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Brain Sciences
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New Approaches in the Exploration of Parkinson’s Disease
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New Approaches in the Exploration of Parkinson’s Disease

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neurodegenerative Diseases".

Deadline for manuscript submissions: 10 September 2025 | Viewed by 10017

Special Issue Editors

Dr. Carla Masala

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Guest Editor
Department of Biomedical Sciences, Section of Physiology, University of Cagliari, 09100 Cagliari, Italy
Interests: olfactory function; gustatory function; neurodegenerative diseases; cognitive function; COVID-19; nutrition
Special Issues, Collections and Topics in MDPI journals
Dr. Paolo Solla

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Guest Editor
Department of Neurology, University of Sassari, Viale S. Pietro 10, 07100 Sassari, Italy
Interests: neurological disorders; Parkinson’s disease; Parkinsonism and related disorders
Special Issues, Collections and Topics in MDPI journals
Dr. Francesco Loy

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Guest Editor
Department of Biomedical Sciences, University of Cagliari, SP 8 Cittadella Universitaria, 09042 Monserrato, Italy
Interests: electron microscopy; scanning electron microscopy; neuroanatomy
Special Issues, Collections and Topics in MDPI journals
Dr. Tommaso Ercoli

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Guest Editor
Department of Neurology, University of Sassari, Viale S. Pietro 10, 07100 Sassari, Italy
Interests: movement disorders; neurology; Parkinsonism and related disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Parkinson’s disease (PD) is a chronic, complex, and progressive neurodegenerative disease defined by the loss of dopaminergic neurons in the substantia nigra pars compacta, situated in the midbrain and associated with Lewy bodies, which are cytoplasmic inclusions of alpha-synuclein aggregates. Clinical diagnosis of PD is based primarily on motor symptoms, such as a slowly progressive asymmetric resting tremor, rigidity, and bradykinesia. Although non-motor symptoms, which include olfactory deficits, constipation, autonomic dysfunction, depression, and REM sleep behavior disorder, usually precede the presence of motor deficits.

Different factors may influence PD risk such as mitochondrial dysfunction, impaired autophagy, oxidative stress, protein aggregation, neuroinflammation, environmental and genetic status.

The aim of this Special Issue is to better characterize PD, covering aspects related to the motor and non-motor symptoms that negatively impact health-related quality of life. With this purpose in mind, we invite colleagues to share their recent research on this topic; original research articles, review articles, short communications, and case reports are all welcome.

Dr. Carla Masala
Dr. Paolo Solla
Dr. Francesco Loy
Dr. Tommaso Ercoli
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. Brain Sciences 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 2200 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
  • neurodegenerative disorders
  • nonmotor symptoms
  • quality of life
  • cognition
  • olfactory deficits

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Published Papers (7 papers)

