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A multitude of steps stands between (oral) levodopa intake and concentration of dopamine available to dopaminergic neurons in the brain.
A multitude of steps stands between (oral) levodopa intake and concentration of dopamine available to dopaminergic neurons in the brain.


1. After oral ingestion of levodopa, the tablets have to dissolve in the stomach, and then be transported to the small intestine for absorption. Many people with Parkinson’s disease have a lower acidity [MB1] of the stomach (e.g. due to medication use or ''Helicobacter pylori'' infection), and an estimated 70-100% of people with Parkinson’s disease have gastroparesis [MB2] (delayed stomach emptying). This leads to impaired dissolution of levodopa and delayed transfer of levodopa to the small intestine, respectively.
1. After oral ingestion of levodopa, the tablets have to dissolve in the stomach, and then be transported to the small intestine for absorption. Many people with Parkinson’s disease have a lower acidity<ref>Fasano, A.; Visanji, N. P.; Liu, L. W. C.; Lang, A. E.; Pfeiffer, R. F. Gastrointestinal Dysfunction in Parkinson’s Disease. ''The Lancet Neurology'' '''2015''', ''14'' (6), 625–639. <nowiki>https://doi.org/10.1016/S1474-4422(15)00007-1</nowiki>.</ref> of the stomach (e.g. due to medication use or ''Helicobacter pylori'' infection), and an estimated 70-100% of people with Parkinson’s disease have gastroparesis<ref>Marrinan, S.; Emmanuel, A. V.; Burn, D. J. Delayed Gastric Emptying in Parkinson’s Disease. ''Movement Disorders'' '''2014''', ''29'' (1), 23–32. <nowiki>https://doi.org/10.1002/mds.25708</nowiki>.</ref> (delayed stomach emptying). This leads to impaired dissolution of levodopa and delayed transfer of levodopa to the small intestine, respectively.


2. Once levodopa has arrived in the duodenum and proximal jejunum for absorption, it has to be actively transported over the bowel mucosa by saturable LNAA transporters (transporters for Large Neutral Amino Acids). These transporters are both sensitive to pH, working optimally at a pH between 6.2 – 7.4,[MB3]  as well as sensitive to so-named ''protein competition''. That is: after a protein-rich meal, dietary proteins/amino acids compete with levodopa [MB4] for the transport system, reducing levodopa’s bioavailability. As noted, stomach acidity is often less pronounced in people with Parkinson’s disease, and due to delayed gastric emptying, dietary proteins may be present in the small intestine for extended periods after a meal. This limits predictability of the speed and magnitude with which levodopa is absorbed into the bloodstream.
2. Once levodopa has arrived in the duodenum and proximal jejunum for absorption, it has to be actively transported over the bowel mucosa by saturable LNAA transporters (transporters for Large Neutral Amino Acids). These transporters are both sensitive to pH, working optimally at a pH between 6.2 – 7.4,<ref>Pedrosa de Menezes, A. L.; Bloem, B. R.; Beckers, M.; Piat, C.; Benarroch, E. E.; Savica, R. Molecular Variability in Levodopa Absorption and Clinical Implications for the Management of Parkinson’s Disease. ''Journal of Parkinson’s Disease'' '''2024''', ''14'' (7), 1353–1368. <nowiki>https://doi.org/10.3233/JPD-240036</nowiki></ref> as well as sensitive to so-named ''protein competition''. That is: after a protein-rich meal, dietary proteins/amino acids compete with levodopa<ref>Contin, M.; Martinelli, P. Pharmacokinetics of Levodopa. ''Journal of Neurology'' '''2010''', ''257'' (Suppl. 2), S253–S261. <nowiki>https://doi.org/10.1007/s00415-010-5728-8</nowiki>.</ref> for the transport system, reducing levodopa’s bioavailability. As noted, stomach acidity is often less pronounced in people with Parkinson’s disease, and due to delayed gastric emptying, dietary proteins may be present in the small intestine for extended periods after a meal. This limits predictability of the speed and magnitude with which levodopa is absorbed into the bloodstream.


