Histopathologic interrogation of laminar microcircuits underlying cognition in frontotemporal dementia

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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 in machine learning and segmentation methods, bioinformatics, and social cognition, all areas that will directly benefit my transition to becoming an independent neuroscientist conducting translational research for dementia syndromes.