Journal of Parkinson's Disease - Volume 10, issue 4

Authors: Isaacson, Stuart H. | Coate, Bruce | Norton, James | Stankovic, Srdjan

Article Type: Research Article

Abstract: Background: Parkinson’s disease psychosis (PDP) is a common nonmotor symptom that affects up to 60% of patients. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is approved for treating hallucinations and delusions associated with PDP. Objective: Evaluate the efficacy and tolerability of pimavanserin in an open-label extension (OLE) study. Methods: Patients completing a pivotal 6-week placebo-controlled trial (Core Study) could enroll in the OLE. All patients pimavanserin 34 mg once daily, blinded to previous treatment allocation. Prespecified blinded assessments at Week 4 were the Scale for the Assessment of Positive Symptoms (SAPS) PD version and SAPS H + D scales, …Caregiver Burden Scale (CBS), and Clinical Global Impression (CGI) Improvement and Severity scales. Results: Of 171 who entered the OLE, 148 (87%) completed Week 4. Among patients who received placebo in the Core Study, mean (SD) change from OLE baseline to OLE Week 4 for the SAPS-PD was – 3.4 (6.3); p  < 0.0001. Mean change from Core Study baseline to OLE Week 4 for SAPS-PD was similar among prior pimavanserin- and placebo-treated patients (–6.9 vs. –6.3). Improvement was similar with CGI-I, CGI-S, CBS, and SAPS-H + D in patients previously treated with placebo. Adverse events occurred in 92 (53.8%) patients during the 4-week OLE. Conclusion: Improvements at OLE Week 4 from pretreatment baseline were similar with placebo and pimavanserin in the Core Study. The beneficial effects observed with pimavanserin in the 6-week Core Study were maintained for 4 weeks in the blinded OLE, supporting the durability of response with pimavanserin 34 mg for PDP over 10 weeks. Show more

Keywords: Efficacy, Parkinson’s disease psychosis, pimavanserin, safety, tolerability

DOI: 10.3233/JPD-202047

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1389-1396, 2020

Authors: Roux, Amandine | Wang, Xinhe | Becker, Katelyn | Ma, Jiyan

Article Type: Research Article

Abstract: Background: Synucleinopathy is a group of neurodegenerative disorders characterized by neurodegeneration and accumulation of alpha-synuclein (α -syn) aggregates in various brain regions. The detailed mechanism of α -syn-caused neurotoxicity remains obscure, which is partly due to the lack of a suitable model that retains the in vivo three-dimensional cellular network and allows a convenient dissection of the neurotoxic pathways. Recent studies revealed that the pre-formed recombinant α -syn amyloid fibrils (PFFs) induce a robust accumulation of pathogenic α -syn species in cultured cells and animals. Objective: Our goal is to determine whether PFFs are able to induce …the pathogenic α -syn accumulation and neurotoxicity in organotypic brain slice culture, an ex vivo system that retains the in vivo three-dimensional cell-cell connections. Methods/Results: Adding PFFs to cultured wild-type rat or mouse brain slices induced a time-dependent accumulation of pathogenic α -syn species, which was indicated by α -syn phosphorylated at serine 129 (pα -syn). The PFF-induced pα -syn was abolished in brain slices prepared from α -syn null mice, suggesting that the pα -syn is from the phosphorylation of endogenous α -syn. Human PFFs also induced pα -syn in brain slices prepared from mice expressing human α -syn on a mouse α -syn-null background. Furthermore, the synaptophysin immunoreactivity was inversely associated with pα -syn accumulation and an increase of neuronal loss was detected. Conclusion: PFF-treatment of brain slices is able to induce key pathological features of synucleinopathy: pα -syn accumulation and neurotoxicity. This model will be useful for investigating the neurotoxic mechanism and evaluating efficacy of therapeutic approaches. Show more

Keywords: Alpha-synuclein, synucleinopathy, organotypic brain slice culture, pre-formed recombinant α-syn amyloid fibrils (PFFs), aggregation, neurotoxicity

DOI: 10.3233/JPD-202026

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1397-1410, 2020

Authors: Kulkarni, Aishwarya S. | del Mar Cortijo, Maria | Roberts, Elizabeth R. | Suggs, Tamara L. | Stover, Heather B. | Pena-Bravo, José I. | Steiner, Jennifer A. | Luk, Kelvin C. | Brundin, Patrik | Wesson, Daniel W.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded α -Synuclein (α -Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of α -Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. α -Syn fibrils injected into the OB of mice cause progressive propagation of α -Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits. Objective: We hypothesized that accumulation of pathogenic α …-Syn in the OB impairs neural activity in the olfactory system. Methods: To address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed α -Syn fibrils in the OB. Results: We detected α -Syn pathology in both the OB and PCX. We also observed that α -Syn fibril injections influenced odor-evoked activity in the OB. In particular, α -Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of α -Syn pathology. Conclusion: Together, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level. Show more

