Journal of Parkinson's Disease - Volume 14, issue 7

Authors: Patel, Bina | Greenland, Julia C. | Williams-Gray, Caroline H.

Article Type: Research Article

Abstract:  Inflammation and immune dysregulation have been linked to the pathogenesis and progression of Parkinson’s disease (PD), and represent an attractive target for therapeutic intervention, given the potential for repurposing of existing anti-inflammatory and immunomodulatory agents. Despite the fact that initial studies of drugs with secondary anti-inflammatory effects did not yield positive results, agents specifically targeting immune and inflammatory pathways may hold more promise. This article will briefly review the evidence base for targeting the immune system and neuroinflammation in PD, and discuss in detail the recently completed and currently active trials of primary anti-inflammatory/immunomodulatory drugs in PD.

Keywords: Clinical trials, Parkinson’s disease, immunosuppressants, inflammation, inflammasome, immune system

DOI: 10.3233/JPD-240353

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1283-1300, 2024

Authors: Mercado, Gabriela | Kaeufer, Christopher | Richter, Franziska | Peelaerts, Wouter

Article Type: Review Article

Abstract: Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson’s disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways …affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies. Show more

Keywords: Parkinson’s disease, multiple system atrophy, infections, α-synuclein

DOI: 10.3233/JPD-240195

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1301-1329, 2024

Authors: Bailey, Hannah M. | Cookson, Mark R.

Article Type: Review Article

Abstract: LRRK2 is a relatively common genetic risk factor for Parkinson’s disease (PD), with six coding variants known to cause familial PD. Non-coding variation at the same locus is also associated with sporadic PD. LRRK2 plays a role in many different intracellular signaling cascades including those involved in endolysosomal function, cytoskeletal dynamics, and Ca2+ homeostasis. PD-causing LRRK2 mutations cause hyperactive LRRK2 kinase activity, resulting in altered cellular signaling. Importantly, LRRK2 is lowly expressed in neurons and prominently expressed in non-neuronal cells in the brain. In this review, we will summarize recent and novel findings on the effects of PD-causing …LRRK2 mutations in different nervous system cell types. This review will also provide novel insight into future areas of research at the intersection of LRRK2 cell biology, cell type specificity, and PD. Show more

Keywords: Astrocytes, genetics, leucine-rich repeat kinase 2, microglia, neurons, Rab proteins

DOI: 10.3233/JPD-230432

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1331-1352, 2024

Authors: Pedrosa de Menezes, Ana Luisa | Bloem, Bastiaan R. | Beckers, Milan | Piat, Capucine | Benarroch, Eduardo E. | Savica, Rodolfo

Article Type: Review Article

Abstract: Levodopa is the most widely used medication for the symptomatic treatment of Parkinson’s disease and, despite being an “old” drug, is still considered the gold standard for offering symptomatic relief. The pharmacokinetic and pharmacodynamics of levodopa have been studied extensively. Our review explores the molecular mechanisms that affect the absorption of this drug, focusing on the large intra- and interindividual variability of absorption that is commonly encountered in daily clinical practice, and on the interaction with other medications. In addition, we will explore the clinical implications of levodopa absorption variability and address current and future strategies for researchers and clinicians.

Keywords: Levodopa, absorption, Parkinson’s disease, transport, molecular pathway

DOI: 10.3233/JPD-240036

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1353-1368, 2024

Authors: Gibbs, Melissa C. | Huxley, Jenna | Readman, Megan Rose | Polden, Megan | Bredemeyer, Oliver | Crawford, Trevor J. | Antoniades, Chrystalina A.

Article Type: Systematic Review

Abstract: Background: Eye tracking assessments in the laboratory have previously highlighted clear differences in eye movements between Parkinson’s disease (PD) and healthy aging. However, laboratory-based eye movement tasks are artificial and limit the ecological validity of observed results. Eye movement tasks utilizing more naturalistic scenarios may provide more accurate insight into cognitive function but research in this area is limited. Objective: This systematic review aims to ascertain what naturalistic tasks have revealed about oculomotor deficits in PD and what this information may help us understand about the underlying sensorimotor and cognitive processes. Methods: Adhering to the Preferred …Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a literature search of PsycInfo, Medline, Scopus, and Web of Science was conducted using predetermined search terms. Articles including both individuals with PD and healthy older adults completing eye tracking tasks involving naturalistic eye movements (e.g., reading, video-watching, unrestricted visual search) or naturalistic stimuli were included. Results: After screening, 30 studies were identified as matching the inclusion criteria. Results revealed consistent findings across tasks, including longer fixation durations and smaller saccadic amplitudes in PD compared to healthy aging. However, inconsistencies in the literature and a lack of standardization in tasks limit interpretation of these results. Conclusions: Naturalistic eye movement tasks highlight some consistent differences in eye movements between people with PD and healthy aging. However, future research should expand the current literature in this area and strive towards standardization of naturalistic tasks that can preferably be conducted remotely. Show more

