Neurological complications such as encephalitis have been associated with influenza outbreaks since the middle ages but links with neurodegenerative diseases are more controversial. The association was strengthened after the 1918 Spanish influenza pandemic when some patients who developed von Economo’s encephalopathy – an atypical form of encephalitis – went on to display symptoms of Parkinson’s disease. Although a recent study showed that a reconstituted virus is not directly neurotropic, the engineered virus did strongly induce a variety of cytokines, some of which have been implicated in the pathophysiology of Parkinson’s disease.
Providing new evidence for an association between influenza infection and neurodegenerative diseases, researchers at St. Jude Children’s Research Hospital, have now shown that mice that survive infection with a virulent H5N1 strain of avian influenza are more likely to show changes in the brain associated with neurological disorders such as Parkinson’s disease and Alzheimer’s disease. Using an antibody to the influenza virus nucleoprotein, the team were able to track the progress of the virus into the CNS: 2-3 days after infection, the virus appeared in the peripheral nervous system; by day 3, the virus had invaded the brain stem and, by day 7, the virus was found in areas of the midbrain including the substantia nigra pars compacta (SNpc), and the mice now showed Parkinson’s disease-like symptoms such as tremor and movement problems.
Although after three weeks there was no evidence of the virus in the nervous systems of the surviving mice, inflammation in the brain triggered by the infection persisted for the entire three month course of the study. The Parkinson’s disease-like symptoms disappeared as the flu symptoms eased but, 60 days later, the mice had lost almost 20% of dopamine-producing neurones in the SNpc. α-Synuclein, a protein which forms insoluble plaques in the brains of Alzheimer’s disease and Parkinson’s disease patients, was also found to accumulate in H5N1-infected cells, including those in the midbrain where key dopamine-producing cells are located. The authors propose that a significant loss of dopaminergic neurons and long lasting immune response caused by influenza infection may worsen the effect of a second trigger, leading to increased risk of neurological disorders, such as Parkinson’s disease, later in life.
The H5N1 strain used in this study is so virulent that 61% of the 433 people who have been infected to date have died and, for the survivors, it is too early to say whether they will develop neurological problems. The influenza pandemic now engulfing the world is caused by an H1N1 strain rather than an H5N1 strain and, although the neurological threat posed by this virus is still being examined, early indications are that the H1N1 pandemic strain carries a low neurologic risk.
The study is published in the August 10th early edition of the Proceedings of the National Academy of Sciences.