Fig. 5.

Implication of NIE modulatory network in the motor and non-motor symptom complexes of PD. Parkinsonian symptom complex encompasses a broad array of motor and non-motor symptoms, with neuroimmune and neuroendocrine networks converging to form an NIE modulatory network. In particular, the neuroinflammation begins at the peripheral olfactory bulb and enteric plexus, and proceeding into the CNS in a Braak disseminating style. While in the RDMP axis, the dysfunctional SCN, hypothalamus, pineal gland, and resultant DA–melatonin imbalance help to interpret the Parkinsonian neuroendocrine abnormities. Based on the neuroendocrine and neuroimmune networks, the four dopaminergic projection pathways (nigrostriatal, mesolimbic, mesocortical, and TIDA pathways) underlie the motor and non-motor symptom complexes in PD