Etiology and Pathology

Before the term MSA was coined by Graham and Oppenheimer in 1969, various pathologically derived
labels were used such as striatonigral degeneration and olivopontocerebeilar atrophy. With the discovery
in 1989 of glial cytoplasmic inclusion bodies (GCI), consisting of a-synuclein aggregates, it became clear
that MSA was and is in. deed a clinicopathological entity. Subsequently, other inclusion bodies were
described: glial nuo clear inclusions (GNI), neuronal nuclear inclusions (N N I), and neuronal cytoplasmic
inclusions (NCI). As in other synucleinopathies, it is still unclear why and when these inclusion bodies are
formed.

MSA is so far the only neurodegenerative disease in Which the predominant lesions are found in the
oligodendroglia. The hallmark of the disease is the a-synuclein-containing GCI, and although other oz-
synuclein inclusion bodies can be found in neurons, it is assumed that the disease starts in the
oligodendroglia and that the neuronal pathology is secondary. The disease trigger is unknown, no
mutations related to the a-synuclein coding gene have been found so far, nor overexpression of any
related gene. In general, the amount and localization of GCIs correlates with the severity of the disease.
Fewer GCIs are needed to produce MSA-P than MSA-C, which explains why in most series MSA-P
dominate. See Wenning and Jellinger (39) for an extensive review. Macroscopically, a varying degree of
atrophy can be found in the cerebellum, cerebellar peduncles, pons, medulla, and posterolateral
putamen. Iron accumulation in the putamen leads to discoloration of the striatum. The substantia nigra
demonstrates a loss of pigmentation. Inclusion bodies (GCI, GNI) can be found in different places, but
most notably in the suprasegmental motor systems

and the higher motor areas of the motor cortex, pyramidal, extrapyramidal, and corticocerebellar
systems. NCIs and NNIs are found most frequently in the striatum, locus ceruleus, substantia nigra,
inferior olives, dorsal motor nucleus of vagus, nu. cleus vestibularis, intermediolateral cell column of the
spinal cord, and Onuf’s nucleus. The hallmark pathological lesions are concentrated in the oli~
godendroglia, leading to white matter lesions and subsequently to gray matter dysmnction. For an
extensive review, see ref’s (40) and (41).

In a large series of 100 patients (34% MSA-P, 17% MSA-C, and 49% equivocal), the frequency of GCIs
correlated with neuronal cell loss, pathological changes, and disease duration. As expected, there is a
strong correlation between the clinical pattern and the distribution of pathology. In MSA-P, With
dominant bradykinesia, the striatonigral system was the one most severely affected, and in MSA-C, the
cerebellum. Putaminal involvement correlated with poor levodopa response. More pathology was
needed to produce ataxia than parkinsonism, which explains why overall MSA-P is seen more often (42).
Sato et al. performed cellular immunohistochemical analysis of the posterior putamen. Cells positive for
calcineurin were severely depleted in the dorsolateral portion of the posterior putamen, whereas
choline acetyltransferase-positive cells were normally distributed, suggesting a selective cell-type-
specific vulnerability to neurodegeneration (43).

Brenneis et a1. (38) compared 13 MSA-C patients with healthy controls using voxel-based morphometry
with a 1.5 Tesla MRI. They found infratentorial atrophy of the cerebellar hemispheres and vermis,
mesencephalon, and pans, while supratentorial atrophy was demonstrated (or' bitofrontal, midfrontal
and temperamesial, and insular) in both hemispheres. No morphometv ric changes were found in the
basal ganglia. The pattern of atrophy was similar to that reported in SCA-z (38). These supratentorial
findings are very diEerent from patterns found in MSA-P, where the motor, insular, and lateral prefmntal
areas

are predominantly involved (44). Seppi et 21. examined MSA-P and PD patients relatively early in the
course of the disease and could demonstrate (using diffusion-weighted imaging) a prominent
involvement of the posterior putamen in MSA-P as compared with PD and controls (45).

Gene expression changes have been found in the postmortem tissue of the pons of a MSA patient; some
of these changes occur also in other parkim sonian diseases, while other changes appear to be unique
for MSA, but further research is needed (46). In a large sample of possible, probable, and definite MSA
patients, Ozawa et a1. looked at the role of polymorphisms of the a-synuclein gene and were unable to
relate polymorphisms to the pathological expression of MSA, nor were they able to detect any
association between a-synuclein and the clinical spectrum of MSA in possible or probable cases. This
suggests that other genes are important for the formation of a-synuclein aggre« gates (47).

Repetitive transcranial magnetic stimulation of the motor cortex leads to an abnormal motorevoked
response in the first dorsal interosseus muscle, with a reduced amplitude already after the second
stimulus compared with PD patients. Also, the silent period following the last stimulus was not
increased, as it was in PD patients, which suggests the cortical dysfunction in MSA-P patients diH'ers
from that in PD (48).