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The Parkinson's-Reversing Breakthrough

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FIGURE 1 Midbrain sections from a variety of disorders associated with parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), cor-ticobasal degeneration (CBD), frontotemporal dementia (FTD) and a disorder not associated with parkinsonism, Alzheimer's disease (AD). Note loss of pigment in the substantia nigra in all disorders, except AD.

FIGURE 1 Midbrain sections from a variety of disorders associated with parkinsonism, including Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), cor-ticobasal degeneration (CBD), frontotemporal dementia (FTD) and a disorder not associated with parkinsonism, Alzheimer's disease (AD). Note loss of pigment in the substantia nigra in all disorders, except AD.

Lewy bodies. In most cases, Lewy bodies are accompanied by a variable number of abnormal neuritic profiles, referred to as Lewy neurites. Lewy neurites were first described in the hippocampus (8), but are also found in other regions of the brain, including the amygdala, cingulate gyrus, and temporal cortex. At the electron microscopic level, Lewy bodies are composed of densely aggregated filaments (9) and Lewy neurites also are filamentous, but they are usually not as densely packed (8).

Neurons that are most vulnerable to Lewy bodies include the monoaminergic neurons of the substantia nigra, locus ceruleus, and dorsal motor nucleus of the vagus,

FIGURE 2 Parkinson's disease: Lewy bodies are hyaline inclusions visible with routine histologic methods in pigmented neurons of the substantia nigra (arrow in A). They are immunostained with antibodies to synuclein (arrow in B).

as well as cholinergic neurons in the basal forebrain. Lewy bodies are rarely detected in the basal ganglia or thalamus, but are common in the hypothalamus, especially the posterior and lateral hypothalamus, and the brainstem reticular formation. The oculomotor nuclear complex is also vulnerable. In the pons, the dorsal raphe and subpe-duncular nuclei are often affected, but neurons of the pontine base are not. Lewy bodies have not been described in the cerebellar cortex. In the spinal cord, the neurons of the intermediolateral cell column are most vulnerable. Lewy bodies can be found in the autonomic ganglia, including submucosal ganglia of the esophagus (10).

Although not usually numerous in typical PD, Lewy bodies can be found in cortical neurons, especially in the limbic lobe. Cortical Lewy bodies can be difficult to detect with routine histology, but are visible with special staining techniques and are usually most numerous in small nonpyramidal neurons in lower cortical layers. Similar lesions in the substantia nigra are referred to as "pale bodies" or as "pre-Lewy bodies." Ultrastructural studies of cortical Lewy bodies demonstrate poorly organized filamentous structures similar to Lewy neurites.

The distribution of Lewy bodies in PD has been placed in a six-stage scheme that hypothesizes the earliest changes are in the lower brainstem and the olfactory bulb, with "spread" of the disease process to progressively higher levels of the neu-raxis (11). In this scheme, the locus ceruleus is involved at stage 2, the substantia nigra is involved at stage 3, the basal forebrain and limbic lobe at stage 4, the multimodal association neocortex at stage 5, and the primary neocortex at stage 6. The hypothesis predicts that preparkinsonian manifestations would be nonmotor (e.g., autonomic dysfunction and anosmia) and that the late stage would be associated with cortical Lewy body dementia. The scheme remains to be confirmed, but there is intriguing evidence that would suggest that sleep disorders, constipation, and anosmia may precede overt parkinsonism in some cases by many years (12-14).

The chemical composition of Lewy bodies has been inferred from immuno-histochemical studies. While antibodies to neurofilament were first shown to label Lewy bodies (15), ubiquitin (16) and more recently a-synuclein (17) (Fig. 2) antibodies are better markers for Lewy bodies, and a-synuclein appears to be the most specific marker currently available. Lewy neurites have the same immunoreactivity profile as Lewy bodies (18). Biochemical studies of purified Lewy bodies have not been accomplished, but evidence suggests that they may contain a mixture of proteins, including neurofilament and a-synuclein (19-21).

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