Written by Emil Koch
Prasinezumab: A Breakthrough in PD Treatment
Recent advancements in the treatment of Parkinson's disease (PD) have shown promise in halting the progression of motor degeneration in people with quickly progressing PD. Prasinezumab is a monoclonal antibody that targets alpha-synuclein aggregation. An exploratory study of the phase 2 PASADENA clinical trial produced positive results.
Although PD pathogenesis is greatly influenced by alpha-synuclein aggregation, there are yet no known disease-modifying therapies. One notable feature of Prasinezumab is its capacity to bind selectively to aggregated alpha-synuclein, which may impede the advancement of the disease.
Additionally, Prasinezumab showed a significant decrease in the worsening of motor symptoms during the trial as compared to placebo-treated subjects with quickly progressing disease, as measured by the Movement Disorder Society Unified PD Rating Scale Part III (MDS-UPDRS Part III).
However, while the findings offer hope for this subgroup of PD patients, further research is necessary to confirm Prasinezumab’s efficacy in broader PD populations and those with slower disease progression. An extended open-label phase of the PASADENA trial aims to explore its effects over longer treatment periods, while ongoing trials, like the PADOVA study, seek to validate these results in larger patient cohorts.
Previous studies found contradictory results, where intravenous placebo or prasinezumab at a dose of 1500 mg or 4500 mg every four weeks for 52 weeks led to no significant changes in global clinical or imaging measures of global clinical or imaging Parkinson’s disease progression. Nonetheless, the new study confirmed the consistent impact of prasinezumab on specific subgroups experiencing rapid disease progression. Those treated with prasinezumab showed a lesser increase in MDS-UPDRS Part III scores compared to those on placebo, suggesting that Prasinezumab's efficacy may be more effective in individuals with rapidly progressing clinical phenotypes. This could help uncover processes differentiating slower and more rapid clinical progression.
Biomarkers: Predicting Disease Progression
Higher baseline neurofilament light (NfL) levels were linked to faster motor deterioration and functional decline, according to a different study by Vijiaratnam et al. (2022). This was demonstrated by higher MDS-UPDRS Part III scores and lower SEADL scores, respectively. Serum NfL levels, however, did not significantly correlate with cognitive or quality-of-life evaluations. While apolipoprotein E (APOE) status was associated with rapid cognitive deterioration, baseline glucocerebrosidase (GBA) status did not predict progression.
The original rating scale, developed in the 1980s, was modified and is now known as the MDS-UPDRS, or Movement Disorder Society Unified Parkinson's Disease Rating Scale. It was created to address issues brought to light by an MDS task force study.
This revised scale aims to comprehensively assess Parkinson’s disease by evaluating both motor and non-motor experiences of daily living, as well as motor complications. The Schwab and England Activities of Daily Living (ADL) (SEADL) scale is a tool used to evaluate the functional abilities of individuals with mobility impairments.
Of significance is the study's insight that a combination of serum NfL with baseline clinical outcomes and patients’ genetic status could potentially be used to enrich a clinical trial cohort for individuals likely to have more rapid disease progression. This personalized approach to treatment selection and intervention timing could lead to more effective therapies and improved outcomes for Parkinson's disease patients. Additionally, early detection of elevated NfL levels could facilitate earlier diagnosis and intervention, potentially allowing for more proactive management of the disease before significant symptoms develop.
Multiple studies support the significance of serum NfL as a biomarker. Elevated blood levels of NfL are linked with greater motor impairment and cognitive decline over time, as demonstrated by several trials (Ygland Rödström et al. 2022; Ye et al. 2021; Choe et al. 2020; Niemann et al. 2021; Lin et al. 2019; Buhmann et al. 2022; Aamodt et al. 2021; Ma et al. 2021).
Advancements in Diagnostic Tools and Personalized Medicine:
A recent breakthrough by Siderowf et al. (2023) demonstrates that pathology in spinal fluid can be accurately detected not only in individuals already diagnosed with Parkinson’s disease but also in those who have not yet displayed clinical symptoms but are at a high risk of developing the condition, achieving an unprecedented accuracy of 93%. The tool called α-synuclein seeding amplification assay (αSyn-SAA) will advance biomarker research but, most importantly, treatment search in combination with other markers like NfL, genetic status, and others such as circular RNAs (circRNAs). Furthermore, it will be worth investigating how biomarkers can predict disease progression and its effects on brain waves, just one of the diagnostic tools that could complement diagnoses and treatments in personalized medicine.
