HAI Book 2025 - Flipbook - Page 190
Brown, Christopher
37
Biological-clinical mismatch reflects co-pathology and vulnerability
to neurodegeneration
Christopher Brown1, Sandhitsu Das1, Long Xie3, Ilya Nasrallah2, John Detre1, Paul Yushkevich2,
Corey McMillan1, David Wolk1
1
Department of Neurology, University of Pennyslvania, Philadelphia, PA, US
Department of Radiology, University of Pennsylvania, Philadelphia, PA, US
3
Siemens Healthineers, Princeton, NJ, US
2
The dissociation of clinical and biological staging in the revised Alzheimer's Association criteria for Alzheimer9s
disease highlight the concept of clinical-biological mismatch as a reflection of resilience/vulnerability factors
(e.g. co-pathologies). We sought to evaluate the usefulness of this concept by specifically assessing mismatch
between Tau-PET and cognitive scales in the ADNI dataset. There were 365 A´+ (based on Core 1 biomarkers)
participants with Tau-PET and cognitive testing with CDR-SB, measuring global function, and ADAS-13, primarily
measuring amnestic impairment. We used Tau-MaX, our recently developed measure which quantifies global tau
magnitude and extent, to measure tau burden. We used linear regression to predict CDR-SB or ADAS13 using TauMaX controlling for age, sex, and education. Results demonstrated moderate association between Tau-MaX and
CDR-SB and ADAS13 (Figure 1A). Standardized residuals (SR) were calculated for each participant, with SR > 0.6
defining vulnerable groups, SR < -0.6 resilient, and -0.6 f SR f 0.6 canonical. Tau-MaX was similar between groups,
but there was higher clinical stage, using Alzheimer9s Association criteria, in vulnerable groups and lower stage in
resilient groups (Figure 1B). We compared differences in cortical thickness, white matter hyperintensity (WMH)
volume, and presence of ³-synuclein between these groups controlling for age, sex, and Tau-MaX. CDR-vulnerable
participants showed reduced thickness in a diffuse set of brain regions with the strongest effects in the temporal
lobe (Figure 2A-B), while ADAS-vulnerable had reduced thickness primarily in temporo-limbic regions, suggestive
of concomitant LATE (Figure 3A-B). CDR-vulnerable participants showed higher levels of ³-synuclein+ compared
to canonical and CDR-resilient participants (Figure 2C), while ADAS-vulnerable had higher levels of ³-synuclein+
than ADAS-resilient (Figure 3C). Overall, these findings point to the value of clinical-biological mismatch to
identify those with greater neurodegeneration and/or likely co-pathology (³-synuclein and LATE). Further,
cognitive domain-based mismatch may allow for detection of more specific co-pathologies.
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