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Optimizing Treatment of Parkinson’s Disease

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Methodology, Drug and Device Discovery".

Deadline for manuscript submissions: closed (5 November 2021) | Viewed by 30931

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Special Issue Editors

Dr. Dag Nyholm

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Guest Editor

Department of Neuroscience, Neurology at Uppsala University, 75124 Uppsala, Sweden
Interests: movement disorders; neuropharmacology; pharmacokinetics; non-oral routes of administration; objective movement analysis

Dr. Filip Bergquist

E-Mail Website
Guest Editor

Department of Pharmacology at Institute of Neuroscience and Physiology, University of Gothenburg, 41296 Gothenburg, Sweden
Interests: movement disorders; pharmacology; objective movement analysis; experimental neuroscience

Special Issue Information

Dear Colleagues,

Effective treatments for symptomatic control of Parkinson’s disease (PD) have developed during the last two decades. These include combinations of oral drugs as well as transdermal delivery and devices for subcutaneous and intestinal infusions that have been developed in parallel with deep-brain stimulation (DBS) for PD and other movement disorders.

The scope of this Special Issue “Optimizing Treatment of Parkinson’s Disease” is the latest approaches for meeting the need of continuous individualization of the therapies.

Current research is expanding on optimization of treatment outcome in terms of efficacy, safety, and quality of life, and the rapid development of wearables and home-based monitoring technologies is encouraging.

We invite researchers in the field to submit original research and review articles including (but not limited to) studies on the fine-tuning of treatments in PD and other movement disorders using objective movement analysis, DBS, personalized and precision medicine, pharmacogenomics, bioinformatics, integrative computational approaches and clinical biomarker discovery.

Dr. Dag Nyholm
Dr. Filip Bergquist
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Parkinson’s disease
Device-aided treatments
Therapy optimization
Objective movement analysis

Published Papers (11 papers)

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Editorial

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3 pages, 178 KiB

Open AccessEditorial

Optimizing Treatment of Parkinson’s Disease

by Dag Nyholm and Filip Bergquist

J. Pers. Med. 2022, 12(2), 245; https://doi.org/10.3390/jpm12020245 - 9 Feb 2022

Viewed by 1659

Abstract

The holy grail of therapy in Parkinson’s disease (PD) is treatment that would halt the disease process or restore the degenerated neuronal circuits [...] Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

Research

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15 pages, 4577 KiB

Open AccessArticle

Analyzing the Effects of Parameters for Tremor Modulation via Phase-Locked Electrical Stimulation on a Peripheral Nerve

by Jeonghee Kim, Thomas Wichmann, Omer T. Inan and Stephen P. DeWeerth

J. Pers. Med. 2022, 12(1), 76; https://doi.org/10.3390/jpm12010076 - 8 Jan 2022

Cited by 2 | Viewed by 2590

Abstract

(1) Background: Non-invasive neuromodulation is a promising alternative to medication or deep-brain stimulation treatment for Parkinson’s Disease or essential tremor. In previous work, we developed and tested a wearable system that modulates tremor via the non-invasive, electrical stimulation of peripheral nerves. In this article, we examine the proper range and the effects of various stimulation parameters for phase-locked stimulation. (2) Methods: We recruited nine participants with essential tremor. The subjects performed a bean-transfer task that mimics an eating activity to elicit kinetic tremor while using the wearable stimulation system. We examined the effects of stimulation with a fixed duty cycle, at different stimulation amplitudes and frequencies. The epochs of stimulation were locked to one of four phase positions of ongoing tremor, as measured with an accelerometer. We analyzed stimulation-evoked changes of the frequency and amplitude of tremor. (3) Results: We found that the higher tremor amplitude group experienced a higher rate of tremor power reduction (up to 65%) with a higher amplitude of stimulation when the stimulation was applied at the ±peak of tremor phase. (4) Conclusions: The stimulation parameter can be adjusted to optimize tremor reduction, and this study lays the foundation for future large-scale parameter optimization experiments for personalized peripheral nerve stimulation. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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11 pages, 717 KiB

Open AccessArticle

Predictive Value of Ambulatory Objective Movement Measurement for Outcomes of Levodopa/Carbidopa Intestinal Gel Infusion

by Gökçe Kilinçalp, Anne-Christine Sjöström, Barbro Eriksson, Björn Holmberg, Radu Constantinescu and Filip Bergquist

