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The principal investigator at Seattle Children’s Research Institute provided commentary on the therapeutic potential and hypothesis behind targeting mTOR pathway hyperactivation using pharmacological inhibitors. [WATCH TIME: 3 minutes]

Thought Process and Promise Behind Targeting mTOR Pathway for Pediatric Epileptic Encephalopathies: Ghayda Mirzaa, MD

Articles

The agent is composed of 2 active ingredients with synergistic anti-oxidant and anti-inflammatory effects which can reduce brain cell injury or impairment caused by acute ischemic stroke. 

FDA Grants Breakthrough Therapy Designation to Edaravone Dexborneol Combination Therapy for Acute Ischemic Stroke

In this discussion, the pair of neurologists explore the latest drug development and ongoing clinical trials for MOGAD, a rare neuroimmune disorder. [WATCH TIME: 4 minutes]

Evaluating the Treatment Pipeline for MOGAD

Neal K. Shah, CEO of CareYaya Health Technologies, discussed how Apple's new health features could potentially be a game-changer for neurological health. 

Apple's Latest Health Updates: A Neurological Game-Changer in Disguise

, has been with the team since October 2019. Follow him on Twitter 

In this segment, Bennett and Greenberg explore the diagnosis, acute treatment, and long-term management of MOGAD, highlighting current therapies and ongoing research. [WATCH TIME: 8 minutes]

Understanding the Treatments and Tools for MOGAD Management

In this episode, Greenberg and Bennett provide some perspective on the fluidity of MOGAD diagnosis and how it could potentially change over time as more is understood about neuroimmune disorders. [WATCH TIME: 5 minutes]

Continuing Evolution of MOGAD Diagnosis, Remaining Questions in Antibody Titer Testing

In this segment, the duo of neurologists provided a number of informative considerations treating clinicians should take when diagnosing MOGAD, emphasizing careful testing and interpretation of data in this complex process. [WATCH TIME: 4 minutes]

Navigating MOGAD Diagnosis: Clinical Insights and Key Considerations

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AAIC 2024

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The Jerold B. Katz professor of neurology and neuroscience at Weill Cornell Medicine.

The Jerold B. Katz professor of neurology and neuroscience at Weill Cornell Medicine talked about a recent study that revealed patients who appeared unresponsive to verbal commands in vegetative or minimally conscious states retained high cognitive function. [WATCH TIME: 6 minutes]

Exploring Cognitive Motor Dissociation in Consciousness Disorders: Nicholas Schiff, MD

According to a new announcement, the FDA has issued a letter of support for using the α-synuclein seed amplification assay (αSyn-SAA) biomarker in clinical trials for Parkinson disease (PD) and related diseases. This decision comes following a multi-stakeholder collaboration between The Michael J. Fox Foundation for Parkinson's Research (MJFF) and the Critical Path Institute (C-Path) to advance PD therapeutics using this recently discovered biomarker.

In the letter, the agency highlighted that its support comes from evidence gathered in the Parkinson's Progression Markers Initiative (PPMI), a longitudinal observational study sponsored by MJFF. The FDA noted that its decision to encourage use of αSyn-SAA also relied on other global studies across industry and academia, which represented the large amount of data as well as the applied collaboration used to validate the tool.

“The biomarker, now with the support of the FDA, will lead to faster, more effective clinical trials for Parkinson’s disease. Researchers can design trials that target specific aspects of disease biology with confidence that participants in the study have similar, important biological features. We anticipate this will speed along potential therapies already in early stages of the pipeline, while also attracting new or sustained interest from drugmakers. Our laser-focused goal remains the same — placing better therapies and a cure in the hands of people and families with Parkinson's," Todd Sherer, PhD, MJFF's chief mission officer, told 

 "Working collaboratively together with partners — people and families living with PD, neuroscience and clinical leaders, industry experts, federal research funders (i.e., the National Institutes of Health), disease-focused nonprofit organizations and regulatory authorities — we are able to leverage the incredible amount of knowledge and expertise in the space. We believe bringing the field together is the fastest way to improve its outcomes.”

 showed that use of an αSyn-SAA technique had high diagnostic accuracy of PD, distinguished molecular subtypes, and detected the disease before primary symptoms.

