Researchers at Stanford Medicine led the study which discovered that approximately one in five individuals carry the gene variant, a protective allele identified as DR4 (aka, HLA-DR4). It’s one of a large number of alleles found in a gene known as DRB1.
DRB1 is part of a family of genes collectively known as the human lymphocyte antigen complex or HLA. The HLA-DRB1 gene plays a crucial role in the ability of the immune system to see a cell’s inner contents.
“In an earlier study, we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Emmanuel Mignot, MD, PhD (above), Director of the Stanford Center for Narcolepsy, in a Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.” Clinical laboratories may soon have new vaccines for both neurodegenerative diseases. (Photo copyright: Stanford University.)
DR4 Found to Impact Both Parkinson’s and Alzheimer’s Diseases
To perform their research, the team examined a large collection of medical and genetic databases from 176,000 people who had either Alzheimer’s or Parkinson’s disease. The people involved in the study were from numerous countries located in East Asia, Europe, the Middle East and South America. Their genomes were then compared with people who did not have the diseases, focusing on the incidence and age of onset.
“In an earlier study we’d found that carrying the DR4 allele seemed to protect against Parkinson’s disease,” said Mignot in the Stanford press release. “Now, we’ve found a similar impact of DR4 on Alzheimer’s disease.”
The team found that about 20% to 30% of people carry DR4, and that they have around a 10% risk reduction for developing the two diseases.
“That this protective factor for Parkinson’s wound up having the same protective effect with respect to Alzheimer’s floored me,” said Emmanuel Mignot, MD, PhD, the Craig Reynolds Professor of Sleep Medicine in the Department of Psychiatry and Behavioral Sciences at Stanford University and the Director of the Stanford Center for Narcolepsy, in the Stanford Medicine press release. “The night after we found that out, I couldn’t sleep.”
The scientists also analyzed data from autopsied brains of more than 7,000 Alzheimer’s patients and discovered that individuals who carry DR4 had fewer neurofibrillary tangles and that those tangles are composed mainly of modified tau proteins, a common biomarker for Alzheimer’s.
The presence of these tangles corresponds with the severity of Alzheimer’s disease. They are not typically seen in Parkinson’s patients, but the Stanford team found that Parkinson’s patients who did carry DR4 experienced later onset of symptoms.
Mignot stated that tau, which is essential in Alzheimer’s, may also play a role in Parkinson’s, but that further research is required to prove its function.
Both diseases are characterized by the progressive loss of certain nerve cells or neurons in the brain and are linked to an accumulation of abnormal proteins. The Stanford researchers suggested that the DR4 gene variant may help protect individuals from Alzheimer’s and Parkinson’s by preventing the buildup of tau proteins.
“This is a very interesting study, providing additional evidence of the involvement of the immune system in the pathogenesis of Alzheimer’s and Parkinson’s,” neurologist Wassim Elyaman, PhD, Assistant Professor of Neurological Sciences in Neurology, the Taub Institute and the Institute for Genomic Medicine at Columbia University, told Live Science.
New Vaccines and Immunotherapies
According to the Alzheimer’s Association, more than six million Americans are currently living with Alzheimer’s disease and approximately one in three Americans die with Alzheimer’s or another dementia.
The Parkinson’s Foundation states that nearly one million Americans are currently living with Parkinson’s disease, and that number is expected to rise to 1.2 million by 2030. Parkinson’s is the second-most common neurodegenerative disease after Alzheimer’s disease.
Even though the genetic analysis of the Stanford research is strong, more immune cell and blood-based research is needed to definitively establish how tau is connected to the two diseases.
This research could have implications for clinical laboratories by giving them biomarkers for a useful new diagnostic test, particularly for diagnosing Alzheimer’s and Parkinson’s.
Further, Mignot suggested that an effective vaccine could delay the onset or slow the progression of both diseases. He hopes to test his hypothesis on genetically modified mice and eventually human subjects.
An assay using mass spectrometry could go to clinical trial within two years
Dark Daily has regularly observed that humans generate a variety of volatile substances—particularly in breath—which can be used for diagnostic purposes. But what if people, like certain trained animals, could smell the presence of disease before the onset of symptoms? What types of clinical laboratory testing biomarkers could be developed based on human-generated volatile organic compounds?
