Page 853 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

Parkinson Disease
Parkinsonism is a clinical syndrome characterized by tremor,
rigidity, bradykinesia and instability. These types of motor
disturbances may be seen in a range of diseases that damage
dopaminergic neurons, which project from the substantia
nigra to the striatum. Parkinsonism can be induced by
drugs such as dopamine antagonists or toxins that selec-
tively injure dopaminergic neurons. Among the neurode-
generative diseases, most cases of parkinsonism are caused
by Parkinson disease (PD), which is associated with charac-
teristic neuronal inclusions containing α-synuclein. Other
diseases in which parkinsonism may be present include
multiple system atrophy (MSA), in which α-synuclein aggre-
gates are found in oligodendrocytes; progressive supranu-
clear palsy (PSP) and corticobasal degeneration (CBD), which
are both associated with tau-containing inclusions in
neurons and glial cells; and postencephalitic parkinsonism,
which was associated with the 1918 influenza pandemic.
PATHOGE NESIS
While PD in most cases is sporadic, both autosomal domi-
nant and recessive forms of the disease also exist. Point
mutations and duplications of the gene encoding α-synuclein,
a protein involved in synaptic transmission, cause autosomal
dominant PD. Even in sporadic PD, the diagnostic feature of
the disease—the Lewy body—is an inclusion containing
α-synuclein. The linkage between α-synuclein and disease
pathogenesis is unclear, but other genetic forms of PD
provide some clues. Two other causative genetic loci encode
the proteins parkin, an E3 ubiquitin ligase, and UCHL-1, an
enzyme involved in recycling of ubiquitin from proteins tar-
geted to the proteasome, suggesting that defects in protein
degradation may have a pathogenic role. Another tantalizing
clue comes from the association of PD with mutations in a
protein kinase called LRRK2; histopathologic examination of
cases associated with LRRK2 mutations may show either
Lewy bodies containing α-synuclein or tangles containing tau.
Finally, some forms of familial PD are associated with muta-
tions in the PARK7 or PINK1 genes, both of which appear to
be important for normal mitochondrial function.
ABC
Figure 22–26 Parkinson disease. A, Normal substantia nigra. B, Depigmented substantia nigra in idiopathic Parkinson disease. C, Lewy body in a
neuron from the substantia nigra stains pink.
Neurodegenerative Diseases 839
MORPHOLOGY
A typical gross finding at autopsy is pallor of the substantia
nigra (Fig. 22–26, A and B) and locus ceruleus. Microscopic
features include loss of the pigmented, catecholaminergic
neurons in these regions associated with gliosis. Lewy
bodies (Fig. 22–26, C) may be found in those neurons that
remain. These are single or multiple, intracytoplasmic, eosin-
ophilic, round to elongated inclusions that often have a dense
core surrounded by a pale halo. On ultrastructural examina-
tion, Lewy bodies consist of fine filaments, densely packed in
the core but loose at the rim, composed of α-synuclein and
other proteins, including neurofilaments and ubiquitin. The
other major histologic finding is Lewy neurites, dystrophic
neurites that also contain abnormally aggregated α-synuclein.
As implied by the occurrence of a broad array of neuro-
logic deficits in PD, immunohistochemical staining for α-
synuclein highlights more subtle Lewy bodies and Lewy
neurites in many brain regions outside of the substantia nigra
and in nondopaminergic neurons. These lesions appear first
in the medulla and then in the pons, before involvement of
the substantia nigra. As implied by the dementia, Lewy bodies
and Lewy neurites eventually appear in the cerebral cortex
and subcortical areas, including the cholinergic cells of the
basal nucleus of Meynert and the amygdala.
Clinical Features
PD commonly manifests as a movement disorder in the
absence of a toxic exposure or other known underlying
etiology. The disease usually progresses over 10 to 15
years, eventually producing severe motor slowing to the
point of near immobility. Death usually is the result of
intercurrent infection or trauma from frequent falls caused
by postural instability.
Movement symptoms of PD initially respond to L-
dihydroxyphenylalanine (L-DOPA), but this treatment
does not slow disease progression. Over time, L-DOPA
becomes less effective and begins to cause potentially prob-
lematic fluctuations in motor function.
While the movement disorder associated with loss of the
nigrostriatal dopaminergic pathway is an important feature
of PD, it is clear that the disease has more extensive clinical
and pathologic manifestations. Lesions can be found lower