About

David John Irwin, MD, MTR, is an Associate Professor of Neurology at the University of Pennsylvania's Perelman School of Medicine. He is a member of the Penn Institute for Translational Medicine and Therapeutics, an Associate Fellow and Internal Advisory Board Member of the Penn Institute on Aging, and co-Director of the Penn Frontotemporal Degeneration Center. His clinical expertise focuses on cognitive neurology and neurodegenerative diseases, including frontotemporal dementia, primary progressive aphasia, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, progressive supranuclear palsy, corticobasal syndrome, and multiple system atrophy, with a particular interest in young-onset dementia and the behavioral variant of frontotemporal dementia. His research interests center on neuropathology and biomarkers of neurodegenerative disease. He leads the Penn Digital Neuropathology Lab, which employs a multidisciplinary approach combining histopathology of human brain tissue with image analysis and bioinformatics to improve understanding of brain-behavior relationships and the diagnosis of neurodegenerative diseases. His work aims to develop objective, reproducible digital image analysis tools for studying postmortem neuropathology, with the goal of translating these findings into new laboratory and imaging tests for detecting pathology in living patients. His research focuses on identifying diagnostic and prognostic markers of disease progression, especially in young-onset and atypical dementias, to facilitate clinical trials and therapeutic development.

Research topics

• Medicine
• Biology
• Pathology
• Neuroscience
• Internal medicine
• Psychology
• Psychiatry
• Cell biology
• Genetics
• Oncology
• Computer Science
• Artificial Intelligence
• Radiology
• Bioinformatics
• Chemistry
• Demography
• Physics
• Developmental psychology
• Clinical psychology
• Biochemistry
• Intensive care medicine
• Nuclear medicine
• Molecular biology
• Family medicine

Selected publications

• An acetylated Tau-174 CSF biomarker discriminates between TDP-43 and tau pathology in patients with frontotemporal lobar degeneration

  Nature Medicine · 2026-04-15

  articleOpen access

  Biomarkers to determine underlying frontotemporal lobar degeneration (FTLD) tau or TAR DNA-binding protein (TDP) pathology during life are needed to advance clinical trials targeting specific FTD pathologies. For this purpose, we developed a new ultrasensitive immunoassay to quantify acetylated tau at lysine 174 (AcTau174) in cerebrospinal fluid (CSF). In a sporadic cohort (n = 513), AcTau174 concentrations were higher in all dementia groups (FTLD-TDP, FTLD-Tau, Alzheimer's disease (AD), mild cognitive impairment (MCI)-AD and dementia with Lewy bodies (DLB)) compared to controls. The largest increase was observed in the FTLD-TDP group, particularly patients with semantic variant primary progressive aphasia (svPPA) and GRN mutation carriers. Notably, AcTau174 discriminated FTLD-TDP from FTLD-Tau (area under the curve (AUC) = 0.83, 95% confidence interval (CI) = 0.75-0.91) and FTLD-TDP from controls (AUC = 0.95, 95% CI = 0.92-0.99) with high accuracy. This was replicated in independent, sporadic and genetic validation cohorts (164 patients and 24 controls), albeit with somewhat lower accuracy (FTLD-TDP versus FTLD-Tau; AUC range = 0.75-0.79) and wider CIs. Within the FTLD-TDP, AD and MCI-AD groups, higher AcTau174 concentrations were associated with a faster cognitive decline over time. In summary, CSF AcTau174 has great potential to discriminate FTLD-TDP from FTLD-Tau as a biomarker reflecting FTLD-TDP disease severity and progression.

  PublisherDOI

• Automated Imaging Differentiation for Dementia

  Neurology Open Access · 2026-04-13

  articleOpen access

  Differentiation of Alzheimer disease dementia (ADD) and dementia with Lewy bodies (DLB) remains a challenge. Free-water (FW) imaging has been investigated in neurodegenerative diseases and was found to be associated with neurodegeneration and neuroinflammation. This retrospective cohort study tested whether Automated Imaging Differentiation for Dementia (AIDD), combining diffusion free-water imaging (FWI) and support vector machine, predicts ADD vs DLB with high accuracy.

  PublisherDOI

• Performance of 123I‐ioflupane SPECT striatal binding in dementia with Lewy bodies

  The Medicine Forum · 2025-09-25

  articleOpen access

  INTRODUCTION: We aimed to determine whether ¹²³I-ioflupane single-photon emission computed tomography (SPECT) striatal binding ratio (SBR) correlated with parkinsonian motor symptoms in dementia with Lewy bodies (DLB) and if SBR predicts worsening of parkinsonism over time. METHODS: A retrospective cohort study of the U.S. Dementia with Lewy Bodies Consortium dataset including individuals with DLB with baseline ¹²³I-ioflupane SPECT analyzed with DaTQUANT and baseline and 24-month Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). A subset had cerebrospinal fluid α-synuclein seed amplification assay (SAA) evaluation. RESULTS: Baseline mean SBRs were significant predictors of baseline and 24-month MDS-UPDRS-III scores, although they did not predict meaningful worsening over time. SAA positivity was associated with lower SBRs; Z score cut-off values are provided. DISCUSSION: In suspected DLB, ¹²³I-ioflupane SPECT, at diagnosis, could be used to confirm underlying dopamine deficiency; it does not predict meaningful worsening of motor parkinsonism. More severe dopamine deficiency increases confidence in presence of synucleinopathy. HIGHLIGHTS: ¹²³I-ioflupane single-photon emission computed tomography (SPECT) can confirm underlying dopamine deficiency. Striatal binding ratio (SBR) Z scores predicted 24-month Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III) scores. SBR Z scores are not predictive of subsequent meaningful worsening of parkinsonism. More severe dopamine dysfunction on SPECT is associated with presence of seed amplification assay (SAA). SBR Z score cut-offs that indicate cerebrospinal fluid SAA positivity are provided.

