Use of α‐synuclein seed amplification assays to assess how clinical features relate to the diagnosis of Dementia with Lewy Bodies

• Published in: Alzheimer's & dementia Vol. 19; no. S14
• Main Authors: Middleton, John, MacLeod, Karen R, Bozoki, Andrea, Galvin, James E, Irwin, David J, Lippa, Carol, Litvan, Irene, Lopez, Oscar L., Berman, Sarah, Tsuang, Debby W, Zabetian, Cyrus P, Honig, Lawrence S., Marder, Karen, Fleisher, Jori E, Sabbagh, Marwan, Wint, Dylan, Taylor, Angela, Bekris, Lynn M., Leverenz, James B, Galasko, Douglas R.
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.078103

Background Dementia with Lewy Bodies (DLB) is defined by abnormal deposits of alpha‐synuclein (Lewy bodies), in the brain. DLB may be accompanied by variable co‐pathology, especially Alzheimer’s Disease (AD). DLB is diagnosed clinically, with definitive diagnosis only possible at autopsy. Misdiagnosis may occur due to overlapping symptoms in different dementias. The alpha‐synuclein (αSyn) seed amplification assay (SAA) is a qualitative test that detects misfolded aggregates of αSyn in synucleinopathies, including DLB, with high sensitivity and specificity. In autopsy‐confirmed AD with limbic or neocortical synuclein pathology, SAA was positive even when DLB phenotypic features were mild (Arnold et al., 2022). We are now evaluating SAA in cerebrospinal fluid (CSF) samples and clinical features in patients with DLB followed through a multi‐Center DLB Consortium (NINDS U01NS100610), which is part of the NINDS Parkinson’s Disease Biomarkers Program (PDBP). Method CSF from 3 groups: 1) analytical controls: youngest available age, no neurological symptoms, normal neurological exam; 2) clinical controls: no symptoms/signs, age and gender match to DLB; 3) DLB. SAA will be run blind to diagnosis using standardized assay methods by Amprion. We will compare Core clinical features of DLB patients and SAA. We hypothesize that SAA‐ patients will have less clear clinical features for DLB, and will be likely to meet clinical and/or CSF biomarker criteria for other diagnoses, e.g., AD. Core clinical features will be defined as strongly or weakly present, e.g., REM Sleep Behavior Disorder: PSG‐proven (strong); +questionnaire (weak); Parkinsonism: ≥ 2 cardinal features (strong); 1 feature (weak). Hallucinations and fluctuations are described in standardized rating scales/interviews. CSF AD biomarkers (Aβ42, t‐Tau and p‐Tau181) were analyzed for almost all DLB subjects. Sensitivity and specificity of each Core clinical feature will be calculated in relation to SAA+ and SAA‐ results. Result Subjects were recruited at 8 clinical sites across the USA from 2017‐2021. Demographics of subjects with available CSF are shown in Table 1. Demographics, clinical features and CSF AD biomarker results will be presented in SAA+ and SAA‐ groups . Conclusion Results will inform how well different core clinical features predict pathological αSyn (CSF SAA+) in people diagnosed with DLB.