J. Pers. Med. 2022, 12(1), 27; https://doi.org/10.3390/jpm12010027 - 2 Jan 2022

Cited by 4 | Viewed by 1381

Abstract

Patients with Parkinson’s disease that may benefit from device-assisted therapy can be identified with guidelines like Navigate PD. The decision to offer advanced treatment and the choice of treatment modality are, however, not straightforward, and some patients respond less favorably to a chosen therapy. Measurements with the Parkinson Kinetigraph (PKG) can detect motor fluctuations and could therefore predict patients that respond better or worse to intestinal levodopa/carbidopa gel infusion (LCIG). In a retrospective analysis of 45 patients that had been selected to start LCIG between 2014 and 2020, the effects of baseline PKG and clinical characteristic on the outcome were determined with ordinal regression. Although all patients had been found to have handicapping medication-related symptom fluctuations, patients without clear objective off fluctuations in the baseline PKG had low odds ratio for success. Lower odds for success were also found with increasing age, whereas gender, medication intensity and baseline PKG summary scores (median bradykinesia and dyskinesia scores, fluctuation dyskinesia score and percent time with tremor) had no significant effect. Absence of easily identified off-periods in the PKG has a negative prognostic value for the effect of LCIG and could prompt noninvasive infusion evaluation before surgery. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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8 pages, 1032 KiB

Open AccessArticle

Personalized Medicine Approach in Treating Parkinson’s Disease, Using Oral Administration of Levodopa/Carbidopa Microtablets in Clinical Practice

by Helga María Grétarsdóttir, Erik Widman, Anders Johansson and Dag Nyholm

J. Pers. Med. 2021, 11(8), 720; https://doi.org/10.3390/jpm11080720 - 26 Jul 2021

Cited by 7 | Viewed by 2280

Abstract

Background: The most effective symptomatic treatment in Parkinson’s disease (PD) is levodopa in standard doses. However, as the disease progresses, there may be a need for a more personalized approach and fine tuning, in accordance with the patients’ needs. This study aims to evaluate the individual experience of levodopa/carbidopa 5/1.25 mg microtablets (LC-5) in clinical practice with respect to efficacy, tolerability, and usability. The method used was as follows: patients answered a questionnaire concerning the effect and usability of LC-5, and their medical records were reviewed. Regarding results, thirty-five survey responses were obtained, and 29 patients’ medical records were reviewed. The LC-5 dose dispenser usability was generally rated positively and facilitated medication adherence. The majority (85%) of patients reported symptom improvement while using LC-5, compared with previous standard treatments. These results suggest that LC-5 therapy is generally well-tolerated, with favorable patient-reported efficacy and user friendliness, as well as the possibility for an individualized, fine-tuned PD treatment. Further studies with a prospective design and larger study population are needed to confirm the results. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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10 pages, 831 KiB

Open AccessArticle

Continuous Subcutaneous Apomorphine Infusion in Parkinson’s Disease: A Single-Center, Long-Term Follow-Up Study of the Causes for Discontinuation

by Tove Henriksen and Harry Staines

J. Pers. Med. 2021, 11(6), 525; https://doi.org/10.3390/jpm11060525 - 8 Jun 2021

Cited by 7 | Viewed by 2499

Abstract

(1) Background: Subcutaneous apomorphine infusion (SCAI) is one of the three main treatment options for motor fluctuations in advanced Parkinson’s disease (PD). The adherence to SCAI is generally considered to be low due to adverse events and because it is perceived as a treatment option to be used for a limited period only. We evaluated the reasons for discontinuation of SCAI in relation to when patients stopped treatment. (2) Methods: We reviewed the medical records of PD patients treated with SCAI at a single center, capturing patient demographics and the reasons for cessation of SCAI. (3) Results: 101 patients were included in the analysis, with a median time on treatment of 6.34 years. The main reasons for stopping SCAI were adverse events, death, and dissatisfaction with treatment. In the first 6 years of treatment, the predominant side effects leading to discontinuation were somnolence and hallucinations. (4) Conclusions: We suggest that SCAI can be an effective long-term treatment option for advanced PD, but it requires careful patient selection, a high level of communication with the patient and carer, and rigorous monitoring of the effects of treatment and for any adverse events so they can be promptly managed. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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9 pages, 225 KiB

Open AccessArticle

Does Information from the Parkinson KinetiGraph™ (PKG) Influence the Neurologist’s Treatment Decisions?—An Observational Study in Routine Clinical Care of People with Parkinson’s Disease

by Mathias Sundgren, Mattias Andréasson, Per Svenningsson, Rose-Marie Noori and Anders Johansson

