Objective: To quantify the deposition of cutaneous phosphorylated alpha-synuclein (P-SYN) and plasma P-Tau217 in patients with mild cognitive impairment (MCI) due to suspected Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).

Background: Dementia with Lew bodies (DLB) is a neurodegenerative disease characterized by progressive accumulation of phosphorylated alpha-synuclein (P-SYN). Quantitative assessment of P-SYN using skin biopsies can facilitate the diagnosis of complex neurological disorders and serve as a potential therapeutic biomarker in clinical trials.

Method: After consent, participants with MCI-AD and MCI-DLB completed neurological examinations, medical history screening, and motor assessments. All participants underwent clinical review by an expert panel blinded to pathology to confirm diagnosis.  Skin biopsies at the distal leg, distal thigh, and posterior cervical sites were performed with quantitation of P-SYN. Plasma was collected for quantification of biofluid biomarkers. Longitudinal follow-up with repeated testing occurred 1 year later.

Results: 103 MCI participants were enrolled with 98 confirmed by an expert panel to meet the inclusion criteria. These included 44 with MCI-DLB (73.3±8.3 years, 11 female), 35 with MCI-AD (73.0±5.1, 18 female), and 19 with MCI-indeterminate (MCI-ind; 67.8 ± 10.0, 8 female). Patient groups did not differ based on demographics or Clinical Dementia Rating (CDR 0.5 for all groups). Unified Parkinson’s Disease Rating Scale scores for parts 2 and 3 were higher in the MCI-DLB group (ANOVA p <0.0001). P-SYN was detected in 77% of MCI-DLB patients and 40% of MCI-AD patients. Quantitative P-SYN was significantly higher in MCI-DLB (ANOVA p<0.0001). Across groups, there was a statistically significant increase in P-SYN over 12 months (p<0.001), which was greater for MCI-DLB compared to MCI-AD (p<0.001) and predicted increases in CDR sum of boxes (p=0.004). Phosphorylated tau217 was detected in 100% of MCI-AD patients and 41% of MCI-DLB patients.

Conclusion: This in vivo biomarker study is consistent with prior autopsy studies that show co-pathology occurs frequently in both MCI-DLB and MCI-AD. Cutaneous P-SYN is quantifiable and repeatable over time. Increasing P-SYN burden is associated with greater cognitive decline and may suggest a role for longitudinal disease monitoring in both AD and DLB.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-syn-d-study-detection-of-longitudinal-changes-in-cutaneous-phosphorylated-alpha-synuclein-in-mild-cognitive-impairment/