Parkinsonism and akinetic–rigid disorders
Akinetic–rigid disorders are characterized clinically by rigidity, bradykinesia, and resting tremor. The combination of these features is often termed parkinsonism, of which the commonest cause is Parkinson’s disease (PD).
PARKINSON’S DISEASE (PD)
PARKINSON’S DISEASE
CAUSES OF PARKINSONISM
Parkinson’s disease (PD) (Table 28.1). In autopsy studies, 20–30% of patients diagnosed clinically as having Parkinson’s disease have been found to have an alternative cause for their parkinsonism.
Table 28.1
Parkinson’s disease and parkinsonism: genetic, clinical and pathologic correlation
Hardy (2010); Hardy et al. (2009).
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication causes parkinsonism associated with degeneration of dopaminergic neurons (see Chapter 25).
LEWY BODIES
The pathologic hallmark of Parkinson’s disease is the presence of neuronal inclusions called Lewy bodies. There are two main types, termed ‘classical’ and ‘cortical’ (Table 28.2), which are found in different locations. The presence of Lewy bodies defines several conditions, termed Lewy body disorders (see Tables 28.3 and 28.4).
Table 28.3
Distribution of Lewy bodies in different disorders and their clinical-pathologic correlation
| Disorder | Main site of Lewy body pathology | Clinical correlate |
| Parkinson’s disease (PD) | Substantia nigra | Akinetic–rigid syndrome |
| Parkinson’s disease with dementia (PDD) | Substantia nigra, cerebral cortex | Dementia occurs ≥1 year after a clinical diagnosis of PD |
| Dementia with Lewy bodies (DLB) | Cerebral cortex, substantia nigra | Dementia with akinetic–rigid syndrome. Dementia occurs within a year of onset of parkinsonian features |
| Autonomic failure | Sympathetic neurons in spinal cord | Autonomic failure |
| Lewy body dysphagia | Dorsal vagal nucleus | Dysphagia |
Table 28.4
Anatomical regions susceptible to Lewy pathology, according to two major classification schemes
Braak et al. (2003); Kosaka et al. (1988).
MACROSCOPIC APPEARANCES
Sections through the midbrain and pons reveal loss of pigment from the substantia nigra and locus ceruleus (Fig. 28.1 – note that pallor of the substantia nigra is normal in childhood and adolescence, the slate-gray color being acquired during early adulthood). The globus pallidus, putamen, and caudate nucleus appear normal.
28.1 Substantia nigra in Parkinson’s disease.Sections through midbrain of normal control (top) and patient with PD (bottom), showing the abnormal pallor of the substantia nigra in PD.
LEWY BODIESThe three major pathologic forms of α-synuclein-containing inclusions are:
Neuronal Lewy bodies and Lewy neurites (Figs 28.4, 28.5).
28.4 Lewy bodies in the substantia nigra.(a) Classical Lewy body with a hyaline eosinophilic core and a pale halo. The core may comprise concentric lamellae of differing staining intensity. (b) A pale body: a round zone of finely granular or homogeneous, weakly eosinophilic material displacing the neuromelanin. In contrast to Lewy bodies, pale bodies do not have a halo. (c) Classical Lewy body with an intensely labeled core and lighter, granular staining in the halo. The nucleus of the neuron is visible above the Lewy body. Several Lewy neurites are also labeled. (d) Occasionally, aggregated or multiple Lewy bodies are present in the cytoplasm. (e) Beaded Lewy neurites. A classical Lewy body is also present, towards the top of the image. (f) Lewy body away from the perikaryon.
28.5 Cortical Lewy bodies.These are homogeneous eosinophilic structures that have an ill-defined edge and usually lack an obvious halo (arrow). (a) Typically, a cortical Lewy body appears as a round eosinophilic inclusion which pushes the nucleus to one side of the cell. The nuclei of affected neurons usually appear somewhat vesicular with a prominent nucleolus. (b) α-synuclein immunostaining: cortical Lewy body with an intensely labeled core. Note too, the dot-like immunopositivity in the neuropil, often present, particularly in patients with many neocortical Lewy bodies. (c) α-synuclein immunostaining of cortical Lewy neurites.
Functional proteins that make up the structure of the Lewy body:
α-synuclein (seen in all Lewy bodies). Mutations in the gene for α-synuclein, SNCA, cause some familial cases of PD.
Neurofilament proteins, which form the cytoskeleton of the inclusion.
Incorporated proteins, probably in the process of being degraded:
Immunohistochemical staining is a sensitive way of detecting cortical Lewy bodies. Antibodies to α-synuclein are most sensitive but antibodies to p62 or ubiquitin are also useful. Pale bodies occur in neurons of the substantia nigra and locus ceruleus (Fig. 28.4b) and have a similar immunohistochemical profile to that of Lewy bodies. Although not always associated with Lewy bodies, the latter should be carefully sought if pale bodies are present. Pale bodies may represent precursors of Lewy bodies.
