Hypoperfusion Precedes Tau Deposition in the Entorhinal Cortex: A Retrospective Evaluation of ADNI-2 Data

Background and Purpose Tau deposition in the entorhinal cortex is the earliest pathologi-cal feature of Alzheimer's disease (AD). However, this feature has also been observed in cogni-tively normal (CN) individuals and those with mild cognitive impairment (MCI). The precise pathophysiology for the development of tau deposition remains unclear. We hypothesized that reduced cerebral perfusion is associated with the development of tau deposition. Methods A subset of the Alzheimer's Disease Neuroimaging Initiative data set was utilized. In-cluded patients had undergone arterial spin labeling perfusion MRI along with [18F]flortaucipir tau PET at baseline, within 1 year of the MRI, and a follow-up at 6 years. The association between baseline cerebral blood flow (CBF) and the baseline and 6-year tau PET was assessed. Univariate and multivariate linear modeling was performed, with p<0.05 indicating significance. Results Significant differences were found in the CBF between patients with AD and MCI, and CN individuals in the left entorhinal cortex (p=0.013), but not in the right entorhinal cor-tex (p=0.076). The difference in maximum standardized uptake value ratio between 6 years and baseline was significantly and inversely associated with the baseline mean CBF (p=0.042, R2=0.54) in the left entorhinal cortex but not the right entorhinal cortex. Linear modeling dem-onstrated that CBF predicted 6-year tau deposition (p=0.015, R2=0.11). Conclusions The results of this study suggest that a reduction in CBF at the entorhinal cortex precedes tau deposition. Further work is needed to understand the mechanism underlying tau deposition in aging and disease.

Automated summary

This study found significant differences in cerebral blood flow (CBF) in the left entorhinal cortex between patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), and cognitively normal (CN) individuals. The difference in CBF was inversely associated with tau deposition in the left entorhinal cortex after 6 years. CBF can predict tau deposition after 6 years.