David J Irwin

David J Irwin
University of Pennsylvania | UP · Department of Neurology

MD

About

294
Publications
32,241
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Introduction
In the Penn Digital Neuropathology Lab, we use a multidisciplinary approach merging techniques in “wet-lab” based histopathology of human brain tissue with “dry-lab” based image analysis tools with the overarching goal of developing tissue-based biomarkers critically-needed to improve the antemortem diagnosis of neurodegenerative diseases, including Frontotemporal dementia, Lewy body disorders and Alzheimer’s disease. Rapid and accurate diagnosis of underlying neuropathology in living patients is critical for the development of effective disease-modifying therapies.
Additional affiliations
July 2014 - November 2015
University of Pennsylvania
Position
  • Instructor
July 2010 - present
Hospital of the University of Pennsylvania
Position
  • PostDoc Position
January 2008 - May 2010

Publications

Publications (294)
Article
Background: Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies. Methods: In this retrospective study, we...
Article
Objective: To test the hypotheses that (1) antemortem cerebrospinal fluid (CSF) tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration (FTLD) and (2) tauopathy patients have higher phosphorylated-tau levels compared to transactivation response element DNA-binding protein 43 (TDP-43) proteinopathy patients while acc...
Article
Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a valida...
Article
Objective To use digital histology in a large autopsy cohort of Lewy Body Disorder (LBD) patients with dementia to test the hypotheses that co‐occurring Alzheimer's disease (AD) pathology impacts the anatomic distribution of α‐synuclein (SYN) pathology and that co‐occurring neocortical tau pathology in LBD associates with worse cognitive performanc...
Article
Objective To measure postmortem burden of frontotemporal lobar degeneration (FTLD) with TDP‐43 (FTLD‐TDP) or tau (FTLD‐Tau) proteinopathy across hemispheres in primary progressive aphasia (PPA) using digital histopathology, and identify clinicopathological correlates of these distinct proteinopathies. Methods In an autopsy cohort of PPA (FTLD‐TDP=...
Chapter
Frontotemporal lobar degeneration (FTLD) is a diverse group of neurodegenerative diseases associated with variable clinical phenotypes. Most FTLD cases are characterized by the accumulation of abnormal protein inclusions comprised of either TDP-43 or tau and in concert with neuron loss and gliosis of frontal and temporal regions. We describe here t...
Article
Full-text available
Background Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 sy...
Article
Background: An understudied variant of Alzheimer’s disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. Objective: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to beh...
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Full-text available
Alzheimer’s disease neuropathologic change (ADNC) is clinically heterogenous and can present with a classic multidomain amnestic syndrome or focal non-amnestic syndromes. Here, we investigated the distribution and burden of phosphorylated and C-terminally cleaved tau pathologies across hippocampal subfields and cortical regions among phenotypic var...
Article
Background: Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday...
Article
Objective: Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. W...
Article
Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique...
Article
Full-text available
Introduction: Lewy body diseases are pathologically characterized by α-synuclein pathology. Alzheimer's disease (AD) co-pathology can influence phenotypes. In vivo AD biomarkers can suggest the presence of this co-pathology in unusual cases, but pathological validation remains essential. Methods: This patient originally presented with corticobas...
Preprint
Objective Plasma phosphorylated tau (p-tau 181 ) is reliably elevated in Alzheimer’s disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here we find novel evidence that plasma p-tau 181 is elevated in amytrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We...
Article
Background: While cutoffs for abnormal levels of the cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ 142), total tau (t-tau), phosphorylated tau (p-tau), and the ratios of t-tau/Aβ 142 and p-tau/Aβ 142, have been established in Alzheimer's disease (AD), biologically relevant cutoffs have not been studied extensively in Parkinson's disease...
Article
Full-text available
Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, w...
Article
Network analyses inform complex systems such as human brain connectivity, but this approach is seldom applied to gold-standard histopathology. Here, we use two complimentary computational approaches to model microscopic progression of the main subtypes of tauopathy versus TDP-43 proteinopathy in the human brain. Digital histopathology measures were...
Article
Full-text available
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by ast...
Article
Full-text available
Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregiona...
Chapter
Autopsy validation is still required for a definitive diagnosis of Parkinson's disease (Postuma et al., 2015), where the presence of Lewy bodies and Lewy neurites, composed primarily of alpha-synuclein, are observed in stereotyped patterns throughout regions of the brainstem, limbic, and neocortical regions of the brain (Braak et al., 2003). In spi...
