Fig. 1: Prototypical Models of Neuronal Loss Patterns in PD.

Illustrative models of dopaminergic neuron loss in the substantia nigra pars compacta, representing possible progression patterns in PD. For modeling, an initial count of 500,000 dopaminergic neurons at birth was assumed, decreasing to approximately 300,000–400,000 neurons by the seventh decade due to normal aging⁴⁴. Motor symptoms in PD were set to emerge when dopaminergic neuron loss reaches 50% relative to age-matched healthy individuals¹³. The shaded region in each panel represents the premotor phase, the interval between the onset of neuronal pathology and the onset of motor symptoms. Green dotted line denotes age-related neuronal loss. A Linear Long Latency Model: This model assumes a congenital predisposition, with neuronal loss following a pattern of accelerated aging over a prolonged premotor phase. B Linear Model with Event: This model suggests an event at age 50 disrupts normal aging, leading to a linear decline in neuron count. The premotor period is estimated at 15 years. C Exponential Decay Model: Here, an acute event causes a sudden 10% reduction in neurons, followed by a rapid, exponential annual loss of 10%. The premotor period is approximately 5 years. D Sigmoidal Model: This model proposes a gradual initiation of pathology starting at age 40, with an accelerating decline that later decelerates, approaching a non-zero asymptote. The premotor phase spans roughly 25 years.