Complementary biomarkers or conflicting signals? DaT SPECT and synuclein skin biopsy in parkinsonian syndromes.

INTRODUCTION: Diagnosing Parkinson's disease (PD) and related synucleinopathies in patients with early or atypical features remains challenging. Dopamine transporter single-photon emission CT (DaT SPECT) imaging and phosphorylated alpha-synuclein (p-Syn) skin biopsy are increasingly used, but their concordance and combined value in diagnostically uncertain, real-world patients are unknown. We evaluated whether these two biomarkers provide complementary rather than redundant diagnostic information. METHODS: We retrospectively analysed patients evaluated at a tertiary movement disorders centre (January 2022-March 2025) who presented with parkinsonism or tremor not meeting established criteria for PD, multiple system atrophy or dementia with Lewy bodies. 86 patients underwent p-Syn skin biopsy; 52 also underwent DaT SPECT. Using the treating neurologist's final clinical diagnosis as the reference standard, we calculated sensitivity, specificity, predictive values and concordance for each test and for combined ('either-positive') testing and compared clinical features between concordant and discordant groups. RESULTS: DaT SPECT and p-Syn biopsy showed similar sensitivity (79.0% and 79.0%) and specificity (74.0% and 81.0%) for synucleinopathy. Combined testing increased sensitivity to 95.6% but reduced specificity to 59.9%. Results were discordant in 30.8% of dual-tested patients; +DaT/-p-Syn patients more often reported hyposmia, whereas -DaT/+p Syn patients more often reported REM sleep behaviour disorder. Almost half of discordant cases ultimately met criteria for idiopathic PD. CONCLUSIONS: DaT SPECT and p-Syn skin biopsy provide complementary, not redundant, diagnostic information. The high discordance, with eventual PD diagnosis in many cases, is consistent with the dual-origin (brain-first vs body-first) model of alpha-synuclein propagation. Both are best used as rule-in tests in early or diagnostically uncertain disease, where a negative result does not exclude a synucleinopathy; in advanced disease meeting full clinical criteria, they may have greater rule-out value. Combined testing improves early detection at a cost to specificity, with implications for trial enrolment and for interpreting biomarkers alongside symptom evolution.