Article
Frontotemporal lobar degeneration (FTLD) includes clinically similar FTLD-tau or FTLD-TDP proteinopathies which lack in vivo markers for accurate antemortem diagnosis. To identify early distinguishing sites of cortical atrophy between groups, we retrospectively analyzed in vivo volumetric MRI from 42 FTLD-Tau and 21 FTLD-TDP patients and validated...
Article
Full-text available
The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Eu...
Preprint
Full-text available
An understudied non-amnestic variant of Alzheimer's disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal deme...
Article
Full-text available
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer’s disease (AD). We aimed to identify the pathological, clinical, and genetic cha...
Article
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In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing...
Article
Full-text available
Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging t...
Article
br/>Background In dementia with Lewy bodies (DLB), amyloid co-pathology is common and associated with an unfavorable prognosis. For targeted treatment development for DLB, we need to establish 1) whether the presence of amyloid marks co-occurring Alzheimer disease (AD), and 2) how DLB with amyloid differs from DLB without amyloid. We employ proteom...
Article
Recent models propose that spread of Alzheimer's disease (AD) pathology may be mediated by white matter connectivity. AD clinical variants exhibit partially distinct patterns of gray matter atrophy. However, it is less clear whether phenotypic differences extend to patients' white matter connectomes. We hypothesized that white matter connectivity w...
Article
Neurogranin (Ng) is a postsynaptic protein involved in long‐term potentiation and is largely expressed in temporal, parietal, and limbic regions (Lista et al., 2017; Kvartsberg et al., 2019). Increased Ng in cerebrospinal fluid (CSF) follows synaptic dysfunction, and is thought to be a marker specific to Alzheimer’s disease (AD) pathology (Porteliu...
Article
Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lo...
Article
Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer’s disease (AD) have noted reduced increases or frank decreases in tau signal. It is unclear whether these reductions reflect measurement/processing error or biological changes in advanced neurodegeneration. We assessed regional and interindividual variation in...
Article
Background: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imper...
Article
Measurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we d...
Article
Quantitative three‐dimensional maps of tau neurofibrillary tangles (NFT) burden derived from dense serial histology have potential application for in‐vivo biomarker studies. We constructed a group‐level NFT burden map from 15 medial temporal lobe (MTL) specimens, majority with Primary Age‐Related Tauopathy (PART) or low‐level Alzheimer’s disease ne...
Article
Lewy Body Spectrum Disorders (LBSD) are hallmarked by α‐synucleinopathy. Up to 50% of LBSD have co‐occurring Alzheimer’s Disease (AD) at autopsy and this is associated with earlier dementia onset, greater cognitive impairments, and reduced survival. In vivo identification of AD co‐pathology is currently achievable with invasive cerebrospinal fluid...
Article
Blood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored. FLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9...
Article
Frontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD. Plasma P‐tau217 was measured cross‐sectionally by elect...
Article
Background: Up to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f-FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f-FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important....
Article
Cortico‐basal degeneration (CBD) and progressive supranuclear palsy (PSP) are 4R‐tauopathies characterized by progressive tau pathology spread that typically starts in the subcortex. Pre‐clinical studies suggest that tau spreads across connected neurons in an activity‐dependent manner, indicating that the brains’ connectome may mediate tau spreadin...
Article
Background: Non-amnestic presentations of Alzheimer's disease (naAD) correspond to focal cortical areas of high tau pathology that map to clinical symptoms. Moreover, previous work finds relative sparing of the hippocampal formation compared to typical amnestic AD (aAD); however, there is limited data on the regional patterns of tau pathology acro...
Article
Background: Genetic mutations in the microtubule-associated protein tau (MAPT) cause frontotemporal lobar degeneration (FTLD-MAPT), associated with severe frontotemporal atrophy antemortem, and highly heterogeneous tau immunoreactivity postmortem, with differential involvement of 3-repeats (3R) or 4-repeats (4R) tau isoforms. To date, there are li...
Article
Full-text available
Alzheimer’s disease (AD) is associated with inner retina (nerve fiber and ganglion cell layers) thinning. In contrast, we have seen outer retina thinning driven by photoreceptor outer nuclear layer (ONL) thinning with antemortem optical coherence tomography (OCT) among patients considered to have a frontotemporal degeneration tauopathy (FTLD-Tau)....
Article
Full-text available