3. Both in the intestinal lumen as well as in peripheral blood, levodopa is metabolized to dopamine and other metabolites. This is unwanted, as dopamine cannot cross the blood-brain barrier; for pharmacotherapeutic effect, levodopa has to cross the blood-brain barrier in unmetabolized form. While peripheral decarboxylase inhibitors are able to partially inhibit peripheral decarboxylation, there is interindividual variability in the activity of levodopa-metabolizing enzymes such as AADC and catechol-O-aminotransferase (COMT). Part of this variability is genetic[MB5] , but AADC activity also varies by sex, disease duration and use of dopaminergic medication. The amount of levodopa that succeeds in being absorbed into the blood stream is therefore not necessarily the amount available at the blood-brain barrier.
3. Both in the intestinal lumen as well as in peripheral blood, levodopa is metabolized to dopamine and other metabolites. This is unwanted, as dopamine cannot cross the blood-brain barrier; for pharmacotherapeutic effect, levodopa has to cross the blood-brain barrier in unmetabolized form. While peripheral decarboxylase inhibitors are able to partially inhibit peripheral decarboxylation, there is interindividual variability in the activity of levodopa-metabolizing enzymes such as AADC and catechol-O-aminotransferase (COMT). Part of this variability is genetic<ref>Devos D, Lejeune S, Cormier-Dequaire F, Tahiri K, Charbonnier-Beaupel F, Rouaix N, Duhamel A, Sablonniere B, Bonnet AM, Bonnet C, et al. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in parkinson’s disease. PARKINSONISM RELAT D. 2014;20(2):170–5.</ref><ref>Sampaio TF, Dos SE, de Lima G, Dos AR, Da SR, Asano A, Asano N, Crovella S, de Souza P. MAO-B and COMT genetic variations associated with Levodopa treatment response in patients with parkinson’s disease. J CLIN PHARMACOL. 2018;58(7):920–6.</ref> , but AADC activity also varies by sex, disease duration and use of dopaminergic medication. The amount of levodopa that succeeds in being absorbed into the blood stream is therefore not necessarily the amount available at the blood-brain barrier.


4. At the blood-brain barrier, protein competition exists as well. [MB6] Speed and magnitude of levodopa transport over the blood-brain barrier thus depends on the concentration of (dietary) amino acids in the blood.
4. At the blood-brain barrier, protein competition exists as well. <ref>Lees, A. J. The On-Off Phenomenon. ''Journal of Neurology, Neurosurgery & Psychiatry'' '''1989''', ''52'' (Suppl. 29), 29–37. <nowiki>https://doi.org/10.1136/jnnp.52.Suppl.29</nowiki>.</ref> Speed and magnitude of levodopa transport over the blood-brain barrier thus depends on the concentration of (dietary) amino acids in the blood.


5. Once in the brain, enzymes such as AADC and COMT metabolize levodopa and, together with monoamine oxidase B (MAO-B), determine the resultant amount of dopamine available in the synaptic cleft of dopaminergic neurons. Here, as well, there is interindividual variation in the activities of the enzymes.
5. Once in the brain, enzymes such as AADC and COMT metabolize levodopa and, together with monoamine oxidase B (MAO-B), determine the resultant amount of dopamine available in the synaptic cleft of dopaminergic neurons. Here, as well, there is interindividual variation in the activities of the enzymes.




Given these multiple steps of which the magnitude is – to a large extent – poorly predictable, levodopa plasma concentration correlates poorly with dopamine available to neurons in the brain.
Given these multiple steps of which the magnitude is – to a large extent – poorly predictable, levodopa plasma concentration correlates poorly with dopamine available to neurons in the brain.


Furthermore, the above-described steps apply in individuals without other levodopa-bioavailability-altering conditions. There are multiple circumstances [MB7] under which the correlation between intake of levodopa and clinical effect becomes even more unpredictable, e.g. if intestinal absorption is limited (e.g. due to inflammation of the intestinal lining), if levodopa is prematurely metabolized by gut bacteria, or if there is an overactivity of the AADC enzyme.
Furthermore, the above-described steps apply in individuals without other levodopa-bioavailability-altering conditions. There are multiple circumstances <ref>Beckers, M.; Bloem, B. R.; Verbeek, M. M. Mechanisms of Peripheral Levodopa Resistance in Parkinson’s Disease. ''npj Parkinson’s Disease'' '''2022''', ''8'' (1), 56. <nowiki>https://doi.org/10.1038/s41531-022-00321-y</nowiki>.</ref> under which the correlation between intake of levodopa and clinical effect becomes even more unpredictable, e.g. if intestinal absorption is limited (e.g. due to inflammation of the intestinal lining), if levodopa is prematurely metabolized by gut bacteria, or if there is an overactivity of the AADC enzyme.
----[MB1]Ref 10.1016/S1474-4422(15)00007-1
 
