David John Irwin
University of Pennsylvania, PA·Neuroscience
Frontotemporal dementia (FTD) is as common as Alzheimer's disease in people under 65. It erodes behavior, social skills, language and planning, and it has no approved treatments.
- Fields
Neuroscience
Medicine & Clinical Research
- Topics
frontotemporal dementia
frontotemporal lobar degeneration
tau
- Grants
- 4 known grants, through Dec 2030
What they work on
- Test whether FTLD-Tau and FTLD-TDP show distinct layer-specific and regional patterns of iron-rich gliosis (activated support cells) in postmortem brain, using multiplexed immunofluorescence and 7T MRI-guided digital histology of the Penn FTLD brain bank.
- Relate microscopic glial and iron-overload measures to patients' cognitive and behavioral data and longitudinal MRI during life, using statistical modeling and network science.
- Model how alpha-synuclein spreads in Lewy body dementia by applying graph theory to digital histopathology from a large autopsy cohort, accounting for co-occurring Alzheimer's tau pathology.
- Integrate cellular alpha-synuclein and tau maps with autopsy- or biomarker-confirmed MRI scans from life to identify vulnerable neurons and define biologically meaningful Lewy body dementia subgroups.
- Compare the cellular environment of layer-specific degeneration in FTLD-TDP vs FTLD-Tau using spatial transcriptomics and multiplex immunofluorescence in tissue sampled under ultra-high-resolution ex vivo MRI.
- Use semi-supervised machine learning, guided by myelin and neuron stains, to divide 7T ex vivo MRI into layer-specific regions and compare whole-hemisphere degeneration patterns between FTLD-TDP and FTLD-Tau.
- Recruit and follow patients with FTD syndromes, including svPPA, ALS-FTD, PSP and carriers of GRN, C9orf72 or MAPT mutations, collecting neuropsychological tests, digital language measures, blood, cerebrospinal fluid and 3T/7T MRI.
More about the research
The same symptoms can come from different underlying brain diseases. In FTD, these are frontotemporal lobar degeneration (FTLD) with clumps of the protein tau (FTLD-Tau) or of the protein TDP-43 (FTLD-TDP). Today the two can only be told apart at autopsy. Related problems arise in Lewy body dementia (LBD), driven by clumps of alpha-synuclein (aSyn). This research links microscope-level analysis of donated human brain tissue with brain imaging and clinical data from patients during life. The goal is to understand how these diseases spread and to build tests that can detect them in living patients.
Why it matters
Patients with frontotemporal dementia and Lewy body dementia lack tests that reveal which protein is damaging their brain, and this blocks targeted drug trials. Autopsy-validated maps of glial inflammation, iron buildup and protein spread could guide MRI and fluid biomarkers that tell FTLD-Tau from FTLD-TDP in living patients and track disease progression. Well-characterized patient cohorts could also supply clinical endpoints and therapeutic targets for future treatment trials.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Allison L Kraus
Case Western Reserve University, OH·Neuroscience
Define the age of onset, amount, brain location and chemical variety of tau seeds in diseased, normal, young and older human brains, using RT-QuIC seed amplification assays specific to 3R, 4R and 3R/4R tau.
David C Perry
University of California-San Francisco, CA·Neuroscience
Determine which factors predict a stable, certain bvFTD diagnosis at the first visit, by following 60 patients over time with neurological exams, cognitive testing and structural and functional neuroimaging.
Nicholas Seyfried
Emory University, GA·Biochemistry
Build a longitudinal Lewy body dementia registry under the Parkinson's Disease Biomarker Program, collecting clinical data and biospecimens to support validation of protein biomarkers.
The school
University of Pennsylvania: 90 labs on PI Pages, $2.2B a year on research, 750 research doctorates a year.
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