ABSTRACT: The pathological features that characterize idiopathic Parkinson's disease have been recognized since the beginning of the last century. Important recent advances include the recognition of α-synuclein as the major biochemical component of Lewy bodies and clarification of the relationship between Parkinson’s disease and other neurodegenerative disorders such as Alzheimer’s disease and dementia with Lewy bodies. In addition to providing insight into disease pathogenesis, this new knowledge may soon provide real benefits in the form of improved disease treatment.
Several recent advances have provided important insights into Parkinson’s disease pathogenesis and its relationship to other conditions.
As described in Dr Calne’s article there is currently some controversy as to what is meant by Parkinson’s disease (PD) and the appropriateness of the terminology. Traditionally, PD has been viewed as a specific entity in which clinical parkinsonism (rigidity, bradykinesia, and tremor) is associated with the pathological findings of neuronal loss and Lewy bodies in the substantia nigra. Although this concept may soon be outdated, no alternative has yet gained wide acceptance. The following discussion describes the pathological changes classically associated with idiopathic PD, with emphasis on some recent developments and concepts.
External examination of the brain is generally unremarkable, although PD patients who develop dementia may have a mild to moderate degree of cerebral atrophy. On cut sections, there is usually loss of pigment from the substantia nigra and locus ceruleus Figure 1. The caudate, putamen, globus pallidus, thalamus, and other brainstem structures appear normal.
The histopathological hallmark of PD is the loss of dopaminergic neurons from the substantia nigra associated with the presence of intraneuronal inclusions called Lewy bodies. Cell loss in the substantia nigra occurs in a region-specific manner, with the lateral ventral tier of the pars compacta being most affected. It is estimated that at least 50% of the nigral neurons must degenerate to produce symptoms and, at autopsy, most cases show more than 80% reduction.
Significant neuronal loss also occurs in the locus ceruleus, dorsal motor nucleus of the vagus, raphe nuclei, and nucleus basalis. Lewy bodies may be found in all of these locations, as well as in numerous other subcortical structures. Neurodegeneration is accompanied by reactive changes including astrogliosis and microglial cell activation. In pigmented nuclei, neuromelanin is released from dying neurons and may lie free within the neuropil (the complex, feltlike net of axonal, dendritic, and glial arborizations that forms the bulk of the central nervous system’s grey matter) or be taken up by macrophages.
Classical (brainstem) Lewy bodies
In 1912, Frederich H. Lewy first described intraneuronal inclusions in the substantia innominata and dorsal motor nucleus of the vagus in patients with paralysis agitans. Seven years later, Tretiakoff recognized similar inclusions in the substantia nigra and called them corps de Lewy. Since then, Lewy bodies have been considered the pathological hallmark of idiopathic PD and most neuropathologists are reluctant to make the diagnosis in their absence.
Classical Lewy bodies are spherical intracytoplasmic neuronal inclusions, measuring 8 µm to 30 µm in diameter, with an eosinophilic hyaline core and a pale staining peripheral halo Figure 2A. They occasionally have a more complex, multilobar shape and more than one Lewy body may occur in a single cell. Following neuronal death, Lewy bodies may remain as an extracellular deposit in the neuropil Figure 2B. Ultrastructurally they are composed of radially arranged 7 nm to 20 nm filaments associated with granular electron dense material.
Lewy bodies are difficult to isolate and purify, so most of our understanding of their chemical composition is based on immunohistochemical studies. Until recently, the two main components were thought to be neurofilament proteins and ubiquitin. Neurofilament is a major component of the neuronal cytoskeleton and all three molecular forms of neurofilament are present in Lewy bodies.
Ubiquitin is a heat shock or cell stress protein that normally has a role in targeting damaged or unwanted cellular proteins for breakdown. The presence of ubiquitin suggests that Lewy bodies may represent a structural manifestation of a cytoprotective response designed to eliminate damaged cellular elements. Lewy bodies are also immunoreactive for other cytoskeletal elements (tubulin, microtubule-associated proteins), other cell stress proteins (αB-crystallin, amyloid precursor protein), synaptic vesicle proteins (synaptophysin, chromogranin), enzymes (protein kinases, ubiquitin-associated enzymes), and some complement proteins.
