Heterogeneity of Multiple System Atrophy: An Update

Abstract

Multiple system atrophy (MSA) is a fatal, rapidly progressing neurodegenerative disease of uncertain etiology, clinically characterized by various combinations of Levodopa unresponsive parkinsonism, cerebellar, autonomic and motor dysfunctions. The morphological hallmark of this α-synucleinopathy is the deposition of aberrant α-synuclein in both glia, mainly oligodendroglia (glial cytoplasmic inclusions /GCIs/) and neurons, associated with glioneuronal degeneration of the striatonigral, olivopontocerebellar and many other neuronal systems. Typical phenotypes are MSA with predominant parkinsonism (MSA-P) and a cerebellar variant (MSA-C) with olivocerebellar atrophy. However, MSA can present with a wider range of clinical and pathological features than previously thought. In addition to rare combined or “mixed” MSA, there is a broad spectrum of atypical MSA variants, such as those with a different age at onset and disease duration, “minimal change” or prodromal forms, MSA variants with Lewy body disease or severe hippocampal pathology, rare forms with an unusual tau pathology or spinal myoclonus, an increasing number of MSA cases with cognitive impairment/dementia, rare familial forms, and questionable conjugal MSA. These variants that do not fit into the current classification of MSA are a major challenge for the diagnosis of this unique proteinopathy. Although the clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers, its distinction from clinically similar extrapyramidal disorders with other pathologies and etiologies may be difficult. These aspects should be taken into consideration when revising the current diagnostic criteria. This appears important given that disease-modifying treatment strategies for this hitherto incurable disorder are under investigation.

Combined regional T1w/T2w ratio and voxel-based morphometry in multiple system atrophy: A follow-up study

“…Interestingly, VBM did not show a significant progression of SN atrophy over time, and therefore, the T1w/T2w ratio, with a 30% variation at 1-year follow-up, could be an MRI parameter more sensitive to change in this brain area. The rationale for studying SN resides in its involvement in MSA as known by neuropathological studies ( 27 , 28 ). In fact, regional neurodegeneration in SN as assessed by neuromelanin-sensitive MRI does not differ between MSA and PD, and the T1w/T2w ratio in SN has been recently proposed as a novel parsimonious biomarker in the PD population ( 15 ).…”

Cognitive Impairment in Neurodegenerative Movement Disorders

“…37 Similarly, fluctuating cognition seems to be absent in other neurodegenerative movement disorders such as MSA. 50 This symptom is defined as "alternating episodes of normal or almost normal function with periods of impaired cognitive performance, inattention, and excessive daytime drowsiness with transient confusion on waking." 51…”

“…57 Since that time, however, several longitudinal studies have shown some MSA patients can eventually experience cognitive impairments. 57 For instance, approximately one-third of patients reference memory complaints, 50,58 and one study of 59 patients diagnosed with probable MSA reported an eventual dementia prevalence of 15% over the course of the disease (nine probable MSA patients with a disease duration of 5.2 AE 2.3 years). 59 The deficits mainly affect performance in executive function, attention, and memory.…”

Glutathione Depletion and MicroRNA Dysregulation in Multiple System Atrophy: A Review

“…Recently, accumulating evidence suggests the existence of distinct strains of α-syn, possibly because of genetic polymorphism or protein modification, and their association with different patterns of disease propagation and atrophic regions [ 47 ]. Interestingly, several studies have indicated that α-syn derived from GCIs of MSA has more potent activity than that from Lewy bodies of PD [ 47 , 48 ]. The diversity of seeding propensities of α-syn in different brain regions supports the notion of the clinical and morphological heterogeneity of MSA as well as clinical difference between MSA and PD/LBD [ 41 , 49 ].…”