Parkinson's Disease

Pathology

Pathologically, PD is characterized by severe loss of substantia nigra (SN) dopaminergic neurons, visible in brain sections as depigmentation of the substantia nigra in the midbrain. It is estimated that approximately 60% to 70% of the SN dopamine cells are lost by the time a patient first presents for clinical evaluation, diagnosis, and treatment. Neuroimaging reveals a typically asymmetric loss of dopamine terminals in the striatum, which progresses over time leading to further clinical deterioration.

Legend: Pathological changes in the basal ganglia, and micrograph of Lewy bodies

Histologically, the hallmark of PD is the Lewy body (LB), a cytoplasmic inclusion composed principally of alpha-synuclein. LBs form in the substantia nigra, but also elsewhere in the brain.

Braak Staging
Braak et al. have carefully studied the evolution of LB pathology in the brains of both PD patients and those with incidental LBs. They propose that LBs begin to accumulate well before diagnosis, and well outside of the substantia nigra, and affect neurotransmitter systems other than dopaminergic ones. They describe a pathologic process proceeding in six stages:

Stage 1: dorsal motor nucleus of the vagal nerve; anterior olfactory structures
Stage 2: lower raphe nuclei; locus coeruleus
Stage 3: substantia nigra; amygdala; nucleus basilis of Meynert (clinical diagnosis)
Stage 4: temporal mesocortex
Stage 5: temporal neocortex; sensory association and premotor areas
Stage 6: neocortex; primary sensory and motor areas

Note that diagnosis is typically delayed until stage 3, further implying a long preclinical period of neuronal decline.

• Braak H, Del Tredici K, Rüb U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211.

Normal and Pathological Functional Anatomy of the Basal Ganglia

Legend: Normal Functional Anatomy of the Basal Ganglia

This first diagram outlines the complex circuitry between the cortex, striatum, subthalamic nucleus and thalamus. The arrows point in the direction of different tracts and the colors indicated on the right show the neurotransmitters involved at each level. The positive sign near the end of the tract indicates that the impulses are excitatory, while the negative sign indicates inhibitory impulses. For reference, keep in mind the width of these tracks is proportional to the strength of the signal. Of special interest are the dopaminergic pathways and the excitatory glutamatergic pathways.

Legend: Pathologic Functional Anatomy of the Basal Ganglia in PD

This second diagram shows the changes in the basal ganglia cortical circuitry after substantia nigra compacta damage. The main features are the reduced dopaminergic impulses from substantia nigra to the striatum, enhanced excitation of the subthalamic nucleus and the globus pallidus internus, and increased inhibition of the thalamus. Although an oversimplification, these dynamic changes are thought to underlie the motor impairments of PD. It is also possible to see in this diagram the theoretical basis for neurosurgery: Surgical lesion or electrode implantation to functionally block the abnormal activity in the subthalamic nucleus and globus pallidus internus could produce symptomatic benefit for motor symptoms in Parkinson's disease.

The many nonmotor aspects of PD are not likely to be directly related to the changes depicted above. Dopaminergic neurons outside of these pathways, and non-dopaminergic neurotransmitter systems, are also affected, and are responsible for significant aspects of the disease.