Non-proteinaceous components include fatty acids, sphingomyelin, and polysaccharides. Recently, genetic studies have led to the discovery of α-synuclein as an important constituent of Lewy bodies, and antibodies against this protein are proving to be highly sensitive and specific markers (see below).
Brainstem Lewy bodies are not specific to PD; they have been described as an occasional finding in a number of neurological conditions and are an age-related incidental autopsy finding occurring in 2% to 10% of neurologically normal individuals. While some have suggested that such individuals may have presymptomatic PD,[2,5] others feel this indicates that Lewy bodies are not disease specific.
Pale bodies are ill-defined rounded areas of granular, pale-staining eosinophilic material that also occur in pigmented neurons of the substantia nigra and locus ceruleus. Although they are distinguished from Lewy bodies histologically, their similar immunocytochemical profile suggests they likely represent precursors to Lewy bodies.
Cortical Lewy bodies
In 1961, Okazaki reported finding Lewy bodies in the cerebral cortex of two patients with PD and atypical dementia. Although subsequent cases of "diffuse Lewy body disease" were published, the condition was initially considered rare. In the late 1980s, with greater awareness of cortical Lewy bodies and the development of more sensitive staining methods, several groups reported finding cortical Lewy bodies in 15% to 25% of elderly demented patients,[7,8] making it the second largest pathological subgroup of dementia, after typical Alzheimer’s disease (AD).
It has recently been proposed that dementia associated with Lewy bodies represents a recognizable clinicopathological syndrome that may be distinguishable during life from other causes of dementia. Although numerous cortical Lewy bodies are most characteristic of dementia associated with Lewy bodies, smaller numbers are found in most (if not all) patients with idiopathic PD, even in the absence of dementia. The clinical and pathological relationship between PD and dementia associated with Lewy bodies and the appropriate terminology remains an ongoing source of controversy.
Cortical Lewy bodies tend to be less well defined and are more difficult to recognize using conventional staining methods. They occur in small and medium-sized pyramidal neurons of the deeper cortical layers and are most abundant in the transentorhinal and cingulate cortex, less numerous in neocortex, and generally spare the hippocampus. It is largely the advent of more sensitive immunohistochemical methods of detection that has allowed the extent of cortical Lewy body pathology to be fully appreciated Figure 3.
A distinctive neuritic degeneration is found in both PD and in dementia associated with Lewy bodies. These abnormally swollen neuronal processes are not seen using HE or conventional silver stains but are well demonstrated using ubiquitin immunohistochemistry Figure 4. They are most concentrated in a sub-region of the hippocampus (CA2), but are also found in the amygdala, nucleus basalis, and various brainstem nuclei.
In 1997, Polymeropoulos and colleagues identified a missense mutation in the α-synuclein gene in four families with autosomal-dominant PD. Subsequent studies have identified additional mutations in other families, but no linkage has been established with sporadic PD. Alpha-synuclein is a presynaptic nerve terminal protein and immunohistochemistry of normal brain tissue shows punctate staining around neuronal perikarya.
Direct invovement of α-synuclein in the pathogenesis of all Lewy body disorders (sporadic as well as familial PD and dementia associated with Lewy bodies) is supported by immunohistochemical studies confirming abnormal aggregrates of α-synuclein as a major component of both brainstem and cortical Lewy bodies as well as pale bodies and Lewy-related neurites.[4,13]
Biochemical abnormalities in the PD brain
Degeneration of the dopaminergic system is responsible for most of the clinical features of PD and levels of dopamine and its metabolite are reduced in the striatum, ventral tegmentum of the brainstem, and less reduced in limbic and neocortical areas. Cholinergic dysfunction is also prominent with a decrease in choline acetyltransferase activity, which may be more severe than that found in AD.[14,15] Norepinephrine and serotonin show more variable reduction.
