Journal of Parkinson's Disease - Volume 12, issue 2

Authors: Tan, Yu-Yan | Jenner, Peter | Chen, Sheng-Di

Article Type: Review Article

Abstract: Monoamine oxidase-B (MAO-B) inhibitors are commonly used for the symptomatic treatment of Parkinson’s disease (PD). MAO-B inhibitor monotherapy has been shown to be effective and safe for the treatment of early-stage PD, while MAO-B inhibitors as adjuvant drugs have been widely applied for the treatment of the advanced stages of the illness. MAO-B inhibitors can effectively improve patients’ motor and non-motor symptoms, reduce “OFF” time, and may potentially prevent/delay disease progression. In this review, we discuss the effects of MAO-B inhibitors on motor and non-motor symptoms in PD patients, their mechanism of action, and the future development of MAO-B inhibitor …therapy. Show more

Keywords: Monoamine oxidase-B inhibitors, Parkinson’s disease, selegiline, rasagiline, safinamide

DOI: 10.3233/JPD-212976

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 477-493, 2022

Authors: Urbi, Berzenn | Corbett, Joel | Hughes, Ian | Owusu, Maame Amma | Thorning, Sarah | Broadley, Simon A. | Sabet, Arman | Heshmat, Saman

Article Type: Systematic Review

Abstract: The legalization of cannabis in many countries has allowed many Parkinson’s disease (PD) patients to turn to cannabis as a treatment. As such there is a growing interest from the PD community to be properly guided by evidence regarding potential treatment benefits of cannabis. This systematic review and meta-analysis aims to compile the best available evidence to help guide patients and their family, clinicians and researchers make informed decisions. A systematic search of the literature was conducted in June 2021. Five randomized controlled studies and eighteen non-randomized studies investigated cannabis treatment in PD patients. No compelling evidence was found to …recommend the use of cannabis in PD patients. However, a potential benefit was identified with respect to alleviation of PD related tremor, anxiety, pain, improvement of sleep quality and quality of life. Given the relative paucity of well-designed randomized studies, there is an identified need for further investigation, particularly in these areas. Show more

Keywords: Cannabis, Parkinson’s disease, efficacy of cannabis, tremor, UPDRS

DOI: 10.3233/JPD-212923

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 495-508, 2022

Authors: Hanff, Anne-Marie | Leist, Anja K. | Fritz, Joëlle V. | Pauly, Claire | Krüger, Rejko | Halek, Margareta | on behalf of the NCER-PD Consortium

Article Type: Systematic Review

Abstract: Background: Self-stigma in people with Parkinson’s disease (PD) can substantially impact quality of life and possibilities for social participation. An integrative analysis of determinants of self-stigma has been lacking. Objective: We sought to explore which complementary insights from qualitative and quantitative studies, as well as from expert consultation, could be gained. Methods: An established mixed methods study design was employed to first conduct a mixed methods scoping review of published qualitative and quantitative literature, and then consult with experts to arrive at an exhaustive list of determinants of self-stigma after a thematic synthesis. Results: …A total of 87 unique determinants of self-stigma were identified. Quantitative studies and expert consultations mainly identified personal determinants of people with self-stigma (e.g., age, anxiety, or apathy). In contrast, qualitative studies identified social situations associated with self-stigma (e.g., joint meals of people with typical PD with others). Notably, self-stigma of people with PD was found to be particularly salient in unfamiliar places, at the working place or in contact with people without PD. Across methods, cognitive impairment, tremor, and abnormal walk and unsteady gait, respectively, were associated with self-stigma. Conclusion: The mixed method study design yielded complementary insights, but also factors commonly associated with self-stigma across methods. Future prioritization exercises may gain further insights into self-stigma of people with PD. Facilitating social encounters by both addressing needs of affected people and raising knowledge and public awareness may improve quality of life in people with PD. Show more

Keywords: Parkinson’s disease, social stigma, shame, social discrimination, review, international classification of functioning, disability and health

DOI: 10.3233/JPD-212869

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 509-522, 2022

Authors: McFarthing, Kevin | Prakash, Neha | Simuni, Tanya

Article Type: Other

DOI: 10.3233/JPD-229001

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 523-536, 2022

Authors: Liguori, Claudio | Stefani, Alessandro | Fernandes, Mariana | Cerroni, Rocco | Mercuri, Nicola Biagio | Pierantozzi, Mariangela