 In total, data on αSyn-SAA was collected from 1123 participants from the PPMI cohort, including patients with a diagnosis of PD and at-risk patients with gene variants (GBA and LRRK2) linked to the disease. In the large-scale analysis, αSyn-SAA was shown to differentiate PD from controls with a sensitivity of 88% and specificity of 96%.

The research was co-led by authors Andrew Siderowf, MD, PPMI investigator and director, PD and Movement Disorders Center at the University of Pennsylvania, and Luis Concha, PhD, director, research and development at Amprion. In the study, samples of cerebrospinal fluid surrounding the brain and spinal cord were analyzed from each participant using αSyn-SAA.

GCase-Targeting Parkinson Drug GT-02287 Shows Target Engagement, Encouraging Safety in Early-Stage Study

In the study, approximately 93% of patients with no known genetic cause had a positive αSyn-SAA result. Results varied for patients with genetic forms of PD, with 96% having the GBA variant and a positive αSyn-SAA result, compared with 68% of patients with LRRK2. Most prodromal patients had positive αSyn-SAA results, suggesting they had α-synuclein aggregates despite no PD diagnosis. Fifty-five percent of women with PD with the LRRK2 variant had a positive αSyn-SAA result compared with 72% of men with PD who had the same the variant. Patients with the LRRK2 variant and a negative αSyn-SAA result tended to be older compared with than those with positive αSyn-SAA results.

Loss of sense of smell was the most strongly predicted clinical feature of a positive αSyn-SAA result. Among all participants with PD who had loss of smell, 97% had positive αSyn-SAA compared with 63% of patients whose sense of smell was unchanged. Also, in patients with REM sleep behavior disorder, positive αSyn-SAA results were present in 85% (28 out of 33 patients) of participants. There were no other clinical features associated with a positive αSyn-SAA result.

Patients who carried the LRRK2 or GBA variants but had no PD diagnosis or prodromal symptoms, nonmanifesting carriers (NMCs), had positive αSyn-SAA results (LRRK2, 9% [14 out of 159 patients]; GBA, 7% [11 out of 151 patients]). Most prodromal participants and NMCs with positive αSyn-SAA had brain scans that did not show a decline in the expected number of dopamine-producing nerve cells, suggesting buildup of α-synuclein aggregates could be an early mark of disease onset.

Since the tool can detect early biological changes related to PD and related diseases before symptoms appear, it could potentially enhance trials assessing therapies that are aimed at delaying or preventing disease onset. Additionally, it supports research into personalized therapies for patients at all stages of these conditions. The biomarker can further accelerate and streamline these trials by providing objective end points, ensuring participants have the relevant pathology, and tracking therapy-induced changes. This efficiency can reduce the risk for industry investment in developing potential blockbuster therapies, including preventive treatments.

“The new biomarker findings that have just emerged in the last two years are truly transforming how we're going to be doing drug development for the future of Parkinson's. We all know that this is a very complex neurodegenerative disease that has so much rapid progression and a huge unmet need for disease-modifying therapies," Diane Stephenson, PhD, executive director of Critical Path for Parkinson's Consortium at C-Path, told 

. "We now have a molecular tool that looks at a signature of what's going on in living individuals that tells you what is the underlying biology of the disease. Very similar to cancer, where we know the molecular features of the disease. We can now do this in Parkinson's where just two years ago, it was only possible by having autopsy postmortem tissues."

"With these new tools, we're able to identify a light that shows us who are the right people to treat with promising new disease-modifying therapies, not only when they're diagnosed, but years before the onset of symptoms," Stephenson said. "This landmark milestone that we achieved through this letter of support was so fast because of the data that was shared thanks to the generous support of The Michael J. Fox Foundation and thousands of patients from around the world who generated their samples. We pulled all that data together in a comprehensive submission to the FDA, and within three months they issued a letter of support. The data was reliable, robust, and showed consistency across multiple studies around the world.”

