Background: Previous research has studied inhibitory neurons in a wide range of psychiatric disorders and some neurological disorders such as epilepsy and Alzheimer’s disease. However, detailed studies examining differences in inhibitory neuron loss between frontotemporal lobar degeneration (FTLD) subgroups, which include FTLD-tau and FTLD-TDP, are lacking. Using a large autopsy cohort, we quantified the density and distribution of calretinin-positive inhibitory neurons across the grey matter of FTLD-Tau and FTLD-TDP patients with a clinical diagnosis of behavioral variant frontotemporal dementia by measuring density and percent area occupied of neurons in the middle frontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex.

Method: Regions of interest were examined in 96 patients representing autopsy-confirmed FTLD-tau (n=27), FTLD-TDP (n=48), and age-matched healthy controls (n=21). Middle frontal cortex, orbitofrontal cortex, and anterior cingulate cortex tissue were cut into 6µm-thick sections and stained for calretinin with 3,3′-Diaminobenzidine (DAB) as the chromogen. Neuron densities and percent area occupied were generated using a semi-automated neuron detection pipeline developed in the lab. 

Results: FTLD-tau patients had lower densities and percent area occupied of inhibitory calretinin-positive neurons than FTLD-TDP patients in the orbitofrontal cortex. In contrast, FTLD-TDP patients had lower neuron densities and percent area occupied in the middle frontal cortex and anterior cingulate gyrus, although no statistically significant differences were observed. 

Conclusions: FTLD-tau showed greater neurodegeneration of inhibitory calretinin-positive neurons in the orbitofrontal cortex compared to FTLD-TDP. These findings suggest that FTLD-tau and FTLD-TDP may differentially target inhibitory neurons in a region-specific manner. Further examination will be conducted in more regions and specific cortical layers enriched for inhibitory neurons to elucidate the divergent vulnerabilities of neuronal populations in the FTLD spectrum.