Breakthrough in Parkinson’s disease diagnosis?
Volume 7, Issue 15 | April 19, 2023
IN THIS ISSUE
COVID Variant Watch: Will Kraken give way to Arcturus or Hyperion?
Genome sequencing: Test utility; addressing bias to ensure equity; data with a side order of interpretation
Does that UTI really matter? Docs urged to embrace uncertainty
New and Noteworthy
Michael J. Fox Foundation’s commitment bears fruit:
A new Parkinson’s disease diagnostic test
Last week, the Michael J. Fox Foundation announced landmark results of a cerebral spinal fluid (CSF) assay that substantially improves Parkinson’s disease (PD) diagnosis. In a large cohort of patients at different stages of disease, this test was reported to be 88% sensitive and 96.3% specific overall, and - crucially - demonstrated the ability to detect PD before characteristic motor problems appear. (A commentary adds perspective.)
To put this in context: Patients are currently diagnosed late in disease progression, when they present to their physicians with one of a portfolio of characteristic neurological symptoms (typically motor problems). More recently, brain-imaging (DAT-SPECT) has improved diagnosis, but the damage this imaging detects only becomes apparent at about the same point at which clinical symptoms appear: when 60-80% of essential dopamine generating neurons in the brain have already been lost. For the 200 years since James Parkinson first documented the disease, the only truly definitive diagnosis has been autopsy.
There are two types of urgent needs for effective PD diagnosis:
An early-stage test that can identify disease in time for effective treatment. While few such treatments exist today, the identification of non-symptomatic people will help researchers better understand the natural history of disease. It will also help pharmaceutical companies design clinical trials for therapies that could be used earlier in the disease process, when it might still be possible to stop - or better yet, reverse - the early course of the disease.
A differential-diagnosis test that distinguishes between key PD subgroups. There are several disorders that generate Parkinson’s-like symptoms but are not PD (e.g., essential tremor; dementia with Lewy bodies). About 15% of PD cases are caused by specific inherited mutations (e.g., LRRK2; PINK1), which gene therapy may address. Within the remaining 85% we already know of at least two subgroups that do not respond to Levodopa, the most frequently used PD drug: MSA (multi system atrophy) and PSP (progressive supranuclear palsy). As diagnostics are developed, there are certain to be more therapy- and prognosis-defining sub-divisions of Parkinson’s.
The test used here, an alpha-synuclein seed amplification assay (SSA), detects if a patient CSF sample can transmit misfolding to normally folded alpha-synuclein provided in the test kit. If it does, PD is diagnosed. This type of test was first developed in the 1990s to detect the presence of prions (proteinaceous infectious particles) proposed to be the infectious agent responsible for “mad cow disease” (bovine spongiform encephalopathy) and variant Creutzfeldt-Jakob disease in humans. The comparative effectiveness of SSA tests from three test vendors to detect PD was previously reported in November 2021.
Commentary: Misfolded alpha-synuclein is clearly present in PD. Whether it is directly causative of - or at the very least directly proportional to - disease progression is not yet conclusive, but this recent work clearly indicates at least the latter and provides a way to detect cases long before clinical symptoms are observed. One caution: This paper’s “gold standard” against which the SAA test is evaluated is not itself a true gold standard. The PD cases used to calculate sensitivity and specificity were cases identified by pre-existing clinical assessment, with all its weaknesses - an inherently circular argument. The authors will undoubtedly seek to address this through long-term individual patient follow-up.
Providing this CSF sampled SSA test continues to prove effective, the next step will be to see if less invasive samples can be equally reliable. There is hopeful evidence that this will be possible, e.g., a successful small 2022 trial using blood. Others are experimenting with different samples, including skin punches, urine, and nasal swabs. More to come.
Arcturus and Hyperion on track to challenge Kraken for US variant dominance
Two new variants may be vying to take over from XBB.1.5 (Kraken) as the dominant COVID strain in the US: XBB.1.16 (Arcturus, which caused India’s most recent wave), and XBB.1.9.1 (Hyperion). Arcturus already represents more than 20% of cases in the CDC’s south-central region (Arkansas, Louisiana, New Mexico, Oklahoma, and Texas).
