α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden.
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Levin Johannes, Baiardi Simone, Quadalti Corinne, Rossi Marcello, Mammana Angela, Vöglein Jonathan, Bernhardt Alexander, Perrin Richard J, Jucker Mathias, Preische Oliver, Hofmann Anna, Höglinger Günter U, Cairns Nigel J, Franklin Erin E, Chrem Patricio, Cruchaga Carlos, Berman Sarah B, Chhatwal Jasmeer P, Daniels Alisha, Day Gregory S, Ryan Natalie S, Goate Alison M, Gordon Brian A, Huey Edward D, Ibanez Laura, Karch Celeste M, Lee Jae-Hong, Llibre-Guerra Jorge, Lopera Francisco, Masters Colin L, Morris John C, Noble James M, Renton Alan E, Roh Jee Hoon, Frosch Matthew P, Keene C Dirk, McLean Catriona, Sanchez-Valle Raquel, Schofield Peter R, Supnet-Bell Charlene, Xiong Chengjie, Giese Armin, Hansson Oskar, Bateman Randall J, McDade Eric, Dominantly Inherited Alzheimer Network, Parchi Piero
Аннотация
METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.
RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo.
DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity.
HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.