Keywords: Parkinson’s disease, dementia, olfaction, synucleinopathy, Lewy pathology, piriform cortex, olfactory bulb, local field potential

DOI: 10.3233/JPD-202241

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1411-1427, 2020

Authors: von Euler Chelpin, Marianne | Söderberg, Linda | Fälting, Johanna | Möller, Christer | Giorgetti, Marco | Constantinescu, Radu | Blennow, Kaj | Zetterberg, Henrik | Höglund, Kina

Article Type: Research Article

Abstract: Background: Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments. Objective: To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α -synuclein protofibrils (α -syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders. Methods: A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer’s disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ 42 )>530 pg/mL, …and phosphorylated tau (p -tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α -synuclein (α -syn) levels were analyzed with a commercial ELISA-kit. Results: The assay is specific to α -syn PF, with no cross-reactivity to monomeric α -syn, or the β - and γ -synuclein variants. CSF α -syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p  = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p  = 0.02). The accuracy of predicting PD using α -syn PF is significantly different from controls (area under the curve 0.68, p  = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α -syn were significantly different between the PD and CBD groups (p  = 0.04). Conclusion: The developed method specifically quantifies α -syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls. Show more

Keywords: Parkinson's disease, alpha-synuclein protofibrils, Simoa, biomarker, CSF, atypical parkinsonian disorders

DOI: 10.3233/JPD-202141

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1429-1442, 2020

Authors: Ye, Guanyu | Li, Yuanyuan | Zhou, Liche | Zhang, Yichi | Zhu, Lin | Zhao, Aonan | Kang, Wenyan | Liu, Jun

Article Type: Research Article

Abstract: Background: Idiopathic rapid eye movement sleep behavior disorder (iRBD) often precedes the development of α -synucleinopathy diseases. Objective: We aimed to assess the predictive value of clinical variables and biomarkers for the early development of α -synucleinopathy diseases in subjects with iRBD. Methods: 56 patients with RBD Screening Questionnaire (RBDSQ) scores ≥5 at baseline and subsequent visit were enrolled as probable iRBD from the Parkinson’s Progression Markers Initiative (PPMI) database. Baseline clinical data and biomarkers were analyzed. The endpoint was defined as disease progression to α -synucleinopathy diseases. Cox proportional hazard and Kaplan-Meier analyses were used …to evaluate the predictive values of the indicators. Results: During a mean follow-up duration of 5.1 years, 15 of 56 patients (26.8%) developed α -synucleinopathy diseases. Baseline clinical variables, including University of Pennsylvania Smell Identification Test (UPSIT, HR = 26.18, p  = 0.004), 15-item Geriatric Depression Scale (GDS, HR = 14.26, p  = 0.001), Montreal Cognitive Assessment (MoCA, HR = 3.56, p  = 0.025), and Hopkins Verbal Learning Test Total recall (HVLT-TR, HR = 3.70, p  = 0.014); genotype status of TMEM175 (HR = 3.74, p  = 0.017), SCN3A (HR = 5.81, p  = 0.022) and NUCKS1 (HR = 0.342, p  = 0.049); ratio of phosphorylated tau to total tau (p-tau/t-tau, HR = 8.36, p  = 0.001) in cerebrospinal fluid; and gray matter atrophy in inferior frontal gyrus (IFG, HR = 15.49, p  = 0.001) were associated with phenoconversion to α -synucleinopathy diseases. A model combined the three independent variables (UPSIT, TMEM175 and gray matter atrophy in IFG) exhibited significantly improved predictive performance. Conclusion: For patients with iRBD, progression to α -synucleinopathy diseases can be predicted with good accuracy using a model combining clinical variables and biomarkers, which could form a basis for future disease prevention. Show more

Keywords: Parkinson’s disease, REM sleep behavior disorder, synucleinopathies, multiple system atrophy, Lewy body dementia

DOI: 10.3233/JPD-202243

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1443-1455, 2020

Authors: Frings, Lars | Henninger, Franziska | Treppner, Martin | Köber, Göran | Boeker, Martin | Hellwig, Sabine | Buchert, Ralph | Meyer, Philipp T.

