Clinical and biomarker predictors of α-synuclein seeding in cognitive impairment and motor parkinsonism.

Dopamine transporter (DAT) imaging and α-synuclein seed amplification assay (SAA) are biomarkers for Lewy body disease (LBD). We aimed to identify clinical and biomarker factors associated with SAA positivity in patients with cognitive impairment and frequent motor parkinsonism. Dual-phase DAT positron emission tomography (PET) scans, cerebrospinal fluid (CSF) phosphorylated-tau/β-amyloid ratio (PTAR) measurement, and SAA were performed in 108 patients, including 99 with motor parkinsonism. Diagnoses, which were not mutually exclusive, included normal pressure hydrocephalus (NPH, N = 60), Alzheimer's disease (AD, N = 53), dementia with Lewy bodies (DLB, N = 43), vascular cognitive impairment (VCI, N = 23), progressive supranuclear palsy (N = 3), and semantic variant primary progressive aphasia (N = 1). We investigated clinical and biomarker factors associated with SAA positivity, including clinical diagnoses, clinical features, striatal DAT uptake, and log-transformed PTAR (LN-PTAR), and examined whether SAA positivity was associated with dopaminergic degeneration and regional perfusion measured by dual-phase DAT PET. SAA was positive in 50 patients (46.3%), including 30 of 43 (69.8%) with DLB and 47 of 99 (47.5%) with motor parkinsonism. Seven (14.0%) SAA-positive patients showed normal DAT uptake. Among clinical diagnoses, DLB and AD were associated with a higher likelihood of SAA positivity, whereas NPH and VCI were associated with a lower likelihood. Among clinical features, cognitive fluctuations and rapid eye movement sleep behavior disorder were independently associated with SAA positivity. Among biomarker measures, lower posterior putamen DAT uptake and a higher LN-PTAR were independently associated with SAA positivity. SAA positivity was associated with lower posterior putamen DAT uptake on delayed-phase DAT PET but not with perfusion changes on early-phase DAT PET. These findings suggest that SAA provides complementary information to clinical diagnosis and DAT imaging for evaluating possible LBD, particularly in patients with biomarker evidence of coexisting AD pathology.