[MB2]Ref 10.1002/mds.25708
 
[MB3]Ref: 10.3233/JPD-240036
 
[MB4]Ref doi 10.1007/s00415-010-5728-8
 
[MB5]Refs:
 
·       Devos D, Lejeune S, Cormier-Dequaire F, Tahiri K, Charbonnier-Beaupel F, Rouaix N, Duhamel A, Sablonniere B, Bonnet AM, Bonnet C, et al. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in parkinson’s disease. PARKINSONISM RELAT D. 2014;20(2):170–5.
 
·       Sampaio TF, Dos SE, de Lima G, Dos AR, Da SR, Asano A, Asano N, Crovella S, de Souza P. MAO-B and COMT genetic variations associated with Levodopa treatment response in patients with parkinson’s disease. J CLIN PHARMACOL. 2018;58(7):920–6.
 
[MB6]Ref: 10.1136/jnnp.52.Suppl.29
 
[MB7]Ref 10.1038/s41531-022-00321-y
 


=== Correlation between bioavailable dopamine and control of PD symptoms ===
=== Correlation between bioavailable dopamine and control of PD symptoms ===
As described earlier in the text, not all PD symptoms respond to levodopa to the same extent. In addition to the presence of non-dopaminergic symptoms (which by definition do not respond to levodopa), even symptoms who are normally levodopa-responsive can display variation in their response. Factors inducing these variation include, amongst others, (psychological and physical) stress[MB1]  as well as energy level/fatigue.
As described earlier in the text, not all PD symptoms respond to levodopa to the same extent. In addition to the presence of non-dopaminergic symptoms (which by definition do not respond to levodopa), even symptoms who are normally levodopa-responsive can display variation in their response. Factors inducing these variation include, amongst others, (psychological and physical) stress<ref>Helmich, R. C. G. and the Systems Neurology Group at the Donders Centre for Cognitive Neuroimaging investigate the cerebral mechanisms of movement disorders, especially the pathophysiology of Parkinson’s disease tremor and compensatory network changes, using neuroimaging and neurophysiological methods. Recent works include neuroimaging studies on tremor circuitry, longitudinal brain compensation in Parkinson’s progression, and clinical trials examining propranolol’s effects on tremor.</ref>  as well as energy level/fatigue.


For the reasons outlined in the above paragraphs, peripheral levodopa pharmacokinetics correlate poorly to the actual level of symptom control. A 2013 study [MB2] demonstrated that the presence of motor fluctuations did not correlate to pharmacokinetic data.
For the reasons outlined in the above paragraphs, peripheral levodopa pharmacokinetics correlate poorly to the actual level of symptom control. A 2013 study <ref>Fasano, A.; Bove, F.; Gabrielli, M.; Petracca, M.; Zocco, M. A.; Ragazzoni, E.; Barbaro, F.; Piano, C.; Fortuna, S.; Tortora, A.; Di Giacopo, R.; Campanale, M.; Gigante, G.; Lauritano, E. C.; Navarra, P.; Marconi, S.; Gasbarrini, A.; Bentivoglio, A. R. The Role of Small Intestinal Bacterial Overgrowth in Parkinson’s Disease. ''Movement Disorders'' '''2013''', ''28'' (9), 1241–1249. <nowiki>https://doi.org/10.1002/mds.25522</nowiki></ref> demonstrated that the presence of motor fluctuations did not correlate to pharmacokinetic data.


Thus, peripheral levodopa concentration monitoring would need to be integrated with measurement of clinical symptoms to be useful in clinical practice.
Thus, peripheral levodopa concentration monitoring would need to be integrated with measurement of clinical symptoms to be useful in clinical practice.
[MB1]See e.g. research works by the group of Rick Helmich
[MB2]Ref 10.1002/mds.25522
== State of the Art ==
== State of the Art ==


