Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Abstract

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA-P and MSA-C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA-C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α-Synuclein (α-Syn). In addition to the ectopic appearance of α-Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α-Syn-triggered neurodegeneration are not completely understood, neuron-to-oligodendrocyte transfer of α-Syn by prion-like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system-specific pattern of neurodegeneration.

18F-FDG PET in Parkinsonism: Differential Diagnosis and Evaluation of Cognitive Impairment

“…MSA is defined as a primary oligodendroglial a-synucleinopathy with consecutive neuronal degeneration (11). MSA pathology most severely affects the substantia nigra, caudate, putamen, cerebellar white matter, pontine nuclei, inferior olivary nucleus, and medullary tegmentum (12).…”

The Utility of Post-Void Residual Volume versus Sphincter Electromyography to Distinguish between Multiple System Atrophy and Parkinson’s Disease

“…We previously reported that the post-void residual urine volume (PVR) and sphincter electromyography (EMG) might be helpful for differentiating MSA from PD [1–4]. Urinary voiding dysfunctions are examined by a urinary symptom questionnaire and measuring the PVR in clinical practice.…”

Serum microRNA expression profiling in patients with multiple system atrophy

“…At present, there are no established biomarkers of MSA and so the clinical diagnosis of MSA is dependent on the assessment of clinical symptoms, thus misdiagnoses are frequent (2). The characteristic pathological hallmark of MSA is the accumulation of α-synuclein positive glial cytoplasmic inclusions in oligodendrocytes (3). The pathogenesis of MSA remains unclear, although it has been reported that α-synuclein accumulation serves a key role in neurodegeneration (3,4).…”

“…The characteristic pathological hallmark of MSA is the accumulation of α-synuclein positive glial cytoplasmic inclusions in oligodendrocytes (3). The pathogenesis of MSA remains unclear, although it has been reported that α-synuclein accumulation serves a key role in neurodegeneration (3,4). microRNA (miRNA) are short RNA molecules that function as post-transcriptional regulators that bind to complementary sequences on target mRNA transcripts, typically resulting in translational repression or target degradation and gene silencing (5).…”