  PublisherDOI

• Where do PDD and DLB SYNdromes fit in neuronal alpha-SYNuclein biological frameworks?

  Journal of Neural Transmission · 2025-12-04 · 1 citations

  articleOpen access1st authorCorresponding

  Lewy body disorders (LBD) are a spectrum of neurodegenerative diseases characterized by the presence of misfolded neuronal alpha-synuclein (aSYN) pathology in the central and peripheral nervous system. LBDs have heterogeneous clinical presentations, which include dementia with Lewy bodies (DLB), Parkinson's disease (PD), and PD with dementia (PDD). Thus, LBD clinical syndromes (PD/PD/DLB) represent clinicopathologic entities (i.e. constellations of symptoms and supportive biomarkers with a high specificity for underlying aSYN pathology), but clinical features between PDD and DLB largely overlap. Indeed, there is longstanding debate over the utility of the clinical designation between PDD and DLB due to shared underlying pathology, genetic risk factors and prodromal features. Recent advances in the ability to detect pathological aSYN from peripheral fluids/tissues in living patients has ushered in a new era of biological classification of LBD, providing opportunity to improve antemortem diagnosis and facilitate disease-modifying therapeutic trials. The clinical interpretation of these and future aSYN-specific biological tests will be complex, and the reconciliation of classic LBD syndromes with emerging biological classification schemes for LBD and other neurodegenerative disorders is a priority. Indeed, varying burden of aSYN is also found postmortem in > 50% of clinical Alzheimer's disease (AD), and to a lesser frequency as co-pathology in other neurodegenerative disorders, and incidentally in adults without neurologic disease. This review summarizes autopsy-confirmed data on the clinical expression of LBDs and the boundaries between PDD, DLB and mixed-pathology AD to inform the interpretation of emerging biological tests for aSYN and biological classification schemes for LBD and AD.

  PublisherOA PDFDOI

• Choroidal evaluation of FTLD-Tau and biomarker-determined Alzheimer’s disease

  Scientific Reports · 2025-07-01

  articleOpen accessSenior author

  Frontotemporal lobar degeneration with tauopathy (FTLD-Tau) can present clinically similar to Alzheimer's disease but lacks a biomarker. Alzheimer's disease has been associated with choroidal thinning compared to controls. We compared the choroid of 25 probable FTLD-Tau (pFTLD-Tau) patients (42 eyes), 26 biomarker-determined probable Alzheimer's disease neuropathologic change (pADNC) patients (49 eyes), and 53 normal controls (80 eyes). Cerebrospinal fluid biomarkers determined presence of ADNC. All pFTLD-Tau patients had a syndrome highly associated with FTLD-Tau. Optical coherence tomography was performed with masked manual choroidal thickness (CT) measurements. With Image J, binarized images determined the choroidal vascularity index (CVI). Linear regression with generalized estimating equations to account for inter-eye correlation was performed. For pFTLD-Tau, pADNC, and controls, the subfoveal CT was 308.9, 286.0, and 301.5 μm, and CVI was 0.72, 0.72, and 0.73, respectively (all p > 0.05 for each group comparison). Adjusting for demographics, the CT and CVI were not significantly different between groups, including 13 CT measurement locations (all p > 0.05). Among pADNC patients, an exploratory analysis found a correlation between CVI and disease duration (Pearson r = 0.32, p = 0.04). We found no significant difference of CT or CVI between pFTLD-Tau, pADNC, and controls. Additional studies are warranted to evaluate how CVI relates to ADNC.

  PublisherOA PDFDOI

• Clinical recognition of frontotemporal dementia with right temporal predominance: a consensus statement from the International Working Group

  Communications Medicine · 2025-12-12 · 4 citations

  reviewOpen access

  Accurate diagnosis of frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance remains challenging due to lack of clinical characterization, and standardized terminology. The recent research of the International Working Group (IWG) identified common symptoms but also unveiled broad terminologies lacking precision and operationalization, with risk of misdiagnoses, inappropriate referrals and poor clinical management. Based on the published evidence (91267 articles screened) and expert opinion (105 FTD specialists across 52 centers) by using the nominal group technique, the IWG delineates three primary domains of impairment causing behavioral, memory and language problems: (i) multimodal knowledge of non-verbal information including people, living beings, landmarks, flavors/odors, sounds, bodily sensations, emotions and social cues; (ii) socioemotional behavior encompassing emotion expression, social response and motivation; and (iii) prioritization for focus on specific interests, hedonic valuation and personal preferences. This study establishes a consensus on clinical profile, phenotypic nomenclature, and future directions to enhance diagnostic precision and therapeutic interventions.