In this regard, Singh et al. (2023) discovered that Parkinson’s Disease (PD) -related cognitive dysfunction, exhibited in 80% of PD patients at some point in their disease, results from decreased delta/theta activity. Could restoring the balance of brainwaves improve Parkinson's symptomology? If so, how?
Exactly that has been a question of research by Calabrò RS et al. (2019). They looked at the reasons why Rhythmic Auditory Stimulation (RAS) can compensate for the loss of automatic and rhythmic movements in patients with idiopathic PD. Their findings indicate that cueing strategies during gait training lead to alterations in sensorimotor rhythms and connectivity in specific brain regions. This reshaping of neural activity, particularly in front-centroparietal and temporal areas, is associated with improved gait performance. The involvement of the cerebellum suggests its role in restoring internal timing mechanisms for motor rhythmicity.
Does that mean that music therapy could complement traditional medical approaches?
Maggioni et al. (2021) revealed that music notably altered the connectivity patterns of PD patients, particularly enhancing frontotemporal inter-hemispheric communication compared to rest. While music was unable to fully compensate for connectivity deficits in PD patients, the study also highlighted the influence of music characteristics on brain responses, with Bach listening producing the most significant group connectivity differences and inducing more widespread communication in healthy individuals compared to PD patients.
Conversely, Mozart and Dona's listening had enhanced effects on PD patients, suggesting potential avenues for selecting music-based interventions tailored to PD patients' needs.
Conclusion:
The recent advancements in Parkinson's disease research herald a new era of personalized treatment approaches. By leveraging biomarkers, analyzing brainwave activity, and considering individualized disease progression rates, age, gender, and symptoms, tailored interventions can be crafted to address the unique needs of each patient. The integration of traditional medical strategies with innovative techniques like EEG-assisted music-based therapies holds tremendous promise in enhancing patient outcomes and improving quality of life. Moving forward, continued research and collaboration across multidisciplinary fields are essential to further refine these personalized treatment modalities and pave the way for transformative advancements in Parkinson's disease management.
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References:
Pagano, G., Taylor, K. I., Anzures-Cabrera, J., Marchesi, M., Simuni, T., Marek, K., Postuma, R. B., Pavese, N., Stocchi, F., Azulay, J., Mollenhauer, B., López-Manzanares, L., Russell, D., Boyd, J. T., Nicholas, A. P., Luquin, M. R., Hauser, R. A., Gasser, T., Poewe, W., . . . Bonni, A. (2022). Trial of prasinezumab in Early-Stage Parkinson’s Disease. New England Journal of Medicine/ the New England Journal of Medicine, 387(5), 421–432. https://doi.org/10.1056/nejmoa2202867.
Pagano, G., Taylor, K.I., Anzures Cabrera, J. et al. Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson’s disease. Nat Med (2024). https://doi.org/10.1038/s41591-024-02886-y.
MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). (n.d.). https://www.movementdisorders.org/MDS/MDS-Rating-Scales/MDS-Unified-Parkinsons-Disease-Rating-Scale-MDS-UPDRS.htm. (04/17/2024)
Vijiaratnam N, Lawton M, Heslegrave AJ PRoBaND clinical consortium, et alCombining biomarkers for prognostic modelling of Parkinson’s diseaseJournal of Neurology, Neurosurgery & Psychiatry 2022;93:707-715.
Ygland Rödström, Emil et al. ‘Serum Neurofilament Light Chain as a Marker of Progression in Parkinson’s Disease: Long-Term Observation and Implications of Clinical Subtypes’. 1 Jan. 2022 : 571 – 584.
Ye R, Locascio JJ, Goodheart AE, Quan M, Zhang B, Gomperts SN. Serum NFL levels predict progression of motor impairment and reduction in putamen dopamine transporter binding ratios in de novo Parkinson's disease: an 8-year longitudinal study. Parkinsonism Relat Disord. 2021;85:11–16. doi: 10.1016/j.parkreldis.2021.02.008.
