Top 5 Movement Disorders Highlights From AAN 2023

This transcript has been edited for clarity.

Indu Subramanian, MD: Hi. Welcome, everyone. We're so excited to bring you the scientific highlights of the American Academy of Neurology (AAN) meeting that we just attended in Boston. Dr Kathrin LaFaver will be presenting these to us. Today we're just going to focus on the science highlights in movement disorders. Dr LaFaver is a neurologist in Saratoga Springs, New York. Kathrin, welcome.

The PD GENEration Study

Kathrin LaFaver, MD: Thank you so much. We're both movement specialists, so that's, of course, our main area of interest. It was hard to pick, but yes, we will be focusing on some of the scientific highlights.

First, I want to mention an abstract presented in scientific session 42 on genetics of movement disorders. These were preliminary findings from the PD GENEration study. As you probably know, this is a very large study that's been going on for a while now, by the Parkinson's Foundation. James Beck, their chief scientific officer, presented the findings, titled, "Frequency of Known Genetic Variants for Parkinson's Disease in the PD GENEration Study Cohort." This is probably the largest-scale genetic testing and counseling study in Parkinson's disease.

They aim to recruit 15,000 participants and have just hit their 50% target. They're really trying to advance our understanding and treatment avenues for Parkinson's disease on these clinically relevant genes. To date, they have found that 14% of participants have a genetic form of Parkinson's disease, and it's actually higher than the previous estimate of around 10%. This is very exciting, and I think it will help us in the future to identify who might qualify for clinical trials, targeting specific genes, such as the LRRK2 or GBA mutation.

What's also really important about this study is that they're trying to increase recruitment of people in marginalized racial and ethnic groups. To date, 11% of their participants identified as Hispanic. Interestingly, in the Hispanic patients, 16% had a genetic link to Parkinson's, which is the highest rate of any ethnic group. It is a very interesting study with more to come.

Subramanian: We're really excited at the VA to be participating. We are definitely excited about the fact that they are specifically trying to recruit patients and various populations that haven't been represented, such as women, African American patients, and Latin patients. For people out there listening, if you have patients living with Parkinson's who are interested in participating in trials of any sort, please have them contact the Parkinson's Foundation. It's a pretty easy enrollment.

PD vs MSA: Will Biomarkers Help?

LaFaver: Absolutely.

Moving on to highlight number two, this was from scientific session 37 on phenotyping and biomarkers in Parkinson's disease. The study I'm talking about is "The Synuclein-One Study: Skin Biopsy Detection of Phosphorylated Alpha Synuclein for Diagnosis of Synucleinopathies." This was presented by Dr Christopher Gibbons.

As we know, we don't have perfect biomarkers at this point for the diagnosis of Parkinson's disease. A large amount of research is focused on cerebrospinal fluid (CSF) biomarkers, which is really important, but from a practical perspective, for diagnosing our patients at the clinic, it's not always the most feasible thing to do.

In the Synuclein-One study, a standardized skin biopsy on three different sites was developed by CND Life Sciences for detection of synucleinopathies. These three skin biopsies are then diagnosed for intraepidermal nerve fiber density and deposition of phosphorylated alpha-synuclein.

Based on their data, the test was very sensitive and specific to detect phosphorylated alpha-synuclein. Of the over 400 patients enrolled in the trial, over 100 had Parkinson's disease, 59 had multiple system atrophy (MSA), 67 recruited had dementia with Lewy bodies, and the rest had pure autonomic failure. They also recruited 151 healthy controls.

The main findings were that, across all patients with clinically diagnosed synucleinopathies, the sensitivity was 95% and the specificity was 96%. These were highest for people with MSA. They were able to distinguish between Parkinson's and MSA. There's also a recent paper in Neurology, published on April 11, that goes into more details on this.

One of the limitations I did want to mention is that the diagnostic accuracy was validated based on clinical established diagnosis and pathology data. Regardless, this is a very promising test that, hopefully, we will be able to use more and more in the clinic to help us with our diagnostic accuracy.

Subramanian: I agree. I think we're always looking for biomarkers. Finding something that's easy and accessible in clinic is really the gold standard that we're looking for. There's a large amount of exciting news in the biomarker area.

Continuous Subcutaneous Levodopa/Carbidopa Infusion

LaFaver: In the interest of time, I want to highlight something in the therapeutic realm. I just picked one of several studies. As we both know, with advancing Parkinson's disease, people have more motor fluctuations and struggle with more off-time and dyskinesias. There are several developments moving into longer-acting deliveries of carbidopa/levodopa, dopamine agonists, and so on.

The specific study I want to talk about briefly today was presented during the contemporary clinical issues plenary session by Dr Ellenbogen and is titled, "Safety and Efficacy of Continuous Subcutaneous Levodopa/Carbidopa Infusion for Parkinson's Disease: Three-Year Data from the Open-Label BeyoND Study." Most people in the movement realm probably know that this has been a long-standing goal to deliver subcutaneous carbidopa/levodopa, and there are many technical issues around this.

In this study, the investigators have shown now that this is actually an effective and safe way of carbidopa/levodopa delivery. The phase 2 clinical trial showed a 2.6-hour increase in "on" time without troublesome dyskinesias, and 2.5-hour reduction in "off" time at 12 months. Now, they presented their 3-year outcome data and compared infusion over 16 vs 24 hours. They found that most people are actually okay with a 16-hour time frame, so they don't have to do the full 24 hours.

