2025 American Academy of Neurology Abstract Website

David Coughlin¹, Lavanya Jain², Maria Khrestian², Karen MacLeod³, Andrea Bozoki⁴, James Galvin⁵, David Irwin⁶, Carol Lippa⁷, Irene Litvan⁸, Oscar Lopez⁹, Sarah Berman⁹, Debby Tsuang¹⁰, Cyrus Zabetian¹¹, Jori Fleisher¹², Angela Taylor¹³, James Leverenz², Lynn Bekris², Douglas Galasko¹
¹University of California San Diego, ²Cleveland Clinic, ³Amprion Clinical Laboratory, ⁴University of North Carolina, ⁵University of Miami Miller School of Medicine, ⁶University of Pennsylvania, ⁷Thomas Jefferson University, ⁸UC San Diego Parkinson and Other Movement Disorder Center, ⁹University of Pittsburgh, ¹⁰VAMC 116 MHC, ¹¹VA Puget Sound Health Care System, ¹²Rush University Parkinson'S and Movement Disorders Program, ¹³Lewy Body Dementia Association

Objective:

To explore association of CSF alpha-synuclein seed amplification (αSyn-SAA) and CSF Alzheimer’s disease (AD) biomarker profiles with presenting features and longitudinal decline in the multicentered prospective Dementia with Lewy Bodies (DLB) Consortium study.

Background:

αSyn-SAA accurately detects αSyn pathology in synucleinopathies including DLB. AD co-pathology occurs in ~70% of DLB participants at autopsy and can be detected using CSF markers. The association of different αSyn/AD biomarker profiles with clinical outcomes in DLB can aid prognostication and inform clinical trial design.

Design/Methods:

CSF samples obtained <1 year of baseline assessments from participants of the DLB consortium study were analyzed for αSyn-SAA (Amprion SynTap assay), Aβ42/40, ptau-181, and total-tau (Luminex-xMAP technology; Millipore). Cut-points were defined as per Jain et al. Alzheimers Dement. 2024. Cross-sectional comparisons of core DLB features, cognitive impairment, and hyposmia (<15^th percentile of predicted performance) in participants with different CSF biomarker profiles was performed. Rates of cognitive decline, measured by MoCA scores, and motor decline, measured by MDS-UPDRS scores, were assessed.

Results:

Ninety-five participants with CSF αSyn-SAA and AD biomarkers were studied; 69% (66/95) were αSyn-SAA+. αSyn-SAA+ participants had worse baseline MoCA scores (p=0.02), worse motor parkinsonism (p=0.003), were more likely to be hyposmic (p<0.0001), and had more core DLB features (p=0.04). Of αSyn-SAA+ participants, 41% (27) had normal AD biomarkers (Aβ42/40, ptau181, t-tau all normal), and 53% (35) had evidence of Amyloid-β co-pathology (Aβ42/40 abnormal, ±p-tau181, ±t-tau) αSyn-SAA+ participants had greater progression in cognitive deficits and parkinsonism than αSyn-SAA- participants (MoCA Coefficient=-0.77, p=0.029. MDS-UPDRSpartIII Coefficient 3.54, p<0.0001). αSyn-SAA+Aβ+ participants had greater declines in MoCA scores than αSyn-SAA+Aβ- participants (Coefficient=-1.98, p<0.0001). MDS-UPDRSpartI subscores increased more in αSyn-SAA+Aβ+ participants than in αSyn-SAA+Aβ- participants (Coefficient=1.86, p=0.02).

Conclusions:

In this well-characterized cohort of DLB participants, αSyn-SAA positivity is associated with greater motor and cognitive decline. AD co-pathology is common and confers additional risk of cognitive decline.