Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer’s Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD...
[18F]MK6240 tau‐PET can detect changes in the early and late stages of tau tangles accumulation. However, off‐target binding, often observed in the meninges and neuromelanin‐containing cells, can interfere with longitudinal tracer quantification. Here, we investigated the association of longitudinal changes in off‐target and target signals using [1...
Recent evidence suggests that microglial activation sets the stage for tau spread in Alzheimer’s disease (AD). However, the underpinnings of microglial activation in early regions of tau accumulation are poorly understood. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for sporadic AD and influences microglial response i...
Although it has been alredy demonstrated that plasma amyloid‐β (Aβ), phosphorylated tau (p‐tau), and glial fibrillar protein (GFAP) can predict with high accuracy Alzheimer's disease (AD) pathophysiology, no previous study has compared their performance in the same set of individuals. Here, we compare the performance of plasma Aβ42/40, p‐tau, GFAP,...
Background
Recent epidemiological studies using population‐based registers showed that patients with Attention‐Deficit/Hyperactivity Disorder (ADHD) are more likely to be diagnosed with mild cognitive impairment (MCI) and Alzheimer’s disease (AD), suggesting a higher risk for cognitive impairment in older age. Here, we aimed to assess whether genet...
[18F]MK6240 tau-PET tracer quantifies brain tau neurofibrillary tangles (NFT) load in Alzheimer's disease (AD). The aims of our study are to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [...
Background: Although longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light (NfL) correlate with Alzheimers disease (AD) progression, it is unknown whether these changes can be used to monitor drug effects in preventive clinical trials. Here, we tested the utility of changes in plasma p-tau181 and NfL as surrogate...
Background
Very few predictive models in Psychiatry had their performance validated in independent external samples. A previously developed multivariable demographic model for attention‐deficit/hyperactivity disorder (ADHD) accurately predicted young adulthood ADHD using clinical and demographical information collected in childhood in three samples...
Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer’s disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD...
Importance:
Transcranial direct current stimulation (tDCS) may improve symptoms of inattention in adults with attention-deficit/hyperactivity disorder (ADHD). However, previous trials are characterized by small sample sizes, heterogeneous methodologies, and short treatment periods using clinic-based tDCS.
Objective:
To determine the efficacy and...
Microglial activation is an early phenomenon in Alzheimer′s disease (AD) that may occur prior to and independently of amyloid-β (Aβ) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E ϵ4 ( APOE ϵ4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOE ϵ4 genotype...
Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Ma...
Introduction
[ ¹⁸ F]MK6240 is a tau-PET tracer that quantifies brain tau neurofibrillary tangles (NFT) load in Alzheimer’s disease (AD). The aims of our study are to test the stability of common reference regions estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention in the longit...
Attention-Deficit Hyperactivity Disorder (ADHD) is a prevalent neuropsychiatric disorder associated with significant impairment and distress throughout the lifespan. Recent investigations have shed light on different aspects regarding the trajectory of ADHD, including reports on risk factors in childhood, that are associated with remission or persi...
Background
Attention-Deficit/Hyperactivity Disorder (ADHD) persists in older age and is postulated to be a risk factor for cognitive impairment and Alzheimer’s Disease (AD). However, this notion relies exclusively on epidemiological associations, and no previous study has linked ADHD with a decline in cognitive performance in older adults or with A...
The objective of this study is to examine the association between preterm infants’ size at 1 year and attention-deficit/hyperactivity disorder (ADHD) assessed categorically and dimensionally in childhood and adolescence. We studied infants born < 37 weeks’ gestation from two Brazilian birth cohorts (n = 653). ADHD was evaluated using the Developmen...
Introduction
Plasma amyloid-β (Aβ), phosphorylated tau (p-tau), and glial fibrillar acid protein (GFAP) can identify Alzheimer’s disease (AD) pathophysiology with high accuracy. However, comparing their performance in the same individuals remains under-explored.
Methods
We compared the predictive performance of plasma Aβ42/40, p-tau(at threonine 1...
Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD...
Understanding whether vascular risk factors synergistically potentiate Alzheimer's disease progression is important in the context of emerging treatments for preclinical Alzheimer's disease. The existence of a synergistic relationship could suggest that the combination of therapies targeting Alzheimer's disease pathophysiology and vascular risk fac...