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The common denominator of virtually all disorders associated with clinical parkinsonism is neuronal loss in the substantia nigra, particularly of dopaminergic neurons in the pars compacta (A9) that project to the striatum (Fig. 8–1). The exception to this concept is parkinsonism due to direct injury to the striatum, such as that seen in vascular parkinsonism, in which infarcts or hemorrhages are present in the basal ganglia, especially the globus pallidus, without necessarily affecting the substantia nigra.1 The ventrolateral tier of neurons appears to be the most vulnerable in many parkinsonian disorders, and these project heavily to the putamen.2 The more medial group of dopaminergic neurons (A10) send projections to the forebrain and medial temporal lobe and are less affected. The basis for selective vulnerability between A9 and A10 neurons has been explored with microarray expression studies, which show different patterns of gene expression in A9 and A10 neurons,3 but much remains to be learned how this translates into selective neuronal loss of A9 neurons in parkinsonian disorders. The dorsal tier of neurons may be most vulnerable to neuronal loss associated with aging.4

Figure 8–1.
Graphic Jump Location

Macroscopic findings in PD. Transverse sections of the hemi-midbrain at the level of the third nerve in a patient with long-standing PD (A) and an elderly normal individual (B). The major difference is loss of neuromelanin pigment that is most marked in the ventrolateral parts of the substantia nigra (arrow).


The clinical features of PD are bradykinesia, rigidity, tremor, postural instability, autonomic dysfunction, and bradyphrenia. The most frequent pathologic substrate for PD is Lewy body (LB) disease.5 Some cases of clinically typical PD have other pathologic processes at autopsy, such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or vascular disease, but these are uncommon, especially when the clinical diagnosis is made after several years of clinical follow-up.6, 7 The diagnostic accuracy rate can approach as high as 90% in some series.8


The brain in PD is usually grossly normal when viewed from the outer surface. There may be mild frontal atrophy is some cases, but this is variable. The most obvious morphologic change in PD is visible after the brain stem is sectioned. The loss of neuromelanin pigmentation in the substantia nigra and locus ceruleus is usually apparent (Fig. 8–1). Neuromelanin pigment is an oxidized by-product of di-oxy-phenylalanine, a precursor to dopamine, norepinephrine, and epinephrine, which accumulates with increasing age in neurons that produce these neurotransmitters. Histologically, there is neuronal loss in the substantia nigra pars compacta along with compensatory astrocytic and microglial proliferation, with the degree of neuronal loss correlating with disease duration.9 Neuromelanin pigment may be found in the cytoplasm of macrophages, a marker of neuronal loss.10 It is less common to find neurons undergoing active neuronophagia (i.e., phagocytosis by macrophages).


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