In many neurological diseases the topography of the lesion, whatever its nature, determines the clinical signs, whereas the nature of the lesion (vascular, inflammatory, degenerative, etc.) whatever its topography, determines the time course. According to J. P. Martin (1), this general principle cannot be simply applied to diseases of the basal ganglia since the nature of the lesions directly influence the clinical signs. Chorea, for instance, is associated with atrophy of the caudate nucleus but infarct of the caudate nucleus does not generally cause chorea.
What is the localizing value of parkinsonism? Parkinsonism is the clinical syndrome that is fully developed in idiopathic Parkinson's disease (IPD). Hypokinesia or bradykinesia, rigidity, and resting tremor are characteristic of IPD. In general, these features are eventually bilateral, but usually largely predominate on one side of the body (2). In parkinsonian disorders not resulting from IPD, resting tremor is usually absent.
When Lewy described the cerebral lesions found in patients with IPD, he correctly identified the cellular inclusions that are now known under his name. He also acknowledged the diffuse nature of the disease. Numerous figures in his monograph (3) show inclusions in the brainstem next to those in the basal nuclei. He mentioned the fact that Tretiakoff "and the French authors" had emphasized the importance of the alteration of the substantia nigra (which was macroscopically visible as a pallor) but he failed to appreciate the importance of this topography. In his view, the tonus was modulated by two antagonist structures, the cerebellum—the destruction of which caused hypotonia—and basal ganglia, the lesions of which caused hypertonia (rigidity). The equilibrium between both was regulated by a hypothetical mesencephalic tonus center that was not clearly identified and certainly not recognized as the substantia nigra (Fig. 1). It may seem surprising that Lewy, who had so many deep insights into the pathogenesis of IPD, did not appreciate the importance of the lesions of the substan-tia nigra. The reason is, probably, the knowledge of the anatomy at that time. The reading of old neuroanatomy books, such as the various editions of the classical Carpenter's Neuroanatomy, makes it clear that the connections of the substantia nigra with the striatum escaped the scrutiny of the anatomists until the development of the histofluorescence technique by Falck and Hillarp (4) (see Fig. 2). This method, which was able to reveal the thin catecholaminergic fibers, finally established that, indeed, the substantia nigra was connected with the striatum and truly belonged to the basal nuclei. The idea that the substantia nigra was the producer of dopamine that flowed into the striatum and that IPD was just caused by the mere interruption of this flow was put forward at that time.
From: Current Clinical Neurology: Atypical Parkinsonian Disorders Edited by: I. Litvan © Humana Press Inc., Totowa, NJ
We now know that IPD cannot be reduced to a pure dopaminergic deficit (5-7). a-Synuclein, which makes up the Lewy bodies, accumulates in many more nuclei or brain structures than just the substantia nigra. However, it remains true that the substantia nigra is involved in most disorders with parkinsonism, and that parkinsonism, as a clinical syndrome, points to a lesion of the substantia nigra. The substantia nigra is indeed, clearly involved in IPD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA) i.e., striatonigral degeneration, although most often in association with other structures. Infarction of the substantia nigra, rarely encountered, has been incriminated in unilateral parkinsonism (8). Lymphoma invading the substantia nigra has been reported to cause parkinsonism (9); postencephalitic parkinsonism, although causing diffuse alterations, massively affects the substantia nigra. It is also the substantia nigra that is involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication, which is responsible for a severe parkinsonian syndrome.
The rule of a nigral involvement in parkinsonism suffers many exceptions, the most noticeable being patients with lacunes of the basal ganglia who frequently develop a shuffling gait, akinesia, and rigidity reminiscent of IPD. Vascular lesions of the basal ganglia can also cause a clinical syndrome of supranuclear palsy (10). How lesions of the basal ganglia cause these symptoms is not clear. Large destructions of the lenticular nucleus in animals (already mentioned by Kinnear Wilson, ref. 11) or in humans (12) do not cause a movement disorder that may be described as parkinsonism.
