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Lee Silverman Voice Treatment (LSVT)-BIG to improve motor function in people with Parkinson's disease: a systematic review and meta-analysis.
McDonnell, MN, Rischbieth, B, Schammer, TT, Seaforth, C, Shaw, AJ, Phillips, AC
Clinical rehabilitation. 2018;(5):607-618
Abstract
OBJECTIVE The technique called Lee Silverman Voice Treatment (LSVT)-LOUD has previously been used to improve voice quality in people with Parkinson's disease. The objective of this study was to assess the effectiveness of an alternate intervention, LSVT-BIG (signifying big movements), to improve functional mobility. DESIGN Systematic review with meta-analysis of randomized trials. DATA SOURCES Medline, Embase, CINAHL, AgeLine, Scopus and Cochrane Library were searched from inception to September 2017 using multiple search terms related to Parkinson's disease and LSVT-BIG. REVIEW METHOD Two researchers searched the literature for studies of the LSVT-BIG intervention of 16 sessions, delivered by a certified instructor over four weeks, to any other intervention. Outcomes related to functional ability were included. Study quality was appraised using the Cochrane Risk of Bias tool. RESULTS Four studies were included, reporting on three randomized trials of 84 participants with mild Parkinson's disease. Compared to physiotherapy exercises, or a shorter training protocol, there was a significant improvement in motor function assessed with the Unified Parkinson's Disease Rating Scale part III (mean difference = -3.20, 95% confidence interval = -5.18 to -1.23) and a trend towards faster Timed Up and Go performance (mean difference = -0.47, 95% confidence interval = -0.99 to 0.06) and 10-metre walk test (mean difference = -0.53, 95% confidence interval = -1.07 to 0.01). CONCLUSION Compared to shorter format LSVT-BIG or general exercise, LSVT-BIG was more effective at improving motor function. This provides preliminary, moderate quality evidence that amplitude-oriented training is effective in reducing motor impairments for people with mild Parkinson's disease.
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Present and Future of Ultra-High Field MRI in Neurodegenerative Disorders.
Donatelli, G, Ceravolo, R, Frosini, D, Tosetti, M, Bonuccelli, U, Cosottini, M
Current neurology and neuroscience reports. 2018;(6):31
Abstract
PURPOSE OF REVIEW With a high signal-to-noise ratio, unparalleled spatial resolution, and improved contrasts, ultra-high field MR (≥ 7 T) has great potential in depicting the normal radiological anatomy of smaller structures in the brain and can also provide more information about morphological, quantitative, and metabolic changes associated with a wide range of brain disorders. By focusing attention on specific brain regions believed to be associated with early pathological change, or by more closely inspecting recognized foci of brain pathology, ultra-high field MR can improve the accuracy and sensitivity of neuroimaging. This article reviews recent studies at ultra-high field about Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). RECENT FINDINGS The research on AD has mainly focused on detecting the thinning of hippocampal layers and the susceptibility effect supposed to be related to beta-amyloid deposition. In patients with PD, atypical parkinsonisms and subjects at risk of developing motor symptoms of Parkinson's disease, the main aim was to detect changes in the substantia nigra, probably related to increased iron deposition. In patients with ALS, both brain and spinal cord were investigated, with the aim of finding changes in the primary motor cortex and corticospinal tract which reflect neurodegeneration and neuroinflammation. Ultra-high field MR was shown to be useful for detecting subtle brain changes in patients with AD, and possible new diagnostic biomarkers in patients with PD and ALS were discovered. The ability of 7 T MR to provide prognostic biomarkers in subjects at risk for developing synucleinopathies is currently under evaluation.
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123I-ioflupane SPET and 123I-MIBG in the diagnosis of Parkinson's disease and parkinsonian disorders and in the differential diagnosis between Alzheimer's and Lewy's bodies dementias.
