High vulnerability of medial prefrontal pyramidal neurons in post‐stroke, vascular, Alzheimer's disease, and aging‐related dementias

Abstract INTRODUCTION The medial prefrontal cortex (mPFC) is critical for executive function, behavioral inhibition, and memory. Its high vulnerability to dementia, compared to other prefrontal regions, remains unclear. METHODS We analyzed post mortem brain tissue from 118 older subjects, including post‐stroke survivors, Alzheimer's disease; vascular, mixed, and frontotemporal dementia (FTD); and cognitively unimpaired controls. Three‐dimensional stereology was used to assess pyramidal neuron densities and volumes in mPFC layers III and V. Immunohistochemistry evaluated metabolic dysfunction via cytochrome c oxidase subunit 1 (COX1), cytochrome c oxidase subunit 4 (COX4), and 78 kDa glucose‐regulated protein expression. RESULTS Pyramidal neuron densities were lowered by ≈ 45% and volumes by ≈ 37% within all dementia groups relative to controls, except for FTD densities. COX1 and COX4 mitochondrial markers were consistently reduced across dementias. Neuronal densities declined with age, especially in the sixth decade of life. Other prefrontal areas were less affected. DISCUSSION The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular–metabolic mechanism, with implications for targeted therapeutic strategies. Highlights Severe pyramidal neuron loss and atrophy arose in the medial prefrontal cortex. Neuronal morphometric changes correlated with cognitive status or aging effects. Metabolic changes decreased by the greatest extent in vascular‐associated dementias. Metabolic neuronal markers correlated with aging and frontal vascular pathology.