PD within the spectrum of Lewy body disorders
There is striking clinical and pathological overlap between PD and dementia associated with Lewy bodies. Approximately one-third of patients with a clinical diagnosis of PD will develop dementia and most (but not all) patients with dementia associated with Lewy bodies display some degree of parkinsonism. Lewy bodies are the defining histopathological feature of both conditions. In PD, Lewy bodies are most numerous in subcortical nuclei, and it is the associated loss of dopaminergic neurons that is largely responsible for the characteristic extrapyramidal features.
However, small numbers of cortical Lewy bodies may be found in virtually all cases of PD, even in the absence of dementia. In dementia associated with Lewy bodies, cortical Lewy bodies are usually more numerous, and some studies have shown a correlation between their number and the degree of dementia. Even in the absence of parkinsonism, however, the vast majority of dementia associated with Lewy bodies cases display some brainstem Lewy bodies.
Recognition of this overlap has led to the concept of a spectrum of Lewy body disorders with differing clinical manifestations dependent on the severity and anatomic distribution of Lewy body involvement.[17,18] When the disease burden is greatest in the brainstem, extrapyramidal features predominate (PD), and when the cerebral cortex is affected, dementia may develop (dementia associated with Lewy bodies).
Other less common clinical manifestations may be associated with involvement of other neuroanatomic regions; autonomic dysfunction with involvement of sympathetic ganglia, dysphagia when the dorsal motor nucleus of the vagus is damaged, and gastrointestinal dysmotility with Lewy bodies in enteric plexi. Each condition may occur in isolation or in various combinations. Although this concept is attractive, at least one recent study failed to demonstrate the degree of clinicoanatomic correlation predicted.
The pathological substrate for dementia in PD
Dementia is a common complication of PD, with rates of between 10% and 40% reported. Several different pathological processes could contribute to this cognitive decline and, in some patients, multiple factors probably have a cumulative effect. The clinical and pathological overlap between PD and dementia associated with Lewy bodies has already been mentioned.
In at least some PD patients, the number and distribution of cortical Lewy bodies is similar to that seen in patients who present with pure dementia (dementia associated with Lewy bodies), while in others, a more limited number of cortical Lewy bodies could still be deleterious. Patients with PD and dementia associated with Lewy bodies also display Lewy-neurite pathology that is concentrated in the hippocampus and amygdala. This could be associated with significant dysfunction of the limbic system.
Many clinicopathological studies have suggested that PD and AD coexist with greater frequency than expected by chance association. AD pathology has been reported in up to 35% of PD cases, with the frequency increasing with patient age.[10,21] However, establishing the true relationship between these two conditions is hampered by the lack of universally accepted pathological diagnostic criteria for AD. Although some PD patients show full-blown AD, it is much more common to find a less severe degree of plaque and tangle pathology. While this pattern of pathology would not fulfill the most current diagnostic criteria for AD, it could combine with other pathologies in an additive way.
Finally, the degeneration of specific subcortical regions in PD results in the disruption of a number of neurotransmitter systems, some of which may influence higher mental function. While reduced domaminergic, noradrenergic, and serotonergic activity could each contribute to cognitive or psychiatric manifestations, most attention has focused on the cholinergic deficit.[14,15] In both PD and dementia associated with Lewy bodies, there is severe neuronal loss in the nucleus basalis and decreased choline acetyltransferase activity in frontal cortex.
These changes are independent of coexisting AD pathology and may be more severe than in AD. Several studies have shown a direct correlation between various measures of cholinergic dysfunction and dementia in PD and dementia associated with Lewy bodies.[14,15] This may provide an explanation for the significant proportion of PD patients with a history of dementia in whom no significant histopathologic abnormality is demonstrated in the cerebral cortex.
The pathological changes traditionally considered to characterize PD were first described almost a century ago. Although these features still form the basis of current pathological diagnosis, several recent advances have provided important new insight to disease pathogenesis and the relationship between PD and other neurodegenerative conditions. It is anticipated that this new knowledge will help to clarify our concepts of what PD is and may soon provide real benefits in the form of improved treatment.
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Dr Mackenzie is an associate professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia and a staff neuropathologist at Vancouver General Hospital.
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