Lewy Body Disease
TAMARA A. SMITH, MD, and RICHARD A. PRAYSON,
MD, Cleveland, Ohio
ABSTRACT: Lewy bodies have historically been considered a histopathologic hallmark of idiopathic Parkinson's disease. Recently, it has become clear that Lewy bodies play a role in neurodegenerative processes other than idiopathic Parkinson's disease, including diffuse Lewy body disease and diffuse Lewy bodies with concomitant Alzheimerís disease changes. It is likely that these processes represent a spectrum of neurodegenerative change in which Lewy bodies play a pivotal role. Although much is known and has been written regarding the histopathology and pathophysiology of Lewy body diseases, specific criteria for their diagnosis remain problematic. Within the spectrum of Lewy body disease, overlap in clinical presentation and histopathologic findings has caused some to dismiss attempts at subcategorizing Lewy body disease as artificial. We present, in brief, current information and theories concerning the pathology and pathogenesis of Lewy body disease.
LEWY BODIES, first described in 1912 by F. H. Lewy, are distinctive neuronal inclusions that historically have been linked to idiopathic Parkinson's disease and have been considered a diagnostic hallmark of this entity. In recent years, however, it has become clear that Lewy bodies may be seen in several different neurodegenerative processes that are clinically similar yet distinct from the prototype Lewy body disease, idiopathic Parkinson's disease. Lewy bodies may be found in several other neurodegenerative processes and diseases (Table); with few exceptions, Lewy bodies are not essential for the diagnosis of most of these entities. The focus of this article is to examine and review the histopathologic findings as they pertain to three categories of disease in which Lewy bodies are diagnostically and clinically essential: (1) idiopathic Parkinson's disease, (2) diffuse Lewy body disease, and (3) diffuse Lewy bodies with Alzheimerís disease changes.
WHAT IS A LEWY BODY?
Lewy bodies are eosinophilic structures located within the cytoplasm of neurons. Characteristically, although not consistently, they are circular and have a dense protein core surrounded by a peripheral halo (Fig 1).
Lewy bodies may be single or multiple within a neuron and their size may vary. Lewy bodies may be seen in a variety of locations, and, depending on the anatomic location in which they are found, their appearance varies. Generally, they retain their characteristic appearance in brain stem locations (substantia nigra and locus ceruleus); however, in other locations such as the cerebral cortex, they are often much less eosinophilic, are more elongate, and usually lack a peripheral halo around the central core.
The ultrastructural appearance of the characteristic Lewy body has often been likened to a sunflower. It has a dense central core of circular-shaped structures with a rim of radiating filaments (7 to 20 nm in diameter), with the largest filaments being located at the periphery of the structure. A looser arrangement of filaments at the periphery corresponds to the halo often observed by light microscopy. In contrast, the ultrastructure of cortical Lewy bodies consists of a random arrangement of intermediate filaments without radial orientation or a distinct core. In addition, degenerate cell organelles have often been incorporated into the structure of the Lewy body.
Generally, the Lewy body is thought to be the result of altered neurofilament metabolism and/or transport due to neuronal damage and subsequent degeneration, causing an accumulation of altered cytoskeletal elements. Immunohistochemically, Lewy bodies stain with a variety of antibodies. Most notable, however, is the invariable staining with antineurofilament and anti-ubiquitin antibodies. There are three types of neurofilament proteins, designated as H (high molecular weight), M (middle molecular weight), and L (low molecular weight). In brain stem Lewy bodies, epitopes from the entire length of H, M, and L neurofilaments are incorporated into the structure, but staining of the tail regions of types H and M is absent in the central core. In cortical Lewy bodies, an epitope in the tail region of neurofilament M stains virtually every Lewy body. In addition, these neurofilaments exist in both phosphorylated and nonphosphorylated states. In particular, Lewy bodies stain well with antibodies to phosphorylated neurofilaments. This suggests that the phosphorylated neurofilament proteins may be instrumental in the formation of Lewy bodies.
Anti-ubiquitin antibodies also stain both brain stem and cortical Lewy bodies. Ubiquitin plays a role in the breakdown of certain cytosolic protein and has been characterized as a ìheat-shock protein,î one induced during times of cell stress.
Pale bodies are spherical areas of eosinophilic material within the cytoplasm of the neuron that displace the melanin to the periphery. They lack a dense core and peripheral halo. While they are not diagnostic of Parkinson's disease, most physicians would agree that their presence should induce a careful search for characteristic and diagnostic Lewy bodies. It is possible that they represent early immature Lewy bodies, since some have been shown to stain with the antibodies to phosphorylated neurofilaments and ubiquitin.