Nuvoli, S, Palumbo, B, Malaspina, S, Madeddu, G, Spanu, A
Hellenic journal of nuclear medicine. 2018;(1):60-68
Abstract
Nuclear medicine procedures are widely used as "in vivo" biomarkers in a large number of brain diseases, especially in the diagnosis of Parkinson's disease (PD) and of parkinsonian disorders (pD). Furthermore, nuclear medicine is used in the differential diagnosis of dementias especially Alzheimer's disease (AD) and dementia with Lewy's bodies (LBD) which share many clinical symptoms and often LBD is misdiagnosed as AD. The differential diagnosis between these clinical entities is crucial for treatment since LBD also shares some clinical symptoms with parkinsonian disorders. We reviewed the most relevant papers that study the usefulness of both iodine-123-ioflupane studied by single photon emission tomography (123I-ioflupane SPET) and of 123I-metaiodobenzylguanidine (123I-MIBG) cardiac scintigraphy in the diagnosis of PD and pD and in the differential diagnosis between AD and LBD in order to contribute to the clinical practice of the diseases.
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Transcriptional alterations in skin fibroblasts from Parkinson's disease patients with parkin mutations.
González-Casacuberta, I, Morén, C, Juárez-Flores, DL, Esteve-Codina, A, Sierra, C, Catalán-García, M, Guitart-Mampel, M, Tobías, E, Milisenda, JC, Pont-Sunyer, C, et al
Neurobiology of aging. 2018;:206-216
Abstract
Mutations in the parkin gene (PRKN) are the most common cause of autosomal-recessive juvenile Parkinson's disease (PD). PRKN encodes an E3 ubiquitin ligase that is involved in multiple regulatory functions including proteasomal-mediated protein turnover, mitochondrial function, mitophagy, and cell survival. However, the precise molecular events mediated by PRKN mutations in PRKN-associated PD (PRKN-PD) remain unknown. To elucidate the cellular impact of parkin mutations, we performed an RNA sequencing study in skin fibroblasts from PRKN-PD patients carrying different PRKN mutations (n = 4) and genetically unrelated healthy subjects (n = 4). We identified 343 differentially expressed genes in PRKN-PD fibroblasts. Gene ontology and canonical pathway analysis revealed enrichment of differentially expressed genes in processes such as cell adhesion, cell growth, and amino acid and folate metabolism among others. Our findings indicate that PRKN mutations are associated with large global gene expression changes as observed in fibroblasts from PRKN-PD patients and support the view of PD as a systemic disease affecting also non-neural peripheral tissues such as the skin.
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Emerging and Alternative Therapies For Parkinson Disease: An Updated Review.
Kabra, A, Sharma, R, Kabra, R, Baghel, US
Current pharmaceutical design. 2018;(22):2573-2582
Abstract
Parkinson's disease (PD) is standout amongst the most common neurodegenerative malady with unpredictable dynamic pathology. At present, accessible traditional choices for PD have certain impediments of their own, and subsequently persistent consistence and fulfillment are low. Current contemporary treatment options just give symptomatic alleviation constrained control to anticipate malady progression, bringing about poor patient consistence and fulfilment. Numerous rising pharmacotherapies for PD are in various phases of medical improvement. Treatments incorporate adenosine A2A receptor antagonists, anti-apoptotic agents, monoamine oxidase inhibitors, glutamate receptor antagonists, and antioxidants for example, N-acetyl cysteine, edaravone, and coenzyme Q10. Other rising nonpharmacotherapies incorporate microRNAs, viral vector gene therapy, stem cells transglutaminases, RTP801, and glial derived neurotrophic factor (GDNF). Furthermore, surgeries including profound pallidotomy, deep brain stimulation, thalamotomy and gamma knife surgery have developed as elective mediations for cutting edge PD patients who have totally used common medications and still suffer from unrelenting motor symptoms. Complementary and Alternative medicine (CAM) modalities, such as Yoga, acupuncture, Tai Chi, Music therapies are highly practiced in several countries, offer some of the safer and effective treatment modalities for PD. While a few of these treatments hold much assurance in postponing the beginning of ailment and moderating its progression, more pharmacotherapies and careful mediations should be examined in various phases of PD. Therefore, the main objective of our review is to fill the gap between the researches and provide updated and productive information about the research reported in the last couple of years and can fulfil the most reassuring plausibility for encourage treatment of Parkinson Disease.