In January 2024, a multistakeholder team made up of academic researchers and clinicians, industry, nonprofits, regulators, and patients published the first biological staging system for Parkinson known as the neuronal alpha-synuclein disease integrated staging system (NSD-ISS).

 the system relies on the biomarker detected by SAA to identify the evolution of NSD into progressive stages.

 The agency’s letter of support recognizes the potential of NSD-ISS with data produced by αSyn-SAA to speed up the success of therapeutic development in PD.

, the proposed system is currently intended for research use only, with the goal to enhance trial design and improve drug development. Simuni, a professor of neurology and head of the division of movement disorder at the Northwestern University Feinberg School of Medicine, sat down with 

 to discuss the long-term impacts this staging system has on the PD research community. She provided clarity on the purpose behind the paper, the role of α-synuclein in PD, and the next steps in expanding drug development.

Tanya Simuni on PD Staging System

REFERENCES
1. FDA Issues 'Letter of Support' Encouraging Use of Synuclein-based Biomarker, αSyn-SAA, in Clinical Trials in Parkinson's and Related Diseases. News Release. The Michael J. Fox Foundation for Parkinson's Research. Published September 9, 2024. Accessed September 9, 2024. https://www.michaeljfox.org/publication/fda-issues-letter-support-encouraging-use-synuclein-based-biomarker-asyn-saa-clinical
2. Michael J. Fox Foundation Announces Significant Breakthrough in Search for Parkinson’s Biomarker. News Release. The Michael J. Fox Foundation for Parkinson’s Research. Published April 12, 2023. Accessed September 9, 2024. https://www.michaeljfox.org/research-news
3. Simuni T, Chahine LM, Poston K, et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research. Lancet Neurol. 2024;23(2):178-190. doi:10.1016/S1474-4422(23)00405-2
4. New Biological Definition and Proposed Staging System for PD: What it means for Researchers, Industry Professionals and Clinicians. News Release. The Michael J. Fox Foundation for Parkinson’s Research. Published January 29, 2024. Accessed September 9, 2024. https://www.michaeljfox.org/news/new-biological-definition-and-proposed-staging-system-pd-what-it-means-researchers-industry 

The agency’s letter of support for using the α-synuclein seed amplification assay biomarker was supported by data observed in the Parkinson's Progression Markers Initiative cohort study. 

Clinical

FDA Supports Alpha-Synuclein Seed Amplification Assay Biomarker for Clinical Trials in Parkinson Disease

In a phase 1, 2-part, open-label, fixed-sequence, single and multiple oral dose study newly published in 

Clinical Pharmacology in Drug Development

, results showed that the pharmacokinetics of vatiquinone (PTC Therapeutics) a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich ataxia (FA), can be adjusted by coadministration of cytochrome P450 isoform 3A4 (CYP3A4) inhibitor itraconazole or CYP3A4 inducer rifampin.

Coadministration of vatiquinone 400 mg with itraconazole 200 mg increased maximum observed concentration (C

) of vatiquinone and systemic exposure (AUC

) by approximately 3.5- and 2.9-fold, respectively. The coadministration of vatiquinone 400 mg with rifampin 600 mg decreased vatiquinone C

 by approximately 0.64- and 0.54-fold, respectively. Notably, the terminal half-life of vatiquinone was not influenced by neither itraconazole or rifampin.

“Vatiquinone has demonstrated a very well-established safety profile in children, including very young children with severe illnesses, as well as in adults in clinical studies," Matthew B. Klein, MD, MS, FACS, chief executive officer at PTC Therapeutics, told 

. "The pharmacology results shared in the publication should not impact the exposure, safety, or use of vatiquinone but can provide guidance for physicians when considering other medications that patients may be receiving."

In this study, investigators assessed the effect of itraconazole and rifampin on the single-dose PKs of vatiquinone. Researchers enrolled participants between 18 and 45 years of age, with a body mass index of 18.5-30 kg/m2. On the first day of each part of the study, patients only received a single dose of vatiquinone 400 mg, which was followed by a washout of 7 days. In Part 1, patients received itraconazole on days 8 through 11, and they received vatiquinone coadministered with itraconazole on day 12, followed by a last dose of itraconazole on day 13. In Part 2, patients received rifampin on days 8 through 21, and then received vatiquinone coadministered with rifampin on day 22, followed by a last dose of rifampin on day 23.

