# Histopathologic interrogation of laminar microcircuits underlying cognition in frontotemporal dementia

> **NIH NIH K01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $127,305

## Abstract

The neural determinants of cognition are not well understood in the human brain and particularly elusive in
patients diagnosed with frontotemporal dementia (FTD). FTD is a heterogeneous spectrum of clinical disorders
often associated with impairments in social cognition, executive function, or language. FTD is typically caused
by frontotemporal lobar degeneration proteinopathies including tau or TDP-43 pathology not yet diagnosable
during life. Thus, identification of the neurons that selectively degenerate in FTD with tau (FTD-tau) and FTD
with TDP-43 (FTD-TDP) may be informative to the development of anatomically-grounded diagnostics and
neuroprotective therapeutics lacking in FTD. However, the clinical relevance of neuron loss remains unclear due
in part to clinicopathologic heterogeneity within the FTD spectrum. Another limiting factor is that traditional, low-
throughput methods preclude large-scale postmortem studies of FTD and rarely examine the cyto- or
myeloarchitectonic subdivisions of brain regions (e.g. cortical layers) where distinct neurons reside and
microcircuits connect local and distant regions.
My recent comparative study of cortical layer pathology found that tau and TDP-43 pathology accumulate distinct
laminar distributions in clinically similar FTD patients. However, the layer-specific neurons that accrue pathology
and the axonal pathways by which pathology may spread are understudied in FTD syndromes, despite the
compelling experimental evidence for trans-synaptic transmission of pathologic proteins in diverse networks. To
address these gaps in knowledge, the current project plans to examine laminar architecture to leverage the
unique cellular organization and connectivity of cortical layers to identify differential loss of laminar microcircuits
embedded in large-scale frontotemporal networks involved in FTD. I propose to develop a new high-throughput
approach to quantify laminar neuronal features comprising short and long-range microcircuits with inhibitory or
excitatory properties. Based on my preliminary data, I hypothesize that tau and TDP-43 pathology will be related
to the loss of partly distinct laminar microcircuits in regional networks vulnerable to FTD, suggesting that different
neural microcircuits may contribute to similar cognitive impairments across the FTD spectrum.
My cortical layer framework is a unique approach to interrogate changes to laminar microcircuits, facilitating the
discovery of new disease-specific patterns of neurodegeneration within gross anatomical regions to identify the
neural substrates of pathologic subgroups and clinical symptoms of FTD. The differential loss of laminar
microcircuits in FTD is a conceptual paradigm for advancing the study of selective vulnerability at the mesoscale,
thereby serving as a critical bridge between emerging microscopic genetic expression data and macroscopic
network/connectome studies. Completing this project will require I obtain interdisciplinary training i...

## Key facts

- **NIH application ID:** 10830401
- **Project number:** 5K01AG081484-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel Timothy Ohm
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $127,305
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830401

## Citation

> US National Institutes of Health, RePORTER application 10830401, Histopathologic interrogation of laminar microcircuits underlying cognition in frontotemporal dementia (5K01AG081484-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10830401. Licensed CC0.

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