The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) in multiple system atrophy: a correlation between the density of GCIs and the degree of involvement of striatonigral and olivopontocerebellar systems

Abstract

The distribution and dynamic density of oligodendroglial cytoplasmic inclusions (GCIs) were studied based on 30 cases of multiple system atrophy (MSA), including striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) and Shy-Drager syndrome. GCIs were widely spread throughout the central nervous system, including the striatonigral and olivopontocerebellar systems. Inclusion-bearing cells appeared to be oligodendrocytes which usually had larger and lighter nuclei than those of normal-looking oligodendrocytes. The distribution of GCIs was similar in all cases, irrespective of the degrees of OPCA and SND, but the frequency of GCIs varied from case to case. We classified all the cases into two categories based on the degree of neuropathological changes of SND (mild and severe) and, independently, into three groups based on that of OPCA (minimal, moderate and severe), i.e., a total of six groups. An association between the frequency of GCIs and the severity of the lesions was obtained. For example, many GCIs were seen the cerebellar white matter in the cases in which OPCA was not histologically confirmed. More GCIs were seen in the cases with moderate OPCA. In the cases with severe OPCA, GCIs were rarer and smaller, in proportion to the devastation of fibers; no GCIs were seen in the cases with more severe OPCA. The incidence of GCIs showed a positive correlation to the severity of OPCA but not that of SND in the corticopontine tracts, of both OPCA and SND in the pyramidal tracts, and of SND but not of OPCA in the pencil fibers of the putamen. It is suggested that GCIs may represent either a change synchronous with neuronal degeneration or a phenomenon preceding neuronal changes, especially in the cerebellar white matter. Thus, they may represent the early changes in MSA and may be a useful neuropathological hallmark for diagnosis of MSA, even in cases with minimal OPCA and SND.

The pathogenesis of multiple system atrophy: Past, present, and future

“…[5][6][7] Neuropathologic changes in neurones follow a similar system-bound distribution. These changes include variable degrees of neuronal loss and densities of NCIs and NNIs in the striatum, substantia nigra, locus ceruleus, inferior olives, pontine nuclei, cerebellar Purkinje cells, dorsal motor nucleus of vagus, nucleus vestibularis, intermediolateral cell column of the spinal cord, and Onuf's nucleus.…”

“…[8][9][10] Because GCIs and oligodendroglial loss show a marked preponderance over NCIs and neuronal loss, it has been suggested that oligodendroglial pathology, perhaps through programmed cell death (apoptosis), may be the primary lesion of MSA. 6,7,10 Evidence for apoptosis occurring in MSA comes from a number of lines of investigation, including increased immunoreactivity of p53 in the striatum and midbrain of MSA cases. 11 Gene upregulation of p53 is recognized to precede apoptosis.…”

Glia cells in amyotrophic lateral sclerosis: New clues to understanding an old disease?

“…Evidence for such a role was presented when studies a decade ago showed that ␣-synucleincontaining aggregates in multiple system atrophy (MSA) were almost completely restricted to oligodendrocytes, with little detection in astroglial or neuronal cells. 2,73,118,145 Here, gray matter areas are affected predominantly with only a limited number of oligodendrocytes. In the following years, postmortem studies in MSA revealed that myelin-forming oligodendrocytes are functionally compromised, leading to demyelination and oligodendroglial cell death.…”

Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy?

“…Results of previous studies suggest that GCI can precede neuronal degeneration [12,26]. In the two individuals we report, neuronal cytoplasmic inclusions were sparse, restricted to the pontine nuclei and inferior olive and not associated with neuronal loss or gliosis.…”