Revision as of 21:38, 24 December 2025

General information

The theme of SensUs 2026 is Parkinson's disease and levodopa monitoring. Parkinson's disease is a progressive neurodegenerative disorder associated with the loss of dopamine-producing neurons in the substantia nigra region of the brain. This results in a severe dopamine deficit in the basal ganglia, which are critical for initiating and smoothing movement. The predominant motor symptoms advancing from this deficit include tremor, muscle stiffness (rigidity) and slowness of movement (bradykinesia)[1] Generally, the management of motor symptoms relies on the administration of levodopa (L-Dopa), a dopamine precursor that can cross the blood-brain barrier, unlike dopamine itself.[2] [3]Levodopa is absorbed into the bloodstream in the gastrointestinal tract, chiefly in the duodenum and proximal jejunum, and transported via the bloodstream to the brain, where it is decarboxylated into dopamine to restore motor function. Consequently, an adequate concentration of levodopa in the blood serum is a prerequisite for the exertion of the therapeutic effect. A standard therapeutic range for plasma levodopa is typically considered to be between 2 - 7.6 µM following a dose.[4] As the disease progresses, the relationship between dose and clinical response becomes unpredictable, manifesting as unpredictable motor fluctuations and dyskinesias. Therefore, monitoring levodopa levels serves as a crucial tool for optimizing dosing regimens. There is no cure for Parkinson's disease, although medications and non-drug therapies can alleviate the symptoms and improve daily functioning. In advanced cases, patients may undergo surgical treatments such as deep brain stimulation to help control motor symptoms.[5][6]

History and Current Situation 0f Parkinson's Disease

Although tremor-like syndromes appeared in historical accounts, Parkinson’s disease was first clearly defined in 1817, when James Parkinson published An Essay on the Shaking Palsy, describing six cases with trembling at rest, slowness, and a peculiar posture. [7] In the late 19th century, Jean-Martin Charcot refined this clinical picture, distinguishing rigidity and bradykinesia, and popularized the eponym “Parkinson’s disease.” [8] Pathological and biochemical studies in the 20th century uncovered degeneration of the substantia nigra and the presence of Lewy bodies, leading to the understanding of dopamine deficit as a core mechanism. [9] Treatment evolved from early anticholinergic drugs to the introduction of levodopa in the 1960s, and later to surgical and neuromodulation techniques such as deep brain stimulation (DBS). [9]

Parkinson’s disease (PD) is now a rapidly growing global health challenge. In 2021, about 11.77 million people worldwide were estimated to be living with PD, with age-standardized prevalence at ~ 138.6 per 100,000 and incidence at ~ 15.63 per 100,000.[10] Over the past three decades, rates of PD incidence, prevalence, and disability (DALYs) have all increased, particularly in men. [10] Projections suggest that by 2050, the number of people with PD could more than double to ~ 25.2 million, largely driven by aging populations. [11]

On a biological level, PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of α-synuclein aggregates (Lewy bodies). [9] Both genetic factors (e.g. LRRK2, GBA) and environmental exposures (e.g. pesticides) contribute to disease risk. [9] Clinically, PD manifests with motor symptoms (bradykinesia, rigidity, resting tremor) and non-motor features (such as loss of smell, sleep disorder, gastrointestinal issues, autonomic problems, depression), many of which may begin years before motor onset. [9] Diagnosis is clinical, based on a neurological examination and response to dopaminergic therapy, with imaging (such as MRI and DaT-SPECT) mainly used to exclude other causes of the symptoms; research into biomarkers is ongoing and their application is not yet standard. [9] Treatment remains symptomatic: levodopa is the cornerstone, although during the course of the disease levodopa-resistant symptoms develop, and advanced therapies (such as deep brain stimulation, DBS) are an option for selected patients. [9] Major challenges include disease heterogeneity, the lack of reliable biomarkers for early detection or progression, and unequal access to advanced therapies — but wearable and biosensor technologies are promising tools for monitoring and early diagnosis.

Broadly speaking, Parkinson’s disease can be subdivided into three disease stages:

* The early stage, in which response to dopaminergic medication is generally stable throughout the day, without response fluctuations. The person with PD can (under drug treatment) function normally in many respects.

* Mid-stage, in which motor fluctuations (the ON-OFF phenomenon) come to the fore. Even with extensive dosing schedules (levodopa doses up to eight or more times a day), some people may still not reach a stable response, limiting daily functioning. In this phase, advanced therapies such as continuous dopaminergic drug administration via subcutaneous/intestinal pump and/or deep brain stimulation surgery may be considered.

