Journal of Parkinson's Disease - Volume 10, issue 2

Authors: Koros, Christos | Simitsi, Athina-Maria | Papadimitriou, Dimitra | Bougea, Anastasia | Prentakis, Andreas | Papagiannakis, Nikolaos | Pachi, Ioanna | Bozi, Maria | Antonelou, Roubina | Angelopoulou, Efthalia | Beratis, Ion | Papageorgiou, Sokratis G. | Trapali, Xenia Geronicola | Stamelou, Maria | Stefanis, Leonidas

Article Type: Research Article

Abstract: Background: Blood uric acid level represents an emerging biomarker in Parkinson’s disease (PD). Whether uric acid levels change in genetic forms of PD is just beginning to be explored. Objective: The aim of the present study was to assess differences in serum uric acid level among PD patients harboring the p.A53T mutation in the alpha-synuclein gene, idiopathic PD, and healthy controls. Methods: Longitudinal 5-year serum uric acid measurement data of 369 de novo idiopathic PD patients and 174 age- and gender-matched healthy controls have been downloaded from the Parkinson’s Progression Markers Initiative (PPMI) database. Furthermore, …we assessed baseline serum uric acid measurements of 24 p.A53T alpha-synuclein PD patients enrolled in PPMI and followed in our site as compared to 24 age-, gender- and disease duration-matched sporadic PD patients and 24 healthy controls. Results: Longitudinal serum uric acid measurements did not differ statistically between idiopathic PD patients and healthy controls (despite a trend for lower uric acid in the PD group) (p  = 0.879). This was also true when male and female subgroups were assessed separately. The p.A53T SNCA mutation carrier PD group exhibited lower baseline serum uric acid level as compared to their matched healthy controls (p  = 0.025). Conclusion: In the present study we did not replicate the established lower serum uric acid measurements in PD patients as compared to controls using PPMI data, possibly due to the fact that PD patients in baseline visit were de novo and the average disease duration was shorter than that observed in most epidemiological PD studies. The faster progression rate and increased disease severity in p.A53T PD possibly correlate with the lower serum uric acid observed in this subgroup. Show more

Keywords: Parkinson’s disease, uric acid, genetic, alpha-synuclein

DOI: 10.3233/JPD-191860

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 481-487, 2020

Authors: Johnson, Rebecca A. | Kelm-Nelson, Cynthia A. | Ciucci, Michelle R.

Article Type: Research Article

Abstract: Background: Individuals with Parkinson’s disease (PD) experience significant vocal communication deficits. Findings in the Pink1 –/– rat model of early-onset PD suggest that ultrasonic vocal communication is impaired early, progressively worsens prior to nigrostriatal dopamine depletion, and is associated with loss of locus coeruleus neurons, brainstem α -synuclein, and larynx pathology. Individuals with PD also demonstrate ventilatory deficits and altered sensory processing, which may contribute to vocal deficits. Objective: The central hypothesis is that ventilatory and sensory deficits are present in the early disease stages when limb and vocal motor deficits also present. Methods: Pink1 –/– …rats were compared to wildtype (WT) controls at longitudinal timepoints. Whole-body flow through plethysmography was used to measure ventilation in the following conditions: baseline, hypoxia, and maximal chemoreceptor stimulation. Plantar thermal nociception, and as a follow up to previous work, limb gait and vocalization were analyzed. Serotonin density (5-HT) in the dorsal raphe was quantified post-mortem. Results: Baseline breathing frequencies were consistently higher in Pink1 –/– rats at all time points. In hypoxic conditions, there were no significant changes between genotypes. With hypercapnia, Pink1 –/– rats had decreased breathing frequencies with age. Thermal withdrawal latencies were significantly faster in Pink1 –/– compared with WT rats across time. No differences in 5-HT were found between genotypes. Vocal peak frequency was negatively correlated to tidal volume and minute ventilation in Pink1 –/– rats. Conclusion: This work suggests that abnormal nociceptive responses in Pink1 –/– rats and ventilatory abnormalities may be associated with abnormal sensorimotor processing to chemosensory stimuli during disease manifestation. Show more

