J Clin Pathol: Mol Pathol 2001;54:419–426 419 Multiple system atrophy: cellular and molecular pathology D J Burn, E Jaros Abstract by Graham and Oppenheimer in 1969 to avoid Multiple system atrophy is an adult onset “unnecessary confusion caused by inventing neurodegenerative disease, featuring par- new names”.2 Recent consensus criteria rec- kinsonism, ataxia, and autonomic failure, ommend that patients with predominantly par- in any combination. The condition is kinsonian features should be designated relentlessly progressive and responds MSA-P, whereas those with predominantly poorly to treatment. Death occurs on cerebellar features are designated MSA-C.3 average six to seven years after the onset These terms are more clinically appropriate of symptoms. No familial cases of multiple than the pathologically derived terms striatoni- system atrophy have been reported, and gral degeneration and olivopontocerebellar no environmental factors have been ro- atrophy types of MSA, respectively. bustly implicated as aetiological factors. The description of argyrophilic glial cyto- However, analytical epidemiological stud- plasmic inclusions (GCIs) in the oligodendro- ies are hampered because the condition is cytes of patients with phenotypically varied relatively rare. The discovery of the glial MSA provided persuasive evidence that MSA cytoplasmic inclusion (GCI) in 1989 is a clinicopathological entity.45Subsequently, helped to define multiple system atrophy similar inclusions were identified in glial nuclei as a clinicopathological entity, and drew (glial nuclear inclusions (GNIs)), and in attention to the prominent, if not primary, neuronal cytoplasm and nuclei (neuronal cyto- role played by the oligodendrocyte in the plasmic inclusions (NCIs), and neuronal nu- pathogenesis of the condition. Subse- clear inclusions (NNIs), respectively), and also quently, GCIs were shown to be positive in axons, although all at lower frequencies than for á-synuclein, with immunostaining for the GCIs.6 However, the mechanisms under- this protein indicating that white matter lying inclusion body formation, and how it pathology was more widespread than had relates to glial and neuronal loss in MSA, previously been recognised. The presence remain to be determined. Understanding these of á-synuclein in GCIs provides a link with processes will be essential before an eVective Parkinson’s disease, dementia with Lewy treatment to halt or reverse the disease can be bodies, and neurodegeneration with brain developed. iron accumulation, type 1 (or Recently, an abnormally insoluble Hallervorden-Spatz syndrome), in which filamentous/tubular form of á-synuclein pro- á-synuclein is also found within Lewy tein was shown to be a major component of bodies. This has led to the term “synuclei- GCIs, NCIs, and NNIs, but not of GNIs (fig nopathy” to embrace this group of condi- 1).7–10 The accumulation of this synaptic tions. The GCIs of multiple system protein in MSA provides an unexpected and as atrophy contain a range of other cytoskel- yet unexplained link with Parkinson’s disease, etal proteins. It is unknown how fibrillo- dementia with Lewy bodies, and neurodegen- genesis occurs, and whether there is eration with brain iron accumulation, type 1 primary oligodendrocytic dysfunction, (NBIA 1 or Hallervorden-Spatz syndrome), in which then disrupts the neurone/axon as a which á-synuclein is an important component consequence of the glial pathology, or of the Lewy bodies. MSA, Parkinson’s disease, Regional whether the oligodendrocytic changes dementia with Lewy bodies, and NBIA 1 are Neurosciences Centre, merely represent an epiphenomenon. thus sometimes referred to as “synucleinopa- 11 12 Newcastle General Further research into this devastating thies”. Hospital, Westgate condition is urgently needed to improve Road, Newcastle upon our understanding of the pathogenesis, Presentation and natural history of MSA Tyne NE4 6BE, UK and also to produce new treatment ap- Although parkinsonism develops in most pa- D J Burn proaches. tients with MSA (84–100%), “pure” cerebellar (J Clin Pathol: Mol Pathol 2001;54:419–426) forms of the disorder are uncommon (0– Institute for the Health 13 of the Elderly, 16%). Autonomic failure was reported in Keywords: multiple system atrophy; glial cytoplasmic Department of 78% of 188 pathologically confirmed cases of inclusion; á-synuclein; oligodendrocyte 14 Neuropathology, MSA. Symptomatic orthostatic hypotension Newcastle General occurring within one year of onset of parkin- Hospital Multiple system atrophy (MSA) is a devastat- sonism has recently been shown to predict E Jaros ing adult onset, sporadic neurodegenerative MSA in 75% of cases, although this study was Correspondence to: disease of unknown aetiology, characterised by