* Late-stage disease. Dopamine-resistant and non-motor symptoms such as postural instability/falling, cognitive deficits/dementia, hallucinations and autonomic failure dominate the clinical picture. The patient’s functioning is determined mostly by these symptoms, which are poorly susceptible to drug treatment.

Role of Levodopa(L-Dopa) in the Treatment of Parkinson's Disease

Levodopa has remained the benchmark treatment for PD since its introduction in 1961. It has a therapeutic reference range of 0.76-1.25 μM in cerebrospinal fluid (CSF) and 2-7.6 μM in blood plasma [4]. It has a short half-life of 30-90 minutes, so it is typically administered in combination with a peripheral decarboxylase inhibitor (PDI), such as carbidopa (exclusively an L- isomer) or benserazide (a racemic mixture), to increase the efficacy of L-Dopa entering into the CNS (central nervous system) by minimizing the peripheral conversion of L-Dopa to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC) [12].

Early in PD, the brain can store and regulate dopamine well, providing stable symptom relief. However, as the disease progresses to later stages, this ability of the brain weakens, resulting in the therapeutic window of levodopa becoming narrower and the development of the ‘ON-OFF phenomenon’[4]which is characterized on one end of the spectrum by hypodopaminergic symptoms (stiffness, slowness, feezing) and on the other end by hyperdopaminergic excessive movement (dyskinesia). This highlights the need for precise L-Dopa dosing. Figure 1 illustrates how the narrowing of the L-Dopa therapeutic window over time leads to levodopa-induced dyskinesia (LID; involuntary, uncontrolled movements) and OFF-time (return of PD symptoms).

(Lack of) correlation between peripheral levodopa concentration and clinical symptoms

Pathophysiological complexity of the disease

Parkinson’s disease is a complex condition. Not only do the symptoms encompass a wide range of motor and non-motor complaints, the underlying pathophysiological mechanisms are also manifold. This limits dopaminergic therapy in important ways:

  • Not all dopaminergic systems in the brain are affected at the same pace[13] , with as a consequence that a certain levodopa dose can result in an eudopaminergic state in the motor circuit but a hyperdopaminergic state in the limbic circuit. The clinical correlate of this is a patient whose motor symptoms may be well-controlled, but cumbersome psychotic symptoms occur as an unintended effect.
  • During the disease course, in addition to the dopaminergic deficit, deficits of other neurotransmitter systems[14] (such as cholinergic, (nor)adrenergic and serotonergic systems) develop in addition to neurotransmitter-independent neurodegeneration. Several debilitating symptoms, such as autonomic and cognitive symptoms and disturbed balance/falling, are therefore levodopa-resistant.
  • Varying extents of postsynaptic dopaminergic degeneration occur. This means that not only is the amount of (pre-synaptic) dopamine limited, but there is also damage to the (postsynaptic) neurons that have to make use of the dopamine. Even an optimal concentration of dopamine in the synaptic cleft may therefore be unable to adequately attenuate hypodopaminergic symptoms.


Correlation between peripheral levodopa concentration and dopamine available to cerebral neurons

A multitude of steps stands between (oral) levodopa intake and concentration of dopamine available to dopaminergic neurons in the brain.

1. After oral ingestion of levodopa, the tablets have to dissolve in the stomach, and then be transported to the small intestine for absorption. Many people with Parkinson’s disease have a lower acidity[15] of the stomach (e.g. due to medication use or Helicobacter pylori infection), and an estimated 70-100% of people with Parkinson’s disease have gastroparesis[16] (delayed stomach emptying). This leads to impaired dissolution of levodopa and delayed transfer of levodopa to the small intestine, respectively.

2. Once levodopa has arrived in the duodenum and proximal jejunum for absorption, it has to be actively transported over the bowel mucosa by saturable LNAA transporters (transporters for Large Neutral Amino Acids). These transporters are both sensitive to pH, working optimally at a pH between 6.2 – 7.4,[17] as well as sensitive to so-named protein competition. That is: after a protein-rich meal, dietary proteins/amino acids compete with levodopa[18] for the transport system, reducing levodopa’s bioavailability. As noted, stomach acidity is often less pronounced in people with Parkinson’s disease, and due to delayed gastric emptying, dietary proteins may be present in the small intestine for extended periods after a meal. This limits predictability of the speed and magnitude with which levodopa is absorbed into the bloodstream.