Article Type: Research Article

Abstract: Background: Dopamine transporter SPECT is an established method to investigate nigrostriatal integrity in case of clinically uncertain parkinsonism. Objective: The present study explores whether a data-driven analysis of [123 I]FP-CIT SPECT is able to stratify patients according to mortality after SPECT. Methods: Patients from our clinical registry were included if they had received [123 I]FP-CIT SPECT between 10/2008 and 06/2016 for diagnosis of parkinsonism and if their vital status could be determined in 07/2017. Specific binding ratios (SBR) of the whole striatum, its asymmetry (asymmetry index, AI; absolute value), and the rostrocaudal gradient of striatal binding …(C/pP: caudate SBR divided by posterior putamen SBR) were used as input for hierarchical clustering of patients. We tested differences in survival between these groups (adjusted for age) with a Cox proportional hazards model. Results: Data from 518 patients were analyzed. Median follow-up duration was 3.3 years [95% C.I. 3.1 to 3.7]. Three subgroups identified by hierarchical clustering were characterized by relatively low striatal SBR, high AI, and low C/pP (group 1), low striatal SBR, high AI, and high C/pP (group 2), and high striatal SBR, low AI, and low C/pP (group 3). Mortality was significantly higher in group 1 compared to each of the other two groups (p  = 0.029 and p  = 0.003, respectively). Conclusion: Data-driven analysis of [123 I]FP-CIT SPECT identified a subgroup of patients with significantly increased mortality during follow-up. This suggests that [123 I]-FP-CIT SPECT might not only serve as a diagnostic tool to verify nigrostriatal degeneration but also provide valuable prognostic information. Show more

Keywords: Parkinsonism, Parkinson’s disease, dopamine transporter, [123I]FP-CIT SPECT

DOI: 10.3233/JPD-202214

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1457-1465, 2020

Authors: Feigl, Beatrix | Dumpala, Sunila | Kerr, Graham K. | Zele, Andrew J.

Article Type: Research Article

Abstract: Background: Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) signal the environmental light to mediate circadian photoentrainment and sleep-wake cycles. There is high prevalence of circadian and sleep disruption in people with Parkinson’s disease, however the underlying mechanisms of these symptoms are not clear. Objective: Based on recent evidence of anatomical and functional loss of melanopsin ganglion cells in Parkinson’s disease, we evaluate the link between melanopsin function, circadian, and sleep behavior. Methods: The pupil light reflex and melanopsin-mediated post-illumination pupil response were measured using chromatic pupillometry in 30 optimally medicated people with Parkinson’s disease and 29 …age-matched healthy controls. Circadian health was determined using dim light melatonin onset, sleep questionnaires, and actigraphy. Ophthalmic examination quantified eye health and optical coherence tomography measured retinal thickness. Results: The melanopsin-mediated post-illumination pupil response amplitudes were significantly reduced in Parkinson’s disease (p  < 0.0001) and correlated with poor sleep quality (r2  = 33; p  < 0.001) and nerve fiber layer thinning (r2  = 0.40; p  < 0.001). People with Parkinson’s disease had significantly poorer sleep quality with higher subjective sleep scores (p  < 0.05) and earlier melatonin onset (p  = 0.01). Pupil light (outer retinal) response metrics, daily light exposure and outer retinal thickness were similar between the groups (p  > 0.05). Conclusion: Our evidence-based data identify a mechanism through which inner retinal ipRGC dysfunction contributes to sleep disruption in Parkinson’s disease in the presence of normal outer retinal (rod-cone photoreceptor) function. Our findings provide a rationale for designing new treatment approaches in Parkinson’s disease through melanopsin photoreceptor-targeted light therapies for improving sleep-wake cycles. Show more

Keywords: Dim light melatonin onset, melanopsin, Parkinson’s disease, photoreceptors, PIPR, post-illumination pupil light response, sleep

DOI: 10.3233/JPD-202178

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1467-1476, 2020

Authors: West, Christine L. | Mao, Yu-Kang | Delungahawatta, Thilini | Amin, Jessica Y. | Farhin, Sohana | McQuade, Rachel M. | Diwakarla, Shanti | Pustovit, Ruslan | Stanisz, Andrew M. | Bienenstock, John | Barbut, Denise | Zasloff, Michael | Furness, John B. | Kunze, Wolfgang A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α -synuclein (α -syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo , have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α -syn. Objective: Here we explore the electrophysiological …effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α -syn mutant. Methods: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD. Show more

Keywords: Parkinson’s disease, squalamine, intestinal motility, intrinsic primary afferent neuron, electrophysiology, gut-brain axis, vagus