“The clinical study results confirm that the CYP3A4 enzyme plays an important role in vatiquinone metabolism and the effect on vatiquinone PK when coadministered with a potent CYP3A4 inhibitor or inducer. Additional work was performed to understand the impact of moderate CYP3A4 inhibitors and inducers on vatiquinone exposures via physiologically based pharmacokinetic modeling and will be presented elsewhere,” coauthor Lee Golden, MD, chief medical officer at PTC Therapeutics, and colleagues wrote.

Specific Biomarkers Detected for Staging and Treatment in Spinocerebellar Ataxia Type 3

Although 3 patients (13.04%) reported 4 treatment-emergent adverse events (TEAEs), investigators observed no treatment-emergent serious adverse events (TESAEs) during the study. Only 2 participants experienced temporary clinically significant elevations in hepatic enzymes. As for the reported TEAEs, they were in the Gastrointestinal System Organ Class (SOC) and, for 1 patient, also in the Nervous System SOC. 

Authors noted that all TEAEs were mild and resolved by the completion of the study or shortly thereafter. The reported TEAES were considered unrelated to vatiquinone although the elevated alanine transaminase and aspartate transaminase enzymes might have possibly been related to itraconazole, according to the principal investigator of the study.

“The results of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant,” Golden et al noted.

 According to a recent company update, PTC Therapeutics has plans to submit a new drug application (NDA) for vatiquinone for the treatment of FA in late 2024.

2024 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference

, held March 3-6, in Orlando, Florida, data from the placebo-controlled phase of the global phase 3 MOVE-FA trial (NCT04577352) assessing vatiquinone in patients with FA showed the treatment demonstrated clinically relevant benefits across multiple end points at 72 weeks.

In the analysis, investigators observed a –1.61 (

=.144) change in modified FA Rating Scale (mFARS)compared with the placebo at 72 weeks in the modified intent-to-treat (mITT) population, which consisted of 123 participants with FA. The researchers reported a sustained vatiquinone treatment benefit observed across all end points including the primary, secondary, and exploratory end points.

"The recently completed MOVE-FA placebo-controlled study results demonstrate a statistically significant and meaningful effect on the upright stability subscale of the disease rating scale – the most relevant and sensitive component of the disease rating scale for pediatric and young adult ambulatory patients," Klein said. "The results in the study support that vatiquinone could have an important effect in delaying loss of ambulation as well as other important and burdensome aspects of the disease."

Conducted by lead author David Lynch, MD, PhD, a neurologist and director of the Friedreich's Ataxia Program at Children's Hospital of Philadelphia, and colleagues, the trial included patients 143 aged at least 7 years, with an mFARS score of between 20 and 70 and the ability to ambulate at least 10 feet in 1 minute with or without assistance. The primary end point of the current analysis was placebo-corrected change from baseline in mFARS at 72 weeks. The intent-to-treat (ITT) population had a mean age of 18.7 years and the primary analysis population—the mITT population—included participants between 7 years and 21 years of age (mean, 14.6).

Investigators observed a nominally significant benefit recorded in the Upright Stability subscale (USS), a relevant metric of disease progression in younger ambulatory patients with FA, of mFARS, with a change of –1.26 (

 = .021). In addition, researchers observed nominally significant benefit in the Modified Fatigue Impact Scale, with a change of –5.05 (

 = .025). Overall, the authors noted that the treatment was safe and well tolerated among the participants, with no differences in treatment-related adverse events observed between treatment and placebo groups.

"The effects observed in this trial along with the established safety profile will form the basis of the planned vatiquinone NDA submission later this year," Klein added.

