Journal of Parkinson's Disease - Volume 11, issue 4

Authors: Zhou, Cheng | Guo, Tao | Wu, JingJing | Wang, Linbo | Bai, Xueqin | Gao, Ting | Guan, Xiaojun | Gu, Luyan | Huang, Peiyu | Xuan, Min | Gu, Quanquan | Xu, Xiaojun | Zhang, Baorong | Cheng, Wei | Feng, Jianfeng | Zhang, Minming

Article Type: Research Article

Abstract: Background: The widely divergent responsiveness of Parkinson’s disease (PD) patients to levodopa is an important clinical issue because of its relationship with quality of life and disease prognosis. Preliminary animal experiments have suggested that degeneration of the locus coeruleus (LC) attenuates the efficacy of levodopa treatment. Objective: To explore the relationship between LC degeneration and levodopa responsiveness in PD patients in vivo . Methods: Neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a good indicator of LC and substantia nigra (SN) degeneration, and levodopa challenge tests were conducted in 57 PD patients. Responsiveness to levodopa was …evaluated by the rates of change of the Unified Parkinson’s Disease Rating Scale Part III score and somatomotor network synchronization calculated from resting-state functional MRI before and after levodopa administration. Next, we assessed the relationship between the contrast-to-noise ratio of LC (CNRLC ) and levodopa responsiveness. Multiple linear regression analysis was conducted to rule out the potential influence of SN degeneration on levodopa responsiveness. Results: A significant positive correlation was found between CNRLC and the motor improvement after levodopa administration (R  = 0.421, p  = 0.004). CNRLC also correlated with improvement in somatomotor network synchronization (R  = –0.323, p  = 0.029). Furthermore, the relationship between CNRLC and levodopa responsiveness was independent of SN degeneration. Conclusion: LC degeneration might be an essential factor for levodopa resistance. LC evaluation using NM-MRI might be an alternative tool for predicting levodopa responsiveness and for helping to stratify patients into clinical trials aimed at improving the efficacy of levodopa. Show more

Keywords: Parkinson’s disease, locus coeruleus, levodopa, magnetic resonance imaging, network

DOI: 10.3233/JPD-212720

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1631-1640, 2021

Authors: Tilley, Bension S. | Patel, Shivani R. | Goldfinger, Marc H. | Pearce, Ronald K.B. | Gentleman, Steve M.

Article Type: Research Article

Abstract: Background: Lewy body dementia (LBD) has two main phenotypes: Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), separated by the ‘one-year-rule’. They also show different symptom profiles: core DLB features include fluctuating cognition, REM-sleep behaviur disorder, and visual hallucinations. These symptoms are sometimes present in PDD, representing an intermediate ‘PDD-DLB’ phenotype. Objective: DLB-like features may reflect deficits in the functions of the noradrenergic nucleus locus coeruleus (LC). Therefore, we compared the LC in the LBD phenotypes, PD, and controls. Methods: 38 PD, 56 PDD, 22 DLB, and 11 age-matched control cases from the Parkinson’s …UK tissue bank were included. LC tissue sections were immunostained for tyrosine-hydroxylase (TH), α-synuclein, tau, and amyloid-β. TH-neurons were quantified and pathologic burden calculated by %-coverage method. Results: The LC shows a stepwise reduction in neuron count from controls, PD, PDD, to DLB. PDD-DLB cases showed an intermediate clinical phenotype that was reflected pathologically. Cell counts were significantly reduced in DLB compared to PDD after correction for demographic factors. LC degeneration contributed significantly to the onset of all DLB symptoms. While α-synuclein was not significantly different between PDD and DLB cases, DLB exhibited significantly less tau pathology. Conclusion: DLB and DLB-like symptoms represent noradrenergic deficits resulting from neuronal loss in the LC. PDD and DLB are likely to represent a clinical continuum based on the presence or absence of DLB-like symptoms mirrored by a pathological continuum in the LC. Show more

