Journal of Parkinson's Disease - Volume 6, issue 1

Authors: Hossein-nezhad, Arash | Fatemi, Roya Pedram | Ahmad, Rili | Peskind, Elaine R. | Zabetian, Cyrus P. | Hu, Shu-Ching | Shi, Min | Wahlestedt, Claes | Zhang, Jing | Faghihi, Mohammad Ali

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a debilitating neurological disorder for which prognostic and diagnostic biomarkers are lacking. Cerebrospinal fluid (CSF) is an accessible body fluid that comes into direct contact with the central nervous system (CNS) and acts as a nuclease-free repository where RNA transcripts shed by brain tissues can reside for extended periods of time. Objective: We studied the RNA species present in the CSF of PD patients to identify novel diagnostic biomarkers. Methods: Small volumes of CSF from 27 PD patients and 30 healthy age- and sex-matched controls were used for RNA extraction …followed by next-generation sequencing (RNA-seq) using the Illumina platform. CSF contains a number of fragmented RNA species that were individually sequenced and analyzed. Comparing PD to control subjects, we observed a pool of dysregulated sequencing tags that were further analyzed and validated by quantitative real-time PCR (qRT-PCR). Results: A total of 201 differentially expressed sequencing tags (DETs), including 92 up-regulated and 109 down-regulated DETs were identified. We validated the following DETs by real time PCR in the patient samples: Dnmt1, Ezh2, CCR3, SSTR5,PTPRC, UBC, NDUFV2, BMP7, SCN9, SCN9 antisense (AC010127.3 ), and long noncoding RNAs AC079630 and UC001lva.4 (close to the LRRK2 gene locus), as potential PD biomarkers. Conclusions: The CSF is a unique environment that contains many species of RNA. Our work demonstrates that CSF can potentially be used to identify biomarkers for the detection and tracking of disease progression and evaluation of therapeutic outcomes. Show more

Keywords: Parkinson disease, RNA sequencing, cerebrospinal fluid, biomarkers, long noncoding RNA

DOI: 10.3233/JPD-150737

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 109-117, 2016

Authors: Barrett, Matthew J. | Koeppel, Alexander F. | Flanigan, Joseph L. | Turner, Stephen D. | Worrall, Bradford B.

Article Type: Research Article

Abstract: Background: Meta-analysis of genome-wide association studies have implicated multiple single nucleotide polymorphisms (SNPs) and associated genes with Alzheimer disease. The role of these SNPs in cognitive impairment in Parkinson disease (PD) remains incompletely evaluated. Objective: The objective of this study was to test alleles associated with risk of Alzheimer disease for association with cognitive impairment in Parkinson disease (PD). Methods: Two datasets with PD subjects accessed through the NIH database of Genotypes and Phenotypes contained both single nucleotide polymorphism (SNP) arrays and mini-mental state exam (MMSE) scores. Genetic data underwent rigorous quality control and we …selected SNPs for genes associated with AD other than APOE . We constructed logistic regression and ordinal regression models, adjusted for sex, age at MMSE, and duration of PD, to assess the association between selected SNPs and MMSE score. Results: In one dataset, PICALM rs3851179 was associated with cognitive impairment (MMSE <  24) in PD subjects >  70 years old (OR = 2.3; adjusted p -value = 0.017; n  = 250) but not in PD subjects≤70 years old. Conclusions: Our finding suggests that PICALM rs3851179 could contribute to cognitive impairment in older patients with PD. It is important that future studies consider the interaction of age and genetic risk factors in the development of cognitive impairment in PD. Show more

Keywords: Parkinson disease, mild cognitive impairment, dementia, Alzheimer disease, genetics

DOI: 10.3233/JPD-150706

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 119-124, 2016

Authors: Hacker, Mallory L. | Currie, Amanda D. | Molinari, Anna L. | Turchan, Maxim | Millan, Sarah M. | Heusinkveld, Lauren E. | Roach, Jonathon | Konrad, Peter E. | Davis, Thomas L. | Neimat, Joseph S. | Phibbs, Fenna T. | Hedera, Peter | Byrne, Daniel W. | Charles, David

