Neuropathologic basis of quantitative susceptibility mapping in the substantia nigra: contributions of tau, pigmented neurons, and iron

Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been reported in Lewy body disease and other parkinsonian disorders, but from existing literature it remains unclear whether these findings are driven by neurodegeneration-related iron deposition or other neuropathologic features. We studied 59 autopsied participants who underwent antemortem 3 T MRI with QSM (median age at death, 78.5 years; MRI-to-death interval, 2.0 years), including clinical diagnoses of 18 with Alzheimer’s-type dementia, 15 cognitively unimpaired, 9 with mild cognitive impairment, and 9 with dementia with Lewy bodies. A machine learning-incorporated digital histopathology pipeline quantified tau burden, iron deposition, and neuronal densities. The SN was divided into geometric quadrants, and QSM values were analyzed in relation to corresponding neuropathologic measures within each quadrant. Iron deposition correlated with QSM in all quadrants ( ρ = 0.41–0.56, all P < 0.005). Tau burden correlated with QSM in the ventromedial (VM) quadrant ( ρ = 0.45, P = 0.002), whereas lower pigmented neuron density was associated with higher QSM in the dorsomedial quadrant ( ρ = – 0.35, P = 0.007). Rank regression analysis confirmed iron as the strongest predictor of QSM across all quadrants ( β = 0.35–1.06, P ≤ 0.026), with tau independently associated with QSM in the VM ( β = 0.45, P = 0.015). Mediation analysis demonstrated that tau exerted direct (0.45, P = 0.018) and indirect effects via iron (0.12, P = 0.046) on QSM in the VM, with 80% of the effect being direct. These findings underscore the contributions of tau pathology, pigmented neuron density, and iron deposition to nigral magnetic susceptibility and highlight the potential for QSM to serve as a sensitive biomarker for diverse neuropathologies.