For now, Kraken is still firmly in charge nationally, with 78% of cases across the country per the most recent CDC data. Good news is that clinicians in the US are not seeing an increase in disease virulence. The situation was different in India, but they were in a different place (think lower immunity) in terms of their “immunity wall”.
Food for Thought
Genome sequencing as a diagnostic: Further developments
You know when you buy a new car, and then you start seeing that car everywhere? Well, we started a short series on genome sequencing, and now it seems like everyone is talking about it.
More evidence of the utility of genome sequencing
A large study of children with developmental delays and hard-to-diagnose diseases, published last week in the New England Journal of Medicine, illustrated how useful genome sequencing can be. Thanks to the study, which included 13,000 families, ~5,500 children received diagnoses - which involved 800 different genes and included the discovery of 60 new genetic conditions. Commentary: As we said last week, getting a diagnosis and the name of a rare disease does not necessarily mean receiving a cure or even a treatment - but it brings peace and clarity to a family, and provides a foundation for focused research on therapies. We call it necessary but not sufficient.
Addressing bias so that access to sequencing is equitable
Last Friday, the American College of Medical Genetics released a statement on addressing biases so that access to genetic and genomic testing can be as equitable as possible. The group identified three types of bias: environmental, clinical, and technical.
Environmental: Includes practices - both past and present - that have led to mistrust in clinicians, lack of inclusion of marginalized groups in genetic and genomic research, and lack of insurance coverage for testing.
Clinical: Includes provider / clinician bias, the need for more diversity in the genetics workforce, and the need for clinicians to communicate more effectively with patients whose culture and / or language differs from their own.
Technical: Involves specifically the lack of diversity in genetics databases. The broadly used Genome-Wide Association Study data (GWAS) is still based primarily on populations with European ancestry.
The conclusion: Clinicians need to address all three types of bias in order to ensure that as sequencing is used as a diagnostic more frequently, all people are able to equitably take advantage of the information it can provide. And crucially, providers need to consider genetic testing as an "integral and indispensable clinical test, which should be fully covered and adequately reimbursed, in line with professional guidelines.”
I have the data, but what does it mean?
One of the fundamental challenges for clinicians who would like to employ genome sequencing is that they may not be quite sure how to interpret the data. The concern is obvious and very real. As a result, we expect to see more services from sequencing providers that integrate interpretation with data. Broad Institute and Fabric Genomics launched just such an offering, at a $1,000 price tag. We expect this type of interpretive service will become more widespread and available more broadly.
Do you really need to treat that UTI? Docs urged to embrace uncertainty
It can be tough for doctors to say “I don’t know.” Our job is to diagnose our patients as quickly and comprehensively as possible and to swiftly and effectively treat our patients, based on those diagnoses. Admitting that we don’t immediately know what’s wrong with a patient, despite having received the results of the tests we’ve ordered, is uncomfortable for the clinician and frustrating for the patient to hear. (Liz has been there - it sucks.)
A recent commentary in the American Journal of Medicine probed the issue of how one particular set of diagnostic tests - urinalysis and urine culture - are especially likely to be unintentionally misused as a result of this pressure. In the hospital inpatient and emergency room settings, it’s not uncommon for patients - especially elderly ones - with nonspecific fevers or “altered mental status in the setting of dementia” to have white blood cells and/or bacteria in their urine. The question is, does that result have anything to do with the illness that brought the patient to the ER or put them in the hospital? Maybe - but a lot of the time, the authors remind us, it doesn’t, and treatment may do more harm than good.
The authors urge clinicians to resist the temptation to jump to treatment upon receiving a positive urine result in these situations. Instead, they propose a thoughtful approach to reassessing the totality of the patient’s presentation and test results (and gently remind clinicians not to order tests if the results aren’t going to change the treatment plan). Uncertainty is uncomfortable, the authors acknowledge. But sometimes, we have to be willing to remain in that state for longer than we’d like in order to arrive at the correct result in the end.
Quick Hits
Pharmacists will still be able to administer COVID vaccines, tests, and treatment even after the end of the COVID-19 Public Health Emergency on May 11, thanks to an extension of certain elements of the PREP Act (Public Readiness and Emergency Preparedness Act) by the HHS Secretary. The extensions last until December 2024.