Two structures that histologically may resemble and thus may be confused with Lewy bodies include the Marinesco body and the ìacidophilic pink granule. The Marinesco body is also a circular eosinophilic inclusion that is generally much smaller in size than the Lewy body and is more typically located within the nucleus of neurons. The Marinesco body may occur within substantia nigra and locus ceruleus and its presence correlates with increasing age. It may also be seen in the setting of Parkinson's disease. To date, its relationship to the Lewy body, if any, is not known. The acidophilic pink granule is a small eosinophilic cytoplasmic granule found in pigmented neurons, distributed among the neuromelanin granules. Its significance at this time is also unknown.
THE INCIDENTAL LEWY BODY
It is now recognized that about 5% to 10% of asymptomatic individuals have presumably insignificant numbers of Lewy bodies, usually located in substantia nigra. In 1990, Perry et al compared the presence of Lewy bodies in a group of patients screened to exclude any neurologic or psychiatric disorders with their presence in a group of patients in a neuropsychiatric ward of a geriatric hospital (excluding patients diagnosed with Alzheimerís disease). The former group had Lewy bodies in 2.3% of cases, while 9% of the latter group were found to have one or more Lewy bodies in brain stem locations. In all cases, the presence of Lewy bodies was associated with at least some degree of neuronal degeneration in substantia nigra. This information is in keeping with the current theory that this population of patients actually represents preclinical, idiopathic Parkinson's disease and, if given enough time, will eventually develop characteristic parkinsonian symptoms.
IDIOPATHIC PARKINSONS DISEASE
Idiopathic Parkinson's disease is a relentlessly progressive neurodegenerative disorder of unknown etiology that has an annual incidence rate of 7.7 to 17.9 cases per 100,000 population. Although first described in 1817 by James Parkinson, the exact etiology and factors that underlie this process of selective neuronal degeneration remain unclear. The onset of symptoms is usually between the ages of 50 and 70 years. The clinical diagnosis is dependent upon three main parameters: (1) clinical symptomatology including tremor, bradykinesia, and rigidity; (2) the exclusion of other entities that cause similar symptoms; and (3) documentation of response to appropriate therapy.
At autopsy, external examination of the brain usually reveals no striking abnormality. The brain weight is typically normal for age. The most noticeable changes center around the pigmented nuclei in the brain stem. The substantia nigra in the mesencephalon is universally pale, due to loss of the pigmented dopaminergic neurons. The locus ceruleus in the pons is often similarly involved (Fig 2).
The histologic correlation to the gross appearance includes selective neuronal degeneration with corresponding cell loss, most notably in substantia nigra and locus ceruleus (Fig 3).
Neuron loss in substantia nigra preferentially involves the zona compacta. It is thought that at least 70% of neurons must be lost in substantia nigra before the patient becomes symptomatic. Pigment incontinence with melanin debris found lying free in the neurophil is a frequent concomitant finding and is due to cell death and release of intracytoplasmic contents, including neuromelanin. Neuromelanin debris may also be found within macrophages. In fact, depigmentation of substantia nigra is often not as visible grossly as one might expect because there still is melanin in the area, even if it is no longer in viable neurons. Gliosis, due to neuronal damage, is invariably present, as are Lewy bodies (Fig 4).
Lewy body formation may also occur in many other locations, such as the nucleus basalis of Meynert, dorsal motor nucleus of the vagus nerve, innominate substance, amygdala and hippocampus region, spinal cord and sympathetic ganglia, and even the cerebral cortex. Lewy bodies in these secondary anatomic locations are often atypical in appearance, ie, less eosinophilic, more elongate, and lacking a peripheral halo.
Selective degeneration of the pigmented neurons in the substantia nigra of the mesencephalon results in a deficiency of the dopamine transmitter synthesized by these neurons. Dopamine normally carries excitatory impulses to the striatum (caudate and putamen) that subsequently travel through the globus pallidus. There are normally excitatory and inhibitory impulses exiting the globus pallidus. The inhibitory impulses use g-aminobutyric acid as their primary neurotransmitter, travel to the thalamus, and, in turn, transmit efferent impulses back to the cortex. This link between the cortex, striatum, palladium, and thalamus serves to modulate that phase of motor activity between the time that one consciously thinks about making a specific movement and the motor activity corresponding to the execution of that movement. Therefore, when there is a deficiency in dopamine (the excitatory nerve transmitter), as there is with idiopathic Parkinson's disease, there is a relative predominance of the inhibitory output of the basal ganglia that is eventually transmitted back to the cortex. The end result can be thought of as a generalized slowing or inhibition of motor impulses producing symptoms of bradykinesia and rigidity.
