In our prior Insights articles exploring systems involved in the pathogenesis of Parkinson’s disease, we reviewed how the gastrointestinal and immune systems have become areas of increasing focus for Parkinson’s-specific research. In this next series of articles, we will explore infectious, toxic, and genetic risk factors that might trigger neuroinflammatory and subsequent neurodegenerative processes that lead to Parkinson’s disease and related conditions. The first of this series of articles will focus on infectious diseases.

The role of infectious agents as triggers for Parkinson’s disease is supported by decades of epidemiologic as well as basic science research. This research has provided evidence for specific infections preferentially attacking the nervous system, including the substantia nigra; the induction of alpha-synuclein expression by specific viruses or gut microbes; and the association of parkinsonism with pandemics. Additionally, infections are associated with the production of high levels of cytokines and chemokines that can cross the blood-brain barrier, leading to microglial activation, inflammation, and ultimately neuronal cell death.

Infection with Helicobacter pylori may be associated not only with Parkinson’s risk but may also affect response to levodopa. Helicobacter pylori infection-induced peripheral inflammation can potentially increase the level of circulating pro-inflammatory mediators, which can cross the blood-brain barrier, activate microglia, and subsequently trigger neurodegeneration.

Studies of the gut microbiome also suggest that resident bacteria play a role in Parkinson’s risk. Desulfovibrio bacteria, found to a greater degree in the gut microbiome of patients with Parkinson’s vs healthy controls, have been shown to produce hydrogen sulfide and lipopolysaccharide (LPS), and several strains synthesize magnetite, all of which likely induce the oligomerization and aggregation of alpha-synuclein protein.

In a recent article published in Movement Disorders, researchers outlined the evidence supporting the endotoxin theory of Parkinson’s disease. In this theory, LPS endotoxins are shed from the outer membrane of gram-negative, common gut bacteria (such as Bacteroides fragilis and Escherichia coli) and may contribute to the pathogenesis of Parkinson’s disease. In addition to gut-resident bacteria, bacterial infections such as periodontitis (gum disease) increase inflammatory LPS found in the blood and brain. The primary cause of increased LPS levels in the blood is increased gut permeability. In the gut, endotoxins are relatively benign; however, when translocated to the bloodstream, they promote alpha-synuclein aggregation, which triggers systemic and brain inflammation that exacerbates neuronal loss.

Encephalitis lethargica was the first recognized pandemic involving the central nervous system, and was associated with postencephalitic parkinsonism, depicted in the movie “Awakenings.” The movie was based on the experience of neurologist Oliver Sacks, depicted by Robin Williams. Sacks recognized the parkinsonian clinical features in patients who had progressed to the chronic form of encephalitis lethargica, and treated some of these patients with levodopa, at the time, a new treatment for Parkinson’s disease. The treatment resulted in dramatic, though tragically short-term, improvement for patients like the character depicted by Robert DeNiro. Pathologically, the brains of patients with chronic encephalitis lethargica showed microscopic evidence of both old and new inflammation, suggestive of persistent infection, as well as atrophy with marked neuronal loss and gliosis throughout the brainstem, particularly in the substantia nigra and the locus coeruleus.

The pandemic of more recent history, Covid-19, has been associated with various neurological symptoms, and may also be associated with an increased risk of Parkinson’s disease. One recent study utilized data from an electronic health records network to determine the relative risk of developing Parkinson’s disease stratified by three-month intervals. Data were collected from over 27 million patients with and without Covid-19 infection from January 1, 2020 through July 26, 2022. After propensity score matching, the authors found significantly increased odds of new onset Parkinson’s disease in the Covid-19 cohort at three, six, nine, and 12 months from the date of infection, with a peak odds ratio at six months. After 12 months, there was no significant difference between the Covid-19 group and non-Covid-19 group. Although several shared features between Covid-19 infection and idiopathic Parkinson’s pathogenesis have been described in the literature, prospective evaluation of patients, particularly with permanent hyposmia and gastrointestinal symptoms after COVID-19, might help to better clarify the relationship.

CND Life Sciences is contributing to important Covid-19-related research with the Long Covid Cutaneous Signatures (LCCS) Study. CND will apply technology from the first-ever Digital Biosignatures Lab to Long Covid syndrome patients by studying changes in their phosphorylated alpha-synuclein, intraepidermal nerve fiber density, and autonomic function. By leveraging and applying CND’s neurocutaneous biosignatures for these patients, it is hoped that insights into potential changes in the peripheral nervous system can be gained that may explain the causes of Long Covid syndrome and provide a basis for therapeutic interventions.

For additional information about the LCCS Study or to enroll, visit:
cndlifesciences.com/lccsstudy

References:

Brown GC, Camacho M, Williams-Gray CH. The endotoxin hypothesis of Parkinson’s disease.
Mov Disord. 2023;38(7):1143-1155. doi:10.1002/mds.29432

Hoffman LA, Vilensky JA. Encephalitis lethargica: 100 years after the epidemic.
Brain. 2017;140(8):2246-2251. doi:10.1093/brain/awx177

Huang HK, Wang JH, Lei WY, Chen CL, Chang CY, Liou LS. Helicobacter pylori infection is associated with an increased risk of Parkinson’s disease: A population-based retrospective cohort study.
Parkinsonism Relat Disord. 2018;47:26-31. doi:10.1016/j.parkreldis.2017.11.331

Iacono S, Schirò G, Davì C, et al. COVID-19 and neurological disorders: what might connect Parkinson’s disease to SARS-CoV-2 infection.
Front Neurol. 2023;14:1172416. doi:10.3389/fneur.2023.1172416

Murros KE, Huynh VA, Takala TM, Saris PEJ. Desulfovibrio bacteria are associated with Parkinson’s Disease.
Front Cell Infect Microbiol. 2021;11:652617. doi:10.3389/fcimb.2021.652617

Smeyne RJ, Noyce AJ, Byrne M, Savica R, Marras C. Infection and risk of Parkinson’s disease.
J Parkinsons Dis. 2021;11(1):31-43. doi:10.3233/JPD-202279

Wang AS, Perez JA, Gunzler SA. Frequency of Parkinson disease following COVID-19 infection: A two-year retrospective cohort study.
Parkinsonism Relat Disord. 2023;111:105433. doi:10.1016/j.parkreldis.2023.105433