H. Braak, U. Rüb and K. Del Tredici (2003) Neuropathology and Applied Neurobiology 29, 60–76
Involvement of precerebellar nuclei in multiple system atrophy
In this semiquantitative study based on 26 post-mortem cases, we describe the involvement of precerebellar nuclei in multiple system atrophy (MSA), a progressive degenerative disorder of the human central nervous system characterized by abnormal, argyrophilic and α-synuclein immunopositive intracellular inclusions within selectively vulnerable oligodendrocytes and nerve cells. The Campbell-Switzer silver-pyridine technique with α-synuclein immunoreactions using 100-µm thick sections is recommended over more conventional methods, thereby permitting visualization of the pertinent lesions in greater detail and facilitating post-mortem diagnosis of MSA specimens. Affected oligodendrocytes occur in specific fibre tracts and grey matters, with most pathology being observed in projections from the precerebellar nuclei to the cerebellum (ponto-cerebellar, olivo-cerebellar, reticulo-cerebellar tracts) and in descending/ascending fibre tracts of the motor system (cortico-pontine, cortico-bulbar, cortico-spinal, spino-reticular, spino-olivary, spino-cerebellar tracts). Three types of abnormal intraneuronal aggregations occur: (i) a loosely woven network within the cell nucleus; (ii) a latticework accumulating in peripheral portions of the cell body; and (iii) irregularly outlined patches of compact, intensely argyrophilic material usually located within deposits of lipofuscin granules. Counter-staining for the presence of extraneuronal lipofuscin can aid neuropathologists in the recognition of lost existent neurones in MSA. Neurones with inclusion bodies occur in the inferior olivary nuclear complex, lateral reticular nucleus, external cuneate nucleus, conterminal nucleus, interfascicular nucleus, nucleus of Roller, dorsal paramedian reticular nucleus, subventricular nucleus, arcuate nucleus, pontobulbar body and pontine grey. The lateral reticular nucleus and accessory nuclei of the inferior olive sustain the most damage and reveal prominent neuronal loss, followed by the pontobulbar body and arcuate nucleus. The uniformly bilateral damage and, in some cases, even obliteration of the nuclei studied, supply additional evidence for the pathoanatomical substrata of the cerebellar dysfunction that reportedly emerges in the clinical course of MSA.