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Research

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15 pages, 1107 KiB  
Article
Performance of a Two-Week Rehabilitation Improves Motor Function in Inpatients with Progressive Supranuclear Palsy: A Pre–Post Study
by Naomi Matsuda, Yasuyuki Takamatsu, Makoto Sawada and Ikuko Aiba
Brain Sci. 2025, 15(1), 88; https://doi.org/10.3390/brainsci15010088 - 17 Jan 2025
Viewed by 451
Abstract
Background: Progressive supranuclear palsy (PSP) is characterized by early postural instability and gait dysfunction, with frequent falls. Rehabilitation is an important therapeutic approach for motor dysfunction in patients with PSP. However, no conclusions have yet been drawn regarding the beneficial effects of [...] Read more.
Background: Progressive supranuclear palsy (PSP) is characterized by early postural instability and gait dysfunction, with frequent falls. Rehabilitation is an important therapeutic approach for motor dysfunction in patients with PSP. However, no conclusions have yet been drawn regarding the beneficial effects of rehabilitation in PSP, including the optimal duration of rehabilitation and differences in treatment effects among PSP subtypes. Herein, we investigated the effects of short-term rehabilitation and separately analyzed the effects on patients with PSP-Richardson’s syndrome (RS) and PSP-progressive gait freezing (PGF). Methods: The participants underwent several therapeutic exercise programs individualized for each participant, performed over 2 weeks. Analysis was performed on 25 patients with PSP-RS and eight with PSP-PGF. Results: Short-term rehabilitation improved the Berg Balance Scale score in both the PSP-RS and PSP-PGF groups, step length on the symptom-dominant side in PSP-RS, the coefficient of variation of step length on the symptom-dominant side, and the stance phase of the Symmetry Index in PSP-PGF. Conclusions: Overall, this 2-week short-term rehabilitation intervention was shown to have beneficial effects on balance in patients with PSP-RS and PSP-PGF. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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14 pages, 969 KiB  
Article
Driving Abilities and Wearing-Off in Parkinson’s Disease: A Driving Simulation Study
by Massimo Marano, Matteo Esposito, Gabriele Sergi, Francesca Proietti, Adriano Bonura, Stefano Toro, Alessandro Magliozzi, Gaia Anzini and Vincenzo Di Lazzaro
Brain Sci. 2024, 14(11), 1072; https://doi.org/10.3390/brainsci14111072 - 27 Oct 2024
Viewed by 1068
Abstract
Background/Objectives: Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson’s disease (DwP) have impaired driving ability, but little is known about the impact of “wearing-off” and therapies in addition to L-DOPA on [...] Read more.
Background/Objectives: Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson’s disease (DwP) have impaired driving ability, but little is known about the impact of “wearing-off” and therapies in addition to L-DOPA on driving capacities. This study aimed to (i) compare driving performance between DwP during different motor states and healthy controls and (ii) assess the impact of add-on therapies on driving abilities. Methods: DwP (n = 26) were enrolled as individuals experiencing wearing-off symptoms and treated (within 6 months before the enrollment) with add-on therapies to L-DOPA, including MAO inhibitors for DwP-A (n = 12) or opicapone for DwP-B (n = 14). Age- and sex-matched controls (CON, n = 12) were also enrolled. DwP received two driving assessments in a driving simulator during their “best-on” time and during their wearing-off time on different days. An anamnestic driving questionnaire was collected with the assistance of partners. A Virtual Driving Rating Scale (VDRS) was calculated, as well as learning curves (LCs) for driving items calculated in minutes. Results: DwP reported worse driving performance than CON at the driving questionnaire. In line with this, DwP showed worse VDRS (p < 0.01) and LC (p = 0.021) than CON. Lower VDRS was associated with wearing-off (p < 0.01), but DwP-B had better driving performance while in their “best-on” time (p = 0.037) and more items improving with LCs (7 vs. 3) than DwP-A. Conclusions: DwP demonstrated impaired driving compared to controls. Wearing-off symptoms can also affect driving ability, but therapies (opicapone more so than MAO inhibitors) may play a role in preserving specific driving skills, possibly through maintaining learning abilities. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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10 pages, 3201 KiB  
Article
Acute Levodopa Challenge in Atypical Parkinsonism: Comprehensive Analysis of Individual Motor Responses
by Lan Ye, Sam Sadeghi Sani, Linda Veith Sanches, Lea Farina Magdalena Krey, Florian Wegner, Matthias Höllerhage, Christoph Schrader, Günter Höglinger and Martin Klietz
Brain Sci. 2024, 14(10), 991; https://doi.org/10.3390/brainsci14100991 - 29 Sep 2024
Viewed by 1079
Abstract
The acute levodopa challenge is widely used to distinguish Parkinson’s disease (PD) from atypical parkinsonian syndromes (APSs) such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). In APSs, very few patients present a clinically relevant response to levodopa. The aim of [...] Read more.