Adverse events mostly occurred in the first year. The most significant ones were infusion-site reactions, which are fairly common in year 1 and mostly include subcutaneous nodules and hematomas, and really leveled off in years 2 and 3. Although these were fairly common side effects, they did not commonly lead to discontinuation of the therapy.

This treatment is not FDA approved yet, but it's one of the promising developments in helping people with motor fluctuations and dyskinesias.

Subramanian: It's always good to get long-term data, isn't it, because sometimes the short-term data are not reflective of what clinical practice is really going to be like. That's a great study. There is new information coming out about all kinds of infusion therapies that we saw at this meeting, with Apokyn pumps and all kinds of really exciting things on the horizon.

LaFaver: It's good to have alternatives, especially for people who are not good candidates for surgical treatment. There is more to come and moving into the clinic, hopefully, soon.

Subramanian: Absolutely.

Is Normal-Pressure Hydrocephalus a Real Diagnosis?

LaFaver: I guess we want to switch gears a little bit away from Parkinson's. I did want to speak a bit about one of the true controversial topics in our field, which is normal-pressure hydrocephalus (NPH). It was actually one of the opening plenary sessions, Controversies in Neurology, with a talk entitled, "Is Normal Pressure Hydrocephalus Overdiagnosed?"

It was a very interesting viewpoint by Dr Clifford Saper, who somewhat provokingly stated that because of the lack of larger placebo-controlled trials for shunting and MPH, he was actually calling for a stop to neurologists to even make this diagnosis and ask people to stop any shunt placements until more study data are available.

Specifically, he was asking for a study where patients would be implanted with a shunt in either the on or off position, randomly turned on, rated by blinded raters 3 months later, and then go for the reverse scenario. He was basically arguing that, without having those data that you really know this is a procedure that has longer benefits, you shouldn't be doing it.

He was calling the existence of idiopathic NPH in question. On Tuesday morning, this was challenged by Dr David Jones, who is co-director of normal-pressure hydrocephalus clinic at Mayo Clinic. He led an extremely well-visited course — standing room only in the educational program — where he argued that NPH is indeed very real, and treatment can have long-standing improvement in gait and cognition.

He did not show aggregated data, but he was essentially arguing that the main problem is that the diagnosis is often not made in a standardized way. He gave many clinical pearls for people to change that. Just to mention a few, it's really important to review brain atrophy patterns very closely, looking for markers of abnormal CSF dynamics, looking really at the pattern of ventriculomegaly, enlarged Sylvian fissures, and tight high convexity very typically seen in NPH. It's good to assess this on sagittal images.

Another really important point made by him was to order an FDG-PET scan if possible. The question is often: Does this patient have NPH or is it Alzheimer's disease?. If you order an FDG-PET scan, it'll answer that question for you. If patients have a normal FDG-PET scan, we have proven that they do not have an underlying neurodegenerative disease.

He showed many videos of follow-up on the convincing benefit on gait and cognition of over 8 years. Although this is certainly not the randomized, blinded, controlled trial Dr Saber was calling for, I do encourage people to review some of Dr Jones' recent publications on NPH. It's such a continuum. I know there's a large amount of research going on. Hopefully, they can move toward a more standardized approach for diagnosis and treatment.

Subramanian: It is a very complicated area. I do think that when we find patients that we think have this and we can shunt them and make them better, we are always pushed to try to look for something that's very treatable. I love those pearls. I think those are very tangible things that we can grasp. I think the setting up of that randomized controlled trial and turning the shunt on and off in this blinded fashion sounds a little complicated. I'm not sure how you would gauge the timeline of response in that trial.

I think that there may be some patients that are overdiagnosed, but I certainly think it's a real diagnosis. I know that we help people every day with these sorts of diagnoses all over our practices.

Functional Neurologic Disorders

LaFaver: I agree. To top it off, let's come to our highlight number five. Switching gears again, I'm going to be highlighting Dr Selma Aybek's presentation on functional neurologic disorders (FND). She covered "Biopsychological Trait Markers Supporting the Stress-Diathesis Model in Functional Neurologic Disorders."

Of course, FND has been a longstanding interest of mine. As you know, there are many problems in making and communicating a diagnosis of an FND. This is often seen by many as a rule-out diagnosis. This can be very costly and time intensive. There's a stigma to the diagnosis.

The search for biomarkers has been ongoing. In the study presented by Dr Aybek, she combined detailed trauma assessments, salivary cortisol, diurnal biomarkers, and voxel-based morphometry in 86 patients with FND and compared this with healthy controls.

The results showed higher emotional-neglect scores in patients with FND, interestingly; a flattened cortisol awakening response; and reduced hippocampal and amygdalar volumes, which were not correlated to cortisol levels.

The conclusion from her study was that she felt that the reduced hippocampal and amygdala volume was actually a predisposing factor rather than a secondary effect related to stress, and might put certain patients at greater risk of developing FND.

Now, there's a large amount of ongoing research on genetic and epigenetic changes in FND. She actually published her research in this very nice study in Brain in November 2022. I will refer you to that for more details.

With that, these were my five highlights on movement disorder updates from the AAN annual meeting in Boston, 2023.

Subramanian: Thank you so much, Kathrin. I think that the FND world has been changed by you and the work of many of your colleagues. I really applaud you getting this out there into the mainstream neurology conferences. I think there was a large amount of exciting content, and I would urge people who are interested in this space — and we all see these patients — to go back and look at that content. I think you can watch it on AAN Rewind or other ways.

There is so much amazing content in that FND space.

Thanks so much for watching with us and allowing us to highlight our exciting moments at the AAN this year.

LaFaver: Thank you so much, Indu.

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