Article Type: Research Article

Abstract: Background: Several biomarkers have been evaluated in Parkinson’s disease (PD); cerebrospinal fluid (CSF) levels of lactate may reflect cerebral metabolism function and CSF amyloid-β42 (Aβ42 ), total tau (t-tau) and phosphorylated tau (p-tau) concentrations may detect an underlying neurodegenerative process. Objective: CSF levels of lactate, Aβ42 , t-tau, and p-tau were measured in patients with mild to moderate PD. CSF levels of dopamine (DA) and its metabolite 3,4-Dihydroxyphenylacetic acid (DOPAC) were also assessed, exploring their relations with the other CSF biomarkers. Methods: 101 drug-naive PD patients and 60 controls were included. Participants …underwent clinical assessments and CSF biomarker analysis. Patients were divided into subgroups according to their Hoehn & Yahr stage (PD-1, PD-2, PD-3). Results: PD patients showed higher lactate levels (M = 1.91; p  = 0.03) and lower Aβ42 (M = 595; p  < 0.001) and DA levels (M = 0.32; p  = 0.04) than controls (Mlactate  = 1.72; MAβ42  = 837; MDA  = 0.50), while no significant differences were found in t-tau, p-tau and DOPAC concentrations. Considering the subgroup analysis, PD-3 group had higher lactate (M = 2.12) and t-tau levels (M = 333) than both PD-1 (Mlactate  = 1.75, p  = 0.006; Mt - tau  = 176, p  = 0.008) and PD-2 groups (Mlactate  = 1.91, p  = 0.01; Mt - tau  = 176, p  = 0.03), as well as the controls (Mlactate  = 1.72, p  = 0.04; Mt - tau  = 205, p  = 0.04). PD-2 group showed higher lactate levels than PD-1 group (p  = 0.04) and controls (p  = 0.03). Finally, CSF lactate levels negatively correlated with DA (r = –0.42) and positively with t-tau CSF levels (r = 0.33). Conclusion: This CSF-based study shows that lactate levels in PD correlated with both clinical disease progression and neurodegeneration biomarkers, such as tau proteins and DA. Further studies should explore the clinical potential of measuring CSF biomarkers for better understanding the role of brain energy metabolism in PD, for research and therapeutic options. Show more

Keywords: Lactate, tau, amyloid-β42, dopamine, motor impairment

DOI: 10.3233/JPD-212936

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 537-544, 2022

Authors: Chen, Gary K. | Yan, Qi | Paul, Kimberly C. | Kusters, Cynthia D.J. | Folle, Aline Duarte | Furlong, Melissa | Keener, Adrienne | Bronstein, Jeff | Horvath, Steve | Ritz, Beate

Article Type: Research Article

Abstract: Background: Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual’s genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. Objective: We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). Methods: We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson’s disease, Environment and …Genes (PEG) study, for whom blood-based methylation data was available. Results: We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. Conclusion: Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients. Show more

Keywords: Parkinson’s disease, epigenetics

DOI: 10.3233/JPD-212834

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 545-556, 2022

Authors: Peterschmitt, M. Judith | Saiki, Hidemoto | Hatano, Taku | Gasser, Thomas | Isaacson, Stuart H. | Gaemers, Sebastiaan J.M. | Minini, Pascal | Saubadu, Stéphane | Sharma, Jyoti | Walbillic, Samantha | Alcalay, Roy N. | Cutter, Gary | Hattori, Nobutaka | Höglinger, Günter U. | Marek, Kenneth | Schapira, Anthony H.V. | Scherzer, Clemens R. | Simuni, Tanya | Giladi, Nir | Sardi, Sergio Pablo | Fischer, Tanya Z. | on behalf of the MOVES-PD Investigators

Article Type: Research Article

Abstract: Background: Glucocerebrosidase gene (GBA ) mutations influence risk and prognosis of Parkinson’s disease (PD), possibly through accumulation of glycosphingolipids, including glucosylceramide (GL-1). Venglustat is a novel, brain penetrant glucosylceramide synthase inhibitor. Objective: Evaluate venglustat pharmacology, safety, and tolerability in patients with PD and GBA mutations (GBA -PD). Methods: Part 1 of the phase 2 MOVES-PD trial (NCT02906020) was a randomized, double-blinded, placebo-controlled, dose-escalation study performed in six countries. Eligible participants included Japanese and non-Japanese patients aged 18–80 years with PD diagnosis and heterozygous GBA mutation. Participants were randomized to three doses of once-daily oral …venglustat or placebo and were followed up to 36 weeks (Japanese participants: 52 weeks). Primary endpoint was venglustat safety and tolerability versus placebo. Secondary and exploratory endpoints included venglustat pharmacokinetics and pharmacodynamics. Results: Participants (N  = 29) received venglustat (Japanese, n  = 9; non-Japanese, n  = 13) or placebo (n  = 3; n  = 4). Eight (89%) Japanese and 12 (92%) non-Japanese venglustat-treated participants experienced at least one adverse event (AE) versus two (67%) and four (100%) participants from the respective placebo groups. Most AEs were mild or moderate; no serious AEs or deaths occurred. Two venglustat-treated non-Japanese participants discontinued due to AEs (confusional state and panic attack). Over 4 weeks, venglustat exposure in plasma and cerebrospinal fluid (CSF) increased, and GL-1 levels in plasma and CSF decreased, both in a dose-dependent manner. At the highest dose, CSF GL-1 decreased by 72.0% in Japanese and 74.3% in non-Japanese participants. Conclusion: Venglustat showed favorable safety and tolerability in MOVES-PD Part 1 and target engagement was achieved in CSF. Show more