Recent advances in spatially resolved transcriptomics (SRT) technologies have enabled comprehensive characterization of gene expression patterns in the context of tissue microenvironment. To elucidate spatial gene expression variation, we present SpaGCN, a graph convolutional network approach that integrates gene expression, spatial location and hi...
Article
Full-text available
Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human p...
Article
Full-text available
Biomarkers to discriminate the main pathologies underlying frontotemporal lobar degeneration (FTLD-Tau, FTLD-TDP) are lacking. Our previous FTLD cerebrospinal fluid (CSF) proteome study revealed that sex hormone-binding globulin (SHBG) was specifically increased in FTLD-Tau patients. Here we investigated the potential of CSF SHBG as a novel biomark...
Article
Objective: Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this stu...
Preprint
Full-text available
INTRODUCTION: Over 50% of logopenic variant primary progressive aphasia (lvPPA) cases are associated with AD pathology, yet their speech is not characterized compared to amnestic AD. In this study, we compared AD and lvPPA patients in a biologically confirmed cohort. METHODS: We extracted language variables with automated lexical and acoustic pipel...
Article
Full-text available
Introduction: Longitudinal positron emission tomography (PET) studies of tau accumulation in Alzheimer's disease (AD) have noted reduced increases or frank decreases in tau signal. We investigated how such reductions related to analytical confounds and disease progression markers in atypical AD. Methods: We assessed regional and interindividual...
Preprint
Full-text available
Background. Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological front...
Preprint
The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy Body Dementia (LBD), which includes Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). The meeting featured eight internationally known scientists from Eur...
Preprint
Full-text available
Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astrogl...
Article
Background: Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias. Clinical trials for individuals with DLB are increasing. We aimed to identify commonly used outcome measures for trials in DLB. Methods: A pragmatic literature search of PubMed and clinicaltrials.gov identified interventional studies including populatio...
Article
Full-text available
Introduction: In primary progressive aphasia (PPA) patients with autopsy-confirmed Alzheimer's disease (AD) or frontotemporal lobar degeneration (FLTD), we tested how the core clinical features of logopenic PPA-naming and repetition-change over time and relate to pathologic burden. Methods: In PPA with AD (n = 13) or FTLD (n = 16) pathology, Bos...
Article
Full-text available
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau....
Article
The T allele in rs1768208 located in or near the myelin oligodendrocyte basic protein gene (MOBP) is a risk factor for frontotemporal degeneration pathology. We evaluated the hypothesis that the presence of a T allele in rs1768208 will be associated with rate of cognitive decline in behavioral variant frontotemporal degeneration (bvFTD) related to...
Article
Full-text available
The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyl...
Article
Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s dis...
Article
Background: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. Objective: Investigate the full range of acoustic and...
Article
Full-text available
Background Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal...
Preprint
Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging t...
Article
Full-text available
Objective We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. Methods Baseline plasma NfL concentrations were measured with Simoa in original (n = 277) and validation (n = 297) cohorts. C9orf72 ,...
Article
Full-text available
Frontotemporal lobar degeneration proteinopathies with tau inclusions (FTLD-Tau) or TDP-43 inclusions (FTLD-TDP) are associated with clinically similar phenotypes. However, these disparate proteinopathies likely differ in cellular severity and regional distribution of inclusions in white matter (WM) and adjacent grey matter (GM), which have been un...
Article
Full-text available
Objective: To determine whether Lewy body dementia (LBD) patients with likely Alzheimer's disease-type (AD-type) co-pathology are more impaired on confrontation naming than those without likely AD-type co-pathology. Methods: We selected 57 LBD patients (dementia with Lewy bodies, DLB, n=38; Parkinson's disease dementia, PDD, n=19) with available...
Article
We implemented an automated analysis of lexical aspects of semi-structured speech produced by healthy elderly controls (n=37) and three patient groups with frontotemporal degeneration (FTD): behavioral variant FTD (n=74), semantic variant primary progressive aphasia (svPPA, n=42), and nonfluent/agrammatic PPA (naPPA, n=22). Based on previous findin...
Article
We are pleased to read Professor Jellinger’s response to our work and his analyses in the Vienna autopsy cohort [1]. These data using expert ordinal ratings of pathology largely align with our analyses using digital histopathological methods and nicely emphasize the importance of tau pathology in Lewy body dementias (LBD). There were minor discrepa...
Preprint
Full-text available
Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on convent...