Journal of Parkinson's Disease - Volume 9, issue 3

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

Article Type: Other

DOI: 10.3233/JPD-199002

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 449-465, 2019

Authors: Loeffler, David A. | Aasly, Jan O. | LeWitt, Peter A. | Coffey, Mary P.

Article Type: Review Article

Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of autosomal dominant Parkinson’s disease (PD) and sporadic PD (sPD). The clinical presentation of LRRK2 PD is similar to sPD, and except for genetic testing, no biochemical or imaging markers can differentiate LRRK2 PD from sPD. Discovery of such biomarkers could indicate neuropathological mechanisms that are unique to or increased in LRRK2 PD. This review discusses findings in 17 LRRK2 - related CSF studies found on PubMed. Most of these studies compared analyte concentrations between four diagnostic groups: LRRK2 PD patients, sPD patients, asymptomatic control …subjects carrying PD-associated LRRK2 mutations (LRRK2 CTL), and healthy control subjects lacking LRRK2 mutations (CTL). Analytes examined in these studies included Aβ1-42, tau, α -synuclein, oxidative stress markers, autophagy-related proteins, pteridines, neurotransmitter metabolites, exosomal LRRK2 protein, RNA species, inflammatory cytokines, mitochondrial DNA (mtDNA), and intermediary metabolites. FINDINGS: Pteridines, α -synuclein, mtDNA, 5-hydroxyindolacetic acid, β-D-glucose, lamp2, interleukin-8, and vascular endothelial growth factor were suggested to differentiate LRRK2 PD from sPD patients; 8-hydroxy-2’-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO), 2-hydroxybutyrate, mtDNA, lamp2, and neopterin may differentiate between LRRK2 CTL and LRRK2 PD subjects; and soluble oligomeric α -synuclein, 8-OHdG, and 8-ISO might differentiate LRRK2 CTL from CTL subjects. CONCLUSIONS: The low numbers of investigations of each analyte, small sample sizes, and methodological differences limit conclusions that can be drawn from these studies. Further investigations are indicated to determine the validity of the analytes identified in these studies as possible biomarkers for LRRK2 PD patients and/or LRRK2 CTL subjects. Show more

Keywords: Biomarkers, cerebrospinal fluid, mutation, Parkinson’s disease

DOI: 10.3233/JPD-191630

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 467-488, 2019

Authors: Angulo, Julio | Fleury, Vanessa | Péron, Julie Anne | Penzenstadler, Louise | Zullino, Daniele | Krack, Paul

Article Type: Review Article

Abstract: Shame is a self-conscious emotion marked by an intensely negative self-evaluation. It is exhibited by an individual upon realizing that she/he has violated an important (usually social) norm. Shame can be a source of emotional distress leading to social withdrawal and depression, with a significant negative impact on quality of life. In Parkinson’s disease (PD), shame is rarely addressed. Based on reports of persons affected with Parkinson’s disease (PwP) as well as a literature review, this article describes PD-related shame. PD-related shame may emerge from motor and non-motor symptoms, from self-perception of inadequacy due to loss of autonomy and need …for help, or from perceived deterioration of body image. The neurobiology of shame delineates neuronal networks involved in cognitive and emotions regulation, self-representation and representation of the others mental states. Although this hypothesis remains to be demonstrated, these substrates could be modulated, at least partially, by dopaminergic depletion related to PD, which may open a window for pharmacotherapy. Owing to the negative impact that shame can produce, shame should be actively explored and addressed in the individual PwP. Teaching PwP how to develop resilience to shame may be a useful strategy in preventing the vicious circle of shame. The paucity of existing data on prevalence and management of PD-specific shame contrasts with the manifold reported situations inducing suffering from shame. There is a crucial need for further investigations of shame in PD and the development of interventions to reduce its impact on PwP’s quality of life. Show more

Keywords: Parkinson’s disease, shame, embarrassment, dopamine, quality of life

DOI: 10.3233/JPD-181462

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 489-499, 2019

Authors: Cerri, Silvia | Mus, Liudmila | Blandini, Fabio

Article Type: Review Article

Abstract: Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson’s disease (PD). Risk of developing PD is twice as high in men than women, but women have a higher mortality rate and faster progression of the disease. Moreover, motor and nonmotor symptoms, response to treatments and disease risk factors differ between women and men. Altogether, sex-related differences in PD support the idea that disease development might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients. This review summarizes the most recent knowledge concerning …differences between women and men in PD clinical features, risk factors, response to treatments and mechanisms underlying the disease pathophysiology. Unraveling how the pathology differently affect the two sexes might allow the development of tailored interventions and the design of innovative programs that meet the distinct needs of men and women, improving patient care. Show more

Keywords: Parkinson’s disease, sex, gender, risk factors, estrogens, signs and symptoms, dopaminergic neurons, neuroinflammation, oxidative stress