Keywords: Eye movements, saccades, Parkinson’s disease, systematic review

DOI: 10.3233/JPD-240092

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1369-1386, 2024

Authors: Boege, Selina | Milne-Ives, Madison | Ananthakrishnan, Ananya | Carroll, Camille | Meinert, Edward

Article Type: Review Article

Abstract: Background: Digital self-management tools including mobile apps and wearables can enhance personalized care in Parkinson’s disease, and incorporating patient and clinician feedback into their evaluation can empower users and nurture patient-clinician relationships, necessitating a review to assess the state of the art and refine their use. Objective: This review aimed to summarize the state of the art of self-management systems used in Parkinson’s disease management, detailing the application of self-management techniques and the integration of clinicians. It also aimed to provide a concise synthesis on the acceptance and usability of these systems from the clinicians’ standpoint, reflecting both …patient engagement and clinician experience. Methods: The review was organized following the PRISMA extension for Scoping Reviews and PICOS frameworks. Studies were retrieved from PubMed, CINAHL, Scopus, ACM Digital Library, and IEEE Xplore. Data was collected using a predefined form and then analyzed descriptively. Results: Of the 15,231 studies retrieved, 33 were included. Five technology types were identified, with systems combining technologies being the most evaluated. Common self-management strategies included educational material and symptom journals. Only 11 studies gathered data from clinicians or reported evidence of clinician integration; out of those, six studies point out the importance of raw data availability, data visualization, and integrated data summaries. Conclusions: While self-management systems for Parkinson’s disease are well-received by patients, the studies underscore the urgency for more research into their usability for clinicians and integration into daily medical workflows to enhance overall care quality. Show more

Keywords: Parkinsonian disorders, Parkinson’s disease, digital health, self-management, telemedicine

DOI: 10.3233/JPD-240137

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1387-1404, 2024

Authors: Zimmermann, Milan | Fandrich, Madeleine | Jakobi, Meike | Röben, Benjamin | Wurster, Isabel | Lerche, Stefanie | Schulte, Claudia | Zimmermann, Shahrzad | Deuschle, Christian | Schneiderhan-Marra, Nicole | Joos, Thomas O. | Gasser, Thomas | Brockmann, Kathrin

Article Type: Research Article

Abstract: Background: Prior investigations have elucidated pathophysiological interactions involving blood coagulation and neurodegenerative diseases. These interactions pertain to age-related effects and a mild platelet antiaggregant function of exogenous α -Synuclein. Objective: Our study sought to explore whether cerebrospinal fluid (CSF) levels of tissue factor (TF), the initiator of the extrinsic pathway of hemostasis, differ between controls (CON) compared to patients with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), considering that these conditions represent a spectrum of α -Synuclein pathology. We further investigated whether TF levels are associated with longitudinal progression in PD. Methods: We examined …CSF levels of TF in 479 PD patients, 67 patients diagnosed with DLB, and 16 CON in order to evaluate potential continuum patterns among DLB, PD, and CON. Of the 479 PD patients, 96 carried a GBA1 variant (PD GBA1 ), while the 383 non-carriers were classified as PD wildtype (PD WT ). We considered both longitudinal clinical data as well as CSF measurements of common neurodegenerative markers (amyloid-β 1-42, h-Tau, p-Tau, NfL, α -Synuclein). Kaplan-Meier survival and Cox regression analysis stratified by TF tertile levels was conducted. Results: Higher CSF levels of TF were associated with an older age at examination in PD and a significant later onset of postural instability in PD GBA1 . TF levels were lower in male vs. female PD. DLB GBA1 exhibited the lowest TF levels, followed by PD GBA1 , with CON showing the highest levels. Conclusions: TF as representative of blood hemostasis could be an interesting CSF candidate to further explore in PD and DLB. Show more

Keywords: Tissue factor, neurodegenerative diseases, blood coagulation, aging, Parkinson’s disease

DOI: 10.3233/JPD-240115

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1405-1416, 2024

Authors: Bosch, Taylor J. | Cole, Rachel C. | Vuong, Shawn M. | Flouty, Oliver | Singh, Arun

Article Type: Research Article

Abstract: Background: Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has emerged as a potent treatment for alleviating motor symptoms in Parkinson’s disease (PD). Despite its effectiveness, the impact of high frequency STN-DBS on cerebellar oscillations remains unclear, posing an intriguing challenge for neural modulation. Given the direct and indirect connections between the STN and cerebellum, we investigated whether STN-DBS affects cerebellar oscillations. Objective: To observe the effects of STN-DBS on cerebellar oscillations in patients with PD. Methods: We recruited 15 PD patients receiving STN-DBS. Electroencephalographic (EEG) signals were recorded from cerebellar regions during resting-state conditions …in both the OFF-DBS and STN-DBS conditions. Our analyses centered on spectral features, particularly theta and beta oscillations, guided by prior research and correlation tests to investigate the relationship between oscillatory changes and motor symptom severity. Results: In the mid-cerebellar (Cbz) region, we observed a significant increase in the relative power in all frequency bands, including theta and beta oscillations during STN-DBS, showing the global effect of DBS. Importantly, the correlation results indicated significant associations between mid-cerebellar (Cbz) beta power during the OFF condition and motor severity, which were not evident during STN-DBS. Interestingly, correlations between beta power and motor severity were not observed at the mid-occipital (Oz) and mid-frontal (Cz) regions. Notably, signal similarity analyses demonstrated no evidence of volume conduction effects between the mid-cerebellar (Cbz) and nearby mid-occipital (Oz) regions. Conclusions: While these findings provide valuable insights into the complex interplay between STN-DBS and neural oscillations, further research is essential to decipher their precise functional significance and clinical implications. Understanding these intricacies may contribute to the optimization of DBS therapies for PD. Show more