The precise etiology of Parkinson's disease continues to be elusive. Epidemiologic studies indicate that, as with Alzheimerís disease, Parkinson's disease appears to be an age-related disorder. Studies examining the geographic variation of Parkinson's disease have shown a higher incidence in Western populations as compared with Mediterranean and Asian populations. In addition, studies have shown a lower prevalence in black people than in white people, prompting some to suggest that cutaneous melanin might somehow serve to protect the neuromelanin in substantia nigra from external toxins. Interestingly, cigarette smoking has been observed to have a negative correlation with the occurrence of Parkinson's disease. It has been hypothesized that nicotine may somehow simulate endogenous dopamine or may serve a protective function against oxidative radicals.
Since the initial descriptions of MPTP (1-methyl,4-phenyl-1,2,3,6-tetrahydropyridine) induced parkinsonism, several studies have attempted to implicate environmental toxins in the pathogenesis of Parkinson's disease. Documented cases of parkinsonism associated with exposure to manganese, mercury, carbon monoxide, carbon disulfide, and agricultural pesticides are anecdotal and do not explain the etiology in the vast majority of cases. MPTP is a meperidine analog that was accidentally discovered as a contaminant of illegally made drugs. The pathology in these cases is characterized by destruction of substantia nigra accompanied by a profound loss of dopamine and other neurotransmitters; however, Lewy bodies are not a prominent feature. As with Parkinson's disease, symptoms are usually controlled by levodopa therapy. The MPTP by itself is not toxic; it is converted by monoamine oxidase B into a substance (MPP+) that binds to mitochondria in dopaminergic neurons, resulting in cell damage and death by a free radical mechanism.
It is well known that monoamine oxidase B generates hydrogen peroxide during the breakdown of dopamine. With increasing age, endogenous protective mechanisms that guard against free radical damage are diminished. Sian et al showed reduced levels of glutathione, which serves as a protection against oxidative stress, within substantia nigra of patients with Parkinson's disease. Increased lipid peroxidation, which may be a consequence of oxygen free-radical production, may also play a role in neuronal cell death. It also appears that neurons containing neuromelanin are intrinsically more susceptible to the effects of free radical damage. Studies have also shown increased iron in substantia nigra and in the Lewy bodies in Parkinson's disease. Iron can bind neuromelanin, producing a complex suspected of inducing oxidative stress and lipid peroxidation.
Recently, several reports have looked for abnormalities of the mitochondrial respiratory chain in Parkinson's disease. These abnormalities, which were initially described in substantia nigra, have now been reported in striatum, skeletal muscle, and platelets. Specific enzyme assays have shown decreased complex I enzyme activity in the substantia nigra region in patients with Parkinson's disease. Evidence of specific mitochondrial deoxyribonucleic acid (DNA) defects in patients with Parkinson's disease is more tenuous. There certainly is an increased likelihood of small mutations within mitochondrial DNA after free radical injury. Whether such mutations play a role in making an individual more susceptible to Parkinson's disease is not known.
Another possible etiologic factor that has been proposed to explain the cell death of neurons containing dopamine includes a reported loss of basic fibroblast growth factor, which has a trophic effect on mesencephalic dopaminergic neurons. Recently, an immunohistochemical study using a monoclonal anti-insulin receptor antibody showed an absence of staining in several areas of the brain, including substantia nigra in patients with Parkinson's disease. Moroo and colleagues suggested that a dysfunction of the insulin receptor system may somehow play a role in the death of dopaminergic neurons.
The exact role of hereditary or genetic factors in the development of Parkinson's disease remains a subject of much debate. A number of problems have plagued studies that have attempted to examine this issue, including lack of agreement regarding criteria of what constitutes Parkinson's disease and the clinical heterogeneity of these patients, as well as incomplete examination of all family members. The first systematic genetic analysis of Parkinson's disease was described by Mjönes in 1949. He described a family history positive for Parkinson's disease in 79 of 194 patients (41%) and concluded that Parkinson's disease was inherited as an autosomal dominant trait with a 60% penetrance. Several recent studies have also indicated a possible autosomal dominant inheritance pattern in a subset of patients with parkinsonism. Others have indicated a multifactorial pattern of inheritance in Parkinson's disease. It has even been suggested that genetic anticipation and perhaps an unstable trinucleotide repeat may be involved. Studies of twins with Parkinson's disease have been generally inconclusive due to the small numbers of patients included. Recently, Smith et al reported a higher risk of Parkinson's disease in individuals with a metabolic defect in the cytochrome P450 CYP2D6-debrisoquine hydroxylase gene.
