Autopsy Validation of Biomarker-derived Biological Classifications in Lewy Body Disease
Parichita Choudhury1, Shannon Chiu2, Cecilia Tremblay1, Abdirahim Aden2, Holly Shill3, Erika Driver-Dunckley2, Shyamal Mehta2, Andrea Mastrangelo4, Piero Parchi4, Christine Belden1, Geidy Serrano1, Thomas Beach1, Charles Adler2
1Banner Sun Health Research Institute, 2Mayo Clinic Arizona, 3Barrow Neurology Clinics, 4Università di Bologna
Objective:
To evaluate biomarker-based classifications for Lewy body disease (LBD) including synuclein pathology (S), nigral degeneration (N), and genetic risk against autopsy-confirmed pathology in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND).
Background:
Analogous to the ATN framework in Alzheimer’s disease (AD), advances in α-synuclein biomarkers have led to proposals for biologically based LBD classifications (SynNeurGe and neuronal α-synuclein disease [NSD]).
Design/Methods:
We analyzed 168 autopsied LBD cases from AZSAND with postmortem CSF synuclein seed amplification assay (SAA) results. SAA status (S+/S-) was compared to Lewy body (LB) pathology. Substantia nigra (SN) pigmented neuronal loss score (0-3) served as proxy for dopaminergic neuronal degeneration, with scores >0 considered N+. We also evaluated stricter cutoffs (>1 or >2) to approximate neuroimaging-based anchors.
Results:
Of 168 LBD cases, 149 were S+, 19 S-. S+ cases were younger (84.2 vs 89.7 years, p=0.004), more functionally impaired (Unified Parkinsons Disease Rating Scale-II 14.2 vs 6.6, p=0.006), and had more frequent RBD (41.6% vs 5.3%, p<0.001). S+ cases had higher Unified Staging System for Lewy body disorders stage, LB density, and SN neuronal loss (p<0.001). All PD (n=71) and DLB (n=28) were S+, as were 26/32 incidental LBD (ILBD) and 21/30 AD with Lewy bodies (ADLB). Using SN score >0 as N⁺, S+N+ cases included all PD (n=71), 25/28 DLB, 9/26 ILBD, and 9/21 ADLB. Using SN score >1, these decreased to 67/71 PD, 17/28 DLB, 4/26 ILBD, and 1/21 ADLB. At SN>2, S+N+ cases were 55/71 PD, 9/28 DLB, 2/26 ILBD, and 0/21 ADLB.
Conclusions:
Using pathology-based N+ definitions,
SynNeurGe and NSD classifications were validated in autopsy-confirmed PD and most DLB. ILBD and ADLB encompassed both S⁺N⁻ and S⁺N⁺ cases, reflecting prodromal and transitional LBD states. The optimal pathology-based threshold for N⁺ corresponding to imaging positivity remains to be defined.
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