Keywords: Subthalamic nucleus, deep brain stimulation, cerebellar, oscillations, Parkinson’s disease

DOI: 10.3233/JPD-240065

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1417-1426, 2024

Authors: Chen, Xiao | Zhang, Zhicheng | Tong, Lin | Wang, Han | Xu, Xinming | Sun, Liang | Li, Yaqi | Gao, Xiang

Article Type: Research Article

Abstract: Background: The association of lung function with the risk of developing prodromal and clinical-diagnosed Parkinson’s disease (PD) and with the risk of mortality among individuals with PD remains unknown. Objective: To prospectively examine the associations of lung function with the risk of prodromal, clinical-diagnosed PD, and PD-related mortality in participants of the UK Biobank. Methods: Included were 452,518 participants free of PD at baseline. Baseline lung function, including forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and FEV1/FVC ratio, was assessed. Eight prodromal features were measured using self-reported diagnoses, hospital …admission, and primary care data. Incident PD cases were identified using linkages with hospital admission, death register, and self-report. Vital status and date of death were provided by the UK National Health Service (NHS) and the NHS Central Register. We used Cox proportional hazard models to evaluate these associations. Results: Poor lung function was associated with higher risk of PD in a dose-response relationship: the adjusted hazard ratio comparing the lowest vs. the highest lung function quintile was 1.18 (95% CI, 1.02– 1.37) for FEV1, 1.14 (95% CI, 0.99– 1.29) for FVC, and 1.23 (95% CI, 1.08– 1.41) for PEF (p -trend <0.05 for all). Similar results were obtained for risk of prodromal PD and mortality among individuals with PD. Conclusions: The current study showed that individuals with poor lung function had a high future risk of prodromal and clinical PD and a higher rate of PD-related mortality. Show more

Keywords: Lung function, Parkinson’s disease, Prodromal Parkinson’s disease, Epidemiology

DOI: 10.3233/JPD-240097

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1427-1439, 2024

Authors: Yoon, Seo Yeon | Choi, Ja Young | Nam, Ga Eun | Jung, Jin-Hyung | Han, Kyungdo | Kang, Sung Hoon | Kim, Chi Kyung | Kim, Yong Wook | Koh, Seong-Beom

Article Type: Research Article

Abstract: Background: Whether body weight changes are associated with Parkinson’s disease (PD) mortality remains uncertain. Objective: To investigate the association between changes in body mass index (BMI) and all-cause mortality in patients with PD. Methods: This nationwide cohort study enrolled 20,703 individuals with new-onset PD (ICD-10 code: G20 and a rare intractable disease registration code: V124) who underwent health screening program by the Korean National Health Insurance Service within two years from pre- and post-PD diagnosis. We identified nine BMI change groups based on three BMI status: underweight (BMI < 18.5 kg/m2 ), normal or overweight (18.5 kg/m2 ≤BMI < 25 kg/m2 ), and …obese (BMI≥25 kg/m2 ). Results: Of 20,703 individuals, 3,789 (18.0%) died during the follow-up period. Excessive weight loss to underweight in the obese group (hazard ratio [HR] = 3.36, 95% CI:1.60–7.08), weight loss in the normal to overweight group (HR = 2.04, 95% CI:1.75–2.39), sustained underweight status (HR = 2.05, 95% CI:1.67–2.52), and weight gain from underweight to normal or overweight (HR = 1.52, 95% CI:1.15–2.02) were associated with increased mortality. Sustained obese status (HR = 0.80, 95% CI:0.74–0.87) and weight gain in the normal to overweight group (HR = 0.82, 95% CI:0.71–0.95) were associated with reduced mortality. Conclusions: We found that BMI change at diagnosis was associated with mortality in patients with PD. Specifically, being underweight either before or after diagnosis as well as experiencing weight loss, were associated with increased mortality. These findings provide valuable insights for weight management planning in PD, highlighting the importance of individualized approach that consider pre-diagnosis BMI. Show more

Keywords: Body mass index, weight change, mortality, Parkinson’s disease, cohort study

DOI: 10.3233/JPD-240181

Citation: Journal of Parkinson's Disease, vol. 14, no. 7, pp. 1441-1450, 2024