Parkinson's disease and parkinsonism: neuropathology

Abstract

Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein α-synuclein or the microtubule binding protein tau. In idiopathic Parkinson's disease (PD), α-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major α-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of α-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, α-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.

Figure 1.

Macroscopic appearance of the brain in PD (A), MSA (B), and PSP (C). There are distinguishing macroscopic features in these three major degenerative parkinsonian disorders, which is also the basis of neuroimaging biomarkers in the living patient. Transverse sections of the midbrain (lower left) and pons (lower right) shows pigment loss in the substantia nigra (white arrows) in all three disorders, which correlates with parkinsonism. In MSA there is atrophy of the pontine base (black asterisk in B), whereas the pontine base is unremarkable in PD and PSP. In PSP the superior cerebellar peduncle (compare structures marked with white arrowheads in A–C) has marked atrophy in C, whereas it has normal thickness in PD and MSA. Sections of the cerebrum at the level of the subthalamic nucleus show atrophy in PSP (C) (double black arrowheads mark the widest diameter of the nucleus), whereas the STN is normal in PD (A) and MSA (B). In MSA there is atrophy and dark discoloration of the posterior putamen (white asterisk in B), but no atrophy or discoloration is noted in PD or PSP. Abbreviations: SN, substantia nigra; Str, striatum; PN, pontine nuclei; SCP, superior cerebellar peduncle; STN, subthalamic nucleus.

Figure 2.

Substantia nigra in PD (A), MSA (B), and PSP (C). All three major degenerative parkinsonian disorders have neuronal loss, extraneuronal neuromelanin pigment, and gliosis in the substantia nigra, especially the ventrolateral tier (shown here). There are no distinctive histologic features in MSA, but in PD there are typical hyaline cytoplasmic inclusions—Lewy bodies (inset in A), whereas PSP is characterized by basophilic globose shaped neurofibrillary tangles (inset in C).

Figure 3.

Microscopic findings in PD with α-synuclein immunohistochemistry. A typical brainstem type Lewy body (A) and a pale staining “cortical type” Lewy body (B), Lewy neurites in CA2 sector of hippocampus (C), and intraneuritic Lewy bodies in medulla (D).

Figure 4.

Microscopic findings in MSA with α-synuclein immunohistochemistry. Glial cytoplasmic inclusions in pencil fibers of the putamen (A), neuronal cytoplasmic inclusion in pontine nuclei (arrow in B), neuronal cytoplasmic inclusions and dystrophic neurites in the inferior olivary nucleus (C), and intranuclear inclusions (arrow) and dystrophic neuritics in the pontine nucleus (D).

Figure 5.

Microscopic examination of PSP with tau immunohistochemistry. Globus neurofibrillary tangles (A), tufted astrocytes (B), and coiled bodies (C). Note also tau positive neurites in A and C.