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

Pyramidal neuron densities in the medial prefrontal cortex were reduced by approximately 45% across all dementia groups relative to controls, except for frontotemporal dementia densities.

• Analysis was performed on post mortem brain tissue from 118 older subjects
• Groups included post-stroke survivors, Alzheimer's disease, vascular, mixed, and frontotemporal dementia, and cognitively unimpaired controls
• Three-dimensional stereology was used to assess pyramidal neuron densities in mPFC layers III and V
• Frontotemporal dementia was the exception to the pattern of reduced neuronal density

Pyramidal neuron volumes in the medial prefrontal cortex were reduced by approximately 37% across all dementia groups relative to controls.

• Volume measurements were obtained using three-dimensional stereology in mPFC layers III and V
• The reduction in volume was described as neuronal atrophy
• Both density and volume changes together represent 'severe pyramidal neuron loss and atrophy' in the medial prefrontal cortex
• Neuronal morphometric changes correlated with cognitive status

Mitochondrial metabolic markers COX1 and COX4 were consistently reduced across all dementia groups.

• Immunohistochemistry was used to evaluate cytochrome c oxidase subunit 1 (COX1) and cytochrome c oxidase subunit 4 (COX4) expression
• Metabolic changes decreased by the greatest extent in vascular-associated dementias
• 78 kDa glucose-regulated protein expression was also assessed as a marker of metabolic dysfunction
• Metabolic neuronal markers correlated with aging and frontal vascular pathology

Neuronal densities in the medial prefrontal cortex declined with age, especially during the sixth decade of life.

• The age-related decline was specifically pronounced in the sixth decade of life
• Neuronal morphometric changes correlated with aging effects
• This aging-related vulnerability was observed in the mPFC specifically

Other prefrontal areas were less affected by neuronal loss compared to the medial prefrontal cortex.

• The medial prefrontal cortex showed higher vulnerability compared to other prefrontal regions
• The differential vulnerability of the mPFC compared to other prefrontal regions had previously remained unclear
• The mPFC is critical for executive function, behavioral inhibition, and memory

The study suggests a vascular-metabolic mechanism underlies the high vulnerability of the medial prefrontal cortex in dementia.

• Metabolic changes decreased by the greatest extent in vascular-associated dementias
• Metabolic neuronal markers correlated with frontal vascular pathology
• The findings have implications for targeted therapeutic strategies
• The pattern of COX1 and COX4 reduction is consistent with mitochondrial dysfunction as a contributing mechanism