American Parkinson Disease Association

The American Parkinson Disease Association is using its 2018 distribution to fund:

Diversity in Biomarker Discovery
Protective role of the oral microbiome in Parkinson’s disease

Menopause as an important transition state in the susceptibility to Parkinson’s disease (PD)

PROJECT TITLE:  Diversity in Biomarker Discovery

Investigator/Author:  Elizabeth Disbrow, PhD

Objective:  The goal is to identify a brain imaging biomarker of disease severity that is applicable to a diverse sample of people with PD. 

Background:  Existing studies suggest that there are racial differences in the incidence and progression of PD. While the incidence of PD appears to be lower in the black compared to white population, progression may be steeper.  However, data from the African American population is sparse.    Recently we identified imaging markers of disease subgroups that were associated with rate of disease progression based on brain imaging markers of neuronal integrity in early stage PD.  We will extend this work to examine differences in disease severity across racial groups.

Methods/Design:  We will collect MRI, motor, cognitive and comorbidity data from black and white PD and control participants.  We will look at particular MRI features and examine the relationship  between imaging data and  clinical measures of disease severity across racial groups.

Relevance to Diagnosis/Treatment of Parkinson’s Disease: The development of biomarkers of PD disease state and progression may provide mechanistic insight and hopefully accelerate the development of disease modifying therapies. 

September 2019 Project Update:

Our project set out to identify a brain imaging biomarker of Parkinson’s disease (PD) severity that is applicable to a diverse sample of people with PD by collecting MRI, motor, cognitive and comorbidity data from black and white PD and control participants.  To date we have tested and scanned 12 people, 10 controls and 2 people with PD, all African American.  

We are not satisfied with the rate of recruitment of African American PD patients.  To improve outreach, we have hired a community outreach coordinator using institutional funds.  Roslyn Goodall was born in our community, worked at University of Texas, Dallas supporting research for many years, and has long standing relationships with medical, religious and political leadership in the Shreveport area.  She is implementing a media campaign targeting an elderly African American population.  We recently recorded an informational spot for “Miracle” 89.1 and next week we will appear on KOKA Radio 980 AM “The Light”. The spots include basic information about the signs of PD and what is involved in volunteering for the study.  We have learned through community focus groups that it is not common practice among our target population to seek care from a specialist.  Thus, we hope to reach a wider volume of patients by appealing to the general public.

On August 12, 2019 we submitted a manuscript that was conceived during the execution of this study.  Discussing diversity led us to examine our data for sex differences in cognitive function.  What we found was very interesting.  It has been established that PD is more common in men than women and that the motor course of the disease can also be steeper in men.  Our analysis showed that cognitive deficits, across several domains, including processing speed and executive function, are more severe in men even in the early stages of the disease.

We have been approved for a 1 year “no cost” extension for this project.

 

November 2020 Project Update:

We tested the hypothesis that there are sex differences in cognitive dysfunction in non-demented people with PD. We evaluated 84 participants (38 females) with PD and 59 controls (27 females) for demographic variables and cognitive function, including attention, working memory, executive function, and processing speed. Statistical analysis revealed no significant differences between groups including age, years of education, daytime sleepiness, predicted premorbid IQ, severity of PD, PD phenotype, or disease duration. For cognitive variables, we found poorer performance in males versus females with PD for measures of executive function and processing speed, but no difference between male and female controls. Specifically, men with PD showed greater deficits in verbal fluency, measures of inhibitory control, and processing speed as compared to women with PD. There were no differences in measures of working memory or attention. Our findings are potentially consistent with a steeper slope of disease progression reported in men with PD.

We continue to collect our MRI, motor, cognitive and comorbidity data from black and white PD and control participants in order to examine the relationship between imaging data and clinical measures of disease severity across racial groups.

PROJECT TITLE:  Protective role of the oral microbiome in Parkinson’s disease

Investigators/Authors:  Cameron Jeter, PhD

Objectives: Our study will determine how changes in oral bacteria are associated with the onset and progression of dysphagia (difficulty swallowing) and the risk of aspiration pneumonia in patients with PD.

Background: Difficulty swallowing, or dysphagia, affects up to 80% of patients with PD, leading to malnutrition, dehydration and aspiration, a process by which contents in the mouth enter the lungs due to a poor swallow. Dysphagia leads to changes in diet and in oral movements, that then can alter the composition of the oral bacteria. Changes in oral bacteria in turn, can affect the risk of whether an aspiration event causes pneumonia, as particular bacteria are more likely to cause pneumonia than others.

Methods/Design: We will take samples of oral bacteria from patients who have had PD for 10 years or longer and track the severity and progression of their dysphagia and oral microbiome for several years.  This will allow us to determine if dysphagia alters the oral bacteria, and what species are associated with high or low risk of aspiration complications.

Relevance to Diagnosis/Treatment of PD: By understanding how the makeup of oral bacteria of patients with PD changes with onset of dysphagia, we may be able to eventually use oral bacteria composition as a biomarker for dysphagia.  Importantly, future studies may determine how dietary and oral care recommendations or oral liquid probiotics can be used as non-invasive therapies to improve the quality and duration of life of patients with PD.

