In this autopsy-based study, α-synuclein immunohistochemistry and lipofuscin pigment-Nissl architectonics in serial sections of 100 μm thickness were used to investigate the spinal cords and brains of 46 individuals: 28 patients with clinically and neuropathologically confirmed Parkinson's disease, 6 cases with incidental Lewy body disease, and 12 age-matched controls. α-Synuclein inclusions (particulate aggregations, Lewy neurites/bodies) in the spinal cord were present between neuropathological stages 2-6 in all cases whose brains were staged for Parkinson's disease-related synucleinopathy. The only individuals who did not have Lewy pathology in the spinal cord were a single stage 1 case (incidental Lewy body disease) and all controls. Because the Parkinson's disease-related lesions were observable in the spinal cord only after Lewy pathology was seen in the brain, it could be concluded that, within the central nervous system, sporadic Parkinson's disease does not begin in the spinal cord. In addition: (1) α-Synuclein-immunoreactive axons clearly predominated over Lewy bodies throughout the spinal cord and were visible in medial and anterior portions of the anterolateral funiculus. Their terminal axons formed dense α-synuclein-immunoreactive networks in the gray matter and were most conspicuous in the lateral portions of layers 1, 7, and in the cellular islands of layer 9. (2) Notably, this axonopathy increased remarkably in density from cervicothoracic segments to lumbosacral segments of the cord. (3) Topographically, it is likely that the spinal cord α-synuclein immunoreactive axonal networks represent descending projections from the supraspinal level setting nuclei (locus coeruleus, lower raphe nuclei, magnocellular portions of the reticular formation). (4) Following the appearance of the spinal cord axonal networks, select types of projection neurons in the spinal cord gray matter displayed α-synuclein-immunoreactive inclusions: chiefly, nociceptive neurons of the dorsal horn in layer 1, sympathetic and parasympathetic preganglionic neurons in layer 7, the cellular pools of α-motoneurons in layer 9, and the smaller motoneurons in Onuf's nucleus in layer 9 (ventral horn). The spinal cord lesions may contribute to clinical symptoms (e.g., pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic Parkinson's disease.