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.