In recent years, a mysterious surge of a Parkinson's-like disorder spread around the world, causing an estimated 10-15% of the ten million worldwide Parkinson's Disease diagnoses , baffling doctors and stunning scientists. For years, no one had any idea where the disease was coming from. 

Many of these patients were survivors of viral diseases that had infected the brain and led to viral encephalitis. Viral encephalitis is brain swelling and damage, which can occur when a virus infects the central nervous system and ends up in the brain, a condition which can be disabling and often fatal. In fact, nearly every Spanish Influenza patient who had an acute episode of encephalitis (brain swelling and damage during infection) from the influenza virus went on to develop what was later termed "Viral Parkisonism". Epidemiologists have determined that Spanish Influenza survivors have a 2-3x higher risk of developing Parkinson's Disease, now termed Viral Parkinsonism, compared to those who did not come into contact with the virus. Since this time, viruses like the West Nile Virus, HIV, and Western Equine Virus have all been attributed to Viral Parkinsonism development later in life. 

Viral Parkinsonism is a disease of neural degeneration from a viral infection that causes encephalitis, or brain inflammation. The strange thing about this illness is how long the delay between infection and disease can be, throwing off a doctor's diagnosis (it's hard to diagnose a cause when it occurred decades before symptoms). There are Parkinson's-like symptoms such as loss of motor control, stiff movements, and loss of balance or difficulty walking. These symptoms arise in eerily high rates post-viral-infection, including in more than 50% of West Nile Virus survivors and nearly 25% of Western Equine Encephalitis Virus patients in a recent Colorado epidemic. But what causes this development of brain damage and its late onset remains a mystery to scientists and doctors alike. 

Researchers Colin Bantle and colleagues primarily from the Department of Environmental and Radiological Health Sciences at Colorado State University, USA, set out to address these gaps. They published their findings in 2019 in the npj Parkinson's Disease journal. They were interested in Viral Parkinsonism caused by Western Equine Encephalitis Virus (WEEV), one of many viral infections known to cause encephalitis. WEEV is transmitted by mosquitoes, and can cause disease in a number of hosts including humans and horses. The worst WEEV outbreak recorded occurred in 1941, with over 3,000 confirmed human cases on record. In the last 50 years, approximately 700 symptomatic cases have been reported in the USA alone, with twice as many women as men affected. 

Bantle and colleagues were able to show that WEEV delivered through the nose of lab mice could cause 100% lethality in the mice. They then prevented this high mortality by introducing immunotherapy in the form of serum to allow the mice to recover. Serum isolated from blood of recovered animals carries antibodies to infection, which can help an animal fight off an overwhelming viral infection. This animal model now serves as a mimicry of human infection and recovery from WEEV. This could solve the animal model barrier for future research of a variety of disorders, including Viral Parkinsonism, Parkinson's Disease, and many others. 

Spread of WEEV in the mice was extremely rapid, with untreated mice (those not receiving serum treatment) not surviving longer than 96 hours post-infection. The virus quickly moved from the nose to the brain, where it caused hypokinesia (decreased bodily movement), lethargy (activity decrease due to tiredness), and hunched posture (a symptom of infection and illness in lab mice). A loss of dopamine neurons in the brain was also seen within 4 days of infection, a hallmark of Parkinson's-like neurological dysfunction development.

Brain images of infected mice showed infection of the substantia nigra (an important structure for movement), and ventral tegmental area (the area of the brain responsible for dopamine production and circulation). Loss of dopaminergic neurons (neurons, or signal-transducing brain cells that transmit dopamine) are also a hallmark sign of Parkinson's-like disease progression.

An increase in microglia levels is also a hallmark of Parkinson's-like disease progression. Microglia are a type of immune cell in the central nervous system, and one of the first contacts of invading pathogens, such as viruses. So, an increased level of these immune "superheros" indicate a disease of the central nervous system, including the brain. In this study, Bantle and colleagues found a 31-46% increase in microglia throughout the brain, indicating infection of the central nervous system. An increase in astrocytes (similar to microglia, these are another first-responder immune cell of the central nervous system) was also noted to increase 56-79% in various areas of the brain. What this virus has in common with other Parkinsonism-inducing viruses is that they are all capable of directly infecting the brain, leading researchers to believe that central nervous system viral infections can often to lead to development of a Parkinson's-like disease later in life.

One fact all scientists can agree on is that protein aggregates in the brain, specifically alpha-synuclein aggregates post-infection are almost always present in Parkinson's Disease development. Consistent with previous findings, Bantle et al. also found these alpha-synuclein aggregates in the brains of surviving mice (those that had been infected with WEEV then treated with serum immunotherapy).

The first is the new potential mouse model for study of Viral Parkinsonism. Researchers were able to stimulate disease symptoms in mice exclusively in the brain. This strengthens the model for research, as widespread disease would be difficult to study (when everything is infected, it's hard to narrow down results to a specific area and function, in addition to the fact that Viral Parkinsonism is seems to be stimulated by encephalitis, which is exclusive to the brain).

The researchers suggest that the increased number of immune cells in the brain could promote inflammation, causing more damage post-infection, also potentially leading to Viral Parkinsonism. The final findings together suggest that the loss of dopamine-producing nerve cells combined with alpha-synuclein aggregates from the viral infection partially explain how encephalitis from a virus can lead to Viral Parkinsonism later in life. 

Though we know there is a connection between these viral infections and disease progression decades later, many mechanisms remain unknown. However, this study suggests a potential new cause of Viral Parkinsonism, and presents a new animal model for future research. In the USA alone, over 50,000 people are diagnosed with Parkinson's disease each year, 10-15% of whom are Parkinsonisms, diseases that share Parkinson's-like symptoms but progress more quickly, a category that includes Viral Parkinsonism. This study could pave the way for future research on how we can prevent encephalitis from leading to future brain disease, restoring quality of life to those suffering from the condition.