Parkinsons Disease

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What is Parkinsons Disease

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The clinical features of Parkinson's disease (PD) include bradykinesia, rigidity, tremor, postural instability, autonomic dysfunction, and bradyphrenia. The most frequent pathologic substrate for PD is Lewy body disease (2). Some cases of otherwise clinically typical PD have other disorders, 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 (3,4). The diagnostic accuracy rate has approached 90% in some series (5).

The brain 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 only visible after the brainstem is sectioned. The loss of neu-romelanin pigmentation in the substantia nigra and locus ceruleus is usually grossly apparent and may be associated with a rust color in the pars reticulata, which correlates with increased iron deposition in the tissue. Histologically, there is neuronal loss in the substantia nigra pars compacta along with compensatory astrocytic and microglial proliferation. Although biochemically there is loss of dopaminergic termini in the striatum, the striatum is histologically unremarkable. In the substantia nigra and locus ceruleus, neuromelanin pigment may be found in the cytoplasm of macrophages. Less common are neurons undergoing neuronophagia (i.e., phagocytosis by macrophages). Hyaline cytoplasmic inclusions or Lewy bodies and less well-defined "pale bodies" are found in some of the residual neurons in the substantia nigra (Fig. 2). Similar pathology is found in the locus ceruleus, the dorsal motor nucleus of the vagus, as well as the basal forebrain (especially the basal nucleus of Meynert). The convexity neocortex usually does not have Lewy bodies, but the limbic cortex and the amygdala may be affected. Depending upon the age of the individual, varying degrees of Alzheimer-type pathology may be detected, but if the person is not demented, this usually falls within the limits for that age. Some cases may have abundant senile plaques, but few or no neurofibrillary tangles (NFTs).

Lewy bodies are proteinaceous neuronal cytoplasmic inclusions (6,7). In some regions of the brain, such as the dorsal motor nucleus of the vagus, Lewy bodies tend to form within neuronal processes and are sometimes referred to as intra-neuritic

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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