The Syn-D Study: Detection of Longitudinal Changes in Cutaneous Phosphorylated Alpha-Synuclein in Mild Cognitive Impairment
Roy Freeman1, Todd Levine2, Bailey Bellaire3, Jourdan Parent3, Sarrah Marcotte3, Manuel Duval3, Christopher Gibbons4
1Beth Israel Deaconess Hosp, 2Honor Health, 3CND Life Sciences, 4Beth Israel Deaconess Medical Center
Objective:
To quantify cutaneous phosphorylated alpha-synuclein (P-SYN) deposition in patients with mild cognitive impairment (MCI) due to suspected Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).
Background:
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. We sought to validate a reproducible marker of synuclein pathology in patients with MCI with DLB phenotype (MCI-DLB) and MCI AD phenotype (MCI-AD).
Design/Methods:
After consent, participants with MCI-AD and MCI-DLB completed neurological examinations, medical history screening, and motor assessments. An expert panel blinded to pathology reviewed clinical assessments to confirm diagnoses. Distal leg, distal thigh, and posterior cervical skin biopsies were performed with quantitation of P-SYN.
Results:
103 MCI patients were enrolled, with 98 confirmed by expert panel to meet inclusion criteria. Of these, 44 were MCI-DLB (73.3±8.3 years, 11 female), 35 were MCI-AD (73.0±5.1, 18 female), and 19 were MCI-indeterminate (MCI-ind; 67.8 ± 10.0, 8 female). Groups did not differ in demographics or baseline Clinical Dementia Rating (CDR 0.5 for all groups). At time of abstract submission, follow-up data were available for 71 patients (33 MCI-DLB, 26 MCI-AD, and 12 MCI-ind). At follow-up, P-SYN was detected in 85% of MCI-DLB and 41% of MCI-AD patients. A continuous measure of total P-SYN increased in 69.7% of MCI-DLB, 15.3% of MCI-AD, and 25% of MCI-ind. 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 significantly predicted increases in CDR sum of boxes (p=0.008).
Conclusions:
Cutaneous P-SYN is detected in most patients with MCI-DLB. The prevalence in MCI-AD is consistent with autopsy reports of co-pathology. P-SYN deposition correlates with declines in cognitive function observed in MCI. Rate of cutaneous P-SYN increases may distinguish between dementia subtype trajectories.
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