REFERENCES
1. Lee L, Thoolen M, Ma J, Kaushik D, Golden L, Kong R. Effect of Itraconazole, a CYP3A4 Inhibitor, and Rifampin, a CYP3A4 Inducer, on the Pharmacokinetics of Vatiquinone. Clin Pharmacol Drug Dev. Published online August 12, 2024. doi:10.1002/cpdd.1461
2. PTC Therapeutics Provides Corporate Update and Reports Second Quarter 2024 Financial Results. News Release. PTC Therapeutics. August 8, 2024. Accessed August 22, 2024. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-provides-corporate-update-and-reports-second-2
3. Lynch D, Duquette A, França MC, et al. Safety and Efficacy of Vatiquinone Treatment in Friedreich Ataxia Patients from MOVE-FA: a Phase 3, Double-blind, Placebo-controlled Trial. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Poster S79.

PTC Therapeutics has plans to submit a new drug application for vatiquinone, a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich ataxia, in late 2024.

Vatiquinone Pharmacokinetics Influenced by CYP3A4 Inhibitors and Inducers in Phase 1 Study

, a cell-based assay (CBA) developed by researchers allowed the testing of novel neuron-/astrocyte-reactive antibodies in patients with suspected immune-mediated neurological syndromes, and negative testing in routine laboratories. This CBA, using neurons and astrocytes derived from human-induced pluripotent stem cells (hiPSCs), can potentially open new viewpoints in establishing a diagnosis of complex diseases such as neuromyelitis optica spectrum disorder (NMOSD).

Using this 96-well CBA, investigators identified antibodies that recognized hiPSC-derived neural cells in 19 out of 99 patients. Antibodies were attached particularly to astrocytes in 9 cases, to neurons in 8 cases, and to both cell types in 2 cases, which were confirmed by microscopy single-cell analyses. Investigators observed that neural-specific antibody binding was more frequent in patients with inflammatory neurological diseases (IND, n = 15) compared with those who had non-IND (NIND, n = 4) (Fisher's exact test,

= .0005), further highlighting the significance of their comprehensive CBA.

"Our CBA using human iPSC-derived neurons and astrocytes allows to detect antibodies that would not be identified by traditional approaches. Indeed, these human central nervous system (CNS) cells naturally express antigens with the appropriate post-translational changes, which is not always the case with other methods reported to date. So, in the future, we envision that this CNS CBA has its place in the cases where an autoimmune neurological condition is strongly suspected, yet traditional detection assays give negative results,” senior author Renaud Du Pasquier, MD, told 

For instance, up to 46% of auto-immune encephalitis (AIE) and up to 16% of NMOSD are seronegative with current traditional assays. So, our CBA, by ascertaining the diagnosis of AIE or NMOSD in some patients, may decrease the area of uncertainty and thus help the physician in therapeutical management."

All told, human iPSC-derived astrocytes or neurons were incubated with serum/CSF from 42 patients with IND and 57 patients with non-IND. Researchers noted that the IND group had 11 patients with established neural antibodies prior, 6 with seronegative NMOSD, 12 with suspension of autoimmune encephalitis/paraneoplastic syndrome (PNS), and 13 with other IND. Immunoglobulin G (IgG) binding to fixed CNS cells was identified utilizing fluorescently-labeled antibodies and evaluated by automated fluorescence measures. IgG neuronal/astrocyte reactivity was further analyzed by flow cytometry. Authors used peripheral blood mononuclear cells (PBMC) as CNS-irrelevant control target cells. Researchers defined reactivity profile as positive through a Robust regression as well as an outlier removal test with a false discovery rate at 10% following each patient readout.

Interim Analysis Confirms Satralizumab's Safety and Efficacy in Japanese Patients With NMOSD

Investigators also observed that 2 out of the 4 patients with aquaporin-4 antibody positive (AQP4+) NMOSD and 4 of 7 definite AIE/PNS with intracellular-reactive antibodies, as detected in diagnostic laboratories, tested also positive with the CBA. Notably, authors demonstrated antibody-reactivity in 2 out of the 6 patients who were seronegative NMOSD, 6 of 12 probable AIE/PNS, and 1 of 13 other IND. Flow cytometry utilizing hiPSC-derived CNS cells or PBMC-identified antibody binding among 13 patients versus no patients, respectively, which established the specificity of the recognized antibodies in the neural tissue.