3. Both in the intestinal lumen as well as in peripheral blood, levodopa is metabolized to dopamine and other metabolites. This is unwanted, as dopamine cannot cross the blood-brain barrier; for pharmacotherapeutic effect, levodopa has to cross the blood-brain barrier in unmetabolized form. While peripheral decarboxylase inhibitors are able to partially inhibit peripheral decarboxylation, there is interindividual variability in the activity of levodopa-metabolizing enzymes such as AADC and catechol-O-aminotransferase (COMT). Part of this variability is genetic[19][20] , but AADC activity also varies by sex, disease duration and use of dopaminergic medication. The amount of levodopa that succeeds in being absorbed into the blood stream is therefore not necessarily the amount available at the blood-brain barrier.

4. At the blood-brain barrier, protein competition exists as well. [21] Speed and magnitude of levodopa transport over the blood-brain barrier thus depends on the concentration of (dietary) amino acids in the blood.

5. Once in the brain, enzymes such as AADC and COMT metabolize levodopa and, together with monoamine oxidase B (MAO-B), determine the resultant amount of dopamine available in the synaptic cleft of dopaminergic neurons. Here, as well, there is interindividual variation in the activities of the enzymes.


Given these multiple steps of which the magnitude is – to a large extent – poorly predictable, levodopa plasma concentration correlates poorly with dopamine available to neurons in the brain.

Furthermore, the above-described steps apply in individuals without other levodopa-bioavailability-altering conditions. There are multiple circumstances [22] under which the correlation between intake of levodopa and clinical effect becomes even more unpredictable, e.g. if intestinal absorption is limited (e.g. due to inflammation of the intestinal lining), if levodopa is prematurely metabolized by gut bacteria, or if there is an overactivity of the AADC enzyme.

Correlation between bioavailable dopamine and control of PD symptoms

As described earlier in the text, not all PD symptoms respond to levodopa to the same extent. In addition to the presence of non-dopaminergic symptoms (which by definition do not respond to levodopa), even symptoms who are normally levodopa-responsive can display variation in their response. Factors inducing these variation include, amongst others, (psychological and physical) stress[23]  as well as energy level/fatigue.

For the reasons outlined in the above paragraphs, peripheral levodopa pharmacokinetics correlate poorly to the actual level of symptom control. A 2013 study [24] demonstrated that the presence of motor fluctuations did not correlate to pharmacokinetic data.

Thus, peripheral levodopa concentration monitoring would need to be integrated with measurement of clinical symptoms to be useful in clinical practice.

State of the Art

Current Methods to Measure L-Dopa

The current gold standards to measure L-Dopa are Liquid-Chromatography-Mass Spectrometry (LC-MS) and High Performance Liquid Chromatography (HPLC). However, these methods are time-consuming, costly, and are performed in centralized laboratories, making them impractical for timely adjustment of L-Dopa does for PD patients. This causes a need for reliable, affordable, quick, and more user-friendly L-Dopa testing.[25]

Matrix

Several matrices are available in which L-Dopa can be measured by a biosensor, namely blood (plasma), sweat, or interstitial fluid (ISF). ISF has been selected as the matrix for SensUs 2026, due to the ease of accessibility compared to blood plasma and the more stable composition compared to sweat [26].

Currently, ISF is used for continuous glucose monitoring. Interstitial skin fluid (ISF) makes up 75% of extracellular fluid and 15-25% of body weight [27]. It surrounds cells and tissues, serving as an interface between blood and cells. It may be a source of biomarkers in addition to blood biomarkers, as research shows that 83% of proteins found in blood serum are also present in ISF, but 50% of proteins in ISF are not found in serum [27].

SensUs 2026 proposes to measure L-Dopa in simulated ISF in the range 3-50 μM, covering therapeutic concentrations as well as concentrations related to the management of levodopa-induced dyskinesia.

Test Stability

In solution, L-Dopa is chemically unstable and naturally degrades over time due to interactions with proteins and oxidative processes, leading to its conversion to dopamine or other byproducts in the L-Dopa metabolic pathway. The degradation rate can be slowed down by [28]:

  • refrigeration or freezing: stable for approximately one week;
  • ascorbate addition: stable for approximately three days.