retrospective, and the numbers involved were Dr Burn parkinsonism, ataxia, and autonomic failure, in small.15 The parkinsonism of MSA is more [email protected] any combination. The age adjusted prevalence variably responsive to levodopa than Parkin- 1 Accepted for publication of MSA in the UK is 4.4/100 000. The term son’s disease itself. Up to one third of patients 8 March 2001 “multiple system atrophy” was first proposed may show a moderate or good response to this www.molpath.com 420 Burn, Jaros drug, but this usually declines over the first one Neuropathology of MSA and to two years of treatment.14 clinicopathological correlation A male predominance of 1.4 : 1 was re- Macroscopically, the brain in MSA shows ported by Quinn in a review of 231 pathologi- varying degrees of atrophy of the cerebellum, cally confirmed MSA cases.14 If confirmed, this cerebellar peduncles (especially the middle and observation may have aetiological relevance. inferior peduncles), pons, medulla, and also the For example, there may be greater environ- posterolateral putamen. There may be loss of mental exposure to putative toxins in men, or pigment in the substantia nigra and also endogenous protective factors (hormonal per- discolouration of the striatum (notably the haps) in women. putamen). Excessive iron accumulation has The mean age at onset in 203 pathologically been demonstrated within the striatum to confirmed cases of MSA was 54.3 (range, account for this pigmentary change.19 33–78) years.16 The upper limit of the age range Oligodendrocyte GCIs and GNIs have a so must be viewed with a degree of caution, how- called “system bound” distribution in the ever, because clinicopathological series are suprasegmental motor systems (primary prone to bias, and older patients are less likely motor, and higher motor areas of the cerebral to undergo postmortem examination.17 A cortex, pyramidal, extrapyramidal, and cortico- population based study is necessary to confirm cerebellar systems), in the supraspinal auto- the age range and mean age of disease onset. nomic systems, and in their targets.20–22 Neu- The mean disease duration was only 6.2 ropathological changes in neurones follow a (range, 0.5–24) years in a recent meta-analysis similar system bound distribution and include of 433 pathologically confirmed cases,18 indica- variable neuronal loss, and densities of NCIs tive of a relentlessly progressive illness. This and NNIs in the striatum, substantia nigra, review was retrospective, however, and may locus ceruleus, inferior olives, pontine nuclei, have been biased towards the most severe cerebellar Purkinje cells, dorsal motor nucleus cases. Cerebellar features were associated with of vagus, nucleus vestibularis, intermedi- marginally increased survival in this review, but olateral cell column of the spinal cord, and this did not reach significance. Onuf’s nucleus.16 23 Rare MSA cases showing Figure 1 á-Synuclein pathology in multiple system atrophy. (A) Glial cytoplasmic inclusions (GCls) (arrows) in cerebellar white matter with cerebellar granule cells in the lower right corner. (B) Neuronal cytoplasmic inclusions (NCIs) (double arrows) and an early formation of a neuronal nuclear inclusion (NNI) (triple arrow) in neurones of pontine nuclei with neurites in the neuropil (arrowheads). (C) A GCI (arrow) and the early formation of an NCI (double arrow) and NNI (triple arrow) in a neurone of the pontine nuclei with neurites in the neuropil (arrowheads). (D) A GCI (arrow) and an NNI (triple arrow) in the pontine nuclei. Immunohistochemistry was performed using monoclonal antibodies to á-synuclein (Novocastra Laboratories, Newcastle upon Tyne,UK) on formalin fixed, paraYn wax embedded sections that had been pretreated with formic acid; Vectastain Elite ABC peroxidase kit (Vector, Peterborough, UK); DAB; Haematoxylin counterstain. Scale bars in A to D, 30 µm. www.molpath.com Multiple system atrophy 421 additional involvement of frontal or temporal Several studies have looked for polymor- lobes, including atrophy, and the presence of phisms or mutations in candidate genes, which GCIs and NCIs have also been reported.24 25 may predispose an individual towards develop- White matter pathology is also increasingly ing MSA. The apolipoprotein å4 allele is not recognised in MSA, with the fibre tracts of the over-represented in MSA when compared with suprasegmental motor and supraspinal auto- controls, and there have been conflicting nomic systems (see above) bearing the brunt of reports of the association of a cytochrome demyelination.26 Furthermore, using mono- P-450-2D6 polymorphism with MSA.38–40 clonal and polyclonal antibodies that recognise There is no evidence to suggest that patients epitope QDENPVV of human myelin basic with MSA have expansions at