MICROSCOPIC APPEARANCES
The substantia nigra and other pigmented brain stem nuclei show:
28.2 Cell loss from the substantia nigra is not random, but occurs in a region-specific manner.The pars compacta of the substantia nigra can be divided into ventral and dorsal tiers, which project to different brain areas, and each tier can be further subdivided into regions (medial to lateral). (a) In normal aging, the estimated rate of cell loss from the dorsal tier of the substantia nigra is 7% per decade, leading to 40–50% cell loss by 65 years of age. (b) In PD, cell loss is greatest in the ventrolateral tier (VL). Typically, 70–90% have been lost by the time a patient dies. The ventromedial tier (VM) is next most affected. Cell loss from the dorsal tier is not significantly different from that in normal aging. (c) It has been suggested that symptoms of PD occur only after 50% of ventral tier neurons have been lost. This is preceded by a subclinical phase that can be regarded as incidental Lewy body disease, in which there is less pronounced cell loss, largely confined to the ventrolateral tier (VL). The age-specific prevalence of Lewy bodies rises from 3.8% to 12.8% between the 6th and 9th decades.
accumulation of neuromelanin in macrophages (Figs 28.6, 28.7)
28.3 α-Synuclein pathology in Parkinson’s disease. (a)Frequency and clinical features of the four major types phenotypes of PD. Brain schematics show increasing severity with age (blue bar). (b,c) Anatomic distribution of α-synuclein pathology. (Adapted from Halliday GM et al. 2011. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol 122(2):187–204 and Braak H et al. 2003. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211.)
28.6 Phagocytosis of neuromelanin.Neuromelanin from neurons that have degenerated is taken up into macrophages (arrows).
28.7 Phagocytosis of neuromelanin.A cluster of pigment-laden macrophages (arrow) marks the site of degeneration of a nigral neuron.
Lewy bodies and pale bodies (see Fig. 28.5) in some remaining neurons
A distinctive form of neuritic degeneration (Lewy neurites), demonstrable by immunostaining for α-synuclein or ubiquitin, but not by silver impregnation, occurs in Lewy body diseases, including PD (see Figs 28.4, 28.5). The Lewy neurites may be detected in the substantia nigra, CA2/3 region of the hippocampus, dorsal motor nucleus of the vagus, nucleus basalis of Meynert, and amygdala.
DRUG AND TOXIN-RELATED PARKINSONISM
Other causes of drug- and toxin-related parkinsonism are described in Chapter 25.
PROGRESSIVE SUPRANUCLEAR PALSY (PSP) (STEELE–RICHARDSON–OLSZEWSKI SYNDROME)
The cause of PSP is not known, but the disease is strongly associated with the H1 haplotype of MAPT, the tau gene (this haplotype is also associated with CBD, see below). In the brain of patients with PSP, as in CBD (and also argyrophilic grain disease, see Chapter 31), four-repeat tau predominates, i.e. tau that is synthesized from transcripts that include exon 10 and therefore encode four microtubule-binding domains rather than three. Approximately 1–8% of patients diagnosed clinically as having PD have PSP.
MACROSCOPIC APPEARANCES
There is loss of pigment from the substantia nigra and locus ceruleus (Fig. 28.8) and, occasionally, atrophy of the midbrain, pontine tegmentum, and globus pallidus.
28.8 PSP.(a) Atrophy of the midbrain and pallor of the substantia nigra (arrows). (b) Pallor of the locus ceruleus (arrows).
PROGRESSIVE SUPRANUCLEAR PALSY
MICROSCOPIC APPEARANCES
Certain abnormalities are common to several regions of the CNS (Fig. 28.9):
28.9 Pathologic changes in PSP.The areas affected in PSP can be divided into those that are consistently and severely affected, and those that are less consistently affected.
Neuronal accumulation of abnormal tau protein (Fig. 28.10), either diffusely distributed and detectable only immunohistochemically, or aggregated into neurofibrillary tangles, many of which are also demonstrable by silver impregnation. The tangles stain poorly for ubiquitin.
28.10 Types of tau-positive inclusion in PSP as demonstrated by labeling with the AT8 antibody.(a) Typical basophilic, rounded or globose tangle in the substantia nigra. (b) Gallyas silver impregnation is a sensitive method of detecting the tangles, as in this section of substantia nigra. (c) Tangles in the pontine nuclei. (d) Cortical neurons containing tau-positive tangles. Scattered neurites are also labeled. (e) Oligodendroglial tau inclusions (coiled bodies and interfascicular threads) in the subcortical white matter. (f) Tufted astrocytes in the cortex. This form of astrocytic tau is specific for PSP and is distinct from the astrocytic plaques of CBD.
Glial accumulation of tau protein. Tufted astrocytes seen in gray matter are especially characteristic of PSP (Fig. 28.10f).
The findings vary in different regions of the CNS:
In the cerebral cortex there are commonly neuronal tangles, tau-immunoreactive glia, and neuropil threads, particularly in the precentral gyrus, entorhinal cortex, and hippocampus. An occasional neuron in the cerebral cortex and basal ganglia may appear swollen and achromasic. An abundance of swollen neurons suggests corticobasal degeneration (CBD).
Criteria for pathologic diagnosis of PSP have been proposed (Table 28.5).
Table 28.5
DIFFERENTIAL DIAGNOSIS OF PROGRESSIVE SUPRANUCLEAR PALSY
Supranuclear palsy may be associated with several other neurologic diseases, including vascular disease, Lewy body disease, corticobasal degeneration (CBD), and Creutzfeldt–Jakob disease.
