Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy?

Abstract

In this study we used immunohistochemistry to screen for α-synuclein pathology in the brains of 241 individuals without clinical evidence of neurologic disease, and discovered 36 cases (15%) with incidental Lewy bodies (LBs) and one case, a 96-year-old woman (0.4%), with inclusions similar to those seen in multiple system atrophy (MSA), a nonfamilial neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction and α-synuclein immunoreactive glial cytoplasmic inclusions (GCI). In a routine hospital autopsy series of 125 brains, we detected GCI in a neurologically normal 82-year-old man (0.8%). Both cases showed widespread GCI in the central nervous system, as well as a few neuronal cytoplasmic inclusions, but no neuronal loss or gliosis in vulnerable brain regions, including the substantia nigra, putamen, inferior olive and pontine base. Applying a recently proposed grading scale for MSA, the two cases showed pathology far below that detected in patients with clinically overt MSA, suggesting the possibility that these two individuals had preclinical MSA. The prevalence of clinically overt MSA is estimated to be about 4 per 100,000 persons (0.004%), which is far less than the frequency of GCI in this series (0.4%-0.8%). Further studies are needed to determine is GCI in neurologically normal elderly represents prodromal MSA or a rare non-progressive age-related α-synucleinopathy.

Diagnostic Accuracy of Apparent Diffusion Coefficient and 123I-Metaiodobenzylguanidine for Differentiation of Multiple System Atrophy and Parkinson’s Disease

“…In previous studies [32], [33], neurologically normal elderly subjects infrequently (0.4–0.8%) had abundant glial cytoplasmic inclusions consistent with MSA. In this context, putaminal diffusivity may be elevated in the preclinical stage of MSA-P.…”

Binding of the Radioligand SIL23 to α-Synuclein Fibrils in Parkinson Disease Brain Tissue Establishes Feasibility and Screening Approaches for Developing a Parkinson Disease Imaging Agent

“…MSA, which has significant potential for phenotypic overlap with PD, is defined by the presence of fibrillar α-syn, but misfolded α-syn is instead deposited in glial cytoplasmic inclusions in a brain distribution pattern that is clearly distinct from PD, based on involvement of cerebellar and cerebral white matter, pontine nuclei in the basis pontis, and inferior olivary nuclei in the medulla [38]. This distinct distribution of pathology for MSA has also been seen in autopsy cases from patients early in the disease course and in asymptomatic individuals [39]–[41]. Spatial resolution of PET and SPECT scans may limit the ability to distinguish some brain regions such as pons and medulla that are differentially affected in PD and MSA, but resolution should be sufficient to identify MSA-specific pathology in regions such as cerebellar and cerebral white matter.…”

The propagation of prion-like protein inclusions in neurodegenerative diseases

“…It is observed in 5-10% of the general population over the age of 60 years and may represent a preclinical form of Lewy body disease. Anecdotal evidence has suggested that a prodromal form of MSA could also exist [79]. In cases with incidental Lewy body disease, the first a-synuclein-positive structures in the brain form in the dorsal motor nucleus of the glossopharyngeal and vagus nerves, the olfactory bulb and the anterior olfactory nucleus [19].…”