J. Pers. Med. 2021, 11(6), 519; https://doi.org/10.3390/jpm11060519 - 5 Jun 2021

Cited by 11 | Viewed by 2143

Abstract

Management of Parkinson’s disease traditionally relies solely on clinical assessment. The PKG objectively measures affected persons’ movements in daily life. The present study evaluated how often PKG data changed treatment decisions in routine clinical care and to what extent the clinical assessment and the PKG interpretation differed. PKG recordings were performed before routine visits. The neurologist first made a clinical assessment without reviewing the PKG. Signs and symptoms were recorded, and a treatment plan was documented. Afterward, the PKG was evaluated. Then, the neurologist decided whether to change the initial treatment plan or not. PKG review resulted in a change in the initial treatment plan in 21 of 66 participants (31.8%). The clinical assessment and the PKG review differed frequently, mainly regarding individual overall presence of motor problems (67%), profile of bradykinesia/wearing off (79%), dyskinesia (35%) and sleep (55%). PKG improved the dialogue with the participant in 88% of cases. PKG and clinical variables were stable when they were repeated after 3–6 months. In conclusion, PKG information changes treatment decisions in nearly a third of people with Parkinson’s disease in routine care. Standard clinical assessment and PKG evaluation are often non-identical. Objective measurements in people living with Parkinson’s disease can add therapeutically relevant information. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

10 pages, 1340 KiB

Open AccessArticle

Initial Experience of the Levodopa–Entacapone–Carbidopa Intestinal Gel in Clinical Practice

by Mezin Öthman, Erik Widman, Ingela Nygren and Dag Nyholm

J. Pers. Med. 2021, 11(4), 254; https://doi.org/10.3390/jpm11040254 - 31 Mar 2021

Cited by 35 | Viewed by 4363

Abstract

Patients in fluctuating stages of Parkinson’s disease (PD) require device-aided treatments. Continuous infusion of levodopa–carbidopa intestinal gel (LCIG) is a well-proven option in clinical practice. We now report the first clinical experience of levodopa–entacapone–carbidopa intestinal gel (LECIG) therapy. An observational study of the first patients to start LECIG in our clinic was performed. Twenty-four patients (11 females, 13 males) were included. The median age was 71.5 years, and the median duration since PD diagnosis was 15.5 years. The median treatment duration was 305 days. Median doses were: 6.0 mL as morning dose, 2.5 mL/h as infusion rate, and 1.0 mL as extra dose. Half of the patients were switched directly from LCIG. These patients express improvements in the size and weight of the pump. Furthermore, most of them considered the new pump to be improved regarding user-friendliness. Six patients discontinued LECIG, three due to diarrhea, one due to hallucinations and two deceased (one cardiac arrest and one COVID-19). LECIG has shown to be possible to use in patients with PD, efficacy and safety as expected. Patients are generally happy with the size and usability of the pump, but some technical improvements of the software are warranted, as well as larger, prospective studies. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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17 pages, 42585 KiB

Open AccessArticle

Amorphous Ropinirole-Loaded Mucoadhesive Buccal Film: A Potential Patient-Friendly Tool to Improve Drug Pharmacokinetic Profile and Effectiveness

by Giulia Di Prima, Giuseppina Campisi and Viviana De Caro

J. Pers. Med. 2020, 10(4), 242; https://doi.org/10.3390/jpm10040242 - 25 Nov 2020

Cited by 14 | Viewed by 2158

Abstract

Nowadays the therapeutic strategies to manage Parkinson’s Disease are merely symptomatic and consist of administering L-DOPA and/or dopamine receptor agonists. Among these, Ropinirole (ROP) is a widely orally-administered molecule, although it is extensively susceptible to hepatic metabolism. Since literature reports the buccal mucosa as a potentially useful route to ROP administration, the development of novel, effective, and comfortable oromucosal formulations should prove desirable in order to both enhance the therapeutic efficacy of the drug and allow a personalized therapeutic strategy able to meet the patient’s needs. The results of the proposed ROP film as a new dosage form show that it is flexible; uniform; and characterized by suitable surface pH; good mucoadhesiveness; low swelling degree; and fast, complete drug release. Moreover, after ex vivo evaluation on a film having an area of 0.282 cm² and dose of 2.29 mg, the results of drug flux through the buccal mucosa are closely comparable to the amount of ROP that reaches the bloodstream at the steady-state condition after ROP-PR 4 mg oral administration, calculated according to the literature (0.237 mg/cm²·h⁻¹ vs. 0.243 mg/h, respectively). Moreover, drug flux and ROP dose could be accurately modulated time-by-time depending on the patient’s need, by varying the administered disk area. In addition, the proposed ROP film displays no lag time, producing an immediate drug input in the bloodstream, which could result in a prompt therapeutic response. These findings make ROP film a potentially comfortable and patient-friendly formulation, and a promising candidate for further clinical trials. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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Review