The acute levodopa challenge is widely used to distinguish Parkinson’s disease (PD) from atypical parkinsonian syndromes (APSs) such as multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). In APSs, very few patients present a clinically relevant response to levodopa. The aim of this study was to determine whether patients with atypical parkinsonism benefit from levodopa in any aspect of their multiple motor deficits despite the generally poor response. This retrospective study analyzed individual motor responses to the acute levodopa challenge using the MDS-UPDRS III in 47 PSP, 26 MSA, and 71 PD patients at Hannover Medical School. Despite the generally poor levodopa response in both PSP and MSA patients, bradykinesia and rigidity were the symptoms most notably affected by levodopa in PSP patients, while MSA patients experienced significant improvements in bradykinesia and action tremor. These findings underscore the variability in levodopa response among PSP and MSA patients and highlight the need for personalized treatment approaches in atypical parkinsonism. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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22 pages, 5336 KiB  
Article
Disrupted Brain Network Measures in Parkinson’s Disease Patients with Severe Hyposmia and Cognitively Normal Ability
by Karthik Siva, Palanisamy Ponnusamy and Malmathanraj Ramanathan
Brain Sci. 2024, 14(7), 685; https://doi.org/10.3390/brainsci14070685 - 8 Jul 2024
Cited by 2 | Viewed by 1425
Abstract
Neuroscience has revolved around brain structural changes, functional activity, and connectivity alteration in Parkinson’s Disease (PD); however, how the network topology organization becomes altered is still unclear, specifically in Parkinson’s patients with severe hyposmia. In this study, we have examined the functional network [...] Read more.
Neuroscience has revolved around brain structural changes, functional activity, and connectivity alteration in Parkinson’s Disease (PD); however, how the network topology organization becomes altered is still unclear, specifically in Parkinson’s patients with severe hyposmia. In this study, we have examined the functional network topological alteration in patients affected by Parkinson’s Disease with normal cognitive ability (ODN), Parkinson’s Disease with severe hyposmia (ODP), and healthy controls (HCs) using resting-state functional magnetic resonance imaging (rsfMRI) data. We have analyzed brain topological organization using popular graph measures such as network segregation (clustering coefficient, modularity), network integration (participation coefficient, path length), small-worldness, efficiency, centrality, and assortativity. Then, we used a feature ranking approach based on the diagonal adaptation of neighborhood component analysis, aiming to determine a graph measure that is sensitive enough to distinguish between these three different groups. We noted significantly lower segregation and local efficiency and small-worldness in ODP compared to ODN and HCs. On the contrary, we did not find differences in network integration in ODP compared to ODN and HCs, which indicates that the brain network becomes fragmented in ODP. At the brain network level, a progressive increase in the DMN (Default Mode Network) was observed from healthy controls to ODN to ODP, and a continuous decrease in the cingulo-opercular network was observed from healthy controls to ODN to ODP. Further, the feature ranking approach has shown that the whole-brain clustering coefficient and small-worldness are sensitive measures to classify ODP vs. ODN, as well as HCs. Looking at the brain regional network segregation, we have found that the cerebellum and limbic, fronto-parietal, and occipital lobes have higher ODP reductions than ODN and HCs. Our results suggest network topological measures, specifically whole-brain segregation and small-worldness decreases. At the network level, an increase in DMN and a decrease in the cingulo-opercular network could be used as biomarkers to characterize ODN and ODP. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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11 pages, 895 KiB  
Article
Exploring the Association between Cathepsin B and Parkinson’s Disease
by Changhao Lu, Xinyi Cai, Shilin Zhi, Xiaofen Wen, Jiaxin Shen, Tommaso Ercoli, Elena Rita Simula, Carla Masala, Leonardo A. Sechi and Paolo Solla
Brain Sci. 2024, 14(5), 482; https://doi.org/10.3390/brainsci14050482 - 10 May 2024
Viewed by 1976
Abstract
Objective: The aim of this study is to investigate the association between Cathepsin B and Parkinson’s Disease (PD), with a particular focus on determining the role of N-acetylaspartate as a potential mediator. Methods: We used summary-level data from Genome-Wide Association Studies (GWAS) [...] Read more.
Objective: The aim of this study is to investigate the association between Cathepsin B and Parkinson’s Disease (PD), with a particular focus on determining the role of N-acetylaspartate as a potential mediator. Methods: We used summary-level data from Genome-Wide Association Studies (GWAS) for a two-sample Mendelian randomization (MR) analysis, exploring the association between Cathepsin B (3301 cases) and PD (4681 cases). A sequential two-step MR approach was applied (8148 cases) to study the role of N-acetylaspartate. Results: The MR analysis yielded that genetically predicted elevated Cathepsin B levels correlated with a reduced risk of developing PD (p = 0.0133, OR: 0.9171, 95% CI: 0.8563–0.9821). On the other hand, the analysis provided insufficient evidence to determine that PD affected Cathepsin B levels (p = 0.8567, OR: 1.0035, 95% CI: 0.9666–1.0418). The estimated effect of N-acetylaspartate in this process was 7.52% (95% CI = −3.65% to 18.69%). Conclusions: This study suggested that elevated Cathepsin B levels decreased the risk of developing PD, with the mediation effect of N-acetylaspartate. Further research is needed to better understand this relationship. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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Review

