Objective The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Center Harmonized Hippocampal Segmentation Protocol (HarP). Methods Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained. Results We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = −0.75, P = .001), tau (ρ = −0.53, P = .034), Aβ burden (ρ = −0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aβ in CA1 (ρ = −0.58, P = .019) and subiculum (ρ = −0.75, P = .001), tau in CA2 (ρ = −0.59, P = .016), and CA3 (ρ = −0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001). Conclusions The observed associations provide the pathological confirmation of hippocampal morphometry as a valid biomarker for AD and the pathologic validation of HarP.

Hippocampal atrophy, amyloid plaques, and neurofibrillary tangles are established pathologic markers of Alzheimer's disease. We analyzed the temporal lobes of 9 Alzheimer's dementia (AD) and 7 cognitively normal (NC) subjects. Brains were scanned post-mortem at 7 Tesla. We extracted hippocampal volumes and radial distances using automated segmentation techniques. Hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet to evaluate neuronal counts. The hippocampal subfields, CA1, CA2, CA3, CA4, and subiculum were manually traced so that the neuronal counts, Aβ, and tau burden could be obtained for each region. We used linear regression to detect associations between hippocampal atrophy in 3D, clinical diagnosis and total as well as subfield pathology burden measures. As expected, we found significant correlations between hippocampal radial distance and mean neuronal count, as well as diagnosis. There were subfield specific associations between hippocampal radial distance and tau in CA2, and cresyl violet neuronal counts in CA1 and subiculum. These results provide further validation for the European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).

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Aperio ImageScopeÒ CS on the digitally scanned stained tissue. Subfield margins were identified based on cytoarchitectonic features. Neuronal counts, Ab and tau burden for each hippocampal subfield were obtained. Results: Kruskal-Wallis comparison of medians showed significant differences between the two groups for total hippocampal tau and Ab burden (p¼0.01 for both) but not neuronal count (p¼0.12). Significant differences in the medians were also seen in all subfields for tau and in the subiculum, CA1 and CA3 for Ab. We found significant correlations between hippocampal volume and fresh brain weight (r¼0.69, p¼0.003), Braak and Braak staging (r¼-0.71, p¼0.002), tau (r¼-0.53, p¼0.034) and Ab burden (r¼-0.61, p¼0.012). Subfield-wise significant association were found for Ab in CA1 (r¼-0.58, p¼0.019) and subiculum (r¼-0.75, p¼0.001), as well as tau in CA2 (r¼-0.59, p¼0.016) and CA3 (r¼-0.5, p¼0.047). Conclusions: The observed associations provide pathologic validation for the EADC-ADNI HarP and pathologic confirmation of hippocampal morphometry as a valid AD biomarker.