Keywords: Alpha-synuclein, Lewy body disease, locus coeruleus, neuropathology, Parkinson’s disease, tau proteins

DOI: 10.3233/JPD-212748

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1641-1650, 2021

Authors: Palermo, Giovanni | Giannoni, Sara | Giuntini, Martina | Belli, Elisabetta | Frosini, Daniela | Siciliano, Gabriele | Ceravolo, Roberto

Article Type: Research Article

Abstract: Background: It has been speculated that stains are neuroprotective and are associated with a reduced risk of Parkinson’s disease (PD), but only a few studies have investigated the influence of statins on the progression of PD. Objective: To evaluate whether long-term statin use may affect motor progression in a large cohort of de novo patients with PD. Methods: We conducted a 4-year retrospective observational cohort study to assess patients with PD. The patients were consecutively recruited from a single tertiary center between January 2015 and January 2017. Information on motor function was obtained using the …MDS-Unified Parkinson Disease Rating Scale (UPDRS)-III and all subjects were extensively characterized, including information about lifestyle habits, cardiovascular risk factors and cholesterol blood levels. Results: Of the 181 participants included in the study, 104 patients were evaluated for eligibility (42 patients were exposed to statin therapies and 62 were not treated with statins). They presented similar scores in UPDRS III at baseline but the statin users had a lower motor impairment at 4 years compared to non-user PD patients. Additionally, statin treatment resulted in slower progression of the rigidity score of UPDRS over 4 years. No other significant differences were observed between PD patients with and without statins. Conclusion: Early PD patients with long-term statin usage showed lower motor deterioration after 4 years of disease duration compared with patients not taking statins at diagnosis, suggesting a possible influence of statins on disease progression in PD. Further investigation is warranted to understand the potential beneficial effects of statin treatment on clinical symptoms in PD. Show more

Keywords: Cholesterol, disease progression, Parkinson’s disease, statin

DOI: 10.3233/JPD-212655

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1651-1662, 2021

Authors: Hauser, Robert A. | Hattori, Nobutaka | Fernandez, Hubert | Isaacson, Stuart H. | Mochizuki, Hideki | Rascol, Olivier | Stocchi, Fabrizio | Li, June | Mori, Akihisa | Nakajima, Yu | Ristuccia, Robert | LeWitt, Peter

Article Type: Research Article

Abstract: Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n  = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the …primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n  = 992; 20 mg/day, n  = 848; 40 mg/day, n  = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p  < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated. Show more

Keywords: Adenosine 2A receptor antagonist, istradefylline, Parkinson’s disease, treatment

DOI: 10.3233/JPD-212672

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1663-1675, 2021

Authors: Knudsen, Karoline | Fedorova, Tatyana D. | Horsager, Jacob | Andersen, Katrine B. | Skjærbæk, Casper | Berg, Daniela | Schaeffer, Eva | Brooks, David J. | Pavese, Nicola | Van Den Berge, Nathalie | Borghammer, Per

Article Type: Research Article

Abstract: Background: We have hypothesized that Parkinson’s disease (PD) comprises two subtypes. Brain-first , where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric brainstem involvement and hence more symmetric nigrostriatal degeneration. Isolated REM sleep behaviour disorder has been identified as a strong marker of the body-first type. Objective: To analyse striatal asymmetry in [18 F]FDOPA PET and [123 I]FP-CIT DaT SPECT data from iRBD patients, de novo PD patients with RBD (PD+RBD ) and de novo …PD patients without RBD (PD-RBD ). These groups were defined as prodromal body-first , de novo body-first , and de novo brain-first , respectively. Methods: We included [18 F]FDOPA PET scans from 21 iRBD patients, 11 de novo PD+RBD , 22 de novo PD-RBD , and 18 controls subjects. Also, [123 I]FP-CIT DaT SPECT data from iRBD and de novo PD patients with unknown RBD status from the PPPMI dataset was analysed. Lowest putamen specific binding ratio and putamen asymmetry index (AI) was defined. Results: Nigrostriatal degeneration was significantly more symmetric in patients with RBD versus patients without RBD or with unknown RBD status in both FDOPA (p  = 0.001) and DaT SPECT (p  = 0.001) datasets. Conclusion: iRBD subjects and de novo PD+RBD patients present with significantly more symmetric nigrostriatal dopaminergic degeneration compared to de novo PD-RBD patients. The results support the hypothesis that body-first PD is characterized by more symmetric distribution most likely due to more symmetric propagation of pathogenic α-synuclein compared to brain-first PD. Show more

