A dome-shaped pattern through disease course on the side of in vitro and in vivo neuroprotective roles suggested for IGF-1 (18, 66, 67), along with our imaging findings of lower white matter QA and CSF biomarkers associated with higher IGF-1 in early PD, may propose a primary compensatory rise in IGF-1 signaling against neural damage of Lewy bodies and neurofibrillary tangles, with consequent depletion of neuroprotective capacity later in the course of the disease (17, 65). The gene discussed is IGF1; the disease is Parkinson disease.