DIFFUSE LEWY BODY DISEASE
A key development in the delineation of Lewy body disorders has been the recent recognition that almost all patients with idiopathic Parkinson's disease have a few Lewy bodies in their cerebral cortex. This previously has been largely unrecognized because cortical Lewy bodies, due to their atypical appearance, are difficult to detect on routine hematoxylin-eosin stains of histologic sections. Recently, it has been found that Lewy bodies are highlighted with anti-ubiquitin antibody and are thus more easily detected. When present, although found throughout the cortex, cortical and neocortical Lewy bodies are typically located in the neurons of cortical layers V and VI of the temporal lobe, the cingulate gyrus, and the insular cortex. Interestingly, Lewy bodies located outside the brain stem do not seem to be associated with the same degree of corresponding cell loss or gliosis. This discovery, along with an increased awareness that some patients previously thought to have idiopathic Parkinson's disease had a prominent component of dementia, led to the separate designation of diffuse Lewy body disease. Estimates of the incidence of dementia in patients with Parkinson's disease are as high as 81%, although the average is probably around 30%. No clear clinical criteria have yet been defined for this disorder. Diffuse Lewy body disease (DLBD) is thought to be a dementing syndrome somewhat akin to Alzheimerís disease, with subtle differences in clinical presentation. In fact, whether it is justified to classify DLBD as distinct from DLBD with Alzheimerís disease changes is still a matter of controversy. The onset of symptoms is at approximately 40 years of age, much earlier than with either Alzheimerís disease or idiopathic Parkinson's disease. The clinical presentation of DLBD can vary widely. Dementia is a prominent feature, characterized by a fluctuating subacute/acute confusional state, and it is often associated with visual hallucinations and behavioral disturbances. Typical parkinsonian symptoms, particularly rigidity, usually develop sometime in the course of the disease. These patients may have dementia and not have extrapyramidal parkinsonian signs until late in the course of the disease.
The histopathologic characteristics of DLBD are distinct. In addition to the typical brain stem pathology of idiopathic Parkinson's disease, numerous widely distributed neocortical Lewy bodies are present (Fig 4).
The pathologic basis for dementia in Lewy body disease or idiopathic Parkinson's disease is controversial. Kosaka et al suggested that, in diffuse Lewy body disease, the dementia was due primarily to the cortical Lewy body. In 75% of patients with typical, brain stem Lewy body disease (idiopathic Parkinson's disease), dementia was thought to be due to degeneration of subcortical nuclei, especially the nucleus basalis of Meynert. In the other 25% of patients with brain stem Lewy body disease, the dementia was thought to be due to coexisting Alzheimerís disease changes.
DIFFUSE LEWY BODIES AND ALZHEIMER&IACUTE;S DISEASE CHANGES
Pure diffuse Lewy body disease, as described, is actually rare. In reality, most cases with both brain stem and numerous neocortical and cortical Lewy bodies will also have some degree of concomitant Alzheimerís disease pathology. The onset of clinical symptoms is usually after the age of 60 years and is gradual, with a slow progression of dementia. The parkinsonian symptoms most commonly seen are bradykinesia and rigidity, and these usually develop late in the course of the disease. In addition, the survival time is shorter than for pure Alzheimerís disease. The histopathology is the same as that of DLBD, with the added feature of associated Alzheimerís-type pathology, including primarily neurofibrillary tangles and senile or neuritic plaques (Fig 4). Rarely, spongiform change in the neurophil has been described. The relative contribution to the clinical presentation of the different histopathologic changes remains unclear.
The pathogenic relationships between Lewy bodies, senile plaques, and neurofibrillary tangles are unclear. Recent work has shown that the apolipoprotein E4 allele, encoded on chromosome 19, is a risk factor for the development of Alzheimerís disease.5 Apolipoprotein E is normally present in the brain and plays a role in cholesterol transport. Only the E4 allele has been shown to be associated with Alzheimerís disease. It appears that there is no association between Parkinson's disease and apolipoprotein E4. Apolipoprotein E4 allele frequencies are intermediate between Alzheimerís and Parkinson's disease in those patients with senile dementia of the Lewy body type.
It is unlikely that the coexistence of these two histopathologic processes is merely a coincidence. In 1993, Förstl and colleagues examined 65 cases of clinically diagnosed Alzheimerís disease. At the time of autopsy, 8 cases (12%) had diffuse neocortical Lewy bodies. Six of the 8 cases with diffuse Lewy bodies met at least minimal histopathologic criteria for Alzheimerís disease, and in 5 of the 8 cases severe parkinsonian rigidity eventually developed. The results of this study proved that the occurrence of diffuse Lewy body disease and Alzheimerís disease together is much higher than that which would be found in a control population. Bergeron and Pollanen studied a series of 150 cases of Alzheimerís disease along with 75 control cases. Thirty-seven patients (25%) with clinical Alzheimerís disease had Lewy bodies along with neurofibrillary tangles, as compared with only 5% of control patients. The majority of the 37 patients had primarily brain stem Lewy bodies; however, 5 patients also had numerous cortical Lewy bodies. Clearly, these studies along with others show that these two histopathologic changes occur together with greater frequency than would normally be expected by chance alone. It is now thought that dementia associated with Lewy body disease is second only to pure Alzheimerís disease as a cause of dementia in the elderly.