Article Type: Research Article

Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is well-known to reduce medication burden in advanced stage Parkinson’s disease (PD). Preliminary data from a prospective, single blind, controlled pilot trial demonstrated that early stage PD subjects treated with STN-DBS also required less medication than those treated with optimal drug therapy (ODT). Objective: The purpose of this study was to analyze medication cost and utilization from the pilot trial of DBS in early stage PD and to project 10 year medication costs. Methods: Medication data collected at each visit were used to calculate medication costs. Medications were …converted to levodopa equivalent daily dose, categorized by medication class, and compared. Medication costs were projected to advanced stage PD, the time when a typical patient may be offered DBS. Results: Medication costs increased 72% in the ODT group and decreased 16% in the DBS+ODT group from baseline to 24 months. This cost difference translates into a cumulative savings for the DBS+ODT group of $7,150 over the study period. Projected medication cost savings over 10 years reach $64,590. Additionally, DBS+ODT subjects were 80% less likely to require polypharmacy compared with ODT subjects at 24 months (p  <  0.05; OR = 0.2; 95% CI: 0.04–0.97). Conclusions: STN-DBS in early PD reduced medication cost over the two-year study period. DBS may offer substantial long-term reduction in medication cost by maintaining a simplified, low dose medication regimen. Further study is needed to confirm these findings, and the FDA has approved a pivotal, multicenter clinical trial evaluating STN-DBS in early PD. Show more

Keywords: Parkinson’s disease, deep brain stimulation, subthalamic nucleus, medication cost, cost, cost analysis, health economics

DOI: 10.3233/JPD-150712

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 125-131, 2016

Authors: Lamberti, Valérie M.J. | Pereira, Bruno | Lhommée, Eugénie | Bichon, Amélie | Schmitt, Emmanuelle | Pelissier, Pierre | Kistner, Andrea | Fraix, Valérie | Castrioto, Anna | Esselink, Rianne A. J. | Durif, Frank | Krack, Paul

Article Type: Research Article

Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms of Parkinson’s disease (PD) and motor complications of dopaminergic treatment. Whether STN-DBS should be considered when PD patients experience neuropsychiatric symptoms is controversial. Lack of systematic behavioral evaluation at baseline hampers the understanding of postoperative neuropsychiatric outcomes. Objective: This study compares the behavioral profile of a surgical population to that in general PD. Methods: Single center data from 234 PD surgical candidates were compared to data from 260 non-demented PD patients consulting in 13 PD expert centers at different stages of disease. The latter were …considered representative of the general PD population. Neuropsychiatric symptoms were assessed using the Ardouin Scale of Behavior in PD, a guided interview quantifying changes in severity of 21 neuropsychiatric symptoms, classified into psychic non-motor fluctuations, hypo- and hyperdopaminergic behaviors. Multivariate analyses were performed to study differences in behavioral items between the two groups. Results: Surgical candidates were younger, had longer disease duration and used significantly higher doses of dopaminergic drugs. After adjustment for covariates, dopaminergic addiction (OR 10.83; p  = 0.002), nocturnal hyperactivity (OR 1.87; p  = 0.04), excessive hobbyism (OR 2.37; p  = 0.008), “excess in motivation” (OR 4.02; p  <  0.001), psychic OFF (2.87; p  <  0.001) and psychic ON (2.10; p  = 0.001) fluctuations were more frequent in the surgical candidates. Depressed mood prevailed in the general PD population (OR 0.53; p  = 0.045). Conclusion: Behavioral complications of dopaminergic treatment are frequent in PD patients candidates for STN-DBS. They cannot be considered as contraindications for STN-DBS but must be taken into account in postoperative management. Show more

Keywords: Parkinson disease, subthalamic nucleus, deep brain stimulation, dopamine, impulse control disorders

DOI: 10.3233/JPD-150698

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 133-142, 2016

Authors: Bousset, Luc | Brundin, Patrik | Böckmann, Anja | Meier, Beat | Melki, Ronald

Article Type: Research Article

Abstract: Background: Preformed α-synuclein fibrils seed the aggregation of soluble α-synuclein in cultured cells and in vivo . This, and other findings, has kindled the idea that α-synuclein fibrils possess prion-like properties. Objective: As α-synuclein fibrils should not be considered as innocuous, there is a need for decontamination and inactivation procedures for laboratory benches and non-disposable laboratory material. Methods: We assessed the effectiveness of different procedures designed to disassemble α-synuclein fibrils and reduce their infectivity. We examined different commercially available detergents to remove α-synuclein assemblies adsorbed on materials that are not disposable and that are most …found in laboratories (e.g. plastic, glass, aluminum or stainless steel surfaces). Results: We show that methods designed to decrease PrP prion infectivity neither effectively remove α-synuclein assemblies adsorbed to different materials commonly used in the laboratory nor disassemble the fibrillar form of the protein with efficiency. In contrast, both commercial detergents and SDS detached α-synuclein assemblies from contaminated surfaces and disassembled the fibrils. Conclusions: We describe three cleaning procedures that effectively remove and disassemble α-synuclein seeds. The methods rely on the use of detergents that are compatible with most non-disposable tools in a laboratory. The procedures are easy to implement and significantly decrease any potential risks associated to handling α-synuclein assemblies. Show more