Keywords: Parkinson’s disease, MOVES-PD, Venglustat (GZ/SAR402671), glucocerebrosidase gene (GBA), glucosylceramide (GL-1), glucosylceramide synthase (GCS) inhibition, GBA-PD

DOI: 10.3233/JPD-212714

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 557-570, 2022

Authors: Ygland Rödström, Emil | Mattsson-Carlgren, Niklas | Janelidze, Shorena | Hansson, Oskar | Puschmann, Andreas

Article Type: Research Article

Abstract: Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson’s disease (PD) but are not sufficiently studied in late PD. Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages. Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either …of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations. Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4–8.5), nursing home living (5.1; 2.1–12.5), motor end-stage (6.2; 2.1–17.8), and death (4.1; 1.7–9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77–0.91) compared to S-NfL levels alone (0.68–0.71) for predicting the five disease milestones. Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy. Show more

Keywords: Parkinson’s disease, biomarkers, dementia, neurofilament proteins, prognosis, mortality

DOI: 10.3233/JPD-212866

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 571-584, 2022

Authors: Giannoccaro, Maria Pia | Avoni, Patrizia | Rizzo, Giovanni | Incensi, Alex | Infante, Rossella | Donadio, Vincenzo | Liguori, Rocco

Article Type: Research Article

Abstract: Background: Previous studies reported skin phosphorylated α-synuclein (p-syn) deposits in Parkinson’s disease (PD) patients but not in patients with parkinsonism due to tauopathies, although data on the latter are limited. Objective: We aimed to assess the presence of skin p-syn deposits in patients with clinical diagnosis of parkinsonism usually due to tauopathy and PD. Methods: We consecutively recruited 26 patients, 18 fulfilling clinical diagnostic criteria of progressive supranuclear palsy (PSP) and 8 of corticobasal syndrome (CBS), 26 patients with PD, and 26 healthy controls (HC). All subjects underwent skin biopsy to study p-syn deposits in skin …nerves by immunofluorescence. Results: Skin p-syn deposits were present in only two of the PSP/CBS patients and none of the HC. Conversely, all PD patients showed p-syn deposition (p  < 0.001, Chi-square). The two p-syn positive patients were diagnosed with PSP and CBS, respectively. Although clinical and MRI findings supported these diagnoses, both patients had some atypical features more typical of synucleinopathies. Conclusion: The detection of skin p-syn deposits may help in the differential diagnosis of parkinsonism. Indeed, in this study, all PD patients and only two out of 26 with a clinical diagnosis of PSP/CBS had skin p-syn deposits. Furthermore, these two patients showed clinical features that could suggest an atypical synucleinopathy presentation or a mixed pathology. Show more

Keywords: Alpha-synuclein, biomarker, corticobasal syndrome, Parkinson’s disease, parkinsonism, progressive supranuclear paly, skin biopsy

DOI: 10.3233/JPD-212904

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 585-591, 2022

Authors: Steiner, Oliver | de Zeeuw, Jan | Stotz, Sophia | Bes, Frederik | Kunz, Dieter

Article Type: Short Communication

Abstract: Neurodegenerative processes in the brain are reflected by structural retinal changes. As a possible biomarker of cognitive state in prodromal α -synucleinopathies, we compared melanopsin-mediated post-illumination pupil response (PIPR) with cognition (CERAD-plus) in 69 patients with isolated REM-sleep behavior disorder. PIPR was significantly correlated with cognitive domains, especially executive functioning (r  = 0.417, p  < 0.001), which was more pronounced in patients with lower dopamine-transporter density, suggesting advanced neurodegenerative state (n  = 26; r  = 0.575, p  = 0.002). Patients with mild neurocognitive disorder (n  = 10) had significantly reduced PIPR (smaller melanopsin-mediated response) compared to those without (p  = 0.001). Thus, PIPR may be a functional—possibly …monitoring—marker for impaired cognitive state in (prodromal) α -synucleinopathies. Show more

Keywords: α-synucleinopathies, melanopsin, pupillometry, post-illumination pupil response, cognition, executive functioning, dopamine-transporter density, biomarker

DOI: 10.3233/JPD-212775

Citation: Journal of Parkinson's Disease, vol. 12, no. 2, pp. 593-598, 2022