Levodopa Biosensors

A continuous wearable L-Dopa sensor would help doctors to make informed decisions about personalized patient treatment and how to adjust medication in real-time to reduce Levodopa fluctuations. Continuous sensing would also help researchers better understand the pharmacokinetics of Levodopa across different bodily fluids, namely ISF, blood, and cerebrospinal fluid (CSF). This could improve treatment strategies for late-stage PD patients and also help make a step towards the long-term vision of closed-loop Levodopa therapy for PD wherein continual oral administration would no longer be required, improving the patients’ quality of life.[4]

  1. ↑ AANS. (2024, April 30). Parkinson’s Disease. American Association of Neurological Surgeons. https://www.aans.org/patients/conditions-treatments/parkinsons-disease
  2. ↑ StatPearls. (n.d.). Levodopa. In NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK482140/ — “Unlike dopamine, levodopa can cross the blood-brain barrier (BBB).”
  3. ↑ Chen, Y., et al. (2025). Translation-Neurodegeneration, 14:10. “Unlike dopamine, levodopa crosses the blood–brain barrier …” https://doi.org/10.1186/s40035-025-00467-8
  4. ↑ 4.0 4.1 4.2 4.3 Probst, D.; Batchu, K.; Younce, J. R.; Sode, K. Levodopa: From Biological Significance to Continuous Monitoring. ACS Sensors 2024, 9 (8), 3828–3839.\href{https://doi.org/10.1021/acssensors.4c00602}{https://doi.org/10.1021/acssensors.4c00602}
  5. ↑ Perestelo-Pérez, L., et al. (2019). Efficacy and Safety of Deep Brain Stimulation in the Treatment of Parkinson’s Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Frontiers in Neurology, 10, 857. https://doi.org/10.3389/fneur.2019.00857
  6. ↑ Odekerken, V. J. J., et al. (2015). Deep brain stimulation in Parkinson's disease: meta-analysis of randomized controlled trials. Movement Disorders, 30(10), 1501–1510. https://doi.org/10.1002/mds.26237
  7. ↑ Parkinson, J. (1817). An Essay on the Shaking Palsy. London: Whittingham & Rowland.
  8. ↑ LaFia, D. J. (1967). The Shaking Palsy 1817–1967. JAMA.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Lees, A. J. (2017). The history of Parkinson’s disease: early clinical descriptions and neurological therapies. Brain, 140(3), 843–848. https://doi.org/10.1093/brain/awx035
  10. ↑ 10.0 10.1 GBD 2021 Parkinson’s Disease Collaborators. (2024). Global burden of Parkinson’s disease from 1990 to 2021: a population-based study. Lancet Neurology / GBD Data.
  11. ↑ Xie, Y., et al. (2024). Projections for prevalence of Parkinson’s disease by 2050: modeling study based on Global Burden of Disease 2021. BMJ / PubMed.
  12. ↑ Carvey, P. M. Dopa-Decarboxylase Inhibitors. Encyclopedia of Movement Disorders 2010, 313–316. https://doi.org/10.1016/b978-0-12-374105-9.00318-x
  13. ↑ Rodríguez-Oroz, M. C.; Jahanshahi, M.; Krack, P.; Litvan, I.; Macías, R.; Bezard, E.; Obeso, J. A. Initial Clinical Manifestations of Parkinson’s Disease: Features and Pathophysiological Mechanisms. The Lancet Neurology 2009, 8 (12), 1128–1139. https://doi.org/10.1016/S1474-4422(09)70293-5.
  14. ↑ Devos, D.; Defebvre, L.; Bordet, R. Dopaminergic and Non-Dopaminergic Pharmacological Hypotheses for Gait Disorders in Parkinson’s Disease. Fundamental & Clinical Pharmacology 2010, 24 (4), 407–421. https://doi.org/10.1111/j.1472-8206.2009.00798.x.
  15. ↑ Fasano, A.; Visanji, N. P.; Liu, L. W. C.; Lang, A. E.; Pfeiffer, R. F. Gastrointestinal Dysfunction in Parkinson’s Disease. The Lancet Neurology 2015, 14 (6), 625–639. https://doi.org/10.1016/S1474-4422(15)00007-1.