Perdita Barran, PhD (right), head of the University of Manchester research team that developed the mass spectrometry Parkinson’s test, is shown above with Joy Milne (left), the retired nurse from Scotland who inspired Barran’s team to develop a new Parkinson’s biomarker and method for identifying it. “We are tremendously excited by these results which take us closer to making a diagnostic test for Parkinson’s Disease that could be used in clinic,” she said in a press release. A viable clinical laboratory test for Parkinson’s disease is greatly needed, as more than 10 million people worldwide currently live with the neurodegenerative disorder. (Photo copyright: University of Manchester.)
Using Mass Spectrometry to Analyze Sebum
The UM scientists hypothesized that the smell could be due to sebum, a light oily substance on skin that was going through a chemical change due to the Parkinson’s disease, Hull Daily Mail explained.
Increased sebum, which is produced by the sebaceous glands, is a hallmark of Parkinson’s, the researchers noted.
Their new method involves analysis of sebum using mass spectrometry, according to the JACS AU paper. The method, the researchers claim, makes it possible to diagnose Parkinson’s disease from skin swabs in three minutes.
“There are no cures for Parkinson’s, but a confirmatory diagnosis would allow [Parkinson’s patients] to get the right treatment and get the drugs that will help to alleviate their symptoms,” Perdita Barran, PhD, told the Hull Daily Mail. Barran is Chair of Mass Spectrometry in the Department of Chemistry and Director of the Michael Barber Centre for Collaborative Mass Spectrometry at UM’s Manchester Institute of Biotechnology. “What we are now doing is seeing if (hospital laboratories) can do what we’ve done in a research lab in a hospital lab,” she added.
Sebum Analyzed with Mass Spectrometry
Parkinson’s disease—the world’s fastest growing neurodegenerative disorder—needs “robust biomarkers” that could advance detection and head off onset of motor symptoms such as tremor, rigidity, and postural instability, the researchers note in their paper.
Their recent study builds on earlier 2019 findings they published in ACS Central Science about volatile compounds in sebum possibly being used as Parkinson’s biomarkers.
“Sebum is an underexplored biofluid, which is readily obtained from non-invasive skin swabs, which primarily consists of a mixture of triglycerides, cholesterol, free fatty acids, waxy esters, and squalene,” the researchers explained in their JACS AU paper.
The scientists sought, “to develop a method to analyze sebum in its native state to facilitate rapid assessment of the Parkinson’s disease status. Paper spray ionization mass spectrometry, which allows the direct analysis of compounds from paper, has previously been demonstrated to detect small molecules from unprocessed biofluids, such as blood and urine, but not to date with sebum,” they wrote.
The UM researchers used mass spectrometry to analyze sebum collected on cotton swabs from the backs of 79 people with Parkinson’s and 71 healthy individuals, BBC Scotland News reported.
Depanjan Sarkar, PhD, Research Associate, University of Manchester, further explained the technique in the UM news release:
Sebum is taken from the swab to filter paper cut in a triangle.
Using a solvent and voltage, sebum compounds transfer into the mass spectrometer.
“When we did this, we found more than 4,000 unique compounds of which 500 are different between people with Parkinson’s compared to the control participants,” Sarkar said.
Fatty Acids Make Assay Possible
Could fatty acids pave the way to an assay? The UM researchers believe so.
“We have identified two classes of lipids, namely [triglycerides] and diglycerides, as components of human sebum that are significantly differentially expressed in PD,” the researchers wrote in JACS AU. “Non-invasive sampling followed by PS-IM-MS [paper spray-ion mobility–mass spectrometry] analysis targeting these compounds could provide an inexpensive assay to support clinical phenotyping for the confirmatory diagnosis of Parkinson’s disease.”
A clinical trial for their test, which costs about $20, may be done within two years in Manchester area, the Daily Mail reported.
When Dark Daily reported in 2020 on Joy Milne’s unique ability to smell her husband’s Parkinson’s disease before it was formally diagnosed, we predicted a diagnostic test for Parkinson’s may be years away. And here it is, albeit with regulatory clearance needed following clinical trials.
It may in fact be possible to leverage sebum analysis to detect other diseases, the UM researchers noted.
For diagnostics developers, this story of Joy Milne and her husband Les Milne is a useful example of how, in tracking the life of a specific patient with a specific disease and close family members, researchers were able to identify a new class of biomarkers that could be used in a diagnostic assay.
It will be interesting to follow the University of Manchester researchers in their quest for a diagnostic mass spectrometry clinical laboratory test for Parkinson’s disease. According to Parkinson’s Foundation statistics, about 10 million people worldwide live with the neurodegenerative disorder. Such a new diagnostic test could be vitally important to medical laboratory care, and to patients and their families.