The distribution of oligodendroglial inclusions in multiple system atrophy and its relevance to clinical symptomatology

Abstract

In this study a semiquantitative mapping of oligodendroglial cytoplasmic inclusions (GCIs), a feature of oligodendroglial degeneration in multiple system atrophy (MSA), was undertaken by means of a sensitive silver technique in 14 brains and 11 spinal cords of patients with various combinations of striatonigral degeneration, olivopontocerebellar atrophy and autonomic failure. The results show a system-bound extensive degeneration of interfascicular, perineuronal and perivascular oligodendrocytes. Oligodendroglial cytoplasmic inclusion-rich structures occur in the supra-segmental motor systems (primary motor and higher motor areas of cerebral cortex, 'pyramidal', 'extrapyramidal' and cortico-cerebellar systems), in the supraspinal autonomic systems and in their targets. In contrast, the visual and auditory pathways, olfactory structures, somatosensory systems, association and limbic cortical areas and subcortical limbic structures contain no or only a few GCIs. Comparison of the severity of oligodendroglial degeneration (GCI-density) with that of the neuronal alterations (neuronal cytoplasmic and nuclear inclusions, degenerated neuronal processes and loss of nerve cells) indicates a striking preponderance of oligodendroglial degeneration and that degeneration neither of axons, nor of neuronal cell bodies is a prerequisite of the development of GCIs. It also suggests that inclusion-bearing oligodendroglial degeneration may cause or contribute to the manifestation of clinical symptomatology in structures with GCI accumulation but without convincing neuronal alterations, i.e. cerebral motor cortical areas and reticular formation of the lower brainstem, both previously thought to be spared in MSA.

White matter hyperintensities in patients with multiple system atrophy

“…Although cognitive dysfunction represents an exclusion criterion in the diagnosis of MSA, several studies reported frontal lobe-associated cognitive dysfunction in patients with MSA, by means of comprehensive neuropsychological testing [26,27]. Pathological studies evaluating neuronal morphology in detail and distribution of GCIs have provided evidence of cortical involvement especially in the frontal cortex and its associated white matter as well as in the striatum of patients with MSA, suggesting that GCIs in these areas may contribute to cognitive deficits [15,24]. Recent longitudinal and voxel-based MRI studies additionally supported the notion of cortical involvement in patients with MSA, demonstrating widespread cortical atrophy of the frontal, parietal, and insular areas [3,14,21].…”

Evidence from spatial pattern analysis for the anatomical spread of α-synuclein pathology in Parkinson’s disease dementia

“…Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by the formation of cellular inclusions containing pathological forms of the pre-synaptic protein α-synuclein. These pathologies include Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG) in PDD and DLB [33] and glial cytoplasmic inclusions (GCI) in MSA [31]. α-Synuclein is a small molecular weight protein which regulates the functioning of dopamine transporter and tyrosine hydroxylase [27].…”

Can neurodegenerative disease be defined by four ‘primary determinants’: anatomy, cells, molecules, and morphology?

“…In addition, a fundamental cytoskeletal alteration of oligodendrocytes occurs in MSA [18,50,170] resulting in the formation of characteristic 'glial cytoplasmic inclusions' (GCI) [135] which can be observed in the substantia nigra, striatum, inferior olivary nucleus, pontine nuclei, and cerebellum [105]. A close association between GCI and microtubules has also been demonstrated [129], aberrant or ectopic expression of cdk5 and MAPK leading to abnormal phosphorylation of microtubule cytoskeletal proteins and the formation of inclusions.…”