  PublisherOA PDFDOI

• Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia

  Molecular Neurodegeneration · 2025-08-27 · 5 citations

  articleOpen access

  Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55). Forty-three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.

  PublisherOA PDFDOI

• Racial/ethnic differences in neuropsychological test performance in frontotemporal degeneration

  Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · 2025-10-01

  articleOpen access

  Abstract BACKGROUND Racial and/or ethnic differences in neuropsychological test performance are understudied in frontotemporal degeneration (FTD) but their identification is critical to identifying ways to improve care of representative FTD populations. METHODS Differences in cognitive scores between Black ( n = 56) and Hispanic ( n = 76) relative to White ( n = 2281) participants and the likelihood of impairment status in cognitive test performance were evaluated. RESULTS Minoritized individuals had lower scores and/or greater likelihood of impairment on measures of lexical retrieval, processing speed, cognitive flexibility, and working memory but not global cognition, verbal recall, attention, and category fluency. Addition of severity, age ( M = 65.18), sex (40% female), education ( M = 15.62), and vascular comorbidities attenuated group differences. DISCUSSION Racial/ethnic differences on neuropsychological tests used in diagnosis and monitoring of FTD were substantially attenuated when accounting for potential contributing factors. To address these differences in FTD, future efforts must increase representative research participation of patients and understand social determinants of health. Highlights Racially/ethnically minoritized individuals with frontotemporal dementia are severely underrepresented in the National Alzheimer's Coordinating Center dataset Racially/ethnically minoritized individuals with frontotemporal dementia obtained lower scores and greater likelihood of impairment on common neuropsychological tests The effect of racial/ethnic group on neuropsychological test scores was substantially attenuated when adjusting for disease severity, education level, sex, and age

  PublisherOA PDFDOI

• Chi-Separation Detects Focal Changes in Cortical Paramagnetism Associated with Behavioral Variant Frontotemporal Dementia

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: Syndrome-specific patterns of iron-rich cortical gliosis have been demonstrated postmortem in Frontotemporal Lobal Degeneration (FTLD) but have not been reliably detected in vivo. Goal(s): Evaluate whether Chi-separation and/or Quantitative Susceptibility Mapping (QSM) can reliably detect regional changes in cortical paramagnetism in behavioral variant frontotemporal dementia (bvFTD) patients. Approach: Patients with bvFTD, Alzheimer's disease, and one age-matched control were imaged at 3T using a multi-gradient echo sequence. Both QSM and Chi-separation maps were analyzed within DKT cortical regions associated with expected pathology. Results: Chi-separation paramagnetic maps showed statistically significant increases in anterior cingulate, a region of expected pathology. Impact: We show that chi-separations maps can be used to detect syndrome-specific paramagnetic cortical changes, demonstrating its ability to quantify the distribution of iron-rich gliosis in vivo in FTLD, which has previously only been reliably visualized postmortem.

  PublisherDOI

• Accelerating biomedical discoveries in brain health through transformative neuropathology of aging and neurodegeneration

  Neuron · 2025-07-18 · 8 citations

  reviewOpen access

  Transformative neuropathology is redefining human brain research by integrating foundational descriptive pathology with advanced methodologies. These approaches, spanning multi-omics studies and machine learning applications, will drive discovery for the identification of biomarkers, therapeutic targets, and complex disease patterns through comprehensive analyses of postmortem human brain tissue. Yet critical challenges remain, including the sustainability of brain banks, expanding donor participation, strengthening training pipelines, enabling rapid autopsies, supporting collaborative platforms, and integrating data across modalities. Innovations in digital pathology, tissue quality enhancement, harmonization of data standards, and machine learning integration offer opportunities to accelerate tissue-level "pathomics" research in brain health through cross-disciplinary collaborations. Lessons from neuroimaging, particularly in establishing common data frameworks and multi-site collaborations, offer a valuable roadmap for streamlining innovations. In this perspective, we outline actionable solutions for leveraging existing resources and strengthening collaboration -where we envision future opportunities to drive translational discoveries stemming from transformative neuropathology.

  PublisherDOI

Recent grants

• NIH Grant K23NS088341

  NIH · $836k · 2019

• Administrative Core

  NIH · $31.1M · 2020–2030

• Microscopic and Large-Scale Networks of Molecular Pathology in Frontotemporal Lobar Degeneration

  NIH · $3.8M · 2019–2025

Frequent coauthors

• Keith A. Johnson

  Massachusetts General Hospital

  729 shared

• D. Cheng

  567 shared

• Murray Grossman

  546 shared

• Joseph C. Wu

  486 shared

• John Q. Trojanowski

  University of Pennsylvania

  455 shared

• Monte S. Buchsbaum

  University of California, Irvine

  405 shared

• Marcelo F. Di Carli

  Harvard University

  405 shared

• Carl K. Hoh

  University of California, San Diego

  405 shared

Labs

• Irwin LabPI