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
(2024) In Alzheimer's and Dementia- Abstract
INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. 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,... (More)
INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. 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.
(Less)
- author
- 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
LU
; Bateman, Randall J.
; McDade, Eric
and Parchi, Piero
(Less) - author collaboration
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- in press
- subject
- keywords
- alpha-synuclein seed amplification assay, Dominantly Inherited Alzheimer Network, Lewy body pathology, real-time quaking-induced conversion
- in
- Alzheimer's and Dementia
- publisher
- Wiley
- external identifiers
-
- pmid:38666355
- scopus:85191289982
- ISSN
- 1552-5260
- DOI
- 10.1002/alz.13818
- language
- English
- LU publication?
- yes
- id
- e5650208-9c96-45e7-a54e-1a3acec898e0
- date added to LUP
- 2024-05-06 13:12:52
- date last changed
- 2024-05-07 03:00:38
@article{e5650208-9c96-45e7-a54e-1a3acec898e0,
abstract = {{<p>INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. 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.</p>}},
author = {{Levin, Johannes and Baiardi, Simone and Quadalti, Corinne and Rossi, Marcello and Mammana, Angela and Vöglein, Jonathan and Bernhardt, Alexander and Perrin, Richard J. and Jucker, Mathias and Preische, Oliver and Hofmann, Anna and Höglinger, Günter U. and Cairns, Nigel J. and Franklin, Erin E. and Chrem, Patricio and Cruchaga, Carlos and Berman, Sarah B. and Chhatwal, Jasmeer P. and Daniels, Alisha and Day, Gregory S. and Ryan, Natalie S. and Goate, Alison M. and Gordon, Brian A. and Huey, Edward D. and Ibanez, Laura and Karch, Celeste M. and Lee, Jae Hong and Llibre-Guerra, Jorge and Lopera, Francisco and Masters, Colin L. and Morris, John C. and Noble, James M. and Renton, Alan E. and Roh, Jee Hoon and Frosch, Matthew P. and Keene, C. Dirk and McLean, Catriona and Sanchez-Valle, Raquel and Schofield, Peter R. and Supnet-Bell, Charlene and Xiong, Chengjie and Giese, Armin and Hansson, Oskar and Bateman, Randall J. and McDade, Eric and Parchi, Piero}},
issn = {{1552-5260}},
keywords = {{alpha-synuclein seed amplification assay; Dominantly Inherited Alzheimer Network; Lewy body pathology; real-time quaking-induced conversion}},
language = {{eng}},
publisher = {{Wiley}},
series = {{Alzheimer's and Dementia}},
title = {{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}},
url = {{http://dx.doi.org/10.1002/alz.13818}},
doi = {{10.1002/alz.13818}},
year = {{2024}},
}