Keywords: Alpha synuclein, cleaning procedures, detergent, fibrils, inactivation, Parkinson’s disease, removal

DOI: 10.3233/JPD-150691

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 143-151, 2016

Authors: Beach, Thomas G. | Adler, Charles H. | Serrano, Geidy | Sue, Lucia I. | Walker, D.G. | Dugger, Brittany N. | Shill, Holly A. | Driver-Dunckley, Erika | Caviness, John N. | Intorcia, Anthony | Filon, Jessica | Scott, Sarah | Garcia, Angelica | Hoffman, Brittany | Belden, Christine M. | Davis, Kathryn J. | Sabbagh, Marwan N.

Article Type: Research Article

Abstract: Background: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson’s disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders. Objective: To provide an estimate of the prevalence of histological synucleinopathy in the …submandibular glands of subjects with PD and other Lewy body disorders. Methods: Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α -synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer’s disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA). Results: Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects. Conclusions: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers. Show more

Keywords: Biopsy, diagnosis, clinical trial, biomarker, pathology, therapy

DOI: 10.3233/JPD-150680

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 153-163, 2016

Authors: Cattaneo, Carlo | Sardina, Marco | Bonizzoni, Ermino

Article Type: Research Article

Abstract: Background: Studies 016 and SETTLE showed that safinamide was safe and effective as adjunct therapy in patients with advanced Parkinson’s disease (PD) and motor fluctuations. The addition of safinamide to a stable dose of levodopa alone or with other antiparkinsonian medications significantly increased ON time with no/non-troublesome dyskinesia, decreased OFF time and improved Parkinson’s symptoms. Objective: To evaluate the clinical effects of safinamide 100 mg/day on motor fluctuations and cardinal Parkinson’s symptoms in specific patient subgroups using pooled data from Studies 016 and SETTLE. Methods: Both studies were double blind, placebo-controlled, randomized, phase 3 trials which …enrolled patients with mid- to late-stage PD experiencing motor fluctuations while receiving optimized and stable doses of levodopa, alone or with other dopaminergic treatments. The present post-hoc analyses assessed the change from baseline in ON time (with no or non-troublesome dyskinesia) and OFF time in subgroups of patients who were receiving only levodopa at baseline, who were classified as “mild fluctuators” (daily OFF time ≤4 h), and who were receiving concomitant dopaminergic therapy, with or without amantadine, and the effects of safinamide versus placebo on individual cardinal PD symptoms during ON time. Results: Safinamide significantly increased mean ON time (with no or non-troublesome dyskinesia) and reduced mean OFF time when used as first adjunct therapy in levodopa-treated patients and patients with mild motor fluctuations. Mean daily ON time (with no or non-troublesome dyskinesia) and OFF time were favorably changed, compared with placebo, to similar extents regardless of whether patients were receiving concomitant dopamine agonists, catechol-O-methyltransferase inhibitors and amantadine. Additionally, safinamide improved bradykinesia, rigidity, tremor and gait. Conclusions: Safinamide was a safe and effective first adjunct therapy in levodopa-treated patients and improved 4/5 cardinal symptoms of PD while providing benefits to mild and non-mild fluctuators and patients receiving other concomitant dopaminergic therapies. Show more

Keywords: Parkinson’s disease, safinamide, levodopa, MAO-B inhibitor, motor fluctuations, glutamate, adjunct therapy

DOI: 10.3233/JPD-150700

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 165-173, 2016

Authors: Hiorth, Ylva Hivand | Larsen, Jan Petter | Lode, Kirsten | Tysnes, Ole-Bjørn | Godfrey, Alan | Lord, Sue | Rochester, Lynn | Pedersen, Kenn Freddy

