Objective: To quantify the deposition of cutaneous P-SYN and blood P-Tau 217 in patients with suspected DLB and AD at the mild cognitive impairment (MCI) stage and track clinical and pathologic changes over time.

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease characterized by progressive accumulation of phosphorylated a-synuclein (P-SYN). Autopsy studies suggest that up to 30% of patients with Alzheimer’s disease (AD) exhibit synuclein co-pathology in the brain. An important unmet need exists for a validated, simple, reproducible marker of synuclein pathology in neurogenerative dementias at the prodromal stage.

Method: After consent, subjects enrolled in a blinded prospective trial of MCI with neurologic and cognitive evaluation, orthostatic vitals and questionnaires. An independent expert panel of reviewers, blinded to pathology, reviewed de-identified medical records to confirm clinical diagnoses. Skin biopsies at the distal leg, distal thigh and posterior cervical sites were performed. P-SYN immunostaining and plasma biomarkers for AD pathology (P-Tau217) were assessed blinded to any clinical data.

Results: A total of 102 subjects (age 73.5±6.4 years with a mean CDR of 0.5) from 15 study sites completed the initial visit of the longitudinal study. After expert panel review, 44 participants were classified with MCI-DLB, 35 with MCI-AD and 19 MCI-indeterminate. Of the enrolled subjects, 56/102 are P-SYN positive (55%) and 63/109 are P-Tau217 positive (62%).  In MCI-DLB 34/44 (77%) are P-SYN positive and 17/44 (39%) are P-Tau217 positive. In MCI-AD 14/35 (40%) are P-SYN positive and 35/35 (100%) are P-Tau217 positive. In MCI-indeterminate 8/19 (42%) are P-SYN positive and 11/19 (58%) are P-Tau217 positive. Quantitative assessment of P-SYN differed between groups: 6.6±6.0 P-SYN Units MCI-DLB, 1.5±2.4 P-SYN Units in MCI-AD and 1.2±2.2 P-SYN Units in indeterminate MCI (P<0.001 ANOVA). Quantitative assessment of P-Tau217 differed between groups: 0.48±0.40 MCI-DLB, 0.77±0.38 pg/ml MCI-AD and 0.71±0.63 pg/ml in the MCI-Indeterminate group (P<0.05, ANOVA).

Conclusion: In patients with MCI, peripheral tissue biomarkers reveal frequent co-occurrence of synuclein and tau, even at early stages of disease. Longitudinal follow-up will offer valuable guidance on differing rates of disease progression amongst those with MCI and either synuclein, tau or co-pathology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-syn-d-study-detection-of-cutaneous-phosphorylated-alpha-synuclein-and-blood-p-tau-217-in-patients-with-mild-cognitive-impairment/