Keywords: Pink1, ventilation, rat, sensory, ultrasonic vocalization, Parkinson’s disease

DOI: 10.3233/JPD-191853

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 489-504, 2020

Authors: Bakshi, Rachit | Macklin, Eric A. | Hung, Albert Y. | Hayes, Michael T. | Hyman, Bradley T. | Wills, Anne-Marie | Gomperts, Stephen N. | Growdon, John H. | Ascherio, Alberto | Scherzer, Clemens R. | Schwarzschild, Michael A.

Article Type: Short Communication

Abstract: Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson’s disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these ‘reduced risk’ factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean …difference –125 mg/day, p  < 0.001) but not in females (mean difference –30 mg/day, p  = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference –0.46 mg/dL, p  = 0.017) and females (mean difference –0.45 mg/dL, p  = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD. Show more

Keywords: Caffeine, uric acid, biomarker, Parkinson’s disease

DOI: 10.3233/JPD-191882

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 505-510, 2020

Authors: Torikoshi, Sadaharu | Morizane, Asuka | Shimogawa, Takafumi | Samata, Bumpei | Miyamoto, Susumu | Takahashi, Jun

Article Type: Research Article

Abstract: Background: Cell transplantation is expected to be a promising treatment for Parkinson’s disease (PD), in which re-innervation of the host striatum by grafted dopamine (DA) neurons is essential. In particular, the dorsolateral part of the striatum is important because it is the target of midbrain A9 DA neurons, which are degenerated in PD pathology. The effect of exercise on the survival and maturation of grafted neurons has been reported in several neurological disease models, but never in PD models. Objective: We investigated how exercise influences cell transplantation for PD, especially from the viewpoint of cell survival and neurite …extensions. Methods: Ventral mesencephalic neurons from embryonic (E12.5) rats were transplanted into the striatum of adult 6-OHDA-lesioned rats. The host rats then underwent treadmill training as exercise after the transplantation. Six weeks after the transplantation, they were sacrificed, and the grafts in the striatum were analyzed. Results: The addition of exercise post-transplantation significantly increased the number of surviving DA neurons. Moreover, it promoted neurite extensions from the graft toward the dorsolateral part of the striatum. Conclusions: This study indicates a beneficial effect of exercise after cell transplantation in PD. Show more

Keywords: Parkinson’s disease, cell transplantation, rehabilitation, exercise, cell survival, neuronal outgrowth

DOI: 10.3233/JPD-191755

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 511-521, 2020

Authors: Zhang, Lingyu | Zhang, Liping | Li, Yanwei | Li, Lin | Melchiorsen, Josefine Ulrikke | Rosenkilde, Mette | Hölscher, Christian

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease for which there is no cure. In a clinical trial, the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 has shown good protective effects in PD patients. The hormone glucose-dependent insulinotropic polypeptide (GIP) has also shown protective effects in animal models of PD. Objective: We tested DA-CH5, a novel dual GLP-1/GIP receptor agonist. Methods: DA-CH5 activity was tested on cells expressing GLP-1, GLP-2, GIP or glucagon receptors. The ability to cross the blood-brain barrier (BBB) of DA-CH5, exendin-4, liraglutide or other dual receptor agonists was tested with fluorescein-labelled peptides. …DA-CH5, exendin-4 and liraglutide were tested in the MPTP mouse model of PD. Results: Analysing the receptor activating properties showed a balanced activation of GLP-1 and GIP receptors while not activating GLP-2 or glucagon receptors. DA-CH5 crossed the BBB better than other single or other dual receptor agonists. In a dose-response comparison, DA-CH5 was more effective than the GLP-1 receptor agonist exendin-4. When comparing the neuroprotective effect of DA-CH5 with Liraglutide, a GLP-1 analogue, both DA-CH5 and Liraglutide improved MPTP-induced motor impairments. In addition, the drugs reversed the decrease of the number of neurons expressing tyrosine hydroxylase (TH) in the SN, alleviated chronic inflammation, reduced lipid peroxidation, inhibited the apoptosis pathway (TUNEL assay) and increased autophagy -related proteins expression in the substantia nigra (SN) and striatum. Importantly, we found DA-CH5 was superior to Liraglutide in reducing microglia and astrocyte activation, improving mitochondrial activity by reducing the Bax/Bcl-2 ratio and normalising autophagy as found in abnormal expression of LC3 and p62. Conclusion: The results demonstrate that the DA-CH5 is superior to liraglutide and could be a therapeutic treatment for PD. Show more