Keywords: Parkinson’s disease, asymmetry, dopaminergic dysfunction, brain- and body-first

DOI: 10.3233/JPD-212761

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1677-1687, 2021

Authors: Cotogni, Marco | Sacchi, Lucia | Sadikov, Aleksander | Georgiev, Dejan

Article Type: Research Article

Abstract: Background: Even though a significant fraction of Parkinson’s disease (PD) patients presents with only minor or no motor asymmetry, the motor symptoms in PD typically start on one side of the body and worse symptoms on the side of the disease onset usually persist long after the disease has become clinically bilateral. The asymmetric presentation of PD has been studied over the years, with some studies showing slower progression in PD subjects with asymmetric disease presentation. In other studies, however, it was not possible to relate the asymmetry to disease progression. Objective: The main objective of the present …study was to assess the effect of asymmetry at disease onset on disease progression. Methods: Using the data available in the Parkinson’s Progression Markers Initiative (PPMI) database, at baseline, 423 subjects with de-novo PD were included in the study. Instead of dichotomizing the subjects in asymmetric and symmetric, we kept the asymmetry index and the non-motor, disability, and motor progression at one-, three-, and five-year follow-up continuous. Pearson’s r correlational analysis and the coefficient of determination R 2 were used to correlate asymmetry indices and disease progression. Results: There was no correlation between neither clinically, nor DatSCAN defined asymmetry and non-motor, motor, and disability progression in the de-novo PD subjects with a 5-year follow-up. Conclusion: Asymmetry at disease onset does not predict progression of PD. Further studies are needed to investigate whether early detection of asymmetry on clinical grounds could successfully distinguish between PD and symmetric types of atypical parkinsonism in the early stages of the disease. Show more

Keywords: Asymmetry index, DatSCAN, disease progression, Parkinson’s disease

DOI: 10.3233/JPD-202525

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1689-1694, 2021

Authors: Rosebraugh, Matthew | Liu, Wei | Neenan, Melina | Facheris, Maurizio F.

Article Type: Research Article

Abstract: Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC …infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window. Show more

Keywords: Levodopa, carbidopa, Parkinson’s disease, pharmacokinetics, NCT03033498

DOI: 10.3233/JPD-212813

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1695-1702, 2021

Authors: Yoo, Han Soo | Lee, Sangwon | Jeong, Seong Ho | Ye, Byoung Seok | Sohn, Young H. | Yun, Mijin | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Olfactory or autonomic dysfunction is one of the earliest prodromal symptoms of Parkinson’s disease (PD). It has not been investigated whether PD patients have different phenotypes depending on the presence of these prodromal symptoms. Objective: To investigate whether hyposmia-dominant and dysautonomia-dominant patients with early PD have different clinical manifestations and nigrostriatal degeneration. Methods: This cross-sectional study recruited 168 drug-naive PD patients and 34 control subjects. PD patients were classified as patients without hyposmia and dysautonomia (PD–H–D–, n  = 51), hyposmia-dominant patients (PD–H+D–, n  = 36), dysautonomia-dominant patients (PD–H–D+, n  = 33), and patients with hyposmia and dysautonomia (PD–H+D+, …n  = 48). We then compared the baseline clinical characteristics, striatal specific to non-specific binding ratio (SNBR), neuropsychological performance, and neuropsychiatric symptoms among the groups. Results: The PD–H+D–group had a lower SNBR in the ventral striatum (p  = 0.013), a greater asymmetric index of striatal SNBRs, and higher prevalence of apathy (p  = 0.021) than the PD–H–D+ group. The PD–H–D+ group had older age at onset (p  = 0.043) and a higher prevalence of REM sleep behavior disorder (p  = 0.041) than the PD–H+D–group. The PD–H+D+ group had higher motor deficits, lower cognitive function, and lower SNBRs in all striatal subregions than the PD–H–D–group. Decreased SNBRs in the anterior caudate, posterior caudate, and ventral striatum were associated with the presence of apathy. Conclusion: The present study suggests that hyposmia-dominant and dysautonomia-dominant PD have different clinical characteristics and patterns of striatal dopamine depletion. Show more

