Objective: Based on the recent recommendations by international neuropathologists [1], we attempted to evaluate the diagnostic accuracy of cerebrospinal fluid (CSF) alpha-synuclein (α-syn) seeding amplification assay (SAA) in our autopsy cohort with systemic assessment including the body.

Background: CSF α-syn SAA has been reported to have high sensitivity and specificity for detecting Lewy body disease (LBD), and recently SAA is proposed to be used for early diagnosis of sporadic Parkinson’s disease (PD) (or neuronal α-syn disease) [2, 3]. However, previous autopsy validation studies demonstrated that the sensitivity of α-syn SAA is not perfect if Lewy pathology is limited in amygdala/brainstem [4-6]. Additionally, the sensitivity may be affected by the presence of Lewy pathology in the body, as observed by cardiac MIBG scintigraphy in patients with early PD [7]. Autopsy validation studies with systemic assessment of Lewy pathology, including the body, are lacking [1].

Method: α-syn SAA [7] of stored CSF samples was carried out using standard methods. Regardless of the diagnosis, systemic Lewy pathology assessment including olfactory bulb, sympathetic ganglia, spinal cord, and multiple organs in the body, including esophagus, heart, and skin, was conducted [8-12].

Results: CSF from 30 patients were analyzed; symptomatic LBD (n=8; PD 2, PD-MCI 1, PDD 1, DLB 4), MSA (n=2), AD (n=3), and other controls (n=17). Despite different clinical stages, autopsy revealed that six with symptomatic LBD were in diffuse neocortical and two were in limbic stage. All the eight patients showed widespread peripheral LBs including those in olfactory bulb, esophagus, and sympathetic ganglia. Incidental LBs in the sympathetic ganglia were identified in one control. SAA was positive in all eight with symptomatic LBD, was weakly positive in one with AD, and was negative in all the others, which included one patient with limited LBs in the sympathetic ganglia and the two patients with MSA.

Conclusion: We confirmed high specificity (95%) and high sensitivity (100%) of our CSF α-syn SAA in symptomatic LBD with widespread pathology in full body. Negative results were observed in one patient with limited LBs in the sympathetic ganglia and the two patients with MSA. Larger studies, including systemic Lewy pathology assessment including the body, may be necessary before fully implementing biomarker-based diagnosis of LBD.

References: 1. Kovacs GG, et al. Biomarker-Based Approach to α-Synucleinopathies: Lessons from Neuropathology. Mov Disord. 2024; 39(12): 2173-2179.
2. Höglinger GU, et al. A biological classification of Parkinson’s disease: the SynNeurGe research diagnostic criteria. Lancet Neurol. 2024; 23(2): 191-204.
3. Simuni T, et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024; 23(2): 178-190.
4. Hall S, et al. Performance of αSynuclein RT-QuIC in relation to neuropathological staging of Lewy body disease. Acta Neuropathol Commun. 2022; 10(1): 90.
5. Bentivenga GM, et al. Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden. Acta Neuropathol. 2024; 147(1): 18.
6. Kurihara M, et al. α-synuclein seed amplification assay sensitivity may be associated with cardiac MIBG abnormality among patients with Lewy body disease. NPJ Parkinsons Dis. 2024; 10(1): 190.
7. Sengoku R, et al. Incidence and extent of Lewy body-related alpha-synucleinopathy in aging human olfactory bulb. J Neuropathol Exp Neurol. 2008; 67(11): 1072-83.
8. Ikemura M, et al. Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol. 2008; 67(10): 945-53.
9. Sumikura H, et al. Distribution of α-synuclein in the spinal cord and dorsal root ganglia in an autopsy cohort of elderly persons. Acta Neuropathol Commun. 2015; 3: 57.
10.Tanei ZI, et al. Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases. Acta Neuropathol. 2021; 141(1): 25-37.
11.Matsubara T, et al. Autopsy Validation of the Diagnostic Accuracy of 123I-Metaiodobenzylguanidine Myocardial Scintigraphy for Lewy Body Disease. Neurology. 2022; 98(16): e1648-e1659.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/validation-of-csf-alpha-synuclein-saa-in-an-autopsy-cohort-with-systemic-assessment-of-lewy-pathology-including-the-body/