Article Type: Research Article

Abstract: Background: A complex relationship exists between motor impairment, physical activity (sedentary behavior, standing and ambulatory activity) and falls in people with Parkinson’s disease (PD). Objective: To explore associations between recent fall history and the ability to retain an active lifestyle as determined by the volume, pattern and variability of physical activity in people with PD. Methods: Forty-eight participants with PD were recruited from the Norwegian ParkWest study. Body posture and ambulatory activity were monitored objectively over 7 days using the activPAL3 TM accelerometer. Clinical assessments included the Hoehn and Yahr stage, Unified Parkinson’s Disease Rating …Scale motor section and Falls Efficacy Scale-International. Structured interviews were performed to obtain information about demographics, fall history last 6 months, mobility and dementia. Results: Participants with a fall history (n  = 20) spent more time sedentary and less time standing than non-falling participants (n  = 28). There were no significant differences regarding pattern or variability of sedentary behavior, standing or ambulatory activity in falling versus non-falling participants. Confidence in being able to get up from floor contributed significantly to time spent in sedentary behavior and ambulatory activity in participants with fall history, whereas motor impairment was significantly associated with time spent in all facets of physical activity for non-falling participants. Conclusions: Fall history in our PD cohort was associated with a more sedentary lifestyle, but not less ambulatory activity. More emphasis on improving the capacity to safely complete activities of daily living and increase confidence in getting up from floor may reduce sedentary behavior in people with PD. Show more

Keywords: Parkinson’s disease, falls, accelerometer, physical activity, sedentary behavior, ambulation

DOI: 10.3233/JPD-150640

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 175-182, 2016

Authors: Rodríguez-Violante, Mayela | de Saráchaga, Adib Jorge | Cervantes-Arriaga, Amin | Millán-Cepeda, Roxanna | Leal-Ortega, Roberto | Estrada-Bellmann, Ingrid | Zuñiga-Ramírez, Carlos

Article Type: Research Article

Abstract: Background: Parkinson’s disease is characterized by motor and non-motor clinical features. The latter may present as pre-motor symptoms several years before the motor onset. Objective: To analyze the association between pre-motor symptoms load and its lead-time in relation to the motor onset and time to diagnosis. Methods: A cross-sectional study was carried including subjects with Parkinson’s disease from five different movement disorders clinics in Mexico. A structured questionnaire was applied to assess the presence of six self-perceived pre-motor symptoms (hyposmia, depression, anxiety, constipation, pain and sleep disorders). Results: Overall frequency of pre-motor symptoms …was 76.2% . Among the most prevalent symptoms were depression (38%), sleep disorders (37%) and anxiety (36.6%). The lead time to motor onset was greater for constipation (9.2±17.89 years) and pain (8.66±13.36 years). Patients with more than two pre-motor symptoms had a later age at motor onset when compared to patients without pre-motor symptoms (52.04±13.11 vs 56.55±12.97 years, p  = 0.037). Late onset patients had a higher frequency of pre-motor symptoms (79% vs 65% in early onset, p  = 0.002) and a higher load (1.75±1.37 vs 1.44±1.38, p  = 0.033) in comparison to those with early onset. Female subjects reported a higher number of pre-motor symptoms (1.91±1.43 versus 1.48±1.29, p ≤0.001). PIGD patients reported a greater frequency of pain (8%) compared to tremor (1%, p  = 0.0064) and bradykinetic-rigid (0.61%, p  = 0.0061). Anxiety lead-time was greater in tremor-dominant (10.83±15.77 years) compared to bradykinetic-rigid patients (3.48±12.56, p  = 0.014). Conclusions: Pre-motor symptoms load is associated to a later motor onset of PD. Pre-motor symptoms are more frequent in subjects with late onset Parkinson’s disease. Female subjects report a higher number of pre-motor symptoms, depression and anxiety being the most common. Show more

Keywords: Parkinson’s disease, pre-motor symptoms, non-motor symptoms, motor onset

DOI: 10.3233/JPD-150705

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 183-190, 2016

Authors: Sorrentino, Pierpaolo | Barbato, Antonio | Del Gaudio, Luigi | Rucco, Rosaria | Varriale, Pasquale | Sibilio, Michelina | Strazzullo, Pasquale | Sorrentino, Giuseppe | Agosti, Valeria

Article Type: Research Article

Abstract: Type 1 Gaucher’s disease (GD1) is traditionally regarded as “non-neurological”. Spatiotemporal and kinematic analysis of gait was carried on thirteen GD1 patients and thirteen healthy controls. We identified a previously unknown subclinical reduction of amplitude of movements in GD1. Articular excursion of ankle, knee and hip was reduced during the swing phase of gait (p  <  0.0001). Furthermore, the excursion of the knee appeared also significantly more asymmetric in GD1 patients (p  = 0.02). Correction for age, BMI and basal walking speed did not modify the significance. Accordingly to the recent observations that GD1 predisposes to Parkinson’s disease, the impaired and …asymmetric gait kinematics that we observed might be interpreted as a form of extrapyramidal involvement. Show more

Keywords: Gaucher’s disease, gait analysis, joint excursion, extrapyramidal system, Parkinson disease, parkinsonism

DOI: 10.3233/JPD-150660

Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 191-195, 2016