September 2019 Project Update:

Methods/Design:
Aim 1. To characterize the oral flora of patients diagnosed with PD for 10 years or longer.
Hypothesis: A subset of patients who have had PD for more than 10 years will have a distinct oral flora that protects them from infections and death.

  • Identify and quantify oral flora of patients with PD for 10 years or longer. We will analyze samples that we have already collected from 30 more patients to expand our pilot study.
  • Determine if dysphagia alters the oral flora composition in patients with PD.


Aim 2. To characterize the progression of dysphagia and its associated oral flora changes in patients with PD, two to four years after the initial screening.
Hypothesis: The oral flora of patients with dysphagia will change as dysphagia severity worsens, enabling aspiration complications.

  • Determine the severity and progression rate of dysphagia in patients with PD.
  • Quantify changes in oral flora in patients with PD as dysphagia severity worsens, and identify ?microbiota associated with high or low risk of aspiration complications.


Update:
Aim 1:

  • We have sorted oral samples from our pre-existing pool and wait to gather new samples to send them for microbiome analysis together. We currently have 17 samples from patients who have had the disease for 10 years or longer.


Aim 2:

  • We have collected longitudinal data from 34 patients with Parkinson’s disease. Data and oral sample collection is still on going.
  • Our preliminary analysis of the data shows that patients who have suffered Parkinson’s disease for 10 years or longer show worsened dietary habits (eat more sugary foods and must chew softer foods) and have worse swallowing ability (it takes longer to eat their meals and have more difficulty swallowing pills).
  • Furthermore, when these patients re-take our survey 2-4 years later, swallowing ability has deteriorated and plaque accumulation has worsened in patients diagnosed with the disease for 10 years of longer.

 

November 2020 Project Update:

Sample collection is now complete.  From approximately 35 patients with Parkinson’s disease, we have collected oral bacteria from both soft (i.e., tongue and cheek) and hard (i.e., teeth) oral tissue at two time points: initial and 2-4 years later.  The COVID-19 pandemic delayed sending samples for analysis, but we anticipate doing so in November 2020.  Results will identify the bacteria present on the two oral tissues across the 2-4 year appointment interval and the quantity of each bacterial species.  Progress through 2020 will include statistical comparison of oral bacteria presence and abundance to clinical factors like duration of Parkinson’s disease and severity of dysphagia.  Ultimately, we seek an oral bacterial marker of disease and dysphagia progression that can be used to assess risk of aspiration pneumonia.  Thank you for your support of this unique study in Parkinson’s disease!

 PROJECT TITLE:  Menopause as an important transition state in the susceptibility to Parkinson’s disease (PD)

Investigators/Authors:  Roberta Marongiu, PhD

Objectives: The goal is to characterize the influence of the estrogen decline during menopause on susceptibility to PD in a mouse model overexpressing alpha-synuclein (αsyn).

Background:
 Pre-menopausal women have about a 2-fold reduced risk of developing PD as compared to men and post-menopausal women, suggesting that estrogen plays an important role in protecting against PD. Early menopause, either natural or surgical, is associated with an increased risk of PD. Menopausal women who had received estrogen are less likely to develop PD than those who had not. However, the mechanisms underlying the protective role of estrogen against PD progression remain unclear.  We hypothesize that loss of estrogen during menopause will decrease the neuroprotective advantage observed in young female mice, accelerating the appearance and progression of PD in our mouse model.

Methods/Design:  We will use a mouse model of PD which was engineered to contain human αsyn and which demonstrates αsyn pathology in the brain, resultant nerve degeneration, and motor impairment. In this model, we will characterize the influence of inducing menopause on PD pathology and motor deficits.

Relevance to Diagnosis/Treatment of PD:
The proposed work will help to clarify the ways in which estrogen influences PD progression. A better understanding of the underlying molecular mechanisms can lead to the development of novel targeted treatments for PD.

September 2019 Project Update:

We started our project by generating the new mouse model of Parkinson’s disease (PD) which will be used in our menopause studies. We injected a virus engineered to produce alpha-synuclein only in dopaminergic neurons, into the substantia nigra of 4 month old mice.  We tested the mice to assess their motor activity at 4-week intervals and detected differences on two well characterized tests – the open field test and the cylinder test.

The next phase of the project is to induce ovarian failure in these mice and determine its effects on various outcomes (pathlogy and motor function) as compared to mice without ovarian failure. One aspect we will study is the effect of ovarian failure on markers of brain inflammation. We have been working on optimizing the conditions for these experiments.

Using the preliminary data generated so far under the APDA funding, we have recently submitted a R21 grant proposal to the NINDS, the outcome of which will be announced in October 2019.  

November 2020 Project Update:

Using our mouse model of PD, we induced ovarian failure in females to determine the effects of menopause on motor function. Males of our PD mouse model showed progressive decrease in distance traveled in a motor test known as the open field test. Intact females showed protection from motor deficits, with only a slight non-significant motor decline observed. Interestingly, female mice treated to induce ovarian failure, had a significant motor decline observed as compared to intact females. Their motor decline was similar to males, but with an approximately 2-week delay in onset. We are continuing to analyze other motor tests on these groups of mice.

After motor tests were complete, mice were euthanized and brains extracted for histological
studies and single nuclei RNA sequencing (snRNAseq). We are currently processing these samples.