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Pharmacokinetic drug evaluation of CVT-301 for the treatment of Parkinson's disease.
Stocchi, F, Vacca, L, Stirpe, P, Torti, M
Expert opinion on drug metabolism & toxicology. 2018;(12):1189-1195
Abstract
Levodopa (LD), in combination with a decarboxylase inhibitor, is a mainstay and the most effective therapeutic agent in the treatment of Parkinson's disease (PD). Unfortunately, during chronic treatment with this agent, ON-OFF phenomena and dyskinesia appear. Despite the many medical treatment options available, unpredictable OFF episodes can still occur and be severe and disabling. A rescue therapy that provides a rapid and predictable ON response for patients with OFF periods would be of great value for such patients. Areas covered: CVT-301 is a self-administered dry powder aerosol inhaled formulation of LD that is being developed as a self-administered treatment for OFF periods. The PK profile of CVT-301, the efficacy, and the safety highlighted in randomized clinical trials will be reviewed. Expert opinion: CVT-301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma-level variability. List of Abbreviations: PD: Parkinson's disease; LD: Levodopa; CD: Carbidopa; AADC aromatic L-amino acid decarboxylase; IR: immediate-release; FPD: fine particle dose; GI: gastrointestinal; PK: pharmacokinetic; CVs: coefficient of variation; UPDRS Unified Parkinson's Disease Rating Scale; AEs: adverse events; FEV: forced expiratory volume; FVC: forced vital capacity; DLCO diffuse lung CO ; tmax: time to maximum concentration.
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Low-fat versus ketogenic diet in Parkinson's disease: A pilot randomized controlled trial.
Phillips, MCL, Murtagh, DKJ, Gilbertson, LJ, Asztely, FJS, Lynch, CDP
Movement disorders : official journal of the Movement Disorder Society. 2018;(8):1306-1314
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Abstract
BACKGROUND Preliminary evidence suggests that diet manipulation may influence motor and nonmotor symptoms in PD, but conflict exists regarding the ideal fat to carbohydrate ratio. OBJECTIVES We designed a pilot randomized, controlled trial to compare the plausibility, safety, and efficacy of a low-fat, high-carbohydrate diet versus a ketogenic diet in a hospital clinic of PD patients. METHODS We developed a protocol to support PD patients in a diet study and randomly assigned patients to a low-fat or ketogenic diet. Primary outcomes were within- and between-group changes in MDS-UPDRS Parts 1 to 4 over 8 weeks. RESULTS We randomized 47 patients, of which 44 commenced the diets and 38 completed the study (86% completion rate for patients commencing the diets). The ketogenic diet group maintained physiological ketosis. Both groups significantly decreased their MDS-UPDRS scores, but the ketogenic group decreased more in Part 1 (-4.58 ± 2.17 points, representing a 41% improvement in baseline Part 1 scores) compared to the low-fat group (-0.99 ± 3.63 points, representing an 11% improvement) (P < 0.001), with the largest between-group decreases observed for urinary problems, pain and other sensations, fatigue, daytime sleepiness, and cognitive impairment. There were no between-group differences in the magnitude of decrease for Parts 2 to 4. The most common adverse effects were excessive hunger in the low-fat group and intermittent exacerbation of the PD tremor and/or rigidity in the ketogenic group. CONCLUSIONS It is plausible and safe for PD patients to maintain a low-fat or ketogenic diet for 8 weeks. Both diet groups significantly improved in motor and nonmotor symptoms; however, the ketogenic group showed greater improvements in nonmotor symptoms. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Excessive Daytime Sleepiness in Parkinson's Disease: Clinical Implications and Management.
