Association of CSF α-Synuclein Seeding Amplification Assay Results With Clinical Features of Possible and Probable Dementia With Lewy Bodies

Abstract

Background and objectives: The clinical diagnosis of dementia with Lewy bodies (DLB) depends on identifying significant cognitive decline accompanied by core features of parkinsonism, visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder (RBD). Hyposmia is one of the several supportive features. α-Synuclein seeding amplification assays (αSyn-SAAs) may enhance diagnostic accuracy by detecting pathologic αSyn seeds in CSF. In this study, we examine how different clinical features associate with CSF αSyn-SAA positivity in a large group of clinically diagnosed participants with DLB.

Methods: Cross-sectional and longitudinal CSF samples from the multicentered observational cohort study of the DLB Consortium and similar studies within the Parkinson's Disease Biomarker Program, contributed by academic medical centers in the United States, underwent αSyn-SAA testing. Participants included those clinically diagnosed with DLB and 2 control cohorts. Associations between core DLB features and olfaction with αSyn-SAA positivity were evaluated using logistic regression.

Results: CSF samples from 191 participants diagnosed with DLB (mean age 69.9 ± 6.8, 15% female), 50 age-matched and sex-matched clinical control participants, and 49 younger analytical control participants were analyzed. Seventy-two percent (137/191) of participants with DLB had positive αSyn-SAAs vs 4% of the control groups. Among participants with DLB, those who were αSyn-SAA-positive had lower Montreal Cognitive Assessment scores (18.8 ± 5.7 vs 21.2 ± 5.2, p = 0.01), had worse parkinsonism on the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (33.8 ± 15.1 vs 25.6 ± 16.4, p = 0.001), were more likely to report RBD (114/133 [86%] vs 33/53 [62%], p < 0.0001), and had worse hyposmia on the University of Pennsylvania Smell Identification Test (UPSIT) (94/105 [90%] below 15th percentile vs 14/44 [32%], p < 0.0001). UPSIT percentile had the highest area under the curve (0.87, 95% CI 0.81-0.94) in predicting αSyn-SAA positivity and participants scoring at or below the 15th percentile of age and sex normative values had 18.3 times higher odds (95% CI 7.52-44.6) of having a positive αSyn-SAA test. Among 82 participants with longitudinal CSF samples, 81 (99%) had the same αSyn-SAA result for initial and follow-up specimens.

Discussion: A substantial proportion of clinically diagnosed participants with DLB had negative αSyn-SAA results. Hyposmia was the strongest clinical predictor of αSyn-SAA positivity. Hyposmia and αSyn-SAA may have utility in improving the diagnostic assessment of individuals with potential DLB.

Classification of evidence: This study provided Class III evidence that CSF αSyn-SAA distinguishes patients with clinically diagnosed DLB from normal controls.

Figure 1. Receiver Operator Curve Areas for Continuous Variables in Predicting αSyn-SAA Positivity in the Patients With Clinically Diagnosed DLB

MoCA, MDS-UPDRS part III scores, and age and sex normative hyposmia percentiles on UPSIT closest to CSF aSyn-SAA sampling were used in calculating receiver operator curves. α-Syn-SAA = α-synuclein seed amplification assay; DLB = dementia with Lewy bodies; MDS-UPDRS part III = Movement Disorder Society Unified Parkinson's Disease Rating Scale part III; MoCA = Montreal Cognitive Assessment; UPSIT = University of Pennsylvania Smell Identification Test.

Figure 2. Longitudinal αSyn-SAA Results in 82 of 191 Clinical Participants With DLB

Red: αSyn-SAA–positive, blue: αSyn-SAA–negative. Open circles: hyposmia ≤15th percentile of age and sex expected performance on the UPSIT at baseline. Closed circles: normosmic (>15th percentile of age and sex expected performance). Diamonds: UPSIT not completed at baseline. Subject 19 was the only subject with a discordant value. α-Syn-SAA = α-synuclein seed amplification assay; DLB = dementia with Lewy bodies; UPSIT = University of Pennsylvania Smell Identification Test.