Biomarkers

Olfactory-associated regions, particularly the piriform cortex, may harbor early pathological changes in Alzheimer's (AD) and Parkinson's disease (PD). Amyloid-tau overlap is strongest in the medial temporal lobe. Amyloid-tau association in the piriform cortex versus other medial temporal structures remains unclear. We used dual PET-MR to quantify simultaneous amyloid/tau uptake in the piriform cortex, entorhinal-perirhinal cortices, amygdala, and hippocampus among AD, mild cognitive impairment (MCI), amyloid-positive/negative healthy controls (HC), and PD cohorts.

We analyzed PET-MR cross-sectional data (n = 47): 7 AD, 8 MCI, 13 amyloid+HC, 8 amyloid-HC, and 11 PD enrolled in Stanford's ADRC and SAMS studies. Amyloid ¹⁸F-Florbetaben and tau-PET ¹⁸F-PI-2620 tracers were used, including sagittal T1-weighted and coronal T2-weighted fast-spin-echo MRI. Automated segmentation of entorhinal-perirhinal cortices and the whole hippocampus= (CA1-4+dentate gyrus+subiculum) was performed. Three sub-regions of the piriform cortex were manually segmented blind to diagnosis: frontal, temporal, and the contiguous periamygdaloid-cortex, Figure 1.

Amyloid SUVr (Figure 2): Global amyloid uptake was positively associated with ordinal disease category (whole-brain centiloid scores: non-parametric Jonckheere-Terpstra test J*=-4.89, p <0.001), including the regional amyloid in entorhinal-perirhinal (J*=-4.31, p <0.001), piriform-PAC (J*=-3.40, p <0.001), and amygdala (J*=-3.91, p <0.001), but not in the whole hippocampus (J*=-1.41, p = 0.080). Rank-sum tests showed that amyloid+HC had higher global amyloid burden than amyloid-HC (centiloid scores: z=3.77, p <0.001). In the medial temporal lobe, this included elevated amyloid in piriform-PAC (z=-2.46, p = 0.014), entorhinal-perirhinal (z=-3.26, p = 0.001), and amygdala (z=-2.58, p = 0.007), but not in whole hippocampus (z=-1.23, p = 0.218). There were no differences between PD and amyloid-HC global amyloid uptake (centiloid scores: z=-1.64, p <0.001), including regional amyloid in entorhinal-perirhinal (z=-0.41, p = 0.680), piriform-PAC (z=-0.33, p = 0.741), amygdala (z=-0.58, p = 0.563), and whole hippocampus (z=-0.83, p = 0.409). Amyloid/Tau Correlations (Figure 3): Amyloid was positively correlated with tau uptake in the entorhinal-perirhinal (Spearman's ρ = 0.57, p <0.001), piriform-PAC (Spearman's ρ = 0.50, p <0.001), and amygdala (Spearman's ρ = 0.53, p <0.001) but not the whole hippocampus (Spearman's ρ = 0.26, p = 0.075). Amyloid within entorhinal-perirhinal, piriform-PAC, and amygdala was correlated with tau in most regions, excluding the whole hippocampus.

We show early increases in primary olfactory cortex amyloid-PET, correlating strongly with tau uptake, similar to entorhinal cortex and amygdala, but distinct from hippocampus.