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Multiple System Atrophy, the hidden cousin of Parkinson’s disease

It’s likely that you have never heard about MSA - short for Multiple System Atrophy. This rare neurodegenerative disorder affects 1 in 50,000 and is often misdiagnosed as Parkinson’s disease. However, MSA comes with an ugly twist - people suffering from MSA decline much faster. After the first symptoms appear, the average life expectancy is 9.5 years, with some aggressive variants causing death within three years.


Symptoms of Multiple System Atrophy

The clinical presentation of the disease consists of autonomic dysfunction. The autonomic nervous system controls blood pressure, body temperature, digestion, urination, and sexual function. The first clinical symptoms often include light-headedness, dizziness, rapid-eye-movement sleep behaviour disorder, snoring, sleep apnea, urinary problems and cardiovascular dysfunction.

As the disease progresses, patients develop motor symptoms specific to the two disease subtypes. Impaired speech, slow movements and rigidity are common symptoms of the Parkinsonian variant (MSA-P). In contrast, wide-based gait, uncoordinated limb movements and involuntary rhythmic eye movement are characteristic of the cerebellar form (MSA-C).

Swallowing difficulties, drooling, and recurrent falls become increasingly common in the later stages of both disease subtypes. Non-motor symptoms frequently include worsening urogenital and cardiovascular dysfunction as well as respiratory and thermoregulation abnormalities. All symptoms rapidly progress, causing patients to become bedridden within 6 to 8 years.


MSA is a disease with an unknown cause but is most likely the result of the interplay between genetic and environmental factors

Identifying the cause of MSA remains challenging as studies are hindered by factors such as limited case numbers, misdiagnosis of the disease, and the inability to confirm a definite diagnosis of MSA before post-mortem examination. Approximately 20-40 % of MSA cases are misdiagnosed as Parkinson’s disease, meaning many patients lack the certainty of a confirmed diagnosis leading to inconclusive results in epidemiological or genetic studies.


Alpha-Synuclein in Multiple System Atrophy (Image courtesy of James Wiseman)



Common and Distinguishing Features of Multiple System Atrophy

Although many clinical symptoms are also present in those with Parkinson’s disease, patients with MSA typically show symptom onset at a younger age, with the average start in the early 50s. After symptoms start to show, the journey to a MSA diagnosis can be long and difficult. Many patients are diagnosed with Parkinson’s disease first. Over time, the unresponsiveness to standard treatment and the changing extent, severity, and type of symptoms make a diagnosis of MSA more likely.


One of the most important symptoms in MSA patients is the presence of sleeping abnormalities such as snoring, apnea, stridor and acting out dreams. Also, subtle changes to a person’s speech, such as low pitch or quivering voice, can be evident, and the clinician may notice symptoms that look slightly different from those of Parkinson’s disease. The diagnosis of MSA is made clinically, but neuroimaging can sometimes assist with the confirmation of clinical suspicion.


People with MSA and Parkinson’s disease have protein clumps consisting of alpha-Synuclein in their brains. The formation of these protein clumps is toxic to the brain and affects the neurons that produce dopamine, a neurotransmitter that controls motor commands.

What distinguishes MSA from Parkinson’s disease is the types of cells involved. While Parkinson’s disease affects the dopamine-producing neurons of a motor-controlling portion of the brain known as the nigro-striatal area, MSA affects both neurons and glial cells. Glial cells outnumber neurons 10:1 and are the support cells that maintain the health of neurons and produce myelin, the fatty substance that insulates neurons.


Myelin loss in Multiple System Atrophy


The overlap in pathology and symptomatology across Parkinson’s disease and MSA raises the question of how a single protein can lead to a spectrum of distinct clinical disorders. A recent shift in the field has seen the emergence of the ‘strain hypothesis’, where it is proposed that alpha-Synuclein can aggregate into distinct pathological conformations, and each strain exhibits a different level of toxicity, lesions, and cell type-specificity. Early evidence shows that the strains found in MSA and Parkinson’s disease differ. As such, distinct α-Synuclein strains may provide a potential explanation for the differences observed in MSA and Parkinson’s disease.


Detecting these strains early on could revolutionise the diagnosis of MSA and Parkinson’s disease.

Recent advancements in research techniques have enabled the generation of these α-Synuclein strains in the laboratory using patient-derived alpha-Synuclein from cerebrospinal fluid and brain tissue. These ultrasensitive amplification assays exploit the self-propagating ability of alpha-Synuclein clumps, in which the addition of alpha-Synuclein units enables the formation of larger aggregates in a strain-specific manner. Products are subsequently assessed, showing differences between MSA and Parkinson’s disease samples, and could be used as a diagnostic test.


What’s next?

Until now, MSA was not studied in New Zealand. Newly awarded funding from the Royal Society of New Zealand will fast-track our laboratory’s work through a collaboration with Prof Glenda Halliday, a renowned expert in MSA from the University of Sydney, Australia. This funding enables the MSA Research in New Zealand. Our goal is to develop novel diagnostics and therapeutics using alpha-Synuclein strains.


These strains provide a new outlook for future research, changing how MSA and Parkinson’s disease are viewed. One major breakthrough would be detecting the MSA strain early in the disease process, enabling early access to clinical studies when the effect of novel MSA therapeutics is most effective.


Want to know more?

Subscribe below or read our review on MSA published in Molecular Neurodegeneration.



© Dr Victor Dieriks

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