Shen, Y, Huang, JY, Li, J, Liu, CF
Chinese medical journal. 2018;(8):974-981
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OBJECTIVE Excessive daytime sleepiness (EDS) is one of the most common sleep abnormalities in patients with Parkinson's disease (PD), yet its multifactorial etiology complicates its treatment. This review summarized recent studies on the epidemiology, etiology, clinical implications, associated features, and evaluation of EDS in PD. The efficacy of pharmacologic and non-pharmacologic treatments for EDS in PD was also reviewed. DATA SOURCES English language articles indexed in PubMed and Cochrane databases and Chinese-language papers indexed in Wanfang and National Knowledge Infrastructure databases that were published between January 1987 and November 2017 were located using the following search terms: "sleepiness", "sleep and Parkinson's disease", and "Parkinson's disease and treatment". STUDY SELECTION Original research articles and critical reviews related to EDS in PD were selected. RESULTS EDS is a major health hazard and is associated with many motor and nonmotor symptoms of PD. Its causes are multifactorial. There are few specific guidelines for the treatment of EDS in PD. It is first necessary to identify and treat any possible factors causing EDS. Recent studies showed that some nonpharmacologic (i.e., cognitive behavioral therapy, light therapy, and repetitive transcranial magnetic stimulation) and pharmacologic (i.e., modafinil, methylphenidate, caffeine, istradefylline, sodium oxybate, and atomoxetine) treatments may be effective in treating EDS in PD. CONCLUSIONS EDS is common in the PD population and can have an immensely negative impact on quality of life. Its causes are multifactorial, which complicates its treatment. Further investigations are required to determine the safety and efficacy of potential therapies and to develop novel treatment approaches for EDS in PD.
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From a Highly Disordered to a Metastable State: Uncovering Insights of α-Synuclein.
Cote, Y, Delarue, P, Scheraga, HA, Senet, P, Maisuradze, GG
ACS chemical neuroscience. 2018;(5):1051-1065
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α-Synuclein (αS) is a major constituent of Lewy bodies, the insoluble aggregates that are the hallmark of one of the most prevalent neurodegenerative disorders, Parkinson's disease (PD). The vast majority of experiments in vitro and in vivo provide extensive evidence that a disordered monomeric form is the predominant state of αS in water solution, and it undergoes a large-scale disorder-to-helix transition upon binding to vesicles of different types. Recently, another form, tetrameric, of αS with a stable helical structure was identified experimentally. It has been shown that a dynamic intracellular population of metastable αS tetramers and monomers coexists normally; and the tetramer plays an essential role in maintaining αS homeostasis. Therefore, it is of interest to know whether the tetramer can serve as a means of preventing or delaying the start of PD. Before answering this very important question, it is, first, necessary to find out, on an atomistic level, a correlation between tetramers and monomers; what mediates tetramer formation and what makes a tetramer stable. We address these questions here by investigating both monomeric and tetrameric forms of αS. In particular, by examining correlations between the motions of the side chains and the main chain, steric parameters along the amino-acid sequence, and one- and two-dimensional free-energy landscapes along the coarse-grained dihedral angles γ and δ and principal components, respectively, in monomeric and tetrameric αS, we were able to shed light on a fundamental relationship between monomers and tetramers, and the key residues involved in mediating formation of a tetramer. Also, the reasons for the stability of tetrameric αS and inability of monomeric αS to fold are elucidated here.
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A novel modelling mechanism of PAEL receptor and GABARAPL2 interaction involved in Parkinson's disease.
Dutta, P, Dargahi, L, O'Connell, KE, Bolia, A, Ozkan, B, Sailer, AW, Dev, KK
Neuroscience letters. 2018;:12-18
Abstract
Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson's disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (γ-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy. We show that the family of GABARAPs interact with the carboxy terminal (ct) of PAELR and find the cysteine rich region (-CCCCCC-EEC) of ct-PAELR interacts with the GABAA binding site of GABARAPL2. This interaction is modelled by in-slico analysis and confirmed using affinity chromatography, showing Myc-tagged GABARAPL2 is retained by a GST fusion of the ct-PAELR. We also demonstrate that transient transfection of GABARAPL2 in HEK293 cells reduces PAELR expression. This study supports the idea that protein levels of PAELR are likely regulated by a multitude of proteins including parkin, PICK1 and GABARAPL2 via mechanisms that include ubiquitination, proteasomal degradagtion and autophagy.