DOI: 10.3233/JPD-191683

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 501-515, 2019

Authors: Smith, Natalie | Brennan, Laura | Gaunt, Daisy M. | Ben-Shlomo, Yoav | Henderson, Emily

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) and frailty are two conditions that are increasingly common with advancing age, yet little is known about their relationship. Objective: The aim of this study was to examine the co-occurrence of frailty in people with PD; to describe the measures used to assess frailty in PD, and assess the prevalence of frailty in subjects with PD. Methods: We conducted a systematic review of Pubmed and Embase in April 2018. Studies that assessed frailty in subjects with PD were included in the review and data was extracted on the prevalence of frailty in …subjects with PD. Due to heterogeneity of studies a meta-analysis was not performed. Results: Eight studies were included in the review, of which 7 were cross-sectional and 1 a prospective cohort study. Mean age of participants with PD in the studies ranged from 66 to 85 years. The majority (6/8) used the 5-item, Fried criteria to measure frailty, with the remainder using index-based measures. 5 studies provided data on the prevalence of frailty in PD, which ranged from 29% to 67%. Conclusions: Few studies have quantified the prevalence of frailty in PD, but those that have suggest a high concurrence of these two conditions. Show more

Keywords: Frailty, Parkinson’s disease, systematic review

DOI: 10.3233/JPD-191604

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 517-524, 2019

Authors: Gupta, Harsh V. | Lyons, Kelly E. | Wachter, Nathaniel | Pahwa, Rajesh

Article Type: Research Article

Abstract: Background: Levodopa is the most efficacious medication in controlling the motor symptoms of Parkinson’s disease (PD). There continues to be a controversy as to whether levodopa remains effective after years of therapy. Objective: To assess the long-term effectiveness of levodopa in PD patients. Methods: The response to levodopa in PD patients undergoing a levodopa challenge for deep brain stimulation (DBS) surgery evaluation from June 1997 through March 2017 were evaluated. The patients were broken into four groups based on disease duration (Group I: 0– 5 years, Group II: 6– 10 years, Group III: 11– 15 years, …and Group IV:≥16 years). Levodopa response was calculated based on the changes in Unified Parkinson’s Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) scores in the medication ON and OFF states. Results: A total of 361 PD patients were included. The mean age in Group I was 59.4 years with a mean disease duration of 3.9 years (n  = 29), Group II was 61 years with a mean disease duration of 8.1 years (n  = 131), Group III was 64 years with a mean disease duration of 12.8 years (n  = 143), and IV was 66.5 years with a mean disease duration of 18.5 years (n  = 58). There was a significant improvement in UPDRS motor and ADL scores after the levodopa challenge for all groups. Conclusions: In a subgroup of PD patients who were evaluated for DBS surgery, there was a marked improvement in UPDRS motor and ADL scores which did not decrease with disease progression. Show more

Keywords: Parkinson’s disease, levodopa, disease duration, long term response

DOI: 10.3233/JPD-191633

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 525-529, 2019

Authors: Poewe, Werner | Bergmann, Lars | Kukreja, Pavnit | Robieson, Weining Z. | Antonini, Angelo

Article Type: Research Article

Abstract: Background: Continuous delivery of levodopa-carbidopa intestinal gel (LCIG) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson’s disease (PD) patients. Objective: To compare the effectiveness and safety of LCIG monotherapy vs polytherapy in patients in the GLORIA registry. Methods: This was a post hoc analysis of a 24-month, multinational observational registry where advanced PD patients with persistent motor complications received LCIG (with adjunctive PD treatment, as necessary). Patients were categorized retrospectively into three stable treatment groups: LCIG monotherapy, LCIG in combination with oral levodopa only (“levodopa monotherapy” [including nighttime oral levodopa]), or …LCIG in combination with any other antiparkinsonian medication (“LCIG polytherapy”). Results: Of 356 patients, 208 were on stable regimens (LCIG monotherapy n  = 80; levodopa monotherapy n  = 47; LCIG polytherapy n  = 81). Baseline characteristics were similar across groups. LCIG monotherapy showed significant improvements until month 18 in activities of daily living and quality of life, and until month 24 for Unified Parkinson’s Disease Rating Scale (UPDRS) motor examination (p  < 0.05), “Off” time (p  < 0.001), “On” time with dyskinesia (p  < 0.01), and non-motor symptoms (p  < 0.01). More patients in the levodopa monotherapy and LCIG polytherapy groups experienced treatment-related adverse drug reactions (ADRs) including dyskinesias and serious ADRs than did patients in the LCIG monotherapy group. There were few polyneuropathy-related ADRs, of which one case of polyneuropathy led to discontinuation from the Levodopa monotherapy group. Conclusions: These data demonstrate that LCIG monotherapy is an effective treatment option in appropriate advanced PD patients; however, definitive baseline clinical predictors identifying patients who can discontinue concomitant oral therapy have not yet been defined. Show more