DOI: 10.3233/JPD-202076

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1477-1491, 2020

Authors: Chiu, Shannon Y. | Tsuboi, Takashi | Hegland, Karen W. | Herndon, Nicole E. | Shukla, Aparna Wagle | Patterson, Addie | Almeida, Leonardo | Foote, Kelly D. | Okun, Michael S. | Ramirez-Zamora, Adolfo

Article Type: Research Article

Abstract: Background: Although earlier studies reported variable speech changes following subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson’s disease (PD) patients, the effects of globus pallidus internus (GPi) DBS on speech performance in PD remain largely unknown. Objective: We aimed to characterize speech changes following PD GPi-DBS. Methods: We retrospectively analyzed clinical and speech outcomes of 25 PD patients treated with bilateral GPi-DBS at a single center. Outcome measures included the Unified Parkinson’s Disease Rating Scale (UPDRS), speech subsystem domains (respiratory, laryngeal, resonance, orofacial, rate, prosody, rhythm, and naturalness), and overall speech intelligibility. Scores at baseline …were compared with those at 6 months, 1 year, and the longest clinical follow-up available. Results: In the off-medication state, activities of daily living and motor function based on UPDRS II and III significantly improved postoperatively. We observed unique patterns of speech changes in patients with PD following GPi-DBS in the short- (n  = 25) and longer-term (n  = 8) follow-up periods. Velopharyngeal (resonance), laryngeal components, and prosody worsened after bilateral GPi-DBS (p  < 0.015). Speech intelligibility did not worsen after GPi-DBS in the short-term, but there was a trend to deteriorate at long-term follow-up (e.g., one year and beyond). We observed worsening of hypokinetic dysarthria in individual patients. Also, a minority of patients developed stuttering, spastic dysarthria, or ataxic dysarthria. Conclusion: Bilateral GPi-DBS worsened several modalities of parkinsonian speech without compromising overall speech intelligibility. GPi-DBS can potentially worsen or induce hypokinetic dysarthria, stuttering, spastic dysarthria, or ataxic dysarthria. GPi-DBS may have different and variable effects on speech function when compared to STN-DBS. Show more

Keywords: Parkinson’s disease, globus pallidus, deep brain stimulation, dysarthria, speech intelligibility

DOI: 10.3233/JPD-202246

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1493-1502, 2020

Authors: Scheggi, Simona | Rossi, Francesca | Corsi, Sara | Fanni, Silvia | Tronci, Elisabetta | Ludovica, Congiu | Vargiu, Romina | Gambarana, Carla | Muñoz, Ana | Stancampiano, Roberto | Björklund, Anders | Carta, Manolo

Article Type: Research Article

Abstract: Background: We recently showed that striatal overexpression of brain derived neurotrophic factor (BDNF) by adeno-associated viral (AAV) vector exacerbated L-DOPA-induced dyskinesia (LID) in 6-OHDA-lesioned rats. An extensive sprouting of striatal serotonergic terminals accompanied this effect, accounting for the increased susceptibility to LID. Objective: We set to investigate whether the BDNF effect was restricted to LID, or extended to dyskinesia induced by direct D1 receptor agonists. Methods: Unilaterally 6-OHDA-lesioned rats received a striatal injection of an AAV vector to induce BDNF or GFP overexpression. Eight weeks later, animals received daily treatments with a low dose of …SKF82958 (0.02 mg/kg s.c.) and development of dyskinesia was evaluated. At the end of the experiment, D1 and D3 receptors expression levels and D1 receptor-dependent signaling pathways were measured in the striatum. Results: BDNF overexpression induced significant worsening of dyskinesia induced by SKF82958 compared to the GFP group and increased the expression of D3 receptor at striatal level, even in absence of pharmacological treatment; by contrast, D1 receptor levels were not affected. In BDNF-overexpressing striata, SKF82958 administration resulted in increased levels of D1 –D3 receptors co-immunoprecipitation and increased phosphorylation levels of Thr34 DARPP-32 and ERK1/2. Conclusion: Here we provide evidence for a functional link between BDNF, D3 receptors and D1 –D3 receptor close interaction in the augmented susceptibility to dyskinesia in 6-OHDA-lesioned rats. We suggest that D1 –D3 receptors interaction may be instrumental in driving the molecular alterations underlying the appearance of dyskinesia; its disruption may be a therapeutic strategy for treating dyskinesia in PD patients. Show more

Keywords: 6-OHDA, BDNF, dyskinesia, D3 receptors, Parkinson’s disease

DOI: 10.3233/JPD-202061

Citation: Journal of Parkinson's Disease, vol. 10, no. 4, pp. 1503-1514, 2020