Cerebrospinal fluid and brain α-synuclein seed amplification in autopsy-confirmed Lewy body disease relates to the distribution of pathology
Authors: Arnold Moriah R. , Coughlin David G. , Brumbach Barbara H. , Smirnov Denis S. , Concha-Marambio Luis , Farris Carly M. , Ma Yihua ,   Amprion Inc., Kim Yongya , Kaye Jeffrey A. , Hiniker Annie , Woltjer Randy L. , Galasko Doug R. , Quinn Joseph F. 
Published: March 2022

Objective

To determine the sensitivity and specificity of α-synuclein seed amplification assay (αSyn-SAA) in antemortem and postmortem CSF and brain homogenate samples of autopsy-confirmed patients with a spectrum of Lewy-related pathology (LRP).

Methods

Antemortem CSF samples were examined from 119 subjects with standardized neuropathological examinations from OHSU and UCSD (56 additional postmortem CSF samples available). The assay was also applied to frontal cortex and amygdala tissue to determine if the results could be explained by a regional variation in the propensity for seed aggregation. Sensitivity, specificity, and assay kinetics were compared across pathology groups and clinical data was compared across αSyn-SAA positive and negative groups.

Results

Fifty-three LRP-individuals and 66 LRP+ individuals (neocortical (n=38), limbic (n=7), and amygdala-predominant (n=21)) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the αSyn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue αSyn-SAA analyses showed a similar detection pattern, with higher positivity in samples from limbic/neocortical cases. Kinetic parameters of aggregation were significantly slower in amygdala-predominant cases compared to limbic and neocortical cases.

Interpretation

In this multicenter study of autopsy-confirmed subjects with a spectrum of Lewy-related pathology, we confirm that the αSyn-SAA using CSF and brain tissue reliably identifies α-synuclein seeds in patients with diffuse pathology and related cognitive symptoms. Pathological α-synuclein in the amygdala appears less likely to form detectable seeds, which may result from differences in abundance, conformation, or strains of α-synuclein.

Summary for Social Media If Published

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Alpha-synuclein seed amplification assays have shown high sensitivity and specificity in clinically defined DLB and PD cohorts

It is less well known how well these assays detect synuclein seeds across a pathologically defined spectrum of Lewy body disease. Here we examine the ability of the αSyn-SAA to detect alpha-synuclein seeds in a multicenter cohort of autopsy-validated cases with a spectrum of Lewy body related pathology.

High sensitivity and specificity of the αSyn-SAA is confirmed in detecting alpha-synuclein seeds in spinal fluid and brain tissue in limbic and neocortical stage Lewy body stage pathology, but markedly decreased sensitivity is observed in detecting alpha-synuclein seeds in both spinal fluid and brain tissue in amygdala-predominant type Lewy body related pathology. A small number of these cases showed seeding capability from the amygdala that was not present in the frontal cortex, suggesting a topographic spread of alpha-synuclein seeds.

The current generation of αSyn-SAAs have a high sensitivity and specificity for detecting the most clinically relevant forms of Lewy body related pathology. Further study is needed to understand the differences in Lewy body related pathology between limbic/neocortical cases and amygdala-predominant cases that result in this difference in seeding capability.