"One of the most difficult aspects was establishing reliable protocols to generate large numbers of hiPSC-derived astrocytes and neurons. These protocols are needed to ensure consistency and high cell quality across experiments and different teams," Du Pasquier, who serves as a full professor and the head of the neurology department at CHUV/University of Lausanne, said. "After rigorous optimization, we successfully created protocols that consistently produce high-quality CNS cells. These protocols are now used by collaborators and other research teams worldwide, ensuring standardization and reliability across various labs."

"Another significant hurdle was automating the detection of antibody reactivity through fluorescence measurements including microscopy assessments. This step is crucial for determining whether autoantibodies in serum or CSF bind to astrocytes or neurons. Such optimization enables us to generate reliable results within a few days," Du Pasquier added.

Authors noted that this current CBA is limited to only astrocytes and neurons; thus, they underscored that other CNS cell types including oligodendrocytes, microglia, endothelial or even ependymal cells could be an asset to broaden the antigenic diversity. Researchers argued the previous research showed that astrocytes and neurons presently cover the majority of CNS antigens associated with neurological disorders expect for myelin oligodendrocyte glycoprotein antibody disease, which is express by oligodendrocytes.

"An advantage of our CBA is that it offers the potential to precisely characterize new antigens that would be expressed exclusively in human brain cells. Once such an antigen is defined, it will be possible to transfect it into HEK cells and implement those cells into routine diagnostic tests. Overall, by broadening the number of antigens recognized by antibodies in autoimmune neurological diseases, our CBA may improve clinical management of patients affected by these severe conditions,” Du Pasquier said.

REFERENCES
1. Mathias A, Perriot S, Jones S, et al. Human stem cell-derived neurons and astrocytes to detect novel auto-reactive IgG response in immune-mediated neurological diseases. Front Immunol. 2024;15:1419712. Published 2024 Jul 24. doi:10.3389/fimmu.2024.1419712
2. Sechi E, Flanagan EP. Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management. Front Neurol. 2021;12:673339. Published 2021 Jul 7. doi:10.3389/fneur.2021.673339
3. Hamid SHM, Whittam D, Mutch K, et al. What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients. J Neurol. 2017;264(10):2088-2094. doi:10.1007/s00415-017-8596-7

Research indicated that up to 46% of patients diagnosed with presumed autoimmune limbic encephalitis tested negative for all currently identified central nervous system antigens.

Novel Cell-Based Assay Enhances Detection of Autoantibodies in Neurological Disorders

Anna Castagna, MD, stressed how new clinical trial designs for cervical dystonia should incorporate more flexible and patient-centered approaches.

The Need for Flexibility and Patient-Centered Approaches in Clinical Trials for Cervical Dystonia: Anna Castagna, MD

"If a patient has difficulties after one treatment they must be reassured that it is possible to be reinjected when they perceive the wearing off effect, even if it is before the considered time."

Patients with cervical dystonia treated with botulinum toxin, a first-line therapy for this condition, typically require injections every 3 to 4 months. The consistency of botulinum toxin's effect is important for maintaining the patients' quality of life, as it helps prevent fluctuations in symptom control between injections. However, there is currently no standardized method for clinicians to assess the duration of botulinum toxin's effect in patients with cervical dystonia in a clinical setting.

A recent scoping review performed by lead author 

, and colleagues summarized available evidence from phase 3 clinical trials assessing botulinum toxin in cervical dystonia and interpretation of the reported duration of its effect. In the review, studies showed that clinical trial outcomes in cervical dystonia were not assessed objectively, and did not prioritize the needs of patients or focus on factors that impacted their daily living activities and quality of life. Authors therefore noted that there is a need for better evidence and consistency of reports for duration of effect for botulinum toxin in cervical dystonia to guide providers on when reinjection is likely to be essential.

