Dr. Margarita Fedorova outlines how genetic, environmental, and pathological factors interact in Parkinson's disease and what this means for patient counseling.

Show citation:

Blauwendraat C, Morris HR, Van Keuren-Jensen K, Noyce AJ, Singleton AB. The temporal order of genetic, environmental, and pathological risk factors in Parkinson's disease: paving the way to prevention. Lancet Neurol. 2025;24(11):969-975. doi:10.1016/S1474-4422(25)00271-6

Show transcript:

Dr. Margarita Federova:

Welcome to Neurology Minute. My name is Margarita Fedorova, and I'm a neurology resident at the Cleveland Clinic. Today we're exploring a framework for understanding how genetic, environmental, and pathological factors interact in Parkinson's disease and what this means for how we counsel our patients.

A personal view paper by Blauwendraat and colleagues, published in The Lancet Neurology in September 2025, addresses a critical question. We've identified over 100 genetic loci for Parkinson's, but how do they act?

The common saying is genetics loads the gun and environment pulls the trigger, but this paper suggests the relationship may be more complex. The key tool here is alpha-synuclein seeding amplification assays or SAAs.

These detect misfolded alpha-synuclein protein in cerebrospinal fluid. Over 90% of Parkinson's patients test positive for misfolded alpha-synuclein using this assay. But here's what's notable. 2% to 16% of neurologically healthy older adults also test positive with prevalence increasing with age.

This means there are more asymptomatic people with detectable alpha-synuclein pathology than people with actual Parkinson's disease. Most of these asymptomatic individuals will never develop symptoms. This raises an important question. What determines who converts to a disease and who doesn't?

By integrating SAA results with genetic data, researchers can examine whether genetic factors drive initial protein misfolding or whether they modulate the response to pathology triggered by environmental or random events.

Preliminary data suggests polygenic risk scores don't strongly associate with SAA positivity in healthy older adults. In other words, people with high genetic risk for Parkinson's aren't necessarily more likely to have misfolded alpha-synuclein if they're healthy.

This suggests most Parkinson's genetic risk factors may not be causing initial misfolding. Instead, they may be determining what happens afterward, such as whether the pathology progresses to clinical disease.

LRRK2 mutations support this model. About 33% of LRRK2 related Parkinson's patients are SAA-negative compared to only 7% in sporadic disease. This means many people with LRRK2 mutations develop Parkinson's without the typical alpha-synuclein pathology.

LRRK2 mutations also show varied pathology. Sometimes alpha-synuclein, sometimes tau, sometimes neither. This suggests LRRK2 may modulate responses to different initiating events rather than directly causing protein misfolding.

What does this mean for us as clinicians? Asymptomatic SAA-positive individuals could represent a window for intervention. If we can understand what protects them from converting to disease or what triggers that conversion, we could enable earlier identification of at risk individuals and potentially intervene before symptoms develop.

The authors call for large scale studies using SAAs in older populations, combined with genetic analysis and longitudinal follow-up. By integrating pathological biomarkers with genetic and environmental data, we can better understand the temporal sequence of events in development of Parkinson's.

This approach could fundamentally change how we think about disease prevention and early intervention, potentially allowing us to identify at risk individuals before symptoms appear and develop targeted prevention strategies.

That's your neurology minute for today. Keep exploring, and we'll see you next time.

If you want to read more, please find the paper by Cornelis Blauwendraat et al titled The Temporal Order of Genetic, Environmental and Pathological Risk Factors in Parkinson's Disease: Paving the Way to Prevention, published online in September 2025 in Lancet Neurology.

Dr. Tesha Monteith highlights the American Headache Society's position statement, which advocates for migraine screening in girls and women.

Show citation:

Schwedt TJ, Starling AJ, Ailani J, et al. Routine migraine screening as a standard of care for Women's health: A position statement from the American Headache Society. Headache. Published online December 10, 2025. doi:10.1111/head.70023

Show transcript:

Dr. Tesha Monteith:

Hi, this is Tesha Monteith with the Neurology Minute. Welcome back to our Women's Health and Headache Medicine series. Did you know the American Headache Society recently published a position statement to encourage screening for migraine in girls and women? The position statement was based on review of the literature to establish if migraine met standards for screening in subpopulations and to assess appropriate screening tools.