There are other lesions outside the basal ganglia nuclei accompanied by parkinsonism, usually without tremor; bradykinesia, rigidity, and gait disturbances have been associated with frontal-lobe infarcts and with periventricular and deep subcortical white matter lesions (13). Bilateral frontal tumors such as meningioma (14) may also cause rigidity and bradykinesia reminiscent of IPD.
In brief, a lesion involving the substantia nigra, whatever its type, regularly causes parkinsonism, whereas only some types of alterations in the lenticular nucleus, or more rarely in other parts of the brain, may be held responsible for similar symptoms.
The Degenerative Processes Affecting the Basal Ganglia and Their Markers
As already briefly outlined, parkinsonism is a syndrome of many causes. The degenerative processes commonly involved are difficult to disentangle since the mechanisms leading to neuronal dysfunction or death are not understood. The topography of the neuronal loss could help to identify these mechanisms, but little is known presently on the reasons of specific regional vulnerability. Moreover, the neurons that are lost leave no information on the causes of their death. Microscopic observation of the brain does not only show neuronal loss ("negative" signs) but can also reveal "positive" alterations. Most of them are characterized by accumulation of proteins in the cell (so-called "inclusions"). For instance, Lewy bodies associated with IPD, consist in the accumulation of a-synuclein in the cell body of neurons. Tau protein fills the processes of so-called "tufted astrocytes" found in PSP or accumulates at the tip of these processes in the "astrocytic plaques," considered to be one of the characteristic lesions of CBD.
Just as are clinical "signs," these positive alterations (Lewy bodies, tufted astrocytes, astrocytic plaques, etc.) are "signs" in the sense that they are but an observable change caused by the disease. What are they the sign of? Some inclusions are seen in a large number of disorders or even in otherwise normal cases: amylaceous bodies belong to that category. Others are encountered but in a subset of disorders: they are described as "markers." Lewy bodies, for instance, are found in only a few circumstances (15), most often IPD or dementia with Lewy bodies (DLB) but also HallervordenSpatz disease (NBIA-1 or neurodegeneration with brain iron accumulation type 1). The presence of the same marker in several diseases strongly suggests that the same metabolic dysfunction occurs in the various disorders where they are found. Obviously, two disorders looking clinically alike, e.g., IPD and parkinsonism owing to parkin mutations, may not share the same marker. In these two disorders the same cell populations are affected, explaining why they are clinically similar, but two different mechanisms lead to cell death. In IPD, a-synuclein accumulates in Lewy bodies because it is overproduced or not correctly consumed or destroyed. By contrast, the accumulation of a-synuclein does not take place in parkin mutation, perhaps because of a defect in ubiquitination, as it has been suggested (16) (Fig. 3). It is unfortunate that the same label (Parkinson's disease, ref. 17) was applied to the two diseases with the logical (but in our view unjustified) conclusion that Lewy bodies, lacking in some cases of Parkinson disease (i.e., those with Parkin mutations), are just an insignificant byproduct. There is no reason to believe that all the morphologic markers play the same pathogenic role. Some may be toxic, others beneficial or innocent bystanders. Markers (or even neuronal loss) are lacking in some disorders (Fig. 4). Neuroleptics, for instance, cause spectacular extrapyramidal syndromes without causing any observable change.
Markers are useful in that they may give important information concerning physiopathology and, as such, contribute to the classification of neurodegenerative diseases. Molecular biology has shown in several cases that there is a direct relationship between the mutated gene and the protein accumulated in the inclusions. To take two striking examples, a-synuclein, which is mutated in some familial cases of IPD, is also present in the Lewy body, the marker of IPD. Tau accumulates in neurons and glia in hereditary fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17); the mutations causing these disorders affect precisely the tau gene. There are many other examples, which suggest that one should "take the markers seriously" and consider them, at the least, as an indication of a pathogenic mechanism (either its cause or its consequence, ref. 18), and at the most as indispensable evidence of a specific disease.