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17 pages, 687 KiB  
Review
The Role of Non-Invasive Brain Modulation in Identifying Disease Biomarkers for Diagnostic and Therapeutic Purposes in Parkinsonism
by Daniele Birreci, Martina De Riggi, Davide Costa, Luca Angelini, Antonio Cannavacciuolo, Massimiliano Passaretti, Giulia Paparella, Andrea Guerra and Matteo Bologna
Brain Sci. 2024, 14(7), 695; https://doi.org/10.3390/brainsci14070695 - 12 Jul 2024
Cited by 2 | Viewed by 1366
Abstract
Over the past three decades, substantial advancements have occurred in non-invasive brain stimulation (NIBS). These developments encompass various non-invasive techniques aimed at modulating brain function. Among the most widely utilized methods today are transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES), which [...] Read more.
Over the past three decades, substantial advancements have occurred in non-invasive brain stimulation (NIBS). These developments encompass various non-invasive techniques aimed at modulating brain function. Among the most widely utilized methods today are transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES), which include direct- or alternating-current transcranial stimulation (tDCS/tACS). In addition to these established techniques, newer modalities have emerged, broadening the scope of non-invasive neuromodulation approaches available for research and clinical applications in movement disorders, particularly for Parkinson’s disease (PD) and, to a lesser extent, atypical Parkinsonism (AP). All NIBS techniques offer the opportunity to explore a wide range of neurophysiological mechanisms and exert influence over distinct brain regions implicated in the pathophysiology of Parkinsonism. This paper’s first aim is to provide a brief overview of the historical background and underlying physiological principles of primary NIBS techniques, focusing on their translational relevance. It aims to shed light on the potential identification of biomarkers for diagnostic and therapeutic purposes, by summarising available experimental data on individuals with Parkinsonism. To date, despite promising findings indicating the potential utility of NIBS techniques in Parkinsonism, their integration into clinical routine for diagnostic or therapeutic protocols remains a subject of ongoing investigation and scientific debate. In this context, this paper addresses current unsolved issues and methodological challenges concerning the use of NIBS, focusing on the importance of future research endeavours for maximizing the efficacy and relevance of NIBS strategies for individuals with Parkinsonism. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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Other

Jump to: Research, Review

12 pages, 778 KiB  
Viewpoint
How Lifetime Evolution of Parkinson’s Disease Could Shape Clinical Trial Design: A Shared Patient–Clinician Viewpoint
by Jules M. Janssen Daalen, Aranka Gerritsen, Gijs Gerritse, Jan Gouman, Hannie Meijerink, Leny E. Rietdijk and Sirwan K. L. Darweesh
Brain Sci. 2024, 14(4), 358; https://doi.org/10.3390/brainsci14040358 - 3 Apr 2024
Viewed by 1935
Abstract
Parkinson’s disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention [...] Read more.
Parkinson’s disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient–clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient–clinician partnerships. Full article
(This article belongs to the Special Issue New Approaches in the Exploration of Parkinson’s Disease)
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