Multiple System Atrophy (MSA)
Introduction
Multiple system atrophy (MSA) was first introduced in 1969. Much remarkable progress in understanding this disorder has been developed in recent years. Together with Parkinson's disease (PD) and dementia with Lewy bodies (DLB), MSA belongs to the group of α-synuclein (αSyn), which are morphologically characterized by abnormal accumulation of fibrillary αSyn. While in patients with PD and DLB, αSyn predominantly accumulates in neurons forming Lewy bodies and Lewy neurites, in patients with MSA, it accumulates in oligodendroglia cells forming glial cytoplasmic inclusions (GCI).
Neuropathology
Although possible MSA can be diagnosed due to clinical presentations, diagnosis of definite MSA requires some neuropathological confirmations. The recognized hallmark neuropathological feature of MSA and the primary pathological event is argyrophilic filamentous GCIs. Neuropathological changes of MSA cases involve a typical lesion pattern of α-synuclein positive GCIs and neuronal loss in the striatum, substantia nigra, olivopontocerebellar pathways, and cerebellum. The duration after diagnosis is usually 6 to 10 years, with few patients surviving more than 15 years.
Clinical Presentation
Depending on their predominant motor deficits, the disease is sub-classified into a levodopa-responsive parkinsonian variant (MSA-P) associated with SND, cerebellar ataxia (MSA-C) variant with OPCA, and a combination of both forms referred to as mixed MSA. MSA-P is characterized by poorly levodopa-responsive akinesia and rigidity, postural hand tremor, impairment of postural stability, and craniocervical dystonia. The other subtype, MSA-C, is dominated by progressive gait and limb ataxia, dysarthria, and cerebellar oculomotor impairment. Age at onset, the prevalence of cardiovascular autonomic dysfunction, sleep disorders, and retinal abnormalities are similar in both phenotypes.
Genetic Risk Factors for HD
Converging evidence suggests misfolded αS to represent a key event in the pathogenic cascade leading to systemic neurodegeneration. Also, some other MSA-related factors have been studied.
- Some studies suggest that SCA1 and other forms of spinocerebellar ataxias may be associated with MSA-like presentations.
- SNCA polymorphism (encoding αS) may be associated with increased risks for MSA.
- MAPT variation has been suggested to be associated with the risk of MSA.
- Gaucher-disease-associated glucocerebrosidase (GBA) variants are associated with MSA, but whether the GBA gene L444P mutation modifies the risk for MSA deserves further studies.
- The p25alpha protein, also called tubulin polymerization promoting protein (TPPP), has been shown to colocalize with alpha-synuclein-positive CGIs and abnormally accumulate in MSA oligodendrocytes.
- Polymorphisms of several genes involved in inflammatory processes have been associated with an elevated MSA risk. These include genes coding for interleukin-1A, interleukin-1B, interleukin-8, intercellular adhesion molecule-1, and tumor necrosis factor.
Animal Models of MSA
Several neurotoxic and transgenic animal models have been developed to better understand the mechanisms underlying oligodendrocytic accumulation in MSA in the recent decade. Since the etiopathogenesis of the disease remains hitherto largely unknown, the design of MSA animal models has been based on phenotypic replication of main pathological features of the disease, which finally result in specific motor dysfunction.
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