What is the pathophysiology of Multisystem Atrophy (MSA)?

From the Guidelines

Multisystem atrophy (MSA) is a progressive neurodegenerative disorder characterized by the abnormal accumulation of alpha-synuclein protein in oligodendrocytes, leading to degeneration in multiple brain regions, particularly the basal ganglia, cerebellum, pons, and autonomic nuclei. The pathophysiology of MSA involves the formation of glial cytoplasmic inclusions, which are composed of ubiquitin and alpha-synuclein, leading to neuronal dysfunction and cell death 1. This protein accumulation affects three major systems: the autonomic nervous system, causing orthostatic hypotension, urinary incontinence, and erectile dysfunction; the motor system, causing parkinsonism with poor levodopa response; and the cerebellar system, causing ataxia and coordination problems.

Some key features of MSA include:

• Degeneration of the olivopontocerebellar and striatonigral pathways, explaining the two clinical subtypes: MSA-P (parkinsonian predominant) and MSA-C (cerebellar predominant) 1
• Neurochemical deficiencies in multiple neurotransmitter systems, including dopaminergic, cholinergic, and noradrenergic pathways
• Widespread and rapid neurodegeneration, explaining its poor response to dopamine replacement therapy and faster progression compared to Parkinson's disease
• Unknown exact trigger for alpha-synuclein aggregation, though oxidative stress, mitochondrial dysfunction, and neuroinflammation likely contribute to the disease process

The clinical presentation of MSA can be challenging to diagnose, as it shares similarities with other Parkinsonian syndromes, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) 1. However, MSA can be distinguished by its unique combination of autonomic, motor, and cerebellar symptoms, as well as its poor response to levodopa therapy. Correct diagnosis and management of MSA require a comprehensive approach, including clinical evaluation, imaging studies, and laboratory tests.

From the Research

Pathophysiology of Multisystem Atrophy

The pathophysiology of multisystem atrophy (MSA) is characterized by:

• The accumulation of aggregated alpha-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions 2, 3
• Selective atrophy and neuronal loss in striatonigral and olivopontocerebellar systems, underlying the division into two main motor phenotypes of MSA-parkinsonian type and MSA-cerebellar type 4
• Mitochondrial dysfunction, including COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction, and altered mitochondrial mass 5

Clinical Characteristics

MSA is clinically characterized by:

• A variable combination of parkinsonism, cerebellar impairment, and autonomic dysfunction 2, 3
• Autonomic failure, parkinsonism, and ataxia, in any combination 6
• Non-motor and motor features, including isolated autonomic failure and REM sleep behavior disorder as common premotor features 4

Diagnostic Challenges

The diagnosis of MSA is challenging due to:

• Suboptimal diagnostic accuracy of the second consensus criteria, particularly in early disease stages 4
• The need for red flags highly specific for MSA to provide clues for a correct diagnosis 4

Pathogenesis

The pathogenesis of MSA is not well understood, but several hypotheses have been proposed, including:

• Alpha-synuclein accumulation in oligodendrocytes due to SNCA expression, neuron-oligodendrocyte protein transfer, impaired protein degradation, and alpha-synuclein spread mechanisms 5
• Inflammation and impaired autophagy as alternative pathogenic mechanisms 5