  16. ↑ Marrinan, S.; Emmanuel, A. V.; Burn, D. J. Delayed Gastric Emptying in Parkinson’s Disease. Movement Disorders 2014, 29 (1), 23–32. https://doi.org/10.1002/mds.25708.
  17. ↑ Pedrosa de Menezes, A. L.; Bloem, B. R.; Beckers, M.; Piat, C.; Benarroch, E. E.; Savica, R. Molecular Variability in Levodopa Absorption and Clinical Implications for the Management of Parkinson’s Disease. Journal of Parkinson’s Disease 2024, 14 (7), 1353–1368. https://doi.org/10.3233/JPD-240036
  18. ↑ Contin, M.; Martinelli, P. Pharmacokinetics of Levodopa. Journal of Neurology 2010, 257 (Suppl. 2), S253–S261. https://doi.org/10.1007/s00415-010-5728-8.
  19. ↑ Devos D, Lejeune S, Cormier-Dequaire F, Tahiri K, Charbonnier-Beaupel F, Rouaix N, Duhamel A, Sablonniere B, Bonnet AM, Bonnet C, et al. Dopa-decarboxylase gene polymorphisms affect the motor response to L-dopa in parkinson’s disease. PARKINSONISM RELAT D. 2014;20(2):170–5.
  20. ↑ Sampaio TF, Dos SE, de Lima G, Dos AR, Da SR, Asano A, Asano N, Crovella S, de Souza P. MAO-B and COMT genetic variations associated with Levodopa treatment response in patients with parkinson’s disease. J CLIN PHARMACOL. 2018;58(7):920–6.
  21. ↑ Lees, A. J. The On-Off Phenomenon. Journal of Neurology, Neurosurgery & Psychiatry 1989, 52 (Suppl. 29), 29–37. https://doi.org/10.1136/jnnp.52.Suppl.29.
  22. ↑ Beckers, M.; Bloem, B. R.; Verbeek, M. M. Mechanisms of Peripheral Levodopa Resistance in Parkinson’s Disease. npj Parkinson’s Disease 2022, 8 (1), 56. https://doi.org/10.1038/s41531-022-00321-y.
  23. ↑ Helmich, R. C. G. and the Systems Neurology Group at the Donders Centre for Cognitive Neuroimaging investigate the cerebral mechanisms of movement disorders, especially the pathophysiology of Parkinson’s disease tremor and compensatory network changes, using neuroimaging and neurophysiological methods. Recent works include neuroimaging studies on tremor circuitry, longitudinal brain compensation in Parkinson’s progression, and clinical trials examining propranolol’s effects on tremor.
  24. ↑ Fasano, A.; Bove, F.; Gabrielli, M.; Petracca, M.; Zocco, M. A.; Ragazzoni, E.; Barbaro, F.; Piano, C.; Fortuna, S.; Tortora, A.; Di Giacopo, R.; Campanale, M.; Gigante, G.; Lauritano, E. C.; Navarra, P.; Marconi, S.; Gasbarrini, A.; Bentivoglio, A. R. The Role of Small Intestinal Bacterial Overgrowth in Parkinson’s Disease. Movement Disorders 2013, 28 (9), 1241–1249. https://doi.org/10.1002/mds.25522
  25. ↑ Kuldeep Mahato; Moon, J.-M.; Chochanon Moonla; Longardner, K.; Ghodsi, H.; Litvan, I.; Wang, J. Biosensor Strip for Rapid On‐Site Assessment of Levodopa Pharmacokinetics along with Motor Performance in Parkinson’s Disease. Angewandte Chemie International Edition 2024. https://doi.org/10.1002/anie.202403583
  26. ↑ Peterson, K. L.; Shukla, R. P.; Daniele, M. A. Percutaneous Wearable Biosensors: A Brief History and Systems Perspective. Advanced Sensor Research 2024. https://doi.org/10.1002/adsr.202400068
  27. ↑ 27.0 27.1 Samant, P. P., Niedzwiecki, M. M., Raviele, N., Tran, V., Mena-Lapaix, J., Walker, D. I., Felner, E. I., Jones, D. P., Miller, G. W., Prausnitz, M. R. (2020). Sampling interstitial fluid from human skin using a microneedle patch. Science Translational Medicine, 12(571). https://doi.org/10.1126/scitranslmed.aaw0285
  28. ↑ Pappert, E. J.; Buhrfiend, C.; Lipton, J. W.; Carvey, P. M.; Stebbins, G. T.; Goetz, C. G. Levodopa Stability in Solution: Time Course, Environmental Effects, and Practical Recommendations for Clinical Use. Movement Disorders 1996, 11 (1), 24–26. https://doi.org/10.1002/mds.870110106
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