In the majority of cases, the lesions, which are observed in degenerative parkinsonism, consist in the accumulation of a-synuclein or of tau protein. a-Synuclein accumulates in the neuronal cell body (Lewy body) and in the neurites (Lewy neurites) of IPD. It may also accumulate in the glial inclusions of MSA. Although a-synuclein accumulates in both IPD and MSA, there is presently no evidence that these two disorders are otherwise linked in any way. Tau accumulates in neurons or glia of many neurodegenerative disorders: PSP, CBD, postencephalitic parkinsonism (PEP), amyotrophic lateral sclerosis parkinsonism-dementia complex of Guam (PDC), and tau mutations. In these diseases, the cellular type and the region of the cell where tau accumulates are important determinants of the inclusions.
SYNUCLEINOPATHY: IPD AND DLB—MULTIPLE SYSTEM ATROPHY
The inclusions that Friedrich H. Lewy observed in the brain of IPD patients are illustrated in the epoch-making monograph that he devoted to that disorder in 1923, titled "Die Lehre vom Tonus und der Bewegung" [The science of tonus and movement]. The variety of their shapes and of their topography demonstrates that F. Lewy had, in a certain sense, a remarkably modern view of the disorder: he had seen inclusions in the cell processes of the neurons (a lesion now described as "Lewy neurite") and in locations such as the nucleus basalis of Meynert, the hypothalamus, and the vegetative centers of the medulla. Historically, the term Lewy body, coined by Tretiakoff (19), came to mean a spherical inclusion underlined by a clear halo located in the cell body of the neuron. This is indeed their manifestation in the substantia nigra where Tretiakoff observed them. The inclusion appears red with standard hematoxylin and eosin (H&E) stain since it exhibits a special affinity for eosin (eosino-philia). This type of Lewy bodies is mainly observed in the brainstem and is today considered the indispensable accompaniment of IPD (15,20).
Lewy bodies were also identified in the cerebral cortex but almost 50 yr after their first description. The initial observation was due to Okazaki and his coworkers (21) who found them in two cases of dementia with quadriparesis in flexion. The peculiar aspect of cortical Lewy bodies explains why they were discovered much later than their brainstem counterparts. They are also eosinophilic, but lack the clear halo seen in the brainstem inclusions. Therefore, they may be mistaken for an abnormal, homogenized cytoplasm. The nucleus of the cell that contains the inclusion is often clear and may lack the large nucleolus typical of neurons: the cell may erroneously be identified as an astrocyte.
The mechanism of formation of Lewy bodies and neurites is still unknown. With electron microscopy, they appear to be made of a dense, osmiophilic center in which vesicles and fibrils, 8-10 nm in diameter, can be identified (22). At the periphery of the inclusion, the fibrils are radially oriented. The first histochemical studies showed that the inclusion was essentially made of proteins. Immu-nohistochemistry revealed the presence of many epitopes. Pollanen et al. (23) listed as many as 26 epitopes, among which neurofilaments were the most regularly found before ubiquitin and a-synuclein, the two constituents thought to be the most significant, were identified.
Anti-ubiquitin antibodies strongly label Lewy bodies and Lewy neurites (24). Ubiquitination of proteins depends on the activity of specific ubiquitin ligases, which target proteins that have to be degraded. Several ubiquitin molecules make a polyubiquitin chain that serves as a signal to direct the protein to the proteasome, a large proteolytic complex located outside the lysosome. Epitopes of the proteasome are also found in the Lewy body (25). Ubiquitin and proteasome components are present in the Lewy body, most likely because the inclusion is enriched in a protein that they are unable to degrade or one that is degraded at a slower pace than it is produced.
a-Synuclein was initially isolated from the torpedo fish electric organ that Marotaux et al. (26) screened for presynaptic proteins. A fragment of a-synuclein was found to be present in an extract of senile plaques and called NAC (non-amyloid component of the senile plaque) (27). The precursor of this protein, called NACP, is identical to a-synuclein. A similar protein, called synelfin, has been identified in the bird (28). Years after the identification of a-synuclein, the finding of mutations in the a-synuclein gene in IPD patients from four families living around the Mediterranean Sea came as a surprise (29). The presence of a-synuclein in the Lewy body was demonstrated shortly after this initial observation (30). The intensity of the labeling by anti-a-synuclein antibody and its sensitivity suggest that it is, indeed, a major component of the Lewy body. a-Synuclein immunohistochemistry facilitates the identification of the lesions and makes it clear that their distribution is more widespread than initially thought (5).
There is indirect evidence that Lewy bodies could be responsible for neuronal death. They are, indeed, associated with neuronal loss in all the subcortical nuclei where they are found. The existence of a neuronal loss in the cerebral cortex is more difficult to ascertain (31). It could be lacking (32).
Lewy body disease is the term proposed by Kosaka (33-35) to describe the disorders in which Lewy bodies are abundant, regardless of the clinical symptoms and signs. It is a neuropathological term that cannot be considered as the final diagnosis, which has to integrate, as we shall see, the clinical data. The distribution of the inclusions is not random. In the brainstem, they selectively involve the pigmented nuclei (substantia nigra, locus coeruleus, dorsal nucleus of the Xth nerve). They are abundant in subcortical nuclei such as the basal nucleus of Meynert, the amygdala, the hypothalamus, and the limbic nuclei of the thalamus (36). In the cerebral cortex, they are predominantly found in the deep layers of the parahippocampal and the cingulate gyri, and in the insula (32,37,38). They are also present in the peripheral nervous system, particularly in the stellate ganglia (39), and in the cardiac (40) and myenteric (41) plexuses.
According to Kosaka (34,35), Lewy bodies may be found in the brainstem ("brainstem type" of Lewy body disease), the brainstem and the limbic cortices (transitional type), and the brainstem, limbic cortices, and the isocortex (diffuse type); see Table 1. The borders between these three types of Lewy body diseases are not as sharp as may appear. It has become apparent (42), particularly with a-synuclein immunohistochemistry, that Lewy bodies were nearly always present in the isocortex when they were found in the substantia nigra.
Association of Cortical Lewy Bodies With Alzheimer's Type Pathology
The frequent association of Alzheimer's lesions and Lewy bodies has been mentioned in IPD as well as in Alzheimer's disease.
Alzheimer's Lesions in IPD Cases
Alzheimer's lesions are often found in cases of IPD (42-48). They have long been considered the principal cause of parkinsonism dementia, the intellectual deficit occurring at the late stages of IPD. The importance of Alzheimer's lesions may, however, have been exaggerated. Recent data, obtained with a-synuclein immunohistochemistry, tend to emphasize the responsibility of cortical Lewy pathology in the cognitive deficit (49).
Lewy Bodies in Alzheimer's Disease
Lewy bodies have often been associated with senile plaques in large postmortem studies of cases with initial or predominant dementia (50-53). They are particularly abundant in the amygdala, where the co-occurrence of a neurofibrillary tangle and of a Lewy body in the same neurone has been reported (54). The low density of neurofibrillary tangles, when Lewy bodies are added to Alzheimer's-type pathology (55), could be owing to a more rapid fatal outcome than in pure Alzheimer's disease. This would explain why Braak stage is usually lower at death in the cases with combined pathology (56). The presence of Lewy bodies in cases suffering from a disorder that is, in many clinical and neuropathological aspects, comparable to Alzheimer's disease, explains terms such as "Lewy body variant of Alzheimer's disease" (57) or "senile dementia of Lewy body type" (58), now replaced by the general appellation "dementia with Lewy bodies" (59,60). A high prevalence of Lewy bodies is not only found in the sporadic form of Alzheimer's disease, but has also been mentioned in familial cases (61,62) or in trisomy 21 (63).
Why are Alzheimers-type and Lewy-type pathology so frequently associated? Alzheimer's disease and IPD are frequent but not to the point of explaining the high prevalence of their common occurrence. The hypothesis, according to which IPD and Alzheimer's disease are extremes of a spectrum of neurodegeneration sharing the same pathogenic mechanism, has been put forward (64). It
The Three Types of Lewy Body Disease According to Kosaka
Brainstem Type Transitional Type Diffuse Type
Basal nucleus of Meynert Limbic Areas Isocortex
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