Pathology

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In MSA-P, the striatonigral system is the main site of pathology but less severe degeneration can be widespread and usually includes the olivopontocerebellar system (51). The putamen is shrunken with gray-green discoloration. When putaminal pathology is severe there may be a cribriform appearance. In early stages the putaminal lesion shows a distinct topographical distribution with a predilection for the caudal and dorsolateral regions (120). Later on during the course of disease, the entire putamen is usually affected with the result that bundles of striatopallidal fibres are narrowed and poorly stained for myelin. Degeneration of pigmented nerve cells occurs in the substantia nigra pars compacta (SNC), whereas nonpigmented cells of the pars reticulata are reported as normal. The topographical patterns of neurodegeneration involving the motor neostriatum, efferent pathways, and nigral neurons, reflect their anatomical relationship and suggest a common denominator or "linked" degeneration (120).

In MSA-C, the brunt of pathology is in the olivopontocerebellar system whereas the involvement of striatum and substantia nigra is less severe. The basis pontis is atrophic, with loss of pontine neurons and transverse pontocerebellar fibers. In sections stained for myelin, the intact descending corticospinal tracts stand out against the degenerated transverse fibers and the atrophic middle cer-

ebellar peduncles. There is a disproportionate depletion of fibers from the middle cerebellar peduncles compared with the loss of pontine neurons, an observation consistent with a "dying back" process.

A supraspinal contribution to the autonomic failure of MSA is now well established. Cell loss is reported in dorsal motor nucleus of the vagus (121) and involves catecholaminergic neurons of ventrolateral medulla (122). It has also been described for the Edinger-Westphal nucleus and posterior hypothalamus (123) including the tuberomamillary nucleus (124). Papp and Lantos (125) have shown marked involvement of brainstem pontomedullary reticular formation with glial cytoplasmic inclusions (GCIs), providing a supraspinal histological counterpart for impaired visceral function. Autonomic neuronal degeneration affects the locus ceruleus, too (20). Disordered bladder, rectal, and sexual function in MSA-P and MSA-C have also been associated with cell loss in parasympathetic preganglionic nuclei of the spinal cord. These neurons are localized rostrally in the Onuf's nucleus between the sacral segments S2 and S3 and more caudally in the inferior intermediolateral nucleus chiefly in the S3 to S4 segments (126). Degeneration of sympathetic preganglionic neurones in the intermediolateral column of the thoracolumbar spinal cord is considered contributory to orthostatic hypotension. If one considers only those reports in which formal cell counts have been made, with very few exceptions all cases of MSA with predominant pathology in either the striatonigral or olivopontocerebellar system show loss of intermediolateral cells (127). However, it is noteworthy that there is not always a strong correlation between nerve cell depletion or gliosis and the clinical degree of autonomic failure. It is estimated that more than 50% of cells within the intermediolateral column need to decay before symptoms become evident (128). In the peripheral component of the autonomic nervous system, Bannister and Oppenheimer have described atrophy of the glossopharyngeal and vagus nerves (129).

A variety of other neuronal populations are noted to show cell depletion and gliosis with considerable differences in vulnerability from case to case. Only a few of the reported lesions are discussed here. Various degree of abnormalities in the cerebral hemisphere, including Betz cell loss, were detected in pathologically proven MSA cases (57,130-132). Furthermore, anterior horn cells may show some depletion but rarely to the same extent as that occurring in motor neuron disease (126,133). Depletion of large myelinated nerve fibres in the recurrent laryngeal nerve that innervates intrinsic laryngeal muscles has been demonstrated in MSA patients with vocal cord palsy (134).

From a neuropathological viewpoint, there is little cause for confusion of MSA with other neurodegenerative conditions. The GCI is the hallmark that accompanies the signs of degeneration involving striatonigral and olivopontocerebellar systems. GCIs are distinctly different from filamentous oligodendroglial inclusions, called coiled bodies, found in other neurodegenerative diseases, including PSP, CBD, and argyrophilic grain disease (135-138). Rarely MSA may be combined with additional pathologies. Lewy bodies (LBs) have been reported in 8-10% of MSA cases and show a distribution comparable with that of PD (139). This frequency is similar to that of controls and suggests an incidental finding related to ageing and/or presymptomatic PD.

The discovery of GCIs in MSA brains in 1989 highlighted the unique glial pathology as biological hallmark of this disorder (140). GCIs are argyrophilic and half-moon, oval, or conical in shape (141) and are composed of 20- to 30-nm tubular filaments (142). Although inclusions have been described in five cellular sites, i.e., in oligodendroglial and neuronal cytoplasm and nuclei as well as in axons (143), GCIs (140) are most ubiquitous and appear to represent the subcellular hallmark lesion of MSA (141). Their distribution selectively involves basal ganglia, supplementary and primary motor cortex, the reticular formation, basis pontis, the middle cerebellar peduncles, and the cerebellar white matter (125,141). GCIs contain classical cytoskeletal antigens, including ubiquitin and tau (141,144). More recently, a-synuclein immunoreactivity has been recognized as the most sensitive marker of GCIs (145) (Fig. 2). In fact, a-synuclein, a presynaptic protein that is affected by point mutations in some families with autosomal dominant PD (146) and that is present in LBs (147), has also been observed in both neuronal inclusions and GCIs (148-152) in brains of patients with MSA. GCI filaments are multilayered in structure, with a-synuclein oligomers forming the central core fibrils of the

Fig. 2. a-Synuclein immunostaining reveals GCIs in subcortical white matter. Courtesy of Prof. K. Jellinger. Reproduced with kind permission of Whitehouse Publishing. Diagnosis and treatment of multiple system atrophy: an update. ACNR 2004;3(6):5-10.

filaments (142). The accumulation of a-synuclein into filamentous inclusions appears to play a key role not only in MSA, but also in a growing number of a-synucleinopathies such as PD, dementia with Lbs (DLB), Down syndrome, familial Alzheimer's disease (AD), and sporadic AD (153). The a-synuclein accumulation in GCIs as well as in neuronal inclusions associated with MSA precedes their ubiquitination (154). Importantly, a-synuclein, but not ubiquitin, antibodies also reveal numerous degenerating neurites in the white matter of MSA cases (154). This suggests that an as yet unrecognised degree of pathology may be present in the axons of MSA cases, although whether neuronal/axonal a-synuclein pathology precedes glial a-synuclein pathology has not been examined.

Recent findings support an important role for glial cells and inflammatory reactions in many neurodegenerative diseases including PD, DLB, and MSA (155-157). Neuronal survival is critically dependent on glial function, which can exert both neuroprotective and neurotoxic influences. Glial cells are a primary target of cytokines and are activated in response to many cytokines, including tumor necrosis factor (TNF)-a (158). This activation can trigger further release of cytokines that might enhance or suppress local inflammatory responses and neuronal survival. These cytokines may also participate in neurodegeneration either indirectly by activating other glial cells or directly by inducing apoptosis (159-161). Several studies indicated that TNF-a is toxic for dopaminergic neurons in vitro (162) and in vivo (163), thus supporting the potential involvement of this pro-inflammatory cytokine in the neurodegenerative processes in PD and other a-synucleinopathies. However, the relationship between intracellular a-synuclein-positive inclusions and the proinflammatory response in a-synucleinopathies remains obscure. The activation of microglial cells may be the final common pathway, contributing both to demyelination and neuronal removal, irrespective of the mode of cell death. PK 11195 selectively binds to benzodiazepine sites on activated microglia. nC PK 11195 PET has demonstrated activated microglia in vivo in the putamen, pallidum, substantia nigra, and pontine region in five patients with MSA (164).

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