Evaluation of quantitative measurements of tau pathology with semi‐quantitative ratings and age
Amanda E Denning, Ranjit Ittyerah, Niyousha Sadeghpour, Eunice Chung, Sadhana Ravikumar, Shokufeh Sadaghiani, Noah Capp, Eric Teunissen‐Bermeo, Sanaz Arezoumandan, Daniel T Ohm, Theresa Schuck, John L. Robinson, Murray Grossman, Eddie B Lee, John Q Trojanowski, Laura EM Wisse, Sandhitsu R. Das, David A. Wolk, David J. Irwin, Paul A. Yushkevich- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
It is assumed quantitative digital neuropathology methods will provide more information than semi‐quantitative ratings, but this presumption lacks formal assessment. Here, we compare quantitative, whole‐slide measurements of phosphorylated tau tangles and threads with semi‐quantitative tau pathology ratings. We evaluate whether quantitative measurements provide additional prediction beyond Braak stage for variables associated with tau pathology, examining the association of quantitative tau measurements in high Braak stages with age at death and measures of severity of TDP‐43 and alpha‐synuclein co‐pathologies. We hypothesized that even within the same high Braak stage, quantitative tau measurements would decrease with age at death, as younger patients often require more tau pathology for disease severity comparable to older patients, and increase with higher co‐pathology ratings, since prior work suggests co‐pathologies increase with disease severity.
Method
We scanned 6µm tissue sections stained with phosphorylated tau PHF1 in 14 brain regions from 215 patients with Alzheimer’s Disease continuum neuropathological diagnoses (53% male, age = 74.37 ± 11.51). A machine learning method (Figure 1) generated summary measures of tangle and thread pathology for each slide (Yushkevich et al., 2021, Sadaghiani et al., 2022). Semi‐quantitative tau ratings (0‐3) were also available in nine regions and compared to quantitative measurements in matching regions. In 150 patients with high Braak stages (V/VI), correlation analyses were performed using summary scores averaging semi‐quantitative ratings of TDP‐43 in medial temporal lobe regions (“TDP‐43 severity”), and alpha‐synuclein in commonly affected regions (“alpha‐synuclein severity”).
Result
Figure 2 shows high overall agreement between quantitative tau measures and corresponding semi‐quantitative ratings. When evaluating quantitative tau measurements in high Braak stage patients, after Bonferroni correction we found significant negative associations between age and tangles in middle frontal cortex, orbital frontal cortex (OFC), and thalamus, and between age and threads in OFC. We found significant positive association between TDP‐43 severity and tangles in substantia nigra, but no associations with alpha‐synuclein severity (Figure 3).
Conclusion
Quantitative tau measurements largely agree with established semi‐quantitative ratings. Significant associations of quantitative tau measurements with TDP43 pathology and age were found within high Braak stage patients, suggesting quantitative pathology measurements can offer additional information beyond stage alone in these patients.