Expanding the spectrum of neuronal pathology in multiple system atrophy

Abstract

Multiple system atrophy 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, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of 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 also were 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% 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 (P = 0.002). 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 (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) 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.

Potential Modes of Intercellular Alpha-Synuclein Transmission

“…This may also explain the presence of inclusion bodies in and degeneration of oligodendrocytes observed in MSA. Curiously, aggregated α-syn was observed primarily in neurons rather than reproducing the mostly glial inclusions observed in MSA tissue (Cykowski et al, 2015). Interestingly, homogenates from PD and DLB patients failed to induce significant neurodegeneration or α-syn pathology in the same study.…”

Re-evaluating the glio-centric view of multiple system atrophy by highlighting the neuronal involvement: Figure 1

“…It is of interest to compare this earlier work (Papp and Lantos, 1994) with the current study and its much newer histochemical techniques (Cykowski et al, 2015) ( Fig. 1D).…”

“…The earliest silver lesions identified in histologically normal basilar pons were GCIs, neuronal nuclear inclusions and abnormal neuropil processes, but not, or only rarely, neuronal cytoplasmic inclusions (Papp and Lantos, 1994;Yoshida, 2007). This contrasts with the use of -synuclein immunohistochemistry (Cykowski et al, 2015), which visualizes a variety of protein structural forms. A more widespread distribution of -synuclein-immunoreactive neuronal inclusions is observed, which includes those regions previously identified with silver stains, but also shows neuronal cytoplasmic inclusions in neo-and limbic cortices, basal forebrain and hypothalamus, dorsal raphe and substantia nigra, and dorsolateral medulla (Cykowski et al, 2015) (Fig.…”

“…This contrasts with the use of -synuclein immunohistochemistry (Cykowski et al, 2015), which visualizes a variety of protein structural forms. A more widespread distribution of -synuclein-immunoreactive neuronal inclusions is observed, which includes those regions previously identified with silver stains, but also shows neuronal cytoplasmic inclusions in neo-and limbic cortices, basal forebrain and hypothalamus, dorsal raphe and substantia nigra, and dorsolateral medulla (Cykowski et al, 2015) (Fig. 1D).…”

“…Importantly, few studies have revisited the question of neuronal inclusions in multiple system atrophy using the enhanced immunohistochemical techniques available today. This is now remedied by Cykowski and colleagues, who use a sensitive -synuclein antibody (LB509) to perform a detailed assessment of neuronal inclusion pathology in 35 cases of multiple system atrophy (Cykowski et al, 2015).…”