Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, MSA is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions have also been reported but remain less well defined.
Mayo Clinic researchers, first author Joseph Parisi, M.D., conducted a study published in the journal Brain to further define the spectrum of neuronal pathology. They set out to define the topography and morphological subtypes of neuronal inclusions, assess interregional relationships in pathological burden for widespread brain regions, and determine the frequency of Lewy body-like inclusions in MSA, and their association with relevant clinical findings.
The study consisted of 35 patients (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years) with clinical features of MSA, who were evaluated at Mayo Clinic Rochester, and subsequently pathologically confirmed to have MSA at autopsy.
The results identified widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions were also identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei.
Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7 percent of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment. However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease.
Finally, interregional correlations in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively).
These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy.