Hippocampus is more susceptible to hypoxic injury: has the Rosetta Stone of regional variation in neurovascular coupling been deciphered?

Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD) are associated with cerebral hypoperfusion or reductions in baseline cerebral blood flow (CBF). The neurovascular coupling (NVC) response or functional hyperemia regulates brain perfusion via a retrograde (capillary-to-arteriole) pathway by increasing regional CBF in response to local neuron activation. The hippocampus plays a significant role in spatial and non-spatial memory. Functional MRI (fMRI) has not established a solid positive correlation between hippocampal blood oxygen level-dependent (BOLD) signal and local neuronal activity. The inconsistency of NVC in the hippocampus compared to the neocortex is possibly due to anatomical and methodological difficulties to accurately detect hippocampal blood flow. A recent study reported that NVC and oxygenation are reduced in the hippocampus compared to the cortex using a novel invasive surgical approach by creating a cranial window with and without removing the neocortex. Results from these studies suggest that the hippocampus is more susceptible to hypoxic injury in pathological conditions when NVC is impaired, such as AD/ADRD, stroke, and traumatic brain injury (TBI). The Rosetta Stone of regional variation in the NVC and its significance in AD/ADRD has not been fully deciphered based on these results without addressing remaining concerns; however, we are one step closer, indeed.