Keywords: Dopamine, growth factors, insulin, mitochondria, neuroprotection, neuron

DOI: 10.3233/JPD-191768

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 523-542, 2020

Authors: Tanner, Caroline M. | Pahwa, Rajesh | Hauser, Robert A. | Oertel, Wolfgang H. | Isaacson, Stuart H. | Jankovic, Joseph | Johnson, Reed | Chernick, Dustin | Hubble, Jean

Article Type: Research Article

Abstract: Background: Gocovri® (amantadine) extended release capsules are approved for the treatment of dyskinesia in patients with Parkinson’s disease (PD) receiving levodopa-based therapy. Objective: To evaluate the long-term safety, tolerability, and efficacy of Gocovri in patients with PD experiencing levodopa-induced dyskinesia. Methods: In this 2-year open-label trial, patients completing double-blind Gocovri clinical trials or excluded from prior trials because of deep-brain stimulation (DBS) received Gocovri 274 mg once daily at bedtime. The primary objective was to evaluate long-term safety and tolerability. In addition, dyskinesia and OFF time were assessed using Part IV (Motor Complications) scores on the …Movement Disorder Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Results: Among 223 enrolled patients (mean PD duration, 11.7 years; mean levodopa use, 9.3 years), 75.8% completed 1 year of treatment and 57.8% completed the trial, with a median treatment duration of 1.9 years. Common adverse events were fall (32.7%), hallucination (24.2%), peripheral edema (16.1%), constipation (13.5%), and urinary tract infection (10.3%); 31 patients (13.9%) discontinued because of adverse events considered related to study drug. At baseline, MDS-UPDRS Part IV scores were lower for patients continuing Gocovri (mean, 6.5 points) than for previous placebo (9.4) or DBS groups (10.5) but were similar for all groups by week 8 (6.3, 6.2, 6.4, respectively), and remained low for the duration of the trial (at week 100: 6.9, 7.3, 7.0, respectively). Conclusions: In patients with PD, Gocovri showed long-term safety and tolerability consistent with double-blind trial findings, and durable reduction in motor complications (dyskinesia and OFF time). Show more

Keywords: Amantadine, double-blind method, dyskinesias, extended-release preparations, Gocovri, hallucinations, humans, Levodopa, motor fluctuations, OFF, Parkinson’s disease, treatment

DOI: 10.3233/JPD-191841

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 543-558, 2020

Authors: D’Cruz, Nicholas | Vervoort, Griet | Fieuws, Steffen | Moreau, Caroline | Vandenberghe, Wim | Nieuwboer, Alice