Keywords: Parkinson’s disease, levodopa-carbidopa intestinal gel, monotherapy, GLORIA, multinational registry

DOI: 10.3233/JPD-191605

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 531-541, 2019

Authors: Driver-Dunckley, Erika D. | Zhang, Nan | Adler, Charles H. | Serrano, Geidy E. | Sue, Lucia I. | Shill, Holly A. | Mehta, Shyamal H. | Belden, Christine M. | Zamrini, Edward Y. | Davis, Kathryn | Beach, Thomas G.

Article Type: Research Article

Abstract: Background: Some epidemiology studies suggest that atherosclerotic cardiovascular disease (ASCVD) risk factors increase the risk of developing Parkinson’s disease (PD). However, conflicting data suggest lower rates of ASCVD in PD. Objective: The objective of this study is to determine, with data from a longitudinal clinicopathological study, whether ASCVD risk factors are associated with a PD diagnosis and/or increased brain or peripheral load of Lewy-type synucleinopathy (LTS). Methods: All subjects were followed to autopsy and neuropathological examination in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Multivariable regression models, including age, gender, and smoking history, were …used to investigate the association of a PD diagnosis or brain or submandibular gland LTS load with ASCVD risk factors. Results: 150 subjects were included (PD n  = 60, controls n  = 90). Univariable comparisons and regression models showed a general trend to inverse associations. The multivariable odds ratio (OR) of brain LTS load for carotid artery disease was 0.93 (95% CI: 0.86 to 0.98; p  = 0.02), for anticoagulant use 0.95 (95% CI: 0.90 to 0.99; p  = 0.04) and for abnormal heart weight 0.96 (95% CI: 0.92 to 0.99; p  = 0.01). Composite clinical and overall (clinical + pathology composite risk scores) composite risk scores were also significantly lower in the PD subjects (p  = 0.0164 and 0.0187, respectively). Submandibular gland LTS load was not significantly related to ASCVD conditions. Conclusions: This study shows associations of higher brain LTS with lower prevalence of both clinical and pathological indices of ASCVD in PD subjects versus age-similar controls. We suggest that this is due to α -synuclein pathology-induced sympathetic denervation in PD. Show more

Keywords: α-synuclein, Parkinson’s disease, atherosclerotic cardiovascular disease, sympathetic nervous system

DOI: 10.3233/JPD-191610

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 543-552, 2019

Authors: Stephenson, Diane | Hill, Derek | Cedarbaum, Jesse M. | Tome, Maria | Vamvakas, Spiros | Romero, Klaus | Conrado, Daniela J. | Dexter, David T. | Seibyl, John | Jennings, Danna | Nicholas, Timothy | Matthews, Dawn | Xie, Zhiyong | Imam, Syed | Maguire, Paul | Russell, David | Gordon, Mark Forrest | Stebbins, Glenn T. | Somer, Ed | Gallagher, Jill | Roach, Arthur | Basseches, Peter | Grosset, Donald | Marek, Kenneth | on behalf of the Critical Path for Parkinson’s Consortium

Article Type: Review Article

Abstract: As therapeutic trials target early stages of Parkinson’s disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson’s Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson’s Progression Markers Initiative (PPMI) study to estimate …the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics. Show more

Keywords: Dopamine transporter, enrichment biomarker, PPMI, PRECEPT, SWEDD, EMA

DOI: 10.3233/JPD-191648

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 553-563, 2019

Authors: Polgar, Stephen | Mohamed, Sheeza

Article Type: Review Article

Abstract: The stated purpose of sham or placebo surgery is to enable the implementation of surgical placebo-controlled trials (SPTs) for evaluating the safety and efficacy of surgical interventions. Exposing the participants to the burdens and harms of sham surgery has been justified on the grounds of the absolute necessity for controlling large placebo effects and observer bias, assumed to be associated with surgical procedures. In the present review, we argue that evidence obtained from SPTs of cellular therapies for the treatment of Parkinson’s disease (PD) has failed to demonstrate either large and consistent placebo effects or decisive methodological advantages for relying …on sham surgical controls. We outline several alternative assessment strategies and designs available to establish the efficacy of cellular therapies. It is concluded that the evidence evaluated in the present analysis indicated that use of sham surgery in the context of developing novel surgical procedures for PD is not necessary, and therefore, unethical under a utilitarian model. Show more

Keywords: Ethics of sham surgery, evidence-based ethics, Parkinson’s disease, patient-centered methods, stem cells, surgical placebo-controlled trials

DOI: 10.3233/JPD-191577

Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 565-574, 2019