The team achieved consensus, agreeing that migraine, due to its prevalence, morbidity, high cost, availability of screening methods and treatments, does meet criteria to justify screening for girls and women. The panel suggested that migraine should be screened annually as part of women's preventative care with tools like ID-Migraine. ID-Migraine is a self-administered three-question survey that has been validated in primary care settings. Patients answer yes or no to having the following with headache over the past three months.

Patients are asked if headaches limited your ability to work, study, or do what they need to do on at least one day. You felt nauseated or sick to your stomach. Light bothered you a lot more than when you don't have headaches. Answering at least two of the three is positive for migraine. The panel acknowledged certain barriers, but they ultimately emphasize the overwhelming benefits of screening for migraine in women and children. Although the focus is for females, they recognize benefits in boys and men as well. Check out this position statement. It's a great read. This is Tesha Monteith. Thank you for listening to the Neurology Minute.

In the final installment of this series, Dr. Justin Abbatemarco and Dr. Divyanshu Dubey discuss the latest findings and some non-occupational exposures.

Show citation:

Hinson SR, Gupta P, Paramasivan NK, et al. Neural synaptic vesicle autoimmunity following aerosolized porcine neural tissue exposure: insights into autoimmune inflammatory polyradiculoneuropathy. EBioMedicine. 2025;122:106053. doi:10.1016/j.ebiom.2025.106053

Show transcript:

Dr. Justin Abbatemarco:

Hello, and welcome back. This is Justin Abbatemarco. I'm here with Divyanshu Dubey, discussing his article, Neural Synaptic Vesicle Autoimmunity Following Aerosolized Porcine Neural Tissue Exposure: Insights Into Autoimmune Inflammatory Polyradiculoneuropathy.

Div, maybe we could talk about non-occupational exposures? I think many of us don't see this cohort of patients commonly, but I really think this helps inform care, beyond just this specific occupational exposure. What did you guys find in your work?

Dr. Divyanshu Dubey:

So, one of the inspirations for this study was driven by the phenotypic characterization of patients who were described in this 2010 paper, which is somewhat similar to some of the patients I currently see in my clinic who don't seem to meet GBS or CIDP criteria. But, based on their MRI findings, based on their CSF studies, the EMG nerve conduction studies, they seem to have this polyradiculoneuropathy presentation, often presenting with asymmetric disease onsets, starting on one leg and then sometimes transitioning to the other side.

In some cases, even a non-length dependent pattern with sort of proximal cervical brachial nerve root plexus involvements, which don't really seem to have a blood test, or a biomarker right now. Currently, many of these cases are a diagnosis of exclusion. I was thinking if there's a biomarker that we can identify from this 2006 to 2008 unfortunate event, that might actually help us diagnose these patients.

So, once we identified synaptophysin and GAP43 antibodies in the swine abattoir cohort, I went back to our storages of these patients with other inflammatory polyradiculoneuropathy, and found about 5% of these patients from a large cohort of close to 300 patients, did have these antibody biomarkers.

Some of these patients had paraneoplastic trigger, where we had patients with neuroendocrine tumors, or hematological malignancies mounting a response to these antibodies. But a good chunk of these patients we did not truly understand, or know what the triggers were. That might be a potential for future studies, as we expand our cohort of these antibodies, as well as study further the phenotypic characterization of these cases.

Dr. Justin Abbatemarco:

Yeah, there's just so much there, really helping to inform future clinical care outside of this very specific occupational exposure. And then, as we talked about in the podcast, I think really helping to think through how neurological autoimmune diseases develop. So, just really exciting work.

We really appreciate you coming on, sharing this. We're excited for how this evolves over the coming years.

Dr. Divyanshu Dubey:

Thank you, Justin.