To describe results of skin biopsy for phosphorylated alpha-synuclein (P-SYN) in patients with essential tremor (ET) with parkinsonism.

Patients with longstanding ET may develop subtle parkinsonian signs, most commonly a rest tremor. Elderly ET patients may present with parkinsonism due to advanced age or orthopedic issues. ET patients have increased risk of developing Parkinson’s disease (PD) compared to the normal population. ET patients who develop parkinsonism or other motor/nonmotor symptoms are referred to as ET-Plus. The dopamine transporter (DaT) scan helps differentiate between ET with parkinsonism (ET-P) and PD, being normal in ET-P and abnormal in PD. The frequency of peripheral synucleinopathy in ET-P is unknown.

A single center retrospective review of all ET-P patients seen from 2012-2023 who had P-SYN skin biopsy mainly due to parkinsonian sign(s). We reviewed demographic data, presence of RBD, extrapyramidal exam, DaT scan, cardiac MIBG scan, and University of Pennsylvania Smell Identification Test (UPSIT).

We identified 34 patients [23/34(68%) men] with ET-P and P-SYN skin biopsy. 25/34(74%) had a rest tremor and 9/34(26%) had RBD. Average age at time of biopsy was 70.6 years (range=30-88). 33/34(97%) had undergone DaT scans, of which 23/33(70%) were normal. Of the 34 ET-P patients, 24/34(71%) were P-SYN(+), of which 21/23(91%) had normal DaT scans. Of the 23 with normal DaT scans, 18/23(78%) were P-SYN(+).  15/34(44%) had cardiac MIBG scans, of which 9/15(60%) were abnormal. Of the 9 with abnormal MIBG scans, 6/9(67%) had normal DaT scans and 7/9(78%) were P-SYN(+). 20/34(59%) ET-P patients had the UPSIT; with smokers excluded, only 7/20(35%) had abnormal UPSIT.

The majority of ET-P patients have evidence of cutaneous P-SYN deposition despite normal DaT scans. Longitudinal studies are required, though our preliminary retrospective data suggest skin biopsy for P-SYN may help identify ET-P patients who are at risk for PD or other synucleinopathies.