These findings were presented at the 3rd Annual 

Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress

 from June 22-25, 2024, by Castagna, a consultant neurologist at Fondazione Don Carlo Gnocchi ONLUS in Milan, Italy. Recently, Castagna sat down with 

 to discuss how the integration of patient-centered measurement scales can improve the outcomes of clinical trials for cervical dystonia. She also talked about the potential benefits and challenges of using mobile apps to monitor the effectiveness and duration of cervical dystonia treatments. Moreover, Castagna spoke about how the flexibility in reinjection schedules may impact patient outcomes and overall treatment effectiveness in real-life settings.

Click here for more coverage of ATMRD 2024

REFERENCES
1. Castagna A, Jinnah HA, Albanese A. Duration of botulinum toxin efficacy in cervical dystonia clinical trials: A scoping review. Parkinsonism Relat Disord. 2024;125:107011. doi:10.1016/j.parkreldis.2024.107011

The consultant neurologist at Fondazione Don Carlo Gnocchi ONLUS stressed how new clinical trial designs for cervical dystonia should incorporate more flexible and patient-centered approaches, including new measurement scales and the use of technology. [WATCH TIME: 5 minutes]

Differentiating patients with atypical parkinsonisms from idiopathic Parkinson disease (PD) can be a significant challenge for clinicians in clinical practice because of the similar symptoms presented in each of them. For instance, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit an overlap of pathological features and have various phenotypic variants. Therefore, it is important for providers to make an accurate diagnosis to determine the most effective treatment and management approach for patients. Prior research even indicated that inappropriate treatment, because of misdiagnosis, provides limited benefits to patients, complicating care and increasing the disease burden.

, delivered a presentation on diagnostic insights in atypical parkinsonism. He discussed methods for clinicians to differentiate the clinical and pathological features of each atypical parkinsonian syndrome from idiopathic PD. Additionally, he highlighted key indicators that may signal atypical parkinsonism and evaluated recent advancements in diagnostics and treatments.

, Shprecher, the director of movement disorders at the Banner Sun Health Research Institute, sat down with 

 at the Congress to discuss the current limitations of diagnostics tests such as the Syn-One skin biopsy test and cerebral spinal fluid (CSF) test for synuclein biomarkers. Shprecher, who also serves as a clinical associate professor at University of Arizona-Phoenix, spoke about how the current biomarkers help differentiate between synucleinopathies and tauopathies. Furthermore, he talked about future developments anticipated in minimally invasive biomarker testing for neurodegenerative diseases.

NeurologyLive: Could you provide an overview of your talk that you presented at ATMRD on diagnostic pearls and atypical Parkinson?

First of all, thanks so much for your interest in the ATMRD program. I was able to kick off the symposium today with the first CME talk in diagnostic pearls and atypical Parkinsonism. I also touched briefly on some of the updates and diagnostic criteria for atypical Parkinsonian disorders and some of the clinical pearls and management. It's an exciting time because we're just at the cusp of having biomarkers that can help us more reliably differentiate what the underlying changes in the nervous system are while patients are still alive, when it really matters to them.

What are the main takeaways from your talk that clinicians should be thinking about regarding developments in diagnostics?

While the data is very promising for synuclein biomarkers—both the Syn-One skin biopsy test and the CSF test from Amperon—we still don't have studies that compare patients with synucleinopathy to those with tauopathies and some of these other proteinopathies. We still need a little bit more time to study the utility of these tests in differentiating some of those tough cases. [In addition,] we want to recognize the limitations of the data sets that are still out there. That said, the synuclein biomarker in the Parkinson Progression Markers Initiative (PPMI) showed extraordinarily high sensitivity, 99%, in clinically well-defined patients with PD who also had anosmia using the University of Pennsylvania smell identification test. We were able to very clearly identify classic patients with PD that show misfolded alpha-synuclein in the CSF that can be confirmed during life with a test that isn't terribly invasive, but we would like something a little less invasive, if possible.

Another important limitation there is we still don't know in other cohorts where patients present with the classic “not reading the textbook” approach to things where they don't have all of the classic features of PD. What's the utility attest in those cases? We don't have any autopsy confirmed cohorts yet, so there are still some limitations. Another thing to emphasize with this, and also with the Syn-One biopsy test, is that we do have 2 well defined, relatively large cohorts for both biomarkers but these studies haven't necessarily been confirmed by independent groups with separate cohorts and separate labs. 

