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

## TL;DR

This study finds that the medial prefrontal cortex is highly vulnerable to neuron loss and metabolic changes in various types of dementia and aging.

## Contribution

The study identifies a shared vulnerability of medial prefrontal pyramidal neurons across multiple dementia types and aging, suggesting a vascular-metabolic mechanism.

## Key findings

- Pyramidal neuron densities and volumes in the medial prefrontal cortex were significantly reduced in dementia groups.
- Metabolic markers COX1 and COX4 were consistently reduced across dementia types.
- Neuronal loss and atrophy correlated with cognitive decline and aging effects.

## Abstract

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.

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.

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.

The mPFC shows high neuronal vulnerability in dementia, while suggesting a vascular–metabolic mechanism, with implications for targeted therapeutic strategies.

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.

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.