Keywords: Olfaction, hyposmia, autonomic function, dysautonomia, Parkinson’s disease

DOI: 10.3233/JPD-212747

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1703-1713, 2021

Authors: Chung, Seok Jong | Lee, Phil Hyu | Sohn, Young H. | Kim, Yun Joong

Article Type: Research Article

Abstract: Background: The concept of motor reserve explains the individual differences in motor deficits despite similar degrees of nigrostriatal dopamine depletion in Parkinson’s disease (PD). Objective: To investigate glucocerebrosidase (GBA) variants as potential determinants of motor reserve for exploratory purposes. Methods: A total of 408 patients with drug-naïve PD were enrolled from the Parkinson’s Progression Markers Initiative cohort database. All patients underwent SPECT dopamine transporter (DAT) scans and had results for Sanger sequencing of GBA . Parkinsonian motor deficits were assessed using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS-III). We compared MDS-UPDRS-III …scores while adjusting for DAT availability in the putamen (i.e., motor reserve) between the PD groups according to the presence of GBA mutations. Results: Fifty-four (13.2%) patients carried GBA mutations. PD patients with GBA mutations were younger than those without mutations. There were no significant differences in sex, disease duration, years of education, and striatal DAT availability between the PD groups. PD patients with GBA mutations had higher MDS-UPDRS-III scores for the less affected side than those without mutations, despite similar levels of DAT availability in the contralateral putamen. The MDS-UPDRS-III sub-scores of the more affected side did not differ between the two PD groups. Conclusion: The results of this study demonstrated the detrimental effect of GBA variants on individual capacity to cope with PD-related pathologies, with different impacts depending on the motor laterality. Show more

Keywords: β-Glucocerebrosidase (GBA), laterality, motor reserve, Parkinson’s disease, Parkinson’s progression markers initiative (PPMI)

DOI: 10.3233/JPD-212758

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1715-1724, 2021

Authors: Schechter, Meir | Sharon, Ronit

Article Type: Review Article

Abstract: Recent data support an involvement of defects in homeostasis of phosphoinositides (PIPs) in the pathophysiology of Parkinson’s disease (PD). Genetic mutations have been identified in genes encoding for PIP-regulating and PIP-interacting proteins, that are associated with familial and sporadic PD. Many of these proteins are implicated in vesicular membrane trafficking, mechanisms that were recently highlighted for their close associations with PD. PIPs are phosphorylated forms of the membrane phospholipid, phosphatidylinositol. Their composition in the vesicle’s membrane of origin, as well as membrane of destination, controls vesicular membrane trafficking. We review the converging evidence that points to the involvement of PIPs …in PD. The review describes PD- and PIP-associated proteins implicated in clathrin-mediated endocytosis and autophagy, and highlights the involvement of α -synuclein in these mechanisms. Show more

Keywords: Parkinson’s disease, phosphoinositides, vesicular membrane trafficking

DOI: 10.3233/JPD-212684

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1725-1750, 2021