Article Type: Research Article

Abstract: Background: The onset of freezing of gait (FOG) represents a turning point in the lives of patients with Parkinson’s disease (PD). FOG increases fall risk and is associated with worse physical and mental health related quality of life, thus increasing disease burden. Moreover, therapeutic studies aiming to ameliorate freezing have had limited success. In a step towards pre-emptive therapy to delay or prevent the onset of FOG, this prospective cohort study set out to uncover clinical markers of conversion to FOG. Objective: Investigate clinical markers of conversion to FOG. Methods: Sixty PD patients without FOG were …followed up for two years and underwent extensive clinical testing each year. FOG classification was made with the New Freezing of Gait Questionnaire. Clinical predictors of conversion to FOG were investigated using univariate analysis and through building a multivariable model using all measured components. Results: Twelve patients developed FOG during the study (Incidence: 11.5% per year). Due to the large number of predictors, univariate analyses did not survive multiple comparison correction, precluding strong inference on any one predictor. Overall, the effect sizes suggested that motor deficits including difficulties with repetitive movement scaling (AUC: 0.71), coordination (AUC: 0.73) and consistency (AUC: 0.76) as well as gait asymmetry (AUC: 0.79) and variability (AUC: 0.71) were most predictive of conversion. Further, converters reported more subjective cognitive difficulty (AUC: 0.74), although their measured performance was similar to non-converters. Multivariable analyses further showed that the two components most consistently selected in the predictive model were: 1) an MDS-UPDRS component with worse axial motor, hand use and non-motor symptoms; and 2) finger tapping abnormalities. Conclusion: Conversion to FOG was predicted mainly by objective and clinical measures of motor dyscontrol, as non-motor disturbances were surfacing. Although based on a small cohort with limited converters, this novel finding informs future studies aimed at FOG prevention. Show more

Keywords: Parkinson’s disease, gait disorders, freezing of gait, prospective cohort study, clinical markers, bootstrapping

DOI: 10.3233/JPD-191759

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 559-571, 2020

Authors: Chen, Yun-Hsiang | Yu, Seong-Jin | Wu, Kuo-Jen | Wang, Yu-Syuan | Tsai, Ho-Min | Liao, Li-Wen | Chen, Shuchun | Hsieh, Wei | Chen, Hsi | Hsu, Shu-Ching | Chen, Mao-Liang | Hoffer, Barry J. | Wang, Yun

Article Type: Research Article

Abstract: Background: Accumulation of α -synuclein (α Syn) in the dopaminergic neurons is a common pathology seen in patients with Parkinson’s disease (PD). Overproduction of α Syn potentiates the formation of oligomeric α Syn aggregates and enhances dopaminergic neuron degeneration. Downregulating intracellular monomeric α Syn prevents the formation of α Syn oligomers and is a potential therapeutic strategy to attenuate the progression of PD. Objective: The purpose of this study is to investigate the efficacy of gene delivery of α Syn-specific single-chain antibodies in vitro and in vivo . Methods and Results: The plasmids for α …Syn and selective antibodies (NAC32, D10, and VH14) were constructed and were transfected to HEK293 and SH-SY5Y cells. Co-expression of α Syn with NAC32, but not D10 or VH14, profoundly downregulated α Syn protein, but not α Syn mRNA levels in these cells. The interaction of α Syn and NAC32 antibody was next examined in vivo . Adeno-associated virus (AAV)-α Syn combined with AAV-NAC32 or AAV-sc6H4 (a negative control virus) were stereotactically injected into the substantia nigra of adult rats. AAV-NAC32 significantly reduced AAV-encoded α Syn levels in the substantia nigra and striatum and increased tyrosine hydroxylase immunoreactivity in the striatum. Also, in the animals injected with AAV-NAC32 alone, endogenous α Syn protein levels were significantly downregulated in the substantia nigra. Conclusion: Our data suggest that AAV-mediated gene transfer of NAC32 is a feasible approach for reducing the expression of target α Syn protein in brain. Show more

Keywords: Adeno-associted virus, intrabody, Parkinson’s disease, alpha synuclein, tyrosine hydroxylase

DOI: 10.3233/JPD-191787

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 573-590, 2020

Authors: Poston, Kathleen L. | Ua Cruadhlaoich, Matthew A. I. | Santoso, Laura F. | Bernstein, Jeffrey D. | Liu, Tian | Wang, Yi | Rutt, Brian | Kerchner, Geoffrey A. | Zeineh, Michael M.

