This patent document discloses techniques, systems, and devices for detecting a target substance using optical nonlinear wave mixing for enhanced detection sensitivity and accuracy. In one aspect, a method for measuring α-synuclein in a body fluid of a patient with high detection sensitivity and accuracy and providing early stage Parkinson's disease detection is provided. The method may comprise: supplying to a capillary analyte cell a fluidic sample that includes a body fluid of a patient containing α-synuclein, wherein the capillary analyte cell is located in a nonlinear optical four-wave mixing device; directing laser light from the nonlinear optical four-wave mixing device into the capillary analyte cell to cause nonlinear optical four-wave mixing in the fluidic sample to generate a four-wave mixing signal that contains information on the α-synuclein in the fluidic sample; and processing the four-wave mixing signal to extract information on the α-synuclein in the fluidic sample.