Choe C-U, Niemann L, Englisch C, Petersen E, Buhmann C, Pötter-Nerger M, Blankenberg S, Gerloff C, Schwedhelm E, Zeller T. Subclinical cardiac microdamage, motor severity, and cognition in Parkinson's disease. Mov Disord. 2020;35(10):1863–1868. doi: 10.1002/mds.28129.
Niemann L, Lezius S, Maceski A, Leppert D, Englisch C, Schwedhelm E, Zeller T, Gerloff C, Kuhle J, Choe C-U. Serum neurofilament is associated with motor function, cognitive decline and subclinical cardiac damage in advanced Parkinson's disease (MARK-PD) Parkinsonism Relat Disord. 2021;90:44–48. doi: 10.1016/j.parkreldis.2021.07.028.
Lin C-H, Li C-H, Yang K-C, Lin F-J, Wu C-C, Chieh J-J, Chiu M-J. Blood NfL: a biomarker for disease severity and progression in Parkinson disease. Neurology. 2019;93(11):e1104–e1111. doi: 10.1212/WNL.0000000000008088.
Buhmann C, Lezius S, Pötter-Nerger M, Gerloff C, Kuhle J, Choe C-U. Age-adjusted serum neurofilament predicts cognitive decline in Parkinson's disease (MARK-PD) Mov Disord. 2022 doi: 10.1002/mds.28909.
Aamodt WW, Waligorska T, Shen J, Tropea TF, Siderowf A, Weintraub D, Grossman M, Irwin D, Wolk DA, Xie SX, Trojanowski JQ, Shaw LM, Chen-Plotkin AS. Neurofilament light chain as a biomarker for cognitive decline in parkinson disease. Mov Disord. 2021;36(12):2945–2950. doi: 10.1002/mds.28779.
Ma L-Z, Zhang C, Wang H, Ma Y-H, Shen X-N, Wang J, Tan L, Dong Q, Yu J-T. Serum neurofilament dynamics predicts cognitive progression in de novo Parkinson's disease. J Parkinsons Dis. 2021;11(3):1117–1127. doi: 10.3233/JPD-212535.
Siderowf, A., Concha‐Marambio, L., Lafontant, D., Farris, C. M., Ma, Y., Urenia, P. A., Nguyen, H., Alcalay, R. N., Chahine, L. M., Foroud, T., Galasko, D., Kieburtz, K., Merchant, K., Mollenhauer, B., Poston, K. L., Seibyl, J., Simuni, T., Tanner, C. M., Weintraub, D., . . . Soto, C. (2023). Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurology, 22(5), 407–417. https://doi.org/10.1016/s1474-4422(23)00109-6.
Singh A, Cole RC, Espinoza AI, et alEvoked mid-frontal activity predicts cognitive dysfunction in Parkinson’s diseaseJournal of Neurology, Neurosurgery & Psychiatry 2023;94:945-953.
Brain waves may predict cognitive impairment in Parkinson’s disease | Carver College of Medicine. (n.d.). https://medicine.uiowa.edu/content/brain-waves-may-predict-cognitive-impairment-parkinsons-disease. (04/17/2024)
McClure, P. (2023, September 21). Mysterious circular RNA linked to Alzheimer’s & Parkinson’s disease. New Atlas. https://newatlas.com/medical/mysterious-circular-rna-linked-to-alzheimers-parkinsons-disease/.
Calabrò, R.S., Naro, A., Filoni, S. et al. Walking to your right music: a randomized controlled trial on the novel use of treadmill plus music in Parkinson’s disease. J NeuroEngineering Rehabil 16, 68 (2019). https://doi.org/10.1186/s12984-019-0533-9.
Maggioni, E., Arienti, F., Minella, S., Mameli, F., Borellini, L., Nigro, M., Cogiamanian, F., Bianchi, A. M., Cerutti, S., Barbieri, S., Brambilla, P., & Ardolino, G. (2021). Effective connectivity during rest and music listening: An EEG study on Parkinson’s disease. Frontiers in Aging Neuroscience, 13. https://doi.org/10.3389/fnagi.2021.657221.