Grading of neuropathology in multiple system atrophy: Proposal for a novel scale

Abstract

Multiple system atrophy (MSA), a sporadic progressive synucleinopathy of advanced age, is separated into two clinic opathological subtypes: MSA-P (striatonigral degeneration [SND]) with predominant parkinsonian features and MSA-C (olivopontocerebellar atrophy [OPCA]) with predominant cerebellar ataxia. We propose a novel morphological grading system for both subtypes to compare lesion intensities and their possible clinical validity. Forty-two autopsy cases of MSA were separated into four grades (SND 0-III and OPCA 0-III) based on semiquantitative assessment of neuronal loss, astrogliosis, and presence of alpha-synuclein-positive glial cytoplasmic inclusions (GCI) in striatum, globus pallidus, substantia nigra, pontine basis, cerebellum, and inferior olives. Whereas a recent grading system restricted to SND reflected disease progression and dopa-responsiveness, there was considerable variation in the morphological combination between SND and OPCA, with only around half the cases with OPCA II (moderate) and III (severe) showing comparable grades of both types, whereas OPCA 0 and I (no or little degeneration) was combined with all grades of SND. Twenty-two cases showing OPCA 0 + SND II (n = 3), OPCA I + SND I-II (n = 11), and OPCA I + SND III (n = 8) were classified as pure or predominant SND, consistent with MSA-P. Twenty cases showing OPCA II + SND II/III (n = 7) and OPCA III + SND III (n = 13) were classified as predominant OPCA, consistent with MSA-C. In MSA-P, the mean age of onset was higher than it was in MSA-C (55.1 vs. 50.5 years), but the mean duration of illness was shorter in MSA-P (5.3 vs. 6.7 years). Presenting symptoms in MSA-P were mainly parkinsonism, whereas in MSA-C they were mainly gait disorders (14 vs. 1; P < 0.001). Among clinical key symptoms, parkinsonism was more frequent than were cerebellar signs in MSA-P; in MSA-C it was the reverse (P < 0.01), whereas other symptoms (autonomic/urinary failure) showed no differences. Parkinsonism was infrequent in MSA-C even when OPCA was associated with SND, suggesting a masking effect by cerebellar system involvement. High terminal Hoehn and Yahr stages were more frequent in MSA-P (P < 0.01), some with good-to-moderate initial levodopa (L-dopa) response. Although the proposed morphological grading of both MSA-P and -C correlates well with initial symptoms and clinical key features of both types, further prospective studies are required to validate the clinical utility of the proposed MSA grading scales for future intervention studies.

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

“…In contrast, GCI were found in many additional brain areas. In comparing the pathology in our two cases with those of 42 MSA cases reported by Jellinger and co-workers, which served as the basis for a proposed neuropathologic staging scheme for MSA [14], our cases had far less pathology and far less neuronal loss and gliosis. On the other hand, GCI had a similar distribution to those in MSA, which is consistent with the hypothesis that these cases have preclinical MSA.…”

“…A recently proposed grading scheme for MSA [14] was applied to both cases. This evaluation included semiquantitative assessment of atrophy, neuronal loss and astrogliosis.…”

“…The distribution of α-synuclein pathology is summarized in Table 1. The case was assigned a grade I of MSA-P and grade 0-I of MSA-C [14].…”

123I-Iodobenzamide SPECT Is Not an Independent Predictor of Dopaminergic Responsiveness in Patients with Suspected Atypical Parkinsonian Syndromes

“…First, the clinical diagnosis of APS is linked per se to a decrease in D 2 R availability (15,16,23,24). The disease-specific progress of neurodegeneration leads to an early effect on basal ganglia and consecutive postsynaptic dysfunction in APS patients (25)(26)(27). Conversely, preserved postsynaptic dopaminergic neurotransmission in PD patients is typical (15).…”

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

“…4 of Cykowski et al (2015). (F-G) Diagrammatic interpretation of the hierarchical regional involvement used to grade the oligodendroglial pathology and cell loss over the disease course in the two major forms of multiple system atrophy, MSA-P (F) and MSA-C (G) (Ozawa et al, 2004;Jellinger et al, 2005). -syn = -synuclein; acc = anterior cingulate cortex; am = amygdala; bf = basal forebrain; BG = basal ganglia; C = caudate nucleus; EN = entorhinal cortex; GP = globus pallidus; H = hippocampus; LCN = lateral cuneate nucleus; LTN = lateral thalamic nuclei; M1 = motor cortex; MSA = multiple system atrophy; ON = inferior olivary nucleus; P = putamen; PN = basilar pons; SN = substantia nigra; STN = subthalamic nucleus.…”