The clinical diagnosis can be set with different degrees of certainty (possible or probable), but the final diagnosis is currently possible only postmortem with the demonstration of GCIs in the brain.
The actual clinical diagnosis of MSA according to the current criteria is possible only after the onset of motor symptoms, which, based on the predominant syndrome, define the Parkinsonian variant (MSA-P) or the cerebellar variant (MSA-C). These may include orthostatic hypotension, urogenital dysfunction, sleep, and respiratory disorder (stridor). The studies on the natural history of the disease indicate that usually, non-motor symptoms are the first to be reported. The spectrum of symptoms in MSA includes parkinsonism, ataxia, autonomic dysfunction, and pyramidal signs in various combinations. The disease duration after first diagnosis is 7.9 ± 2.8 years, i.e., much shorter than in PD. Its incidence ranges between 0.1 and 2.4/100,000 per year increasing with age, and the estimated prevalence is 4.4/100,000. The usual symptom onset is in the fifth decade of life. MSA is a rare, rapidly progressive neurodegenerative disorder with the profile of an orphan disease. The review discusses specifically advantages and limitations of the PLP-a-syn mouse model of MSA, which recapitulates motor and non-motor features of the human disease with underlying striatonigral degeneration, degeneration of autonomic centers, and sensitized olivopontocerebellar system, strikingly mirroring human MSA pathology.
Over the years, the continuous exchange from bench to bedside and backward has been crucial for the advancing of MSA modelling, elucidating MSA pathogenic pathways, and understanding the existing translational gap to successful clinical trials in MSA. In vitro and in vivo models, based on selective neurotoxicity, a-synuclein oligodendroglial overexpression, and strain-specific propagation of a-synuclein fibrils, have been developed, reflecting various facets of MSA pathology. Development of experimental models is crucial to elucidate the disease mechanisms in progression and to provide a tool for preclinical screening of putative therapies for MSA. The neuropathology of MSA classifies the disease in the group of a-synucleinopathies together with Parkinson’s disease and other Lewy body disorders, but features specific oligodendroglial inclusions, which are pathognomonic for MSA. Multiple system atrophy (MSA) is a rare neurodegenerative disorder with unclear etiology, currently difficult and delayed diagnosis, and rapid progression, leading to disability and lethality within 6 to 9 years after symptom onset.
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