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Closing the loop for patients with Parkinson disease: where are we?

Nature Reviews Neurology volume 18, pages 497–507 (2022)Cite this article

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Abstract

Although levodopa remains the most efficacious symptomatic therapy for Parkinson disease (PD), management of levodopa treatment during the advanced stages of the disease is extremely challenging. This difficulty is a result of levodopa’s short half-life, a progressive narrowing of the therapeutic window, and major inter-patient and intra-patient variations in the dose–response relationship. Therefore, a suitable alternative to repeated oral administration of levodopa is being sought. Recent research efforts have focused on the development of novel levodopa delivery strategies and wearable physical sensors that track symptoms and disease progression. However, the need for methods to monitor the levels of levodopa present in the body in real time has been overlooked. Advances in chemical sensor technology mean that the development of wearable and mobile biosensors for continuous or frequent levodopa measurements is now possible. Such levodopa monitoring could help to deliver personalized and timely medication dosing to alleviate treatment-related fluctuations in the symptoms of PD. Therefore, with the aim of optimizing therapeutic management of PD and improving the quality of life of patients, we share our vision of a future closed-loop autonomous wearable ‘sense-and-act’ system. This system consists of a network of physical and chemical sensors coupled with a levodopa delivery device and is guided by effective big data fusion algorithms and machine learning methods.

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Fig. 1: Oral administration of levodopa and the associated symptom fluctuations in Parkinson disease.
Fig. 2: Vision of a future closed-loop autonomous system for the management of Parkinson disease.

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Acknowledgements

The authors’ work is supported by the NIH National Institute of Neurological Disorders and Stroke (grant number R21 NS114764-01A1).

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Author notes

  1. These authors contributed equally: Hazhir Teymourian, Farshad Tehrani and Katherine Longardner.

Authors and Affiliations

  1. Department of Nanoengineering, University of California San Diego, La Jolla, CA, USA

    Hazhir Teymourian, Farshad Tehrani, Kuldeep Mahato, Tatiana Podhajny, Jong-Min Moon, Yugender Goud Kotagiri, Juliane R. Sempionatto & Joseph Wang

  2. Department of Neurosciences, University of California San Diego, La Jolla, CA, USA

    Katherine Longardner & Irene Litvan

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Contributions

H.T., F.T. and K.L. along with J.W. and I.L. all contributed to researching data for the article, discussing the content and writing the article, as well as editing before submission. K.M. contributed to researching data for the article, discussing the content and writing the article. T.P., J.M., Y.G.K. and J.S. contributed to researching data for the article and discussing the content.

Corresponding authors

Correspondence to Irene Litvan or Joseph Wang.

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Competing interests

J.W.’s research is supported by the National Institutes of Health (NIH) grant 1R21NS114764-01A1. I.L.’s research is supported by the NIH grants 2R01AG038791-06A, U01NS100610, U01NS80818, R25NS098999, U19 AG063911-1 and 1R21NS114764-01A1, the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Abbvie, Biogen, Biohaven Pharmaceuticals, Brain Neurotherapy Bio, Centogene, EIP Pharma, Novartis, Roche, United Biopharma and UCB. She is a Scientific adviser for Amydis and The Rossy Center for Progressive Supranuclear Palsy at the University of Toronto. K.L.’s research is partially supported by NIH grant 1R21NS114764-01A1. The other authors declare no competing interests.

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Related links

HeartGuide: https://omronhealthcare.com/products/heartguide-wearable-blood-pressure-monitor-bp8000m/

Kinesia 360: http://glneurotech.com/kinesia/products/kinesia-360/

MoveMonitor: https://www.mcroberts.nl/products/movemonitor/

Personal Kinetigraph: https://pkgcare.com/

SleepImage: https://sleepimage.com/

Glossary

Accelerometers

Electronic tools that measure linear acceleration along one or several axes.

Amperometric transduction

The electrochemical recording of current signals; a constant potential is maintained between the electrodes, with the resulting current related to the concentration of a target biomarker.

Bradykinesia

Slowness in the execution of movement; also implies hypokinesia (low amplitude) of the movement.

Chemical sensors

Devices capable of converting a chemical quantity into a measurable signal.

Diffusion mechanism

The underlying mechanism governing the diffusion of biomolecules from blood capillaries to other bodily fluids such as interstitial fluid or sweat.

Disposable electrode strip

An electrode pattern, usually screen-printed on semi-rigid plastic material, for one-time measurements of a chemical quantity.

Dyskinesias

Involuntary, erratic, rocking, twisting or writhing movements reflecting high levodopa levels.

Electrochemical devices

Devices that quantify the concentration of target analytes (for example, drugs, biomarkers or metabolites) by converting electrode–analyte interactions into measurable electrical signals (that is, current or voltage).

Freezing of gait

Brief episodes during which the patient is unable to generate active stepping movements.

Gyroscopes

Devices that measure angular rotational velocity, also known as angular velocity sensors.

Holter device

A monitoring device consisting of signal recording hardware and data analysis software; this technology is most commonly used for monitoring heart rhythm and rate.

Internal consistency testing

Assessing the correlation between multiple items in a single test to provide a measure of the reliability of the test overall.

Magnetometers

Devices that measure orientation by sensing the direction of the earth’s magnetic field; ideal for measuring falls and changes in position (seated versus standing).

Microneedle sensor patches

An epidermal device with micro-dimensional needle-shaped projections that attach painlessly to the skin for minimally invasive detection of biomarkers.

‘Off’ states

When medication is no longer working well and parkinsonian symptoms re-emerge.

‘On’ states

When a patient experiences a good response to medication and parkinsonian symptoms (for example, tremor, stiffness, slowness) are well controlled.

Test–retest reliability

A measure of reliability, where the given test is applied twice over a period of time to the same group of individuals.

The Internet of things

A network of physical objects that can connect and exchange data over the internet through their embedded sensors, software and other technologies.

Voltammetric

The electrochemical recording of current signals by varying the applied potential between the electrodes.

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Teymourian, H., Tehrani, F., Longardner, K. et al. Closing the loop for patients with Parkinson disease: where are we?. Nat Rev Neurol 18, 497–507 (2022). https://doi.org/10.1038/s41582-022-00674-1

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