Skin Biopsy for Phosphorylated α-Synuclein in Mild Cognitive Impairment or Dementia Due to Lewy Body Disease in a Convenience Cohort from a Subspecialty Behavioral Neurology Practice.

BACKGROUND

Immunohistochemically detected phosphorylated α-synuclein (p-α-syn) in cutaneous nerves has been found in >95% of patients meeting consensus criteria for dementia with Lewy bodies (DLB); however, its performance in prodromal stages (mild cognitive impairment-Lewy body [MCI-LB]) and clinical practice is unknown.

OBJECTIVE

We evaluated skin biopsy for p-α-syn in a convenience cohort of patients with suspected MCI-LB or DLB in a tertiary care setting.

METHODS

53 patients underwent commercially available skin biopsy for skin nerve p-α-syn as part of a clinical evaluation for suspected MCI-LB/DLB. Consensus MCI-LB/DLB criteria blinded to skin biopsy result were applied through retrospective chart review; those not definitively meeting criteria were considered questionable synucleinopathy (QS).

RESULTS

Median age at skin biopsy was 70 years (range, 43-87 years) with 81% men. 36 patients (68%) had positive skin biopsies. 32/43 (74%) patients meeting clinical consensus criteria for DLB/MCI-LB had a positive skin biopsy, with higher frequency in MCI-LB (87%) compared with DLB (60%). 4/10 (40%) QS had positive biopsies. One patient with a positive skin biopsy had no evidence of central nervous system (CNS) α-syn on autopsy.

CONCLUSIONS

Positive skin biopsy for p-α-syn occurs across the spectrum of cognitive presentations of Lewy body disease including prodromal DLB, albeit at a lower frequency in this retrospective review of atypical cases compared with typical clinical presentations. A positive skin biopsy may not reflect CNS synucleinopathy as the etiology for a patient's symptoms in some cases. Longitudinal studies of skin biopsies for p-α-syn in suspected MCI-LB/DLB with autopsy confirmation are needed. © 2025 International Parkinson and Movement Disorder Society.