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20 pages, 1680 KiB

Open AccessReview

Gastrointestinal Dysfunction in Parkinson’s Disease: Current and Potential Therapeutics

by Myat Noe Han, David I. Finkelstein, Rachel M. McQuade and Shanti Diwakarla

J. Pers. Med. 2022, 12(2), 144; https://doi.org/10.3390/jpm12020144 - 21 Jan 2022

Cited by 18 | Viewed by 5707

Abstract

Abnormalities in the gastrointestinal (GI) tract of Parkinson’s disease (PD) sufferers were first reported over 200 years ago; however, the extent and role of GI dysfunction in PD disease progression is still unknown. GI dysfunctions, including dysphagia, gastroparesis, and constipation, are amongst the most prevalent non-motor symptoms in PD. These symptoms not only impact patient quality of life, but also complicate disease management. Conventional treatment pathways for GI dysfunctions (i.e., constipation), such as increasing fibre and fluid intake, and the use of over-the-counter laxatives, are generally ineffective in PD patients, and approved compounds such as guanylate cyclase C agonists and selective 5-hyroxytryptamine 4 receptor agonists have demonstrated limited efficacy. Thus, identification of potential targets for novel therapies to alleviate PD-induced GI dysfunctions are essential to improve clinical outcomes and quality of life in people with PD. Unlike the central nervous system (CNS), where PD pathology and the mechanisms involved in CNS damage are relatively well characterised, the effect of PD at the cellular and tissue level in the enteric nervous system (ENS) remains unclear, making it difficult to alleviate or reverse GI symptoms. However, the resurgence of interest in understanding how the GI tract is involved in various disease states, such as PD, has resulted in the identification of novel therapeutic avenues. This review focuses on common PD-related GI symptoms, and summarizes the current treatments available and their limitations. We propose that by targeting the intestinal barrier, ENS, and/or the gut microbiome, may prove successful in alleviating PD-related GI symptoms, and discuss emerging therapies and potential drugs that could be repurposed to target these areas. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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9 pages, 771 KiB

Open AccessReview

Effect of Foot Orthoses and Shoes in Parkinson’s Disease Patients: A PRISMA Systematic Review

by María Reina-Bueno, César Calvo-Lobo, Daniel López-López, Patricia Palomo-López, Ricardo Becerro-de-Bengoa-Vallejo, Marta Elena Losa-Iglesias, Carlos Romero-Morales and Emmanuel Navarro-Flores

J. Pers. Med. 2021, 11(11), 1136; https://doi.org/10.3390/jpm11111136 - 2 Nov 2021

Cited by 8 | Viewed by 2479

Abstract

Reduced plantar foot sensation, postural instability, and gait difficulties are characteristic of Parkinson´s disease patients. A systematic review was carried out to determine the effect of the different types of insoles and shoes in these patients. Several databases were used to search for relevant articles reporting Parkinson´s disease patients undergoing treatment with any type of insole and footwear. All titles and abstracts were reviewed independently by two reviewers and the available data were extracted. The study eligibility criteria were any type of experimental study that included Parkinson’s disease patients treated with any type of insole or footwear. Eight studies were selected. Interventions used were textured insoles, footwear modifications, and habitual footwear. Three different outcomes were evaluated in each study: gait parameters, balance, and plantar sensation. According to the data available from this systematic review, the most important conclusion is that more controlled studies are needed in this research field. There are indications to suggest that textured insoles have positive effects on gait parameters, balance, and plantar sensation in Parkinson’s disease patients. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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14 pages, 586 KiB

Open AccessReview

Combined and Sequential Treatment with Deep Brain Stimulation and Continuous Intrajejunal Levodopa Infusion for Parkinson’s Disease

by Daniël van Poppelen, Annelie N.M. Tromp, Rob M.A. de Bie and Joke M. Dijk

J. Pers. Med. 2021, 11(6), 547; https://doi.org/10.3390/jpm11060547 - 12 Jun 2021

Cited by 6 | Viewed by 2002

Abstract

(1) Background: Deep brain stimulation (DBS) and continuous intrajejunal levodopa infusion (CLI) are efficacious treatments of medication related motor response fluctuations in advanced Parkinson’s disease (PD). Literature regarding the use of both advanced treatments within one patient is scarce. (2) Methods: We present a retrospective single center case series and a review of the literature. Patients with PD who were treated with both DBS and CLI in our tertiary referral center between 2005 and 2020 were identified and medical records were assessed. Additionally, literature on patients treated with both therapies was systematically searched for in Medline and Embase. (3) Results: Nineteen patients were included. Medication related motor response fluctuations were a major indication for the second therapy in all but one. Of nine patients initially treated with DBS, five reported improvement with CLI. Seven of ten patients initially treated with CLI experienced benefits from DBS. The systematic literature search resulted in fifteen previous publications comprising 66 patients. Of the 59 patients, for whom the effect of the second treatment was known, 57 improved. (4) Conclusions: PD patients, who have persisting medication related motor response fluctuations, despite DBS or CLI treatment, may benefit from an additional or alternative treatment with either CLI or DBS. Full article

(This article belongs to the Special Issue Optimizing Treatment of Parkinson’s Disease)

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