When it comes to the Syn-One biopsy test, an important limitation is that all of the participants enrolled were very well defined patients with synucleinopathies, PD, dementia with Lewy bodies, pure autonomic failure, and multiple system atrophy. There were no patients with some of the other atypicals, the tauopathies, for example. In addition, there were very well defined healthy controls, but the healthy controls, on average, were younger than the disease patients. That is a limitation of the data. Still, it is a useful test in select cases, but we really need to understand the limitations of the test. That is just another piece of information. It's not a simple yes or no answer either you have synucleinopathy or you don't and that there isn't anything else going on.

What other developments for enhanced diagnostics should the clinical community look forward to?

We really would like to see tests that are minimally invasive, that could be therefore more broadly available and broadly utilized. If the Syn-One biopsy test could be studied in a much larger cohort, such as the PPMI cohort, that would be very helpful. I would be very excited to see that happen. I think another area that would be super exciting—if it can happen—is if we could have a blood biomarker, of course, for synucleonopathy, or even for tauopathy, that would be what we consider our most minimally invasive test, other than maybe an imaging ligand. We're still a ways off from a synuclein imaging ligand.

Are there any closing remarks that you have regarding your presentation and regarding the Congress?

There are 2 imaging ligands just to keep an eye on. First of all, there is a synuclein imaging ligand that, while it doesn't necessarily differentiate all synucleinopathies, does show promise specifically separating multiple system atrophy from the other synucleinopathies. Another exciting development is we have several different tau ligands in development. Some are mainly being developed for Alzheimer disease, but one in particular from Molecular Life Sciences is also showing promise because of a different pattern of deposition in PSP. Where it clearly differentiates people with the classic presentation of Richardson syndrome from, say, PD or healthy controls. This is now being studied in a much larger cohort of neurodegenerative disease patients who are all at end of life and also consented for brain autopsy. Hopefully, over the next few years, we’ll have autopsy-confirmed data about the utility of this ligand for identifying these 4 repeat telepathies like PSP or CBD during life, when it matters the most to our patients.

REFERENCES
1. McFarland NR. Diagnostic Approach to Atypical Parkinsonian Syndromes. Continuum (Minneap Minn). 2016;22(4 Movment Disorders):1117-1142. doi:10.1212/CON.0000000000000348

The director of movement disorders at the Banner Sun Health Research Institute talked about recent, promising advancements for diagnosing atypical Parkinsonian disorders and the questions that remain.

NeuroVoices: David Shprecher, DO, MSci, FAAN, on Current and Future Directions in Biomarker Testing for Atypical Parkinsonism

According to a recent announcement, the FDA has granted the approval of Myogenica’s investigational new drug (IND) application to study MyoPAXon, an induced pluripotent stem cell-derived muscle stem cell product to regenerate skeletal muscle. The company noted that a proposed early-stage clinical trial would assess the safety, tolerability, and engraftment of the therapy among patients with Duchenne muscular dystrophy (DMD).

, a pediatric neuromuscular neurologist and director of the Greg Marzolf Jr. Muscular Dystrophy Center at the University of Minnesota Medical School, plans to administer intra-muscular injections of MyoPAXon in adult patients with nonambulatory DMD. Kang and colleagues in the trial will then monitor any potential site reactions or immune response and investigate the presence of dystrophin-producing myofibers.

"I was thrilled to see this milestone in testing cell therapies for muscular dystrophy in humans. There is enormous potential to provide lasting relief for patients with muscular dystrophy. Our planned initial study will focus on safety considerations, and we will be injecting MyoPAXon into a small foot muscle to assess safety and tolerability of various doses," Kang told 

. "What makes MyoPAXon distinct is that it has the exciting potential for muscle regeneration. Once injected, the MyoPAXon cells can survive indefinitely and thus yield long term beneficial effects."

Pending positive results from an early-stage trial, a mid-stage study evaluating MyoPAXon’s effect on other targeted muscles and muscle function will be initiated.

Nicholas Schiff, MD

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