Objective:

The Synuclein-One study is an NIH-funded 30-site multicenter trial that included 50 patients with dementia with Lewy bodies (DLB) and 27 with mild cognitive impairment.  Here we report the detection of cutaneous phosphorylated alpha-synuclein (P-SYN) in patients with DLB and MCI. 

Background:

An unmet need exists for a validated, well-characterized, simple, reproducible biomarker of synuclein pathology. The number of individuals with neurodegenerative diseases continues to grow and misdiagnosis within and among synuclein and non-synuclein dementias persists, resulting in incorrect medication choices, iatrogenic complications, inaccurate prognostication and patient frustration.

Design/Methods:

After signed consent, study participants completed neurologic examinations (MDS-UPDRS, Hoehn and Yahr scale), medical history review, cognitive evaluation (MOCA), orthostatic vital signs and neurodegenerative disease questionnaires.  DLB was defined using consensus criteria.  MCI was defined as MOCA score of 18-25. Skin biopsies at the distal leg, distal thigh and posterior cervical sites were performed on all participants with quantitation of P-SYN and intra-epidermal nerve fiber density (IENFD).

Results:

In the 50 DLB participants (MDS-UPDRS 68±28, Hoehn and Yahr 2.4±1.0, MOCA 16±5.4), P-SYN was detected in 48/50 (96%).  Of 27 participants with MCI (MDS-UPDRS 3.5±6.0, Hoehn and Yahr 0.1±0.4, MOCA 23±2.8), P-SYN was detected in 8/27 (30%).  Detection of P-SYN in healthy controls is 3.3%.

Conclusions:

Cutaneous P-SYN testing is a sensitive and specific test for phosphorylated alpha-synuclein in patients with DLB.  The detection of P-SYN in individuals with MCI is 10-times that of the healthy population.  Longitudinal follow up of MCI participants is needed to understand the long-term implications of these results and the risk of co-pathology associated with other conditions such as Alzheimer’s disease.