Article Type: Research Article

Abstract: Background: In postmortem analysis of late stage Parkinson’s disease (PD) neuronal loss in the substantial nigra (SN) correlates with the antemortem severity of bradykinesia and rigidity, but not tremor. Objective: To investigate the relationship between midbrain nuclei volume as an in vivo biomarker for surviving neurons in mild-to-moderate patients using 7.0 Tesla MRI. Methods: We performed ultra-high resolution quantitative susceptibility mapping (QSM) on the midbrain in 32 PD participants with less than 10 years duration and 8 healthy controls. Following blinded manual segmentation, the individual volumes of the SN, subthalamic nucleus, and red nucleus …were measured. We then determined the associations between the midbrain nuclei and clinical metrics (age, disease duration, MDS-UPDRS motor score, and subscores for bradykinesia/rigidity, tremor, and postural instability/gait difficulty). Results: We found that smaller SN correlated with longer disease duration (r = –0.49, p  = 0.004), more severe MDS-UPDRS motor score (r = –0.42, p  = 0.016), and more severe bradykinesia-rigidity subscore (r = –0.47, p  = 0.007), but not tremor or postural instability/gait difficulty subscores. In a hemi-body analysis, bradykinesia-rigidity severity only correlated with SN contralateral to the less-affected hemi-body, and not contralateral to the more-affected hemi-body, possibly reflecting the greatest change in dopamine neuron loss early in disease. Multivariate generalized estimating equation model confirmed that bradykinesia-rigidity severity, age, and disease duration, but not tremor severity, predicted SN volume. Conclusions: In mild-to-moderate PD, SN volume relates to motor manifestations in a motor domain-specific and laterality-dependent manner. Non-invasive in vivo 7.0 Tesla QSM may serve as a biomarker in longitudinal studies of SN atrophy and in studies of people at risk for developing PD. Show more

Keywords: Parkinson’s disease, substantia nigra, ultra-high field MRI, quantitative susceptibility mapping

DOI: 10.3233/JPD-191890

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 591-604, 2020

Authors: Ahn, Jong Hyeon | Kim, Minkyeong | Mun, Jun Kyu | Cho, Yoonsu | Kim, Ji Sun | Youn, Jinyoung | Kim, Joong-Seok | Cho, Jin Whan

Article Type: Research Article

Abstract: Background: Fatigue is a common and disabling non-motor symptom in Parkinson’s disease (PD). Autonomic dysfunction is suggested as the possible pathophysiology of fatigue, but it has not been investigated in drug-naïve PD patients. Objective: In the present study, the relationship between fatigue and autonomic dysfunction in drug-naïve PD patients was investigated. Methods: In the present study, 89 drug-naïve PD patients were analyzed. The Parkinson’s disease fatigue scale (PFS) was used to divide the patients into fatigue (mean PFS≥3.3) and non-fatigue groups (mean PFS < 3.3). The autonomic function test (AFT), Scale for Outcomes in Parkinson’s Disease-Autonomic (SCOPA-AUT), Unified …Parkinson’s Disease Rating Scale (UPDRS)-I, -II, -III, modified Hoehn and Yahr (H&Y) scale, Montreal Cognitive Assessment (MoCA), Parkinson’s Disease Questionnaire-39 (PDQ-39), Parkinson’s Disease Sleep Scale (PDSS), and Beck Depress Index (BDI) were performed in all the participants. The AFT results and clinical scales were compared using multiple logistic regression analysis. Results: The prevalence of fatigue was 23.6% (n  = 21) in drug-naïve PD patients. Total SCOPA-AUT score was higher in the fatigue group than in the non-fatigue group. The fatigue group had lower inspiratory:expiratory (I:E) ratio and Valsalva ratio. The prevalence of abnormal sympathetic skin response and orthostatic hypotension (OH) was 19% and 38.1%, respectively, in the fatigue group. Regression model analysis revealed that SCOPA-AUT and OH were the most related factor of fatigue in drug-naïve PD patients. Conclusion: Autonomic dysfunction in drug-naïve PD patients was investigated using a subjective scale as well as objective tests. The results indicated that fatigue is associated with autonomic dysfunction, especially OH, in drug-naïve PD patients. Show more

Keywords: Fatigue, autonomic dysfunction, drug naïve, Parkinson’s disease

DOI: 10.3233/JPD-201919

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 605-612, 2020