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According to Kosaka (34,35), the topography of the Lewy bodies is organized in three different distributions. An "X" rectangle means presence of Lewy bodies. The brainstem type is commonly found in Parkinson's disease. The diffuse type is usually associated with DLB. In the transitional type, cognitive symptoms are common; they may be primary or complicate IPD. The borders between the three types may be difficult to draw. It has been shown that even in cases of apparently uncomplicated IPD, the presence of a few Lewy bodies in the isocortex is common (42).

should, however, be stressed that there are differences in the genetic background of IPD and Alzheimer's disease cases. The prevalence of the ApoE4 allele, a known risk factor for Alzheimer's disease, is normal in IPD cases even with dementia (65,66), but is increased in cases of dementia even with Lewy bodies (67). Moreover, the mutations causing Alzheimer's disease are clearly different from those related to IPD, indicating that at least some causal factors are not shared by the two disorders: they cannot simply be considered as phenotypic variants of the same disease. At the cellular level, direct interaction between tau and a-synuclein proteins could enhance their fibrillization (68).

Clinico-Pathological Correlations

The final diagnosis in cases with Lewy bodies is clinico-pathological since long-standing IPD and DLB may present with similar, or possibly identical, neuropathological phenotype. The most characteristic diagnostic combinations are the following (see Table 2):

  1. The initial and main complaints concern the motor system. The disorder slowly progresses during decades. Lewy bodies and Lewy neurites are mainly found in the brainstem (brainstem type of Lewy body disease). The diagnosis of IPD should be made.
  2. The initial and main complaints concern the motor system but in the late stages of the disease, visual hallucinations occurred and a cognitive deficit was present. Lewy bodies are found not only in the brainstem and in the limbic cortices, but also in large numbers in the cerebral cortex, often associated with Alzheimer's lesions (diffuse type of Lewy body disease). The diagnosis of PD with dementia is then warranted.
  3. Finally, the disease starts with a fluctuating cognitive deficit that remains as the main symptom and is associated with visual hallucinations. Numerous Lewy bodies are found not only in the brainstem and in the limbic cortices, but also in the isocortex. The diagnosis of dementia with Lewy bodies should be made.

Multiple System Atrophy

Striatonigral degeneration (69,70) was initially an autopsy finding since the symptoms are very similar to those of IPD, except that there is a resistance to treatment by L-dopa (71). The gross examination shows a peculiar and often severe atrophy along with a green discoloration of the putamen that is distinctive of the disease. The substantia nigra is pale. As already mentioned by Adams et al. ("Dégénérescences nigro-striées et cérébello-nigro-striées"), the cerebellum is often atrophic (69). This introduces a second group of disorders, which were identified at the beginning of the 20th century by Dejerine and Thomas under the descriptive term of olivopontocerebellar atrophy. The sporadic nature of this atrophy contrasted with familial cases previously described by Menzel. Here, the severity of the cerebellar syndrome is striking. Again, the progression of the disease is relentless, but it had been noticed since the initial descriptions that parkinsonism may develop secondarily (see

Table 2

Various Types of Lewy Body Disease Are Clinico-Pathological Diagnoses


Distribution of Lewy Bodies



Brainstem type of Lewy body disease

Diffuse type of Lewy body disease +/- Alzheimer lesions

Idiopathic Parkinson's disease

Initial parkinsonism. Late cognitive symptoms

Idiopathic Parkinson disease with dementia

Dementia with Lewy bodies

Initial and predominant cognitive Diffuse type of Lewy body symptoms.

disease +/- Alzheimer's lesions

Brainstem type of Lewy body disease

Probable idiopathic Parkinson's disease, possibly incipiens

Idiopathic Parkinson's disease with dementia or dementia with Lewy bodies

Diffuse type of Lewy body disease

The diagnosis of the common diseases with Lewy bodies is clinico-pathological. It mainly relies on the chronological order in which the motor symptoms and the cognitive deficit appear (see first column) and on the distribution of the Lewy bodies, which can be classified, according to Kosaka, into three types (brainstem, transitional, diffuse)—see second column. When only the pathological information is available (? in the first column), the final diagnosis is ambiguous in case of diffuse type of Lewy body disease.

e.g., ref. 72). Parkinsonism, when present, masks the cerebellar symptoms. Finally, orthostatic hypotension is frequently associated both with striatonigral degeneration and olivopontocerebellar atrophy. Autonomic failure may be the main symptom. Primary autonomic failure is also known under the eponym of Shy-Drager syndrome.

The frequent association of the three disorders (striatonigral degeneration, olivopontocerebellar atrophy, and primary autonomic failure) led Graham and Oppenheimer, in a case report, to suggest that they were in fact syndromes belonging to the same disease. They tentatively named it multiple system atrophy (MSA) (73), the name that is still in use today (71) (see Fig. 5).

An unexpected validation of this concept came from neuropathology. In many of the cases that were recorded as suffering from MSA, peculiar inclusions were identified by Papp and Lantos (74). They were initially demonstrated by Gallyas staining method but were perfectly visible with other silver impregnations (75). They mainly involve the cell body of the oligodendrocytes but may also affect neurons or astrocytes (see Chapter 4, Neuropathology of Atypical Parkinsonian Disorders, for detailed description). The high frequency of oligodendroglial lesions helps to understand why the myelin appears so massively affected in MSA.

It is by chance that these inclusions were found to include a-synuclein epitopes that were identified by immunohistochemistry. The expression of a-synuclein in glia is poorly explained but can probably occur normally (76). The attempt of reproducing the disease by introducing an